Deprecated: The each() function is deprecated. This message will be suppressed on further calls in /home/zhenxiangba/zhenxiangba.com/public_html/phproxy-improved-master/index.php on line 456
NZ624784B2 - New cyclohexylamine derivatives having ?2 adrenergic agonist and m3 muscarinic antagonist activities - Google Patents
[go: Go Back, main page]

NZ624784B2 - New cyclohexylamine derivatives having ?2 adrenergic agonist and m3 muscarinic antagonist activities - Google Patents

New cyclohexylamine derivatives having ?2 adrenergic agonist and m3 muscarinic antagonist activities Download PDF

Info

Publication number
NZ624784B2
NZ624784B2 NZ624784A NZ62478412A NZ624784B2 NZ 624784 B2 NZ624784 B2 NZ 624784B2 NZ 624784 A NZ624784 A NZ 624784A NZ 62478412 A NZ62478412 A NZ 62478412A NZ 624784 B2 NZ624784 B2 NZ 624784B2
Authority
NZ
New Zealand
Prior art keywords
group
methyl
amino
hydroxy
ethyl
Prior art date
Application number
NZ624784A
Other versions
NZ624784A (en
Inventor
Bosch Jose Aiguade
Roig Silvia Gual
Quinones Maria Prat
Duran Carlos Puig
Original Assignee
Almirall Sa
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from EP11382344.7A external-priority patent/EP2592078A1/en
Application filed by Almirall Sa filed Critical Almirall Sa
Publication of NZ624784A publication Critical patent/NZ624784A/en
Publication of NZ624784B2 publication Critical patent/NZ624784B2/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/06—Antiabortive agents; Labour repressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Abstract

Disclosed are cyclohexylamine compounds of formula (A) having ?2 adrenergic agonist and M3 muscarinic antagonist dual activity, wherein the substituents are as defined in the specification. Also disclosed is the use of compounds of formula (A) as bronchodilator agents for the treatment of respiratory disorders such as COPD and asthma. An example of a compound of formula (A) is: Trans-4-[{3-[6-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-2-oxo-1,3-benzoxazol-3(2H)-yl]propyl}(methyl)amino]-cyclohexyl hydroxy(di-2-thienyl)acetate dihydrofluoride y disorders such as COPD and asthma. An example of a compound of formula (A) is: Trans-4-[{3-[6-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-2-oxo-1,3-benzoxazol-3(2H)-yl]propyl}(methyl)amino]-cyclohexyl hydroxy(di-2-thienyl)acetate dihydrofluoride

Description

New cyclohexylamine derivatives having β2 adrenergic agonist and M3 inic antagonist activities FIELD OF THE INVENTION.
The present invention relates to novel compounds having β2 adrenergic agonist and M3 muscarinic antagonist dual activity. This invention also relates to pharmaceutical itions containing them, and their use in respiratory therapies. Processes for ing the novel compounds are also described BACKGROUND OF THE INVENTION.
Bronchodilator agents play an outstanding role in the treatment of respiratory disorders such as COPD and asthma. Beta-adrenergic agonists and ergic muscarinic antagonists are well established bronchodilator agents in widespread clinical use. Betaadrenergic agonists currently used by the inhaled route include short-acting agents such as salbutamol (qid) or terbutaline (tid) and long-acting agents such as erol and erol (bid). These agents produce bronchodilation through stimulation of rgic receptors on airway smooth , ing the bronchoconstrictor responses to a variety of mediators, such as acetylcholine. Inhaled muscarinic antagonists currently used e the short-acting ipratropium bromide or oxitropium bromide (qid) and the long-acting tiotropium (qd). These agents produce bronchodilation by reducing vagal cholinergic tone of airway smooth muscle. In addition to improve lung function, these agents also improve quality of life and reduce exacerbations. There are in the clinical literature a number of studies strongly demonstrating that the administration of a combination of a beta-2 agonist and a M3 antagonist is more efficacious for the treatment of COPD than either of the components alone (for example, van Noord, J.A., et al., Eur.Respir.J., 2005; 26: 214-222).
Pharmaceutical compositions containing a ation of both types of bronchodilator agents are also known in the art for use in respiratory therapy. As an e, WO2009013244 discloses a medical composition containing salmeterol as betaadrenergic agonist agent and tiotropium as antimuscarinic agent.
The class of beta2 adrenergic is well known and widely used by the persons skilled in the art, such as physicians, pharmacists or pharmacologists, for the treatment of respiratory disease, in particular asthma and chronic obstructive pulmonary disease (COPD) (Paul A. Glossop et al., Annual Reports in Medicinal Chemistry, 2007, 41, 237- 248). Most of the beta2 adrenergic ts are derivatives of natural catecholamines (e.g. epinephrine and nephrine) with which they share some common structural features, which are responsible for the similar ction of these nds with the beta 2 receptors ("Goodman & Gilman’s The Pharmacological Basis of Therapeutics", th edition, chapter 10, pages 3, Textbook of respiratory medicine, third edition, r 11, p. 267-272). In fact, most of the beta2 adrenergic agonist compounds have a general ure type that is present in the catechol (epinephrine and isoproterenol), namely an aminoethanol core flanked by an aryl group (J.R.Jacobsen, Future Mwedicinal Chemistry, 2011, 3 (13), 1607-1622). Examples of the aryl group that afford beta2 potency are but not limited to ol, saligenin, formamide and 8-carbostyril groups (Paul A. Glossop et al., Annual Reports in Medicinal Chemistry, 2007, 41, 237- 248).
Dual-phamacology muscarinic antagonists-beta2 agonist (MABA) molecules present an exciting new ch to the treatment of respiratory disease by combining muscarinic antagonism and beta2 agonisn in a single entity. In the literature there have been disclosed various nds having both muscarinic receptor antagonist and beta2-agonist activity (A.D. Hughes et al., Future Medicinal Chemistry, 2011, 3(13), 1585-1605). All of these molecules s a great y of covalent linker fragments between the M3 antagonist and the beta2 agonist moieties, indicating that the structure of the linker radical is not critical to preserve both ties, although such linker fragments has showed to be an important tool for modulating physical properties and potency at each target.
A single molecule possessing dual activity at muscarinic M3 and adrenergic β2 ors (MABA) would therefore be desirable both in terms of efficacy and sideeffects in the treatment of COPD. It would show also a relevant advantage in terms of formulation compared with the two-component combination. It also would be easier to co-formulate with other therapeutic agents such as inhaled anti-inflammatories to create triple therapy combinations. Thus there is a need for new compounds having both beta2 receptor agonist and muscarinic receptor antagonist activity and being suitable for the treatment of respiratory es, such as asthma and COPD. It is an object of this invention to provide compounds which go at least some way to addressing this need; and/or which at least provide the public with a useful choice.
In this specification where reference has been made to patent specifications, other external documents, or other sources of information, this is generally for the purpose of providing a context for discussing the features of the invention. Unless specifically stated otherwise, reference to such al documents is not to be construed as an admission that such documents, or such s of information, in any jurisdiction, are prior art, or form part of the common general knowledge in the art.
In the description in this specification reference may be made to subject matter that is not within the scope of the claims of the current application. That subject matter should be readily identifiable by a person skilled in the art and may assist in putting into ce the invention as defined in the claims of this application.
SUMMARY OF THE INVENTION.
The invention provides novel compounds that possess both β2 adrenergic receptor agonist and inic receptor antagonist activities. Accordingly, there is provided a compound of formula (I), or pharmaceutically acceptable salts or N-oxides or solvates or deuterated derivatives thereof: A1 L1 N B G O A2 R3 Formula (I) wherein • R1 and R2 independently are ed from the group consisting of a hydrogen atom and a linear or branched C1-4 alkyl group, • R3 represents a group of formula: R5 R4 R4 ∗ i) ∗ or ii) Q wherein: o R4 ents a hydrogen atom, a hydroxy group, a hydroxymethyl group or a linear or branched C1-4 alkyl group, o R5 represents a saturated or unsaturated C3-8 cycloalkyl group, a C5-6 aryl group, a 5- to 6- membered heteroaryl group containing at least one heteroatom selected from N, S, and O; a (C1-4 alkyl)-(C5-6 aryl) group, a (C1-4 alkyl)-(C3-8 cycloalkyl) group or a (C1-4 alkyl)-(5- to 6- membered heteroaryl group containing at least one atom selected from N, S, and O) group, which groups independently are optionally substituted by one or more substituents Ra, o R6 represents a C5-6 aryl group, a 5- to 6- ed heteroaryl group containing at least one heteroatom selected from N, S, and O, a saturated or rated C3-8 cycloalkyl group, a C1-8 alkyl group, a C2-8 alkenyl group, a C2-8 alkynyl group, a (C1-4 alkyl)-(C5-6 aryl) group, a (C1-4 -(C3-8 cycloalkyl) group or a (C1-4 alkyl)-(5- to 6- membered heteroaryl group containing at least one heteroatom selected from N, S, and O) group, which groups independently are optionally substituted by one or more substituents o Ra and Rb independently represent a halogen atom, a hydroxy group, C1-4 alkyl group, C1-4 alkoxy group, -SH, a C1-4 alkylthio group, a nitro group, a cyano group, -CO2R’, -NR’R’’, -C(O)NR’R’’, -N(R’’’)C(O)-R’, -N(R’’’)- C(O)NR’R’’, whererin R’, R’’ and R’’’ each independently represents a hydrogen atom or a C1-4 alkyl group, or R’ and R’’ together with the nitrogen atom to which they are attached from a 3 to 6 membered heterocyclic ring. o Q ents a direct bond, –CH2-, -CH2-CH 2-, -O-, -O-CH2-, -S-, -S-CH2-, - NH-, -NH-CH2- or –CH=CH-, o * ents the point of attachment of R3 to the remainder of the molecule of formula (I), • A1 and A2 independently are selected from the group consisting of a C1-10 alkylene group, a C2-10 alkenylene group and a C2-10 alkynylene group, wherein said groups are optionally substituted with one or more tuents selected from a halogen atom, a hydroxy group, a linear or branched C1-4 alkyl group, a linear or branched a C1-4 alkoxy group, a C5-6 aryl group and a C3-7 cycloalkyl group, • L1 is selected from a direct bond, -O-, -NRc-, -S-, -S(O)-, -SO2-, -NRc(CO)-, - (CO)NR c-, –NRc(CO)(CH 2)qO-, –O(CH2)q(CO)NR c-, –NRc(CH 2)qO-, – O(CH c-, –NRc(CO)NR d-, -C(O)-, -C(O)O-, -OC(O)-, -S(O)2NR c-, 2)qNR -NR cS(O) cS(O) d-, –C(O)NRcS(O) cC(O)-, wherein Rc 2-, -NR 2NR 2- and –S(O)2NR and Rd are ndently selected form a en atom and a linear or branched C1-4 alkyl group and q has a value of 0, 1 or 2, • G is selected from the group consisting of a C3-10 mono- or bicyclic cycloalkyl group, a C5-C14 mono- or bicyclic aryl group, a 3- to 14-membered ted or unsaturated mono- or bicyclic heterocyclyl group having one or more heteroatoms selected from N, S and O, a 5- to 14-membered mono- or bicyclic heteroaryl group having one or more heteroatoms selected from N, S and O and a bicyclic ring system consisting of two monocyclic ring systems which are linked between each other by a covalent bond n said monocyclic ring systems are independently selected from a C3-8 cycloalkyl group, a C5-C6 aryl group, a 3- to 8-membered saturated or unsaturated heterocyclyl group having one or more heteroatoms selected from N, S and O and a 5- to 6-membered heteroaryl group having one or more heteroatoms selected from N, S and O, wherein the cyclic groups independently are optionally substituted with one or more tuents selected from a n atom, a C1-4 alkyl group, a C1-4 alkoxy group, a carboxy, group, a cyano group, a nitro group, a hydroxy group, an oxo group, a trifluoromethyl group and a trifluoromethoxy group, • B is a moiety having a beta2-adrenergic binding activity, and ents a group of formula (IB): Ar ∗ Formula (IB) wherein: o R7 is selected from the group consisting of a hydrogen atom, a linear or branched C1-4 alkyl group and a linear or branched C1-4 alkoxy group,Ar is selected from the group ting of a C3-10 saturated or unsaturated, mono- or bicyclic cycloalkyl group, a C5-C14 mono- or bicyclic aryl group, a 3- to 14-membered saturated or unsaturated mono- or bicyclic heterocyclyl group having one or more heteroatoms selected from N, S and O, a 5- to 14-membered mono- or bicyclic heteroaryl group having one or more heteroatoms selected from N, S and O and wherein the cyclic groups ndently are optionally substituted with one or more substituents selected from a halogen atom, a cyano group, a nitro group, a oxo group, a carboxy group, a C1-4 alkyl group, a C1-4 alkoxy group, - CF3, –OCF3, , -(CH2)p-OH, -NRe(CO)Rf, -NRe-SO2-Rg, -SO2NReRf, -OC(O)Rh, and –NRe(CH2)(0-2)-Ri, wherein p has a value of 0, 1 or 2 and wherein: o Re and Rf independently represent a hydrogen atom or a linear or branched C1-4 alkyl group, o Rg is selected from the group consisting of a linear or branched C1-4 alkyl group, a C6-5 aryl group, a saturated or unsaturated C3-8 cycloalkyl, wherein the cyclic groups independently are optionally substituted with one or more substituents selected from halogen atom, a C1-4 alkyl group and a C1-4 alkoxy group, o Rh is selected from a hydrogen atom,-NReRf and a C5-6 aryl group which is optionally substituted with one or more substituents selected from a C1-4 alkyl group and a C1-4 alkoxy group, o Ri is selected from the group consisting of a C5-6 aryl group, C3-8 cycloalkyl group and a 3 to 8 ed saturated or unsaturated heterocyclyl group, which groups independently are optionally substituted with one or more substituents selected from an halogen atom, a C1-4 alkyl group and a C1-4 alkoxy group. with the proviso that when G is a phenyl group, L1 is not one of the group selected from a direct bond, -O-, -NHC(O)-, -C(O)NH- and –NH(CO)O- group.
Also described are synthetic processes and intermediates described herein, which are useful for preparing compounds of the invention.
The invention further provides a pharmaceutical composition comprising at least a compound of the invention and a pharmaceutically-acceptable carrier.
The invention also provides a compound of the invention as described herein for use in the treatment of human or animal body by therapy.
The invention is also directed to the compounds as described , for use in the treatment of a ogical condition or disease associated with dual β2 adrenergic receptor and muscarinic receptor ties in ular wherein the pathological ion or disease is ed from a pulmonary disease, such as asthma or chronic obstructive ary disease, rm labor, glaucoma, a ogical disorder, a cardiac er, mation, urological disorders such as urinary incontinence and gastrointestinal disorders such as irritable bowel syndrome or spastic colitis, preferably asthma and chronic obstructive pulmonary disease.
The invention also provides the use of the compounds of the invention as described herein, for the manufacture of a medicament for use in the treatment of apulmonary disease, such as asthma or c obstructive pulmonary disease, pre-term labor, glaucoma, a neurological disorder, a cardiac disorder, inflammation, urological ers such as urinary incontinence and gastrointestinal disorders such as irritable bowel syndrome or spastic colitis, preferably asthma and chronic obstructive pulmonary disease.
Also described is the use of the compounds of the invention, for the manufacture of a ment for use in the treatment of a pathological condition or disease associated with dual β2 adrenergic receptor and muscarinic receptor activities.
Also bed is a method of treatment of a pathological condition or disease ated with dual β2 rgic receptor and muscarinic receptor activities, in particular wherein the pathological condition or disease is selected from a pulmonary disease, such as asthma or chronic obstructive pulmonary disease, pre-term labor, glaucoma, a neurological disorder, a cardiac disorder, inflammation, urological disorders such as urinary incontinence and gastrointestinal disorders such as irritable bowel syndrome or spastic colitis, preferably asthma and chronic obstructive pulmonary disease, comprising administering a eutically effective amount of the compounds of the invention or a pharmaceutical composition of the ion to a subject in need of such treatment.
The invention also es a combination product comprising (i) at least a compound of the invention as described herein; and (ii) another compound selected from a corticosteroid and/or a PDE4 tor, for simultaneous, separate or sequential use in the treatment of the human or animal body.
DETAILED DESCRIPTION OF THE ION.
When describing the compounds and itions of the invention, and methods described, the following terms have the following meanings, unless otherwise indicated.
The term "comprising" as used in this specification means "consisting at least in part of". When interpreting each statement in this specification that includes the term ising", features other than that or those prefaced by the term may also be t. Related terms such as "comprise" and "comprises" are to be interpreted in the same manner.
As used herein the term C1-C4 alkyl embraces linear or branched radicals having 1 to 4 carbon atoms. Examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl and t-butyl radicals.
As used herein, the term C1-C10 alkylene es divalent alkyl es typically having from 1 to 10 carbon atoms. Examples of C1-C10 ne radicals include methylene, ethylene, propylene, butylene, pentylene and hexylene radicals.
As used herein, the term C2-C10 alkenylene embraces divalent alkenyl moieties typically having from 2 to 10 carbon atoms. Examples of C2-C10 alkenylene radicals e vinylene, propenylene, butenylene, pentenylene, hexenylene, heptenylene, octenylenyl radicals.
As used herein, the term C2-C10 alkynylene embraces divalent alkynyl moieties having 2 to 10 carbon atoms. es include propynylene, lene, ylene, octynylene.
As used herein, the term C1-C4 alkoxy (or alkyloxy) embraces optionally substituted, linear or branched oxy-containing ls each having alkyl ns of 1 to 4 carbon atoms. Exmaples include y, ethoxy, oxy, i-propoxy, n-butoxy, sec-butoxy and t-butoxy.
As used herein, the term C1-C4 alkylthio embraces radicals containing a linear or branched alkyl radicals of 1 to 4 carbon atoms attached to a divalent –S- radical.
Examples include methylthio, ethylthio, n-propylthio, i-propylthio, n-butylthio, secbutylthio and t-butylthio.
As used herein, the term C3-C10 cycloalkyl radical embraces saturated monocyclic carbocyclic radicals having from 3 to 10 carbon atoms. Examples of monocyclic cycloalkyl groups e cyclobutyl, cyclopentyl and cyclohexyl group.
As used herein, the term C5-C14 aryl l embraces typically a C5-C14 , preferably a C6-C14 , more preferably a C6-C10 monocyclic or polycyclic aryl radical. Examples of aryl radicals include phenyl, naphthyl, naphthalenyl, anthranyl and phenanthryl.
As used herein, the term 5- to 14- membered heteroaryl radical embraces typically a 5- to 14- membered ring system comprising at least one heteroaromatic ring and ning at least one heteroatom selected from O, S and N. A 5- to 14- membered heteroaryl radical may be a single ring or two or more fused rings wherein at least one ring contains a heteroatom.
Examples include pyridyl, pyrazinyl, pyrimidinyl, zinyl, furyl, benzofuranyl, oxadiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, thiadiazolyl, thienyl, pyrrolyl, hiazolyl, indolyl, indazolyl, purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, quinolizinyl, cinnolinyl, lyl, indolizinyl, indolinyl, isoindolinyl, isoindolyl, imidazolidinyl, pteridinyl, thianthrenyl, pyrazolyl, 2H-pyrazolo[3,4-d]pyrimidinyl, 1H-pyrazolo[3,4-d]pyrimidinyl, thieno[2,3-d] pyrimidinyl and the s pyrrolopyridyl radicals.
As used herein, the term 3- to 14-membered heterocyclyl l es typically a non-aromatic, saturated or unsaturated C3-C14 carbocyclic ring system in which one or more, for example 1, 2, 3 or 4 of the carbon atoms preferably 1 or 2 of the carbon atoms are replaced by a heteroatom ed from N, O and S. A cyclic radical may be a single ring or two or more fused rings wherein at least one ring contains a heteroatom, and may have one or more double bonds Examples of 3 to 14-membered heterocyclic radicals include piperidyl, pyrrolidyl, pyrrolinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolyl, pyrazolinyl, pirazolidinyl, quinuclidinyl, triazolyl, pyrazolyl, tetrazolyl, imidazolidinyl, imidazolyl, oxiranyl, nyl, aziridinyl, oxetanyl, thiatanyl, azetidinyl, 4,5-dihydro-oxazolyl, 2-benzofuran-1(3H)-one, 1,3-dioxolone, tetrahydrofuranyl, 3-aza-tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,4-azathianyl, oxepanyl, anyl, azepanyl, 1,4-dioxepanyl, 1,4-oxathiepanyl, 1,4-oxaazepanyl, 1,4-dithiepanyl, 1,4- thiezepanyl, 1,4-diazepanyl, tropanyl, (1S,5R)aza-bicyclo[3.1.0]hexyl, 3,4-dihydro- 2H-pyranyl, 5,6-dihydro-2H-pyranyl, 2H-pyranyl, 2,3-hydrobenzofuranyl, 1,2,3,4- tetrahydropyridinyl, 1,2,5,6-tetrahydropyridinyl, isoindolinyl and indolinyl.
As used herein, the term halogen atom embraces chlorine, ne, bromine or iodine atoms. A halogen atom is lly a fluorine, chlorine or bromine atom. The term halo when used as a prefix has the same meaning.
Also included within the scope of the invention are the isomers, polymorphs, ceutically able salts, N-oxides, isotopes, solvates and prodrugs of the compounds of formula (I). Any reference to a compound of a (I) throughout the present specification includes a reference to any isomer, polymorph, pharmaceutically acceptable salt, N-oxide, isotope, solvate or prodrug of such compound of formula (I).
Isomers Compounds containing one or more chiral centre may be used in enantiomerically or diastereoisomerically pure form, in the form of racemic mixtures and in the form of mixtures enriched in one or more stereoisomer. The compounds of the present invention as bed and claimed encompass the c forms of the compounds as well as the individual enantiomers, diastereomers, and stereoisomer-enriched mixtures. tional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate using, for e, chiral high pressure liquid chromatography (HPLC). Alternatively, the racemate (or a racemic precursor) may be d with a suitable optically active compound, for example, an alcohol, or, in the case where the compound contains an acidic or basic moiety, an acid or base such as tartaric acid or ylethylamine. The resulting diastereomehc mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure omer(s) by means well known to one skilled in the art. Chiral compounds of the invention (and chiral precursors thereof) may be ed in enantiomerically-enriched form using chromatography, typically HPLC, on an tric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, ning from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to % of an alkylamine, typically 0.1 % diethylamine. Concentration of the eluate affords the enriched mixture. Stereoisomer conglomerates may be separated by conventional techniques known to those skilled in the art. See, e.g. "Stereochemistry of Organic Compounds" by Ernest L. ElieI (Wiley, New York, 1994).
The compounds of a (I) may exhibit the phenomena of tautomerism and structural isomerism. ers exist as mixtures of a tautomeric set in solution. In solid form, y one tautomer predominates. Even though one tautomer may be described, the present invention includes all tautomers of the compounds of Formula (I).
Polymorphs The compounds of the present invention may exist in different physical forms, i.e. amorphous and lline forms.
Moreover, the compounds of the invention may have the ability to crystallize in more than one form, a characteristic which is known as polymorphism. Polymorphs can be distinguished by various physical properties well known in the art such as X-ray diffraction pattern, g point or solubility. All physical forms of the compounds of the present invention, including all polymorphic forms morphs") thereof, are included within the scope of the invention.
Salts As used herein, the term pharmaceutically acceptable salt refers to a salt prepared from a base or acid which is acceptable for administration to a patient, such as a mammal. Such salts can be derived from pharmaceutically-acceptable inorganic or organic bases and from ceutically-acceptable inorganic or organic acids.
As used herein, the term ceutically acceptable salt embraces salts with a pharmaceutically acceptable acid or base. Pharmaceutically acceptable acids include both inorganic acids, for example hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic, odic and nitric acid; and organic acids, for example , c, gluconic, glutamic, lactic, , malic, mandelic, mucic, ascorbic, , pantothenic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, esulphonic, p-toluenesulphonic acid, xinafoic (1-hydroxynaphthoic acid), napadisilic (1,5-naphthalenedisulfonic acid) and the like. Particularly preferred are salts derived from fumaric, hydrobromic, hydrochloric, acetic, sulfuric, methanesulfonic, xinafoic, and tartaric acids.
Salts derived from pharmaceutically-acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like. ularly preferred are um, calcium, magnesium, potassium and sodium salts.
Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including alkyl amines, arylalkyl amines, heterocyclyl amines, cyclic amines, naturally-occurring amines and the like, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2- laminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, ine, hydrabamine, isopropylamine, lysine, methylglucamine, line, piperazine, piperidine, ine resins, procaine, purines, omine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
Other preferred salts according to the invention are quaternary ammonium compounds wherein an equivalent of an anion (X-) is associated with the positive charge of the N atom. X- may be an anion of various mineral acids such as, for example, chloride, bromide, iodide, sulphate, nitrate, phosphate, or an anion of an organic acid such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, te, , mandelate, trifluoroacetate, methanesulphonate and p-toluenesulphonate. X- is preferably an anion selected from chloride, bromide, iodide, sulphate, nitrate, acetate, maleate, oxalate, succinate or trifluoroacetate. More preferably X- is chloride, bromide, oroacetate or methanesulphonate.
N-oxides As used herein, an N-oxide is formed from the tertiary basic amines or imines present in the molecule, using a convenient ing agent.
Isotopes The invention also includes isotopically-labeled compounds of the invention, wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of en, such as 2H and 3H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 CI, fluorine, such as 18 F, iodine, such as 123 I and 125 I, nitrogen, such as 13 N and 15 N, oxygen, such as 15 O, 17 O and 18 O, phosphorus, such as 32 P, and sulfur, such as 35 S. Certain isotopically-labeled compounds of the invention, for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, 3H, and carbon- 14, 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium, 2H, may afford n therapeutic advantages ing from greater metabolic ity, for example, increased in vivo half-life or d dosage ements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as 11 C, 18 F, 15 O and 13 N, can be useful in Positron Emission aphy (PET) studies for examining substrate receptor occupancy.
Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes ous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.
Preferred isotopically-labeled compounds e deuterated derivatives of the nds of the invention. As used , the term ated derivative embraces compounds of the invention where in a particular position at least one hydrogen atom is replaced by deuterium. Deuterium (D or 2H) is t at a natural abundance of 0.015 molar %.
Solvates The compounds of the invention may exist in both unsolvated and solvated forms. The term solvate is used herein to describe a molecular x comprising a compound of the invention and an amount of one or more pharmaceutically acceptable t molecules. The term hydrate is employed when said solvent is water. Examples of solvate forms include, but are not limited to, compounds of the invention in association with water, acetone, dichloromethane, 2-propanol, ethanol, methanol, dimethylsulfoxide (DMSO), ethyl e, acetic acid, ethanolamine, or mixtures thereof. It is specifically contemplated that in the t invention one solvent molecule can be associated with one molecule of the compounds of the present invention, such as a e.
Furthermore, it is specifically contemplated that in the present invention, more than one solvent molecule may be associated with one molecule of the compounds of the present invention, such as a ate. Additionally, it is specifically contemplated that in the t invention less than one solvent molecule may be associated with one molecule of the compounds of the present invention, such as a hemihydrate.
Furthermore, solvates of the present invention are contemplated as solvates of compounds of the present invention that retain the biological effectiveness of the nonsolvate form of the compounds.
Prodrugs Prodrugs of the compounds described herein are also within the scope of the invention.
Thus certain derivatives of the compounds of the present invention, which derivatives may have little or no pharmacological activity themselves, when administered into or onto the body may be ted into compounds of the present invention having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as 'prodrugs'. Further information on the use of prodrugs may be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS ium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. E. B. Roche, American Pharmaceutical Association).
Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of the present invention with n moieties known to those skilled in the art as 'pro-moieties' as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985).
Typically G is selected from the group ting of a C5-C6 aryl group, a 8- to 10- membered saturated or rated bicyclic heterocyclyl group having one or more atoms selected from N, S and O, a 8- to 10-membered bicyclic aryl group having one or more heteroatoms ed from N, S and O and a C5-C6 aryl group linked to a ring system selected from a C5-6 aryl group, a C3-7 cycloalkyl group and a 5- to 6-membered heteroaryl group having two or three heteroatoms selected from N, S and O, wherein the cyclic groups independently are optionally substituted with one or more substituents selected from a n atom, a C1-4 alkyl group, a C1-4 alkoxy group, a cyano group, a nitro group, a y group and an oxo group.
Preferably, G is ed from a phenyl group, a 9- to 10-membered unsaturated ic heterocyclyl group having one or more heteroatoms selected from N, S and O, a 9- to 10-membered bicyclic heteroaryl group having one or more heteroatoms selected from N, S and O and a C5-C6 aryl group linked to a ring system selected from a C5-6 aryl group and a 5- to 6-membered heteroaryl group having two or three heteroatoms selected from N, S and O, wherein the cyclic groups independently are optionally substituted with one or two substituents selected from a halogen atom, a methyl group, a methoxy group, a cyano group, a hydroxy group and an oxo group.
Typically, L1 is selected from the group consisting of direct bond, -NRc-, -S-, -SO2-, - C(O)-, -C(O)O-, -S(O)2NRc-, -NRcS(O) c(CO)(CH c-, - 2-, –NR 2)O-, –O(CH2)(CO)NR NR c(CO)NR d- and -CONRcS(O) c and Rd independently are selected from 2-, wherein R a hydrogen atom and a methyl group.
Preferably L1 is selected from a direct bond, -NH-, -S-, -SO2-, -C(O)-, O)NRcand –O(CH2)(CO)NRc-, more preferably L1 is selected from a direct bond, -NH-, -SO2-, -NH(CO)NH- and –O(CH2)(CO)NRc-, being most preferably a direct bond or – (CO)NRc-.
In a preferred embodiment of the present ion, -G-L1- has the following formula: W or Z Lx Formula (Iwa) Formula (Iwb) wherein - V, W and Z are independently selected from a –N-, -C-, -S-, -O- and –C (O)- - Lx represents a 5 to 6 membered heteroaryl group having at least one heteroatom selected from N, S and O, or Lx represents a -CO-NRd-, wherein Rd represents a hydrogen atom or a methyl group. - * represents the point of attachment with A 2 and - • represents the point of attachment with A1.
In a preferred embodiment of the present invention, -G-L1- has the following formula (Iwa): Formula (Iwa) wherein V, W and Z are as defined above.
In a still preferred embodiment, - Z is a nitrogen atom, - V represents a nitrogen atom, an oxigen atom, a carbon atom or a sulphur atom and, - W represents a nitrogen atom, a carbon atom or a carbonyl atom.
More preferably, G-L1- has the following a (Iwaa): Formula (Iwaa) wherein V and W are as d above.
Typically R3 represents a group of formula: R5 R4 R4 ∗ i) ∗ or ii) Q wherein: o R4 represents a hydrogen atom, a hydroxy group, a ymethyl group or a linear or branched C1-4 alkyl group, o R5 and R6 independently represent C5-6 aryl group, a 5- to 6- membered heteroaryl group containing at least one heteroatom selected from N, S, and O; (C1-4 alkyl)-(C5-6 aryl) group, a C3-8 cycloalkyl group, o Q represents a direct bond or a –CH2-, -CH2-CH2-, -O-, -O-CH2-, -S-, -SCH2- , or –CH=CH-, o * represents the point of attachment of R3 to the der of the molecule of formula (I), More preferably R3 represents a group of formula i) or ii), n: o R4 represents a en atom, a hydroxy group, a hydroxymethyl group or a linear or branched C1-4 alkyl group, o R5 and R6 independently represents a thienyl group, a phenyl group, a benzyl group or a C4-6 cycloalkyl group, o Q represents a direct bond or an oxygen atom, o * represents the point of attachment of R3 to the remainder of the molecule of formula (I), In another embodiment, compounds of the present invention have the following formula (IA): V R2 N N O A1 A2 R3 Formula (IA) wherein R1, R2, R3, A1, A2, V, W and B are as defined above.
Typically, A1 and A2 independently are selected from the group consisting of a C1-6 alkylene group, C2-6 alkenylene group and C2-6 alkynylene group, wherein said groups are optionally tuted with one or more substituents selected from halogen atom, a hydroxy group, a C1-2 alkyl group, a C1-2 alkoxy group, a C5-6 aryl group and a C3-6 cycloalkyl group.
Preferably, A1 and A2 independently represent a C1-6 alkylene group ally substituted with one or more substituents selected from a C1-2 alkyl group, a C1-2 alkoxy group and a phenyl group, preferably substituted with one or two substituents ed from a methyl group and a methoxy group, more preferably a methyl group.
B is a moiety having a beta2-adrenergic binding activity such that the IC50 of the compound is 1mM or less, preferably 100 µM or less, more preferably 10 µM or less, more ably 1µM or less, more ably 500 nM or less, most ably 250 nM or less, as measured in a beta2-adrenergic binding assay. lly said beta2-adrenergic binding assay comprises: a) providing a membrane suspension comprising Sf9 cells in an assay buffer b) incubating with 12177 in plates previously treated with assay buffer containing a coating agent c) measuring binding of test compound in the presence of propanolol d) maintaining incubation e) terminating the binding reactions f) determining the affinity of the test compound for the receptor by repeating steps a) to e) using multiple different test compound concentrations. g) calculating an IC50 using the four parameters-log equation.
B represents a group of formula (IB): Ar ∗ Formula (IB) wherein: • R7 is selected from the group consisting of a hydrogen atom, a linear or branched C1-4 alkyl group and a linear or ed C1-4 alkoxy group, • Ar is selected from the group consisting of a C3-10 saturated or rated, mono- or bicyclic cycloalkyl group, a C5-C14 mono- or bicyclic aryl group, a 3 to 14-membered saturated or unsaturated mono- or bicyclic heterocyclyl group having one or more heteroatoms selected from N, S and O, a 5- to 14- membered mono- or bicyclic heteroaryl group having one or more heteroatoms ed from N, S and O and wherein the cyclic groups independently are optionally substituted with one or more substituents selected from a halogen atom, a cyano group, a nitro group, an oxo group, a carboxy group, a C1-4 alkyl group, a C1-4 alkoxy group, -CF3, –OCF3, -NReRf, -(CH2)p-OH, -NRe(CO)Rf, - NRe-SO2-Rg, -SO2NReRf, Rh, and –NRe(CH2)(0-2)-Ri, wherein p has a value of 0, 1 or 2 and wherein: o Re and Rf ndently represent a hydrogen atom or a linear or branched C1-4 alkyl group, o Rg is selected from the group consisting of a linear or branched C1-4 alkyl group, a C6-5 aryl group, a saturated or unsaturated C3-8 cycloalkyl, wherein the cyclic groups independently are optionally substituted with one or more substituents selected from a halogen atom, a C1-4 alkyl group and a C1-4 alkoxy group, o Rh is selected from a hydrogen NReRf and a C5-6 aryl group which is ally substituted with one or more substituents selected from a C1-4 alkyl group and a C1-4 alkoxy group, o Ri is selected from the group ting of a C5-6 aryl group, C3-8 cycloalkyl group and a 3- to 8- membered saturated or unsaturated heterocyclyl group, which groups independently are optionally substituted with one or more substituents selected from a halogen atom, a C1-4 alkyl group and a C1-4 alkoxy group.
Preferably, Ar represents a group of formula: Ga O Gb N HO Y (R) T r X O Rj O (c) (d) wherein • Ga and Gb independently are selected from a nitrogen atom and a carbon atom, • r has a value of 0, 1, 2 or 3 and • R is seleted from the group consisting of a halogen atom, an amino group, a cyano group, a nitro group, an oxo group, a carboxy group, a C1-4 alkyl group, a C1-4 alkoxy group, -CF3, –OCF3, p-OH, -NH(CO)H, -NH-SO2-Rg, -SO2NH2, -OC(O)H, -(4-methyl)phenyl, –O(CO)-N(CH3)2, -OC(O)NH2 and – NH(CH2)(1-2)-Ri, group, wherein p is as defined above and Rg and Ri independently are selected from a phenyl group optionally substituted with a substituent selected from a methyl group or a methoxy group.
• Rj represents a n atom, • T is selected from the group consisting of –CH2- and –NH-, • Both X and Y represent a hydrogen atom or X together with Y form the group – CH2-CH2-, -CH=CH-, - or –S-, wherein in the case of -CH2-O- the methylene group is bound to the carbonyl group holding X and the oxygen atom is bound to the carbon atom in the phenyl ring holding Y.
Preferably, Ar represents a compound of formula (a) or (b) wherein: or HO Y (R)r T X • Both Ga and Gb represent a carbon atom, • R is seleted from the group ting of a halogen atom, an amino group, a cyano group, a nitro group, -(CH2)p-OH, -NH(CO)H, -NH-SO2-CH3, -SO2NH2, - OC(O)H, –O(CO)-(4-methyl)phenyl, –O(CO)-N(CH3)2, -OC(O)NH2 and -CF3 group, wherein p has a value of 0, 1 or 2, • T represents –NH- group, • Both X and Y represent a hydrogen atom or X er with Y form the group – CH=CH-, -CH2-CH2-, - or –S-, wherein in the case of -CH2-O- the methylene group is bound to the carbon atom in the amido substituent holding X and the oxygen atom is bound to the carbon atom in the phenyl ring g In a still prefered embodiment Ar is selected from the group consisting of 3- bromoisoxazolyl, 3,4-dihydroxyphenyl, 4-hydroxy(methylsulfonamido)phenyl, 3,4- bis(4-methylbenzoyloxy)phenyl, 3,5-bis(dimethylcarbamoyloxy)phenyl, (5-hydroxy hydroxymethyl)pyridyl, (4-amino-3,5-dichloro)phenyl, 4-hydroxyphenyl, 4-hydroxy (2-hydroxyethyl)phenyl, 4-hydroxy(hydroxymethyl)phenyl, [4-aminochloro (trifluoromethyl)]phenyl, (3-formamidohydroxy)phenyl, 8-hydroxyoxo-1,2- dihydroquinolinyl, 8-hydroxyoxo-1,2,3,4-tetrahydroquinolinyl, 5-hydroxyoxo- 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, oxyoxo-2,3-dihydrobenzo[d]thiazol yl. Preferably Ar is selected from the group consisting of oxy (hydroxymethyl)phenyl, (3-formamidohydroxy)phenyl, 8-hydroxyoxo-1,2- dihydroquinolinyl, 8-hydroxyoxo-1,2,3,4-tetrahydroquinolinyl and 5-hydroxy oxo-3,4-dihydro-2H-benzo[b][1,4]oxazinyl.
In another embodiment Ar represents a compound of formula (b) wherein X and Y are as defined above and T represents a –NH- group.
Still in another embodiment of the present invention, compounds of the present invention have the following formula (IC): OH O G L1 O n m N R8 R9 R10 HO Y HN X Formula (IC) Wherein: • R3 represents a group of formula: R5 R4 R4 ∗ i) ∗ or ii) Q wherein: o R4 represents a en atom, a hydroxy group, a hydroxymethyl group or a linear or branched C1-4 alkyl group, o R5 and R6 independently represent C5-6 aryl group, a 5- to 6- membered heteroaryl group containing at least one heteroatom selected from N, S, and O; (C1-4 alkyl)-(C5-6 aryl) group, a C3-8 cycloalkyl group, o Q ents a direct bond or a –CH2-, -CH2-CH2-, -O-, -O-CH2-, -S-, -SCH2- , or –CH=CH-, o * represents the point of ment of R3 to the remainder of the molecule of formula (I), • Both X and Y represent a hydrogen atom or X together with Y form the group – CH=CH-, H2-, -CH2-O- or –S-, wherein in the case of -CH2-O- the methylene group is bound to the carbon atom in the amido substituent holding X and the oxygen atom is bound to the carbon atom in the phenyl ring holding Y, • n has a value of 0, 1 or 2, • m has a value of 2, 3 or 4, • R8, R9 and R10 independently represent a hydrogen atom or a linear or branched C1-4 alkyl group, • -G-L1- represents a group of formula (IG): W or ∗ Z Lx Formula (Iw) wherein - V, W and Z are independently selected from a –N-, -C-, -S-, -O- and –C (O)- - Lx represents a 5 to 6 membered heteroaryl group having at least one heteroatom selected from N, S and O, or Lx represents a –O-CH2-CO-NRd-, wherein Rd ents a hydrogen atom or a methyl group. - * represents the point of attachement with the moiety containing the cycl ohexyl group and - • represents the point of attachement with the moiety containing the thylphenol moiety, In a still preferred embodiment, Lx represents a 5 to 6 membered heteroaryl group having at least one heteroatom selected from N, S and O, ably Lx is selected from a l, a pyrazinyl, a furyl, an oxadiazolyl, a imidazolyl, a thiazolyl and a thienyl group, more preferably, Lx represents a pyridyl, an oxadiazolyl, a imidazolyl or a lyl group, being most preferably an oxadiazolyl group.
In a preferred embodiment, compounds of the present invención have the following formula (IDa): H R3 N V O n W R8 R9 O HO Y N HN X N Formula (IDa) wherein V, W, X, Y, R8, R9, R10, n and m are as defined above.
In a still preferred embodiment, compounds of the present ion have the following formula (ID): H R3 N V O n W R8 R9 O HO Y N HN X N Formula (ID) Wherein: • V, W, X, Y, R8, R9, R10, n and m are as defined above, • R3 represents a group of formula: R5 R4 R4 ∗ i) ∗ or ii) Q wherein: o R4 represents a hydrogen atom, a hydroxy group, a hydroxymethyl group or a linear or branched C1-4 alkyl group, o R5 and R6 independently represents a thienyl group, a phenyl group, a benzyl group or a C4-6 cycloalkyl group, o Q represents a direct bond or an oxygen atom, o * ents the point of attachment of R3 to the remainder of the molecule of formula (I), Typically, X together with Y form the group -CH=CH- or –CH2-O-. Preferably, X together with Y form the group –CH=CH-.
Typically W ents a nitrogen atom or a carbonyl group, preferably W ents a nitrogen atom.
Typically, V represents a nitrogen atom, an oxygen atom or a sulphur atom, preferably V is a nitrogen atom or an oxygen atom.
In a preferred embodiment V represents a nitrogen atom or an oxygen atom while W represents a carbonyl group.
In another red embodiment both V and W represent a nitrogen atom. ll, n has a value 0.
Typically, m has a value of 3.
Typically R10 represents a hydrogen atom or a methyl group, preferably a methyl group.
Typically, R8 and R9 independently represent a hygrogen atom or a methyl group, preferably both R8 and R9 represent a hydrogen atom.
Typically, R3 represents a group of a ii), wherein Q is an oxygen atom and R4 is selected from a en atom, a hydroxy group and a methyl group. Preferably R4 represents a hydroxy group or a methyl group, more preferably a methyl group.
Typically, R3 represents a group of formula i) wherein: • R4 represents a hydrogen atom, a methyl group or a hydroxy group, preferably R4 represents a hydroxy group, • R5 and R6 ndently represent a thienyl group, a entyl group or a benzyl group, preferably both R5 and R6 are l groups.
In one embodiment of the t invention, in compounds of formula (IC) - -G-L 1- represents a group of formula: N Lx Wherein o V is selected from –N-, -C-, -S- and -O-, o W is selected from –N-, -C-, and –C(O)-, o Lx represents an oxadiazolyl group or –O-CH2-CO-NRd-, n Rd represents a hydrogen atom or a methyl group. o * represents the point of attachment with the moiety containing the cyclohexyl group and o • represents the point of attachment with the moiety containing the aminoethylphenol fragment, - R 8 and R9 independently are selected from a hydrogen atom and a methyl group, - R 10 represents a methyl group, - n has a value of 0 or 1, - m has a value of 2, 3 or 4, - Both X and Y represents a hydrogen atom or X together with Y form –CH=CH-, -CH2-O-, or –S- group, - R 3 represents a group of formula: R5 R4 R4 ∗ i) ∗ or ii) Q wherein: o R4 represents a methyl group or a hydroxy group, o R5 and R6 independently represents a thienyl group, a phenyl group, benzyl group or a cyclopentyl group, o Q represents a direct bond or an oxygen atom, o * represents the point of attachment of R3 to the remainder of the molecule of formula (I).
Preferably, - -G-L 1- represents a group of formula: Wherein o W represents a nitrogen atom or a carbonyl group, o V represents a nitrogen or an oxygen atom, - Both R 8 and R9 represents a hydrogen atom, - X together with Y form –CH=CH-, - R 4 represents a hydroxy group and 3 represents a group of formula i) wherein R both R5 and R6 ent a thienyl group. ular individual compounds of the invention include: Trans[{3-[6-({[(2R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolinyl)ethyl] amino}methyl)oxo-1,3-benzoxazol-3(2H)-yl]propyl}(methyl)amino]-cyclohexyl hydroxy(dithienyl)acetate, dihydrofluoride, trans[{3-[5-({[(2R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolin yl]amino}methyl)oxo-2,3-dihydro-1H-benzimidazolyl]propyl} (methyl)amino]cyclohexyl hydroxy(dithienyl)acetate dihydrofluoride, Trans[{3-[5-({[(2R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolin yl)ethyl]amino}methyl)-1H-1,2,3-benzotriazolyl]propyl}(methyl)amino] cyclohexylhydroxy(dithienyl)acetate dihydrofluoride, Trans[{3-[5-({[(2R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolin yl]amino}methyl)-1H-indolyl]propyl}(methyl)amino]cyclohexylhydroxy (di thienyl)acetate dihydrofluoride, Trans[{3-[5-({[(2R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolin yl)ethyl]amino}methyl)-1H-benzimidazolyl]propyl}(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate, Trans[{3-[5-({[(2R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolinyl) ethyl]amino}methyl)-1H-indazolyl]propyl}(methyl)amino]cyclohexylhydroxy(di thienyl)acetate, Trans[{3-[6-({[(2R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolin yl)ethyl]amino}methyl)oxo-1,3-benzothiazol-3(2H)-yl]propyl}(methyl)amino] cyclohexyl hydroxy(dithienyl)acetate, Trans[(3-{5-[({(2R)[3-(formylamino)hydroxyphenyl]- 2- hydroxyethyl}amino)methyl]-1H-1,2,3-benzotriazolyl}propyl)(methyl)amino] cyclohexyl hydroxy(dithienyl)acetate, Trans[{3-[5-({[(2R)hydroxy(4-hydroxyoxo-2,3-dihydro-1,3-benzothiazol- 7-yl)ethyl]amino}methyl)-1H-1,2,3-benzotriazolyl]propyl}(methyl) amino]cyclohexyl y(dithienyl)acetate, Trans[{3-[6-(2-{[(2R)hydroxy(8-hydroxymethylene-1,2-dihydroquinolin yl)ethyl]amino}ethyl)oxo-1,3-benzoxazol-3(2H)-yl]propyl}(methyl)amino] cyclohexyl hydroxy(dithienyl)acetate, Trans[{2-[6-({[(2R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolin yl)ethyl]amino}methyl)oxo-1,3-benzoxazol-3(2H)-yl]ethyl}(methyl)amino] cyclohexylhydroxy(dithienyl)acetate, Trans[{4-[6-({[(2R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolin yl)ethyl]amino}methyl)oxo-1,3-benzoxazol-3(2H)-yl]butyl}(methyl)amino] cyclohexylhydroxy(dithienyl)acetate, Trans[{3-[5-({[(2R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolin yl)ethyl]amino}methyl)-1H-1,2,3-benzotriazolyl]propyl}(methyl)amino] cyclohexylcyclopentyl(hydroxy)2-thienylacetate, Trans[{3-[6-({[(2R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolin yl)ethyl]amino}methyl)oxo-1,3-benzoxazol-3(2H)-yl]propyl}(methyl)amino] exylmethyl-9H-xanthenecarboxylate, Trans[{3-[6-({[(2R)hydroxy(5-hydroxyoxo-3,4-dihydro-2H-1,4- benzoxazinyl)ethyl]amino}methyl)- 2-oxo-1,3-benzothiazol-3(2H)-yl]propyl} (methyl)amino]cyclohexyl y(dithienyl)acetate, Trans[(2-{5-[({(2R)[3-(formylamino)hydroxyphenyl]hydroxyethyl} amino)methyl]-1H-indolyl}ethyl)(methyl)amino]cyclohexyl 9H-fluorene ylate, Trans[(3-{5-[({(2R)[3-(formylamino)hydroxyphenyl]hydroxyethyl} amino)methyl]-1H-indolyl}propyl)(methyl)amino]cyclohexyl 2-hydroxyphenyl (2-thienyl)propanoate, Trans[{3-[5-(2-{[(2R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolin yl)ethyl]amino}methylpropyl)oxo-2,3-dihydro-1H-benzimidazolyl]propyl} (methyl)amino]cyclohexyl 2,2-diphenylpropanoate, Trans[{2-[5-(2-{[(2R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolinyl) ethyl]amino}methylpropyl)-1H-indazolyl]ethyl}(methyl)amino]cyclohexyl 2- phenyl(2-thienyl)propanoate, Trans[{3-[6-(2-{[(2R)hydroxy(8-hydroxymethylene-1,2-dihydroquinolin yl)ethyl]amino}propyl)oxo-1,3-benzoxazol-3(2H)-yl]propyl}(methyl)amino] cyclohexyl y(dithienyl)acetate, Trans[(3-{3-[4-({[(2R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolin yl)ethyl]amino}methyl)phenyl]-1,2,4-oxadiazolyl}propyl)(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate, Trans[{2-[{[4-({[(2R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolin yl)ethyl]amino}methyl)phenoxy]acetyl}(methyl)amino]ethyl}(methyl)amino]cyclohexy l hydroxy(dithienyl)acetate, 4-[[2-({[4-({[(2R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolin yl)ethyl]amino}methyl)phenoxy]acetyl}amino)ethyl](methyl)amino]cyclohexyl hydroxy(dithienyl)acetate, Trans[(3-{3-[2-chloro({[(2R)hydroxy(8-hydroxyoxo-1,2- dihydroquinolinyl)ethyl]amino}methyl)methoxyphenyl]-1,2,4-oxadiazol yl}propyl)(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate and Trans[{2-[{[2-chloro({[(2R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolin- -yl)ethyl]amino}methyl)methoxyphenoxy]acetyl}(methyl)amino]ethyl}(methyl) amino]cyclohexyl hydroxy(dithienyl)acetate, trans [{3-[1-(2-{[(2 R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolin yl]amino}ethyl)-1H-indolyl]propyl}(methyl)amino]cyclohexyl hydroxy(di thienyl)acetate dihydrofluoride, trans [(3-{5-[({(2 R)[3-(acetylamino)hydroxyphenyl] hydroxyethyl}amino)methyl]oxo-2,3-dihydro-1H-benzimidazol yl}propyl)(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate dihydrofluoride, trans -[6-[({(2 R)[3-(formylamino)hydroxyphenyl] hydroxyethyl}amino)methyl]oxo-1,3-benzoxazol-3(2 H)- yl]propyl}(methyl)amino]cyclohexyl 9-methyl-9H-xanthenecarboxylate dihydrofluoride trans [{3-[5-({[(2R)hydroxy(5-hydroxyoxo-3,4-dihydro-2H-1,4-benzoxazin- 8-yl)ethyl]amino}methyl)-1H-1,2,3-benzotriazol yl]propyl}(methyl)amino]cyclohexyl (2S)-cyclopentyl(hydroxy)2-thienylacetate dihydrofluoride, trans {[2-({2-[4-(2-{[(2 R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolin yl)ethyl]amino}propyl)phenoxy]acetyl}amino)ethyl]amino}cyclohexyl hydroxy(di thienyl)acetate ofluoride, and trans [{3-[5-({[(2 R)hydroxy(4-hydroxyoxo-2,3-dihydro-1,3-benzothiazol yl)ethyl]amino}methyl)-1H-1,2,3-benzotriazolyl]propyl}(methyl)amino]cyclohexyl (2 S)-cyclopentyl(hydroxy)2-thienylacetate or pharmaceutically acceptable salts or N-oxides or solvates or deuterated derivative f: Of particular interest are the compounds: Trans[{3-[6-({[(2R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolinyl)ethyl] amino}methyl)oxo-1,3-benzoxazol-3(2H)-yl]propyl}(methyl)amino]-cyclohexyl hydroxy(dithienyl)acetate, dihydrofluoride, trans[{3-[5-({[(2R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolin yl)ethyl]amino}methyl)oxo-2,3-dihydro-1H-benzimidazolyl]propyl} (methyl)amino]cyclohexyl hydroxy(dithienyl)acetate dihydrofluoride, Trans[{3-[5-({[(2R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolin yl)ethyl]amino}methyl)-1H-1,2,3-benzotriazolyl]propyl}(methyl)amino] exylhydroxy(dithienyl)acetate ofluoride, Trans[{3-[5-({[(2R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolin yl)ethyl]amino}methyl)-1H-indolyl]propyl}(methyl)amino]cyclohexylhydroxy (di thienyl)acetate dihydrofluoride, Trans[{3-[6-({[(2R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolin yl)ethyl]amino}methyl)oxo-1,3-benzothiazol-3(2H)-yl]propyl}(methyl)amino] cyclohexyl hydroxy(dithienyl)acetate, Trans[(3-{5-[({(2R)[3-(formylamino)hydroxyphenyl]- 2- hydroxyethyl}amino)methyl]-1H-1,2,3-benzotriazolyl}propyl)(methyl)amino] cyclohexyl hydroxy(dithienyl)acetate, Trans[{3-[5-({[(2R)hydroxy(4-hydroxyoxo-2,3-dihydro-1,3-benzothiazol- 7-yl)ethyl]amino}methyl)-1H-1,2,3-benzotriazolyl]propyl}(methyl) amino]cyclohexyl hydroxy(dithienyl)acetate, 4-[{2-[6-({[(2R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolin yl)ethyl]amino}methyl)oxo-1,3-benzoxazol-3(2H)-yl]ethyl}(methyl)amino] cyclohexylhydroxy(dithienyl)acetate, Trans[{3-[5-({[(2R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolin yl)ethyl]amino}methyl)-1H-1,2,3-benzotriazolyl]propyl}(methyl)amino] cyclohexylcyclopentyl(hydroxy)2-thienylacetate, Trans[{3-[6-({[(2R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolin yl)ethyl]amino}methyl)oxo-1,3-benzoxazol-3(2H)-yl]propyl}(methyl)amino] cyclohexylmethyl-9H-xanthenecarboxylate, Trans[{2-[{[4-({[(2R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolinyl)ethyl] amino}methyl)phenoxy]acetyl}(methyl)amino]ethyl}(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate, Trans[[2-({[4-({[(2R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolinyl)ethyl] amino}methyl)phenoxy]acetyl}amino)ethyl](methyl)amino]cyclohexyl hydroxy(di thienyl)acetate, Trans[(3-{3-[2-chloro({[(2R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolinyl )ethyl]amino}methyl)methoxyphenyl]-1,2,4-oxadiazolyl}propyl) (methyl)amino]cyclohexyl hydroxy(dithienyl)acetate, and Trans [{3-[5-({[(2R)hydroxy(5-hydroxyoxo-3,4-dihydro-2H-1,4- benzoxazinyl)ethyl]amino}methyl)-1H-1,2,3-benzotriazol yl]propyl}(methyl)amino]-cyclohexyl (2S)-cyclopentyl(hydroxy)2-thienylacetate dihydrofluoride or ceutically able salts or N-oxides or solvates or deuterated derivative thereof: Of ular interest is the compound 4-[{3-[5-({[(2R)hydroxy(8-hydroxy oxo-1,2-dihydroquinolinyl)ethyl]amino}methyl)-1H-1,2,3-benzotriazol yl]propyl}(methyl)amino] cyclohexylhydroxy(dithienyl)acetate dihydrofluoride, or pharmaceutically acceptable salts or N-oxides or solvates or deuterated derivative thereof.
The invention is also directed to a compound of the invention as described herein for use in the treatment of the human or animal body by therapy.
According to another embodiment the present invention covers pharmaceutical compositions comprising at least a compound of the invention, as hereinabove described, in admixture with pharmaceutically able diluents or carriers.
In an embodiment of the present invention the pharmaceutical composition further ses a therapeutically effective amount of one or more other eutic agents, in particular one or more drugs selected from the group consisting of corticosteroids, and PDE4 inhibitors.
It is also an embodiment of the present invention that the pharmaceutical composition is ated for administration by inhalation.
The compounds of the present invention as hereinabove defined may also be combined with one or more other therapeutic agents, in particular one or more drugs selected from the group consisting of corticosteroids and PDE4 inhibitors, for simultaneous, separate or sequential use in the treatment of the human or animal body.
The invention is also directed to compounds of the present invention for use in the treatment of a pathological condition or disease associated with both β2 adrenergic or and muscarinic receptor activities such as a pulmonary disease. In ular the pulmonary disease is asthma or chronic obstructive pulmonary disease.
The pathological condition or disease can also be applied within the scope of the present invention to the treatment of a disease or condition selected from the group consisting of pre-term labor, glaucoma, neurological disorders, cardiac disorders, and mation, urological disorders such as urinary inence and gastrointestinal disorders such as irritable bowel syndrome or spastic colitis.
The ion is also directed to the use of compounds of the present invention for the cture of a ment for the treatment of pathological ion or disease ated with one or both β2 adrenergic receptor and muscarinic receptor activities such as a pulmonary disease, in particular asthma or chronic obstructive pulmonary disease, pre-term labor, glaucoma, neurological disorders, cardiac disorders, inflammation, urological disorders and gastrointestinal disorders, preferably, asthma and chronic obstructive pulmonary disease.
Also described is a method of treating these diseases, which comprises administering a eutically effective amount of a ceutical composition comprising a dual β2 adrenergic receptor agonists and muscarinic receptor antagonists according to the present invention. The method further comprises administering a therapeutically effective amount of one or more other therapeutic agent selected from the group ting of a corticosteroid and a PDE4 inhibitor.
Also described is a method of modulating the activity of a β2 adrenergic and/or a M3 receptor, the method comprising stimulating a β2 rgic receptor and/or blocking a M3 receptor with a modulatory amount of nds of the present invention.
The term "therapeutically effective amount" refers to an amount sufficient to effect treatment when stered to a patient in need of treatment.
The term "treatment" as used herein refers to the treatment of a disease or medical condition in a human patient which includes: (a) preventing the disease or medical ion from occurring, i.e., prophylactic treatment of a t; (b) ameliorating the disease or medical condition, i.e., causing regression of the e or medical condition in a patient; (c) suppressing the disease or l condition, i.e., slowing the development of the disease or medical condition in a patient; or (d) alleviating the symptoms of the disease or medical condition in a patient.
The phrase "disease or condition associated with β2 adrenergic receptor and muscarinic activities" includes all disease states and/or conditions that are ledged now, or that are found in the future, to be associated with both β2 adrenergic receptor and muscarinic receptor activity. Such disease states include, but are not limited to, pulmonary diseases, such as asthma and chronic obstructive pulmonary disease (including chronic bronchitis and emphysema), as well as neurological disorders and cardiac ers. β2 rgic receptor activity is also known to be associated with pre-term labor (see International Patent Application Publication Number WO 98/09632), glaucoma and some types of inflammation (see International Patent Application Publication Number WO 99/30703 and Patent Application Publication Number EP 1 078 629).
On the other hand M3 receptor activity is associated with gastrointestinal-tract disorders such as Irritable bowel me (IBS) (see, for ex., US5397800), GI ulcers , spastic s (see, for ex., US 4556653); urinary-tract disorders such as urinary incontinence (see, for ex., Chem., 2005, 48, 6597-6606), pollakiuria; motion sickness and vagally induced sinus ardia.
GENERAL SYNTHETIC PROCEDURES The compounds of the invention can be prepared using the methods and procedures described herein, or using similar methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given; other process ions can also be used unless otherwise stated. Optimum reaction ions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
Additionally, as will be apparent to those skilled in the art, tional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable ting group for a particular functional group, as well as suitable ions for protection and deprotection, are well known in the art. For example, numerous protecting groups, and their introduction and removal are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein.
The term -protecting group" refers to a protecting group suitable for preventing undesired reactions at amino nitrogen. Representative protecting groups include, but are not limited to, formyl; acyl groups, for e alkanoyl groups such as acetyl; alkoxycarbonyl groups such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl groups such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl groups such as benzyl (Bn), trityl (Tr), and 1,1-di-(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS); and the like.
The term "hydroxy-protecting group" refers to a protecting group le for preventing undesired ons at a hydroxy group. Representative hydroxy-protecting groups include, but are not limited to, alkyl groups, such as methyl, ethyl, and tert-butyl; acyl groups, for example alkanoyl groups, such as acetyl; thyl groups, such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), and diphenylmethyl (benzhydryl, DPM); silyl groups, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS); and the like.
Processes for preparing compounds of the invention are described and are illustrated by the ures below.
One of the most ient synthetic route for the preparation of compounds of formula (ID) is depicted in Scheme 1.
Scheme 1 H R3 N X1 P2 V O n W R8 R9 O P3O Y N (III) HN X (II) N N OH m H R3 O N N V O W O n W R' V O R8 R9 O Y N n-1 R3 HO (IV) HN X N (ID) m X1 R3 H2N V O n W P3O Y R8 R9 O HN X (VI) N m (V) O R10 Compounds of formula (ID) may be prepared by ng Intermediates of formula (II), wherein X1 represents a leaving group such as a halogen atom or an active ester as mesylate or tosylate, with intermediates of formula (III), wherein P1 and P3 independently represent a hydrogen atom or an oxygen-protecting group such as a silyl or benzyl ether and P2 represents a en atom or a nitrogen-protecting group such as for example a benzyl group. This reaction is best carried out in an aprotic polar solvent such as dimethylformamide (DMF), 1-methylpyrrolidone or dimethtylsulfoxie (DMSO) in a range of temperatures between room temperature and 200ºC, in the presence of an acid ger such as sodium hydrogen carbonate or a tertiary amine.
Alternatively, compounds of formula (ID) may be prepared by reacting ediates of formula (V) with intermediates of a (VI) wherein X1, P1 and P3 have the same meaning as disclosed above, following the same synthetic procedure disclosed above; and subsequently removing whichever protecting group present in the intermediate to provide a compound of formula (ID). Such deprotection processes involve, for example, a desilylation process, by using triethylamine trihydrofluoride, TBAF, hydrogen chloride or other acidic ts in an inert solvent like THF in a range of atures between 0ºC and 50ºC. The deprotection could also be carried out by a debenzylation process, for example, by hydrogenating the compound in the presence of a catalyst such as palladium on charcoal in an inert solvent like ethanol or THF or a mixture of solvents.
This reaction is typically carried out at a hydrogen pressure between 10 and 60 psi and in a range of temperatures between room temperature and 50ºC.
In r alternative way, compounds of a (ID) with R9 = H may also be prepared by reacting intermediates of formula (IV) with intermediates of formula (III).
This reaction is best carried out in a solvent or mixture of ts like THF, methanol, romethane or DMSO at a temperature between 0ºC and 60ºC using a hydride like sodium borohydride or sodium toxyborohydride as reducing agent.
Intermediates of formula (II) may be ed from commercially available starting materials and reagents using well known procedures, as depicted in Scheme 2.
Scheme 2 O R3 R10 R3 N OH N O N O P4 O R3 P4 (XII) H (XI) (X) (VIII) HO V n W R8 R9 (IX) X3 R3 HO X1 V O V O n W n W O R8 R9 O R8 R9 N N (VII) m (II) m R10 Intermediates of formula (II) may be prepared from alcohol derivatives of formula (VII) via acylation with sulphonyl halides in the presence of an acid scavenger or by halogenation with a variety of halogenating agents.
Intermediates of formula (VII) may be prepared by direct alkylation of an amine of formula (VIII) with the corresponding alkylating fragment (IX) wherein X3 represents a leaving group such as a halogen atom or an active ester as mesylate or tosylate, in the presence of an acid scavenger such as a ry amine.
The amino-ester derivatives of formula (VIII) may be prepared by deprotecting compounds of formula (X) , wherein P4 represents a protecting group, for example, by removing tert-butoxycarbonyl group (BOC) in the presence of acidic media such as hydrogen chloride in THF.
Intermediates of formula (X) may be prepared by a transesterification s ng from literature-known aminoalcohol tives of a (XII) and methyl esters derivative of formula (XI) , typically in the presence of a base as sodium hydride and and by displacing the equilibrium by distillation of a solvent like toluene.
Intermediates of a (III) are widely described in the literature (see, for example, US2004242622 example 6; 149110 intermediate 65; US2007249674 example 3B), and may be prepared following the same synthetic procedure described therein.
Intermediates of a (IV) may be prepared from commercially available starting materials and reagents using well known procedures, as depicted in Scheme 3.
Scheme 3 OH N W O R8 V O n-1 R3 (XIII) O m m N H O O N R3 W O W N O V R8 V R8 O R10 R1 n-1 R3 (XIV) (VIII) (IV) W O O V O (XVIII) X1 N m m N O N O O W H R3 W O N O V R8 V R8 O n-1 R10 n-1 R3 (XIX) (VIII) (XX) Intermediates of formula (IV) may be prepared either by oxidation of intermediates of formula (XIII) with an oxidizing agent such as manganese dioxide or artin reagent or by direct alkylation of an intermediate of a (VIII) with an alkylating agent of formula (XIV) in the presence of an acid scavenger.
Compounds (IV) wherein n=2 are also available by homolagation of aldehydes (XVIII) through reaction with methoxymethyltriphenylphosphine in the presence of a base such as lithium bis(trimethylsilyl)amidure and subsequent acidic hydrolysis of the intermediate enolic ether or by ion of the vinyl derivatives (XX), ed in turn by alkylation of (VIII) with intermediates (XIX). This oxidation can be accomplished with a variety of agents, such as osmium tetroxide in the presence of N-methylmorpholine N-oxide.
Intermediates of formula (V) may be prepared from their N-protected homologues (XV) by a specific deprotecting process such as the ent of N-BOC derivative with acidic media like hydrogen de in THF, as depicted in Scheme 4.
Scheme 4 H H R3 N V N O H P5 R3 n W R10 N V O R8 R9 P5 N n W R8 R9 O (XVI) (VIII) N m N R10 (XV) H2N V O n W R8 R9 O (V) N Intermediates of formula (XV) are in turn prepared from intermediates of formula (VIII) by procedures well known in the art, such as alkylation procedures with intermediates of formula (XVI) in the presence of an acid scavenger such as a tertiary amine. ediates (XVIII) are obtained from known compounds as depicted in Scheme 5.
Scheme 5 OH OH m m m NH N W W V NC NH2 NC V O (XXIII) (XXI) (XXII) R10 O N H R3 X m N O m N N W O R10 R1 W H H V V O (VIII) O (XXIV) (XVIII) H V (XXV) Compounds of formula (XXI) are transformed into the corresponding benzoimidazolones (XXII) (wherein W represents a –CO- and V represents a –NH-) by ent with carbonylimidazole or triphosgene, or alternatively are transformed into the ponding benzotriazoles (XXII) (wherein both W and V are –N-) by treatment with sodium nitrite in an acidic medium. Reduction of intermediate nitriles (XXII) with NiAl alloy in formic acid give raise to the intermediate aldehydes ), which in turn are transformed into the alkylating agents (XXIV) (X represents halide or active ester) and finally reacted with intermediate (VIII) to give intermediates (XVIII). Intermediates (XXIV) n W represents –CO- and V represent an oxygen atom, can also be obtained by direct N-alkylation of intermediates (XXV) with an haloalkane in the presence of an acid scavenger.
When the linker of the compounds of the present invention is other than the benzoheterocyclic moiety, the same general synthetic scheme applies for the preparation of final compounds, as depicted in Scheme 6: Scheme 6 Synthetic scheme depicted in Scheme 6 is homologous to that depicted in Scheme 1 and represents the most convenient routes for the synthesis of compounds (XXIX) ng from the same synthons (III) and (VI) shown in scheme 1 and involving very similar chemical synthetic steps as described there. The definitions of the groups X1, A1, G, L1, A2 and R’ are the same given above, whilst A3 denotes a carbon chain with one less carbon atom than the chain A1.
The ation of the corresponding intermediates (XXVI) and (XXVII) is shown in the synthetic scheme ented in Scheme 7, being the synthetic steps close analogous of that shown in Schemes 2 and 3. The group A3 in the general structure (XXVII) denotes a carbon chain with one carbon atom less than the A1 group. P corresponds to an oxygen-protecting group.
Scheme 7 In the particular case of the group L1 being d as –CONRd- the specific (XXXI) compounds (XXXVII) (being Rd as defined above) may be prepared by the route shown in Scheme 8: Scheme 8 According to this route the amine derivatives (VIII) react with a ted amino aldehyde (XXXIII) in the presence of a reducing agent to give intermediates (XXXIV) .
This reaction is best d out in a solvent or mixture of solvents such as THF or methanol at a temperature between 0ºC and 60ºC using a hydride,such as, sodium borohydride or sodium triacetoxyborohydride as reducing agent. Intermediates (XXXIV) are deprotected according to the nature of the ting group. In the particular case of P being the tert-butyl carbamate (BOC) group, this step can be carried out in the presence of strong acids, such as, hloric or trifluoroacetic acids. The resulting amino compound (XXXV) is then reacted with a carboxylic acid or ester (T = H, alkyl) (XXXVI) to give the amide (XXXVII) . This reaction is best carried out in the presence of coupling agents such as HBTU in the case of acids (T = H) or directly by heating the mixture in a solvent like ethanol in the case of esters (T = alkyl). l . Reagents, starting materials, and solvents were purchased from commercial suppliers and used as received. Concentration refers to evaporation under vacuum using a Büchi rotatory evaporator. Reaction products were purified, when necessary, by flash chromatography on silica gel (40-63 µm) with the solvent system ted or using preparative HPLC conditions (see bellow description of two systems used).
Spectroscopic data were recorded on a Varian Gemini 300 spectrometer. S were med on a Gilson instrument equipped with a Gilson piston pump 321, a Gilson 864 vacuum degasser, a Gilson liquid handler 215, a Gilson 189 injection module, a Gilson Valvemate 7000, a 1/1000 splitter, a Gilson 307 make-up pump, a Gilson 170 diode array detector, and a Thermoquest Finnigan aQa detector.
HPLC system 1: C-18 reversed phase column silica from MERCK, water/acetonitrile as eluents [0.1% v/v ammonium formate buffered] using a gradient from 0% to 100%.
HPLC system 2: C-18 reversed phase column silica from MERCK, water/acetonitrile (without buffer) as s using a gradient from 0% to 100%.
Intermediate 1. tert -butyl (trans hydroxycyclohexyl)carbamate To a solution of (1R,4 R)aminocyclohexanol (15 g, 0.13 mol) in itrile (240 mL) was added in portions di-tert -butyl dicarbonate (31.2 g, 0.14 mol). The mixture was stirred overnight at room temperature. The precipitate obtained was washed with hexane/ethyl acetate (3:1) and hexane giving the title compound as a white solid (83%). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.17 (br. s., 2 H) 1.44 (br. s., 9 H) 1.32 - 1.40 (m, 2 H) 1.99 (br. s., 4 H) 3.44 (br. s., 1 H) 3.61 (br. s., 1 H) 4.38 (br. s., 1 Intermediate 2. trans (Methylamino)cyclohexanol To a mixture of m aluminium hydride (9 g, 0.23 mol) in tetrahydrofuran (425 mL) was added slowly tert -butyl (trans hydroxycyclohexyl)carbamate (intermediate 1, 10 g, 0.046 mol). The mixture was refluxed overnight. Once the mixture was cooled to room temperature, 9 ml of water, 9 ml of 4N NaOH solution and 18 ml of water were carefully and successively dropped. The organic solvent was removed under reduced pressure and the crude obtained was dissolved with chloroform and dried over magnesium sulphate. The filtrate was evaporated to dryness and co evaporated with hexane to give the title compound as a white solid (89%). This intermediate is also described in JMC, 1987, 30(2), p313. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.04 - 1.20 (m, 2 H) 1.25 - 1.40 (m, 2 H) 1.97 (br. s., 4 H) 2.27 - 2.40 (m, 1 H) 3.57 - 3.70 (m, 1 H) Intermediate 3. tert -butyl (trans roxycyclohexyl)methylcarbamate To a solution of trans (methylamino)cyclohexanol (intermediate 2, 5.3 g, 0.04 mol) in acetonitrile (92 mL) was added in ns di-tert -butyl dicarbonate (9.9 g, 0.04 mol).
The mixture was stirred overnight at room temperature. The t was removed under reduced pressure and the crude was purified by column chromatography with silica gel, eluting with a mixture of form/methanol (from 75:1 to 4:1)) to give the title compound as a colourless oil (87%). 1H NMR (300 MHz, CHLOROFORM-d) δ \\ppm 1.34 - 1.43 (m, 2 H) 1.46 (s, 9 H) 1.49 - 1.57 (m, 2 H) 1.70 (d, J=9.89 Hz, 2 H) 2.03 (br. s., 3 H) 2.71 (br. s., 3 H) 3.57 (br. s., 1 H) Intermediate 4. trans [( tert -butoxycarbonyl)(methyl)amino]cyclohexyl hydroxy(dithienyl)- acetate To a solution of methyl hydroxy(dithienyl)acetate (5.8 g, 0.02 mol) (prepared according to Acta a Scandinavica 24 (1970) 596) in anhydrous toluene (95 mL) was first added a solution of tert -butyl (trans hydroxycyclohexyl)- carbamate (intermediate 3; 6 g, 0.02 mol) in anhydrous toluene (95 mL) and secondly sodium hydride (60%, 0.45 g, 0.01 mol). After few minutes the mixture was warmed to 155ºC and the solvent was distilled and simultaneously replaced. This procedure was carried on during 1 hour and a half. The mixture was cooled to room temperature and diluted with ether (300 mL). The organic layer was washed with sodium bicarbonate 4% (2 x 200 mL) and brine, dried, filtered and evaporated over reduced pressure giving the title compound as a yellow solid (69%), which was used in the next step without further purification.
LRMS (m/z): 452 .
Intermediate 5. trans (methylamino)cyclohexyl hydroxy(dithienyl)acetate To a on of trans [( tert ycarbonyl)(methyl)amino]cyclohexyl hydroxy(di thienyl)acetate mediate 4; 8.1 g, 0.01 mol) in dioxane (13.5 mL) was added hydrogen chloride 4M in dioxane (27mL). The mixture was stirred at room temperature for 24 hours. The precipitate obtained was filtrated and washed with ether. The crude was dissolved in water and potassium carbonate was added until pH=8-9. The product was extracted with ethyl e and the c layer was washed with brine, dried and evaporated to dryness giving the title compound as a white solid (78%).
LRMS (m/z): 352 (M+1)+. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.14 - 1.30 (m, 2 H) 1.42 - 1.57 (m, 2 H) 1.88 - 2.11 (m, 4 H) 2.36 - 2.48 (m, 1 H) 3.71 (s, 3 H) 4.82 - 4.95 (m, 1 H) 6.94 - 7.00 (m, 2 H) 7.14 - 7.19 (m, 2 H) 7.25 - 7.30 (m, 2 H) Intermediate 6. 2-oxo-2,3-dihydro-1,3-benzoxazolecarbonitrile A mixture of 6-bromo-1,3-benzoxazol-2(3H)-one (2 g; 9.34 mmol) and copper (I) cyanide (1.42 g; 15.86 mmol) in 6 ml DMF is heated at 150ºC under nitrogen atmosphere for 22 hr. After cooling to room temperature, a solution of 1.55 g (31.6 mmol) of sodium cyanide in 32 ml water is added ed by 1 hr stirring. The system is extracted thoroughly with ethyl acetate, washed with brine, dried and concentrated in vacuo to provide 1.5 g (93 % yield) of the title compound enough pure as to prosecute the syntesis.
Intermediate 7. 2-oxo-2,3-dihydro-1,3-benzoxazolecarbaldehyde A mixture of 2-oxo-2,3-dihydro-1,3-benzoxazolecarbonitrile (Intermediate 6, 220 mg; 1.37 mmol) and aluminium/nickel 1:1 alloy (223.6 mg; 2.61 mmol) in 2.25 ml of formic acid and 0.75 ml of water is stirred at 90ºC for 24 hr. The solid is filtered and washed with ethanol. The filtrate is concentrated in vacuo and dried overnight at 45ºC in a vacuum dessicator. The solid obtained (219 mg; 97 % yield) is pure enough as to prosecute with the sis.
Intermediate 8. 3-(3-bromopropyl)oxo-2,3-dihydro-1,3-benzoxazolecarbaldehyde A mixture of 290 mg (1.64 mmol) of 2-oxo-2,3-dihydro-1,3-benzoxazole carbaldehyde (Intermediate 7), 272.8 mg (1.96 mmol) of 3-bromo-propanol, 514 mg (1.96 mmol) of triphenylphospine and 0.855 ml (1.96 mmol) of 40 % toluene on of DEAD in 7 ml THF is stirred overnight. After concentration in vacuo the residue is chromatographically purified over silicagel eluting with hexane/ethyl ether (100/0 to 0/100), obtaining 423 mg of the title product (58 % ; 52 % total yield) that is used per se in the next tic step.
Intermediate 9. trans[[3-(6-formyloxo-1,3-benzoxazol-3(2H)-yl)propyl](methyl)amino] cyclohexylhydroxy(dithienyl)acetate A solution of 418 mg (0.85 mmol) of 58 % pure 3-(3-bromopropyl)oxo-2,3-dihydro- 1,3-benzoxazolecarbaldehyde (Intermediate 8), 250 mg (0.71 mmol) of trans (methylamino)cyclohexyl hydroxy(dithienyl)acetate (Intermediate 5) and 0.14 ml (1.01 mmol) of triethylamine in 8 ml acetonitrile and 6 ml THF is heated to 90ºC under argon atmosphere for 44 hr. After concentration in vacuo the residue is chromatographically purified over silicagel eluting with dichloromethane/EtOH (from 100/0 to 80/20), obtaining 376 mg of the title product (51 % purity; 48 % total yield) that is used per se in the next tic step.
Intermediate 10. trans[{3-[6-({[(2R){[tert-butyl(dimethyl)silyl]oxy}(8-hydroxyoxo-1,2- dihydroquinolinyl)ethyl]amino}methyl)oxo-1,3-benzoxazol-3(2H)-yl]propyl} (methyl)amino]cyclohexyl hydroxy(dithienyl)acetate A e of 370 mg (0.34 mmol) of 51 % pure trans[[3-(6-formyloxo-1,3- benzoxazol-3(2H)-yl)propyl](methyl)amino]cyclohexylhydroxy(dithienyl)acetate (Intermediate 9), 167 mg (0.42 mmol) of 5-((1R)amino{[tert-butyl(dimethyl)- silyl]oxy}ethyl)hydroxyquinolin-2(1H)-one acetate (prepared according to preparation 8 from US20060035931), 0.075 ml (0.43 mmol) of diisopropilethylamine and 379 mg (1.79 mmol) of sodium triacetoxyborohydride in 2 ml MeOH and 1 ml THF is stirred under argon atmosphere for 24 hr at room temperature. After adding 20 ml of 4% aqueous solution of sodium hydrogen carbonate the system is extracted thrice with ethyl acetate and the c solution washed thoroughly with 4% aqueous sodium hydrogen carbonate. After dryiyng and concentrating, the residue is chromatographically purified over silicagel eluting with chloroform/EtOH (100/0 to 0/100). 133 mg of 88 % pure title compound are obtained (39 % yield).
EXAMPLE 1. trans[{3-[6-({[(2R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolinyl)ethyl] amino}methyl)oxo-1,3-benzoxazol-3(2H)-yl]propyl}(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate, dihydrofluoride. 115 mg (0.12 mmol) of 88% pure trans[{3-[6-({[(2R){[tert-butyl(dimethyl)silyl]oxy}- ydroxyoxo-1,2-dihydroquinolinyl)ethyl]amino}methyl)oxo-1,3-benzoxazol- 3(2H)-yl]propyl} l)amino]cyclohexyl hydroxy(dithienyl)acetate (Intermediate ) are dissolved in 3 ml THF. 0.075 ml (0.46 mmol) of triethylamine trihydrofluoride are added and the system stirred overnight at room temperature. The supernatant is discarded and the residue is washed (ultrasound bath) with 5 onal ml of THF and the supernatant is again discarded. Acetonitrile (5 ml) is added to the residue and after some stirring the solid is filtered and washed with acetonitrile and ethyl ether. 87 mg (94 % yield) of pure title compound are obtained.
LRMS (m/z): 759 . 1H NMR (400 MHz, DMSO-d 6) δ ppm: 1.34 (m. 4H); 1.61-1.72 (b.s. 2H); 1.80 (t. 2H); .96 (b.s. 2H); 2.11 (s. 3H); 2.32-2.51 (b.s. 3H); 2.66-2.76 (b.s. 2H); 3.77-3.90 (c.s. 5H); 4.62-4.74 (b.s. 1H); 5.09-5.17 (b.s. 1H); 6.47 (d. J=12 Hz 1H); 6.89-7.01 (c.s. 3H); 7.04-7.09 (c.s. 3H); 7.19-7.29 (c.s. 4H); 7.36 (s. 1H); 7.44-7.49 (m. 2H); 8.13 (d. J=12 Hz 2H); 10.21-10.54 (b.s. 1H).
Intermediate 11. 4-[(3-hydroxypropyl)amino]nitrobenzonitrile A e of 4-fluoronitrobenzonitrile (1.0 g; 6.02 mmol), 0.502 ml (6.62 mmol) of 3- amino-propanol and 1.15 ml (6.62 mmol) of diisopropylethylamine in 5 ml THF is stirred at rt for 1 hr rature raises somewhat at the beginning). After concentration in vacuo the residue is dissolved in 50 ml of ethyl acetate, washed with 50 ml of 4% aqueous sodium hydrogen ate and brine, dried and concentrated. 1.32 g of pure title compound as a solid are thus obtained (99 % yield).
Intermediate 12. 3-amino[(3-hydroxypropyl)amino]benzonitrile A mixture of 1.12 g (5.06 mmol) of 4-[(3-hydroxypropyl)amino]nitrobenzonitrile (Intermediate 11) and 26.94 mg of 10% Pd on charcoal in 39 ml of EtOH is shaken in an hydrogen atmosphere (14 psi) for 20 hr at rt. After filtration and evaporation 1.012 g of the pure title compound are obtained.
Intermediate 13. 1-(3-hydroxypropyl)oxo-2,3-dihydro-1H-benzimidazolecarbonitrile 100 mg (0.52 mmol) of 3-amino[(3-hydroxypropyl)amino]benzonitrile (Intermediate 12) are dissolved in 2.5 ml of 2N aqueous HCl and 1.5 ml of toluene are added. 150 mg (0.51 mmol) of sgene are added and the system is stirred at rt for 18 hr. After adding 75 additional mg of sgene and prosecuting the stirring for 1 hour 5 ml of brine and 25 ml of ethyl acetate are added and the system is d for 10 minutes.
The organic layer is isolated and the aqueous one is extracted with 4x10 ml of ethyl acetate. The combined organic phases are washed with brine, dried and trated to give 106 mg (93 % yield) of 100 pure (UPLC) title compound.
Intermediate 14. 1-(3-hydroxypropyl)oxo-2,3-dihydro-1H-benzimidazolecarbaldehyde A mixture of 930 mg (4.28 mmol) of 1-(3-hydroxypropyl)oxo-2,3-dihydro-1H- benzimidazolecarbonitrile (Intermediate 13) and 949 mg of Ni-Al alloy 1:1 in 7.3 ml of 75 % formic acid in water is stirred at 90ºC for 6.5 hr. After filtration, the residue is again dissolved in 7.3 ml of 75 % formic acid, 949 mg of Ni-Al alloy are added and the system is stirred at 90º C for 1 hr. After filtration, 5 ml of 2N NaOH and 5 ml of EtOH are added and the system is stirred at rt overnight. The pH is made 6-7 by addition of 2N HCl and the solution is concentrated. The residue is chromatographically ed over silicagel eluting with hexane/EtOH (100/0 to 0/100). 0.91 g of pure title compound are obtained (96 % yield).
Intermediate 15. 1-(3-bromopropyl)oxo-2,3-dihydro-1H-benzimidazolecarbaldehyde 1185 mg (5.38 mmol) of 1-(3-hydroxypropyl)oxo-2,3-dihydro-1H-benzimidazole carbaldehyde (Intermediate 14) are ded in 56 ml of dichloromethane. 2285 mg (6.89 mmol) of carbon tetrabromide and then 6890 mg of polymer-supported triphenyl ine (1 mmol/g; 6.89 mmol) are added. The mixture is shaken at rt for 24 hr. The polymer is filtered and sequentially washed with dichloromethane, EtOH and MeOH.
The filtrates are concentrated and the residue (2.2 g) is tographically purified over silicagel eluting with chloroform/EtOH (100/0 to 90/10). 0.3 g of pure title compound are obtained (20 % yield). ediate 16. trans[[3-(5-formyloxo-2,3-dihydro-1H-benzimidazolyl)propyl](methyl) amino] cyclohexyl hydroxy(dithienyl)acetate A e of 179 mg (0.56 mmol) of 1-(3-bromopropyl)oxo-2,3-dihydro-1H- benzimidazolecarbaldehyde (Intermediate 15), 163 mg (0.46 mmol) of trans (methylamino)cyclohexyl hydroxy(dithienyl)acetate (Intermediate 5) and 0.09 ml (0.65 mmol) of triethylamine in 6 ml acetonitrile and 4 ml THF is stirred at 90ºC overnight. After concentration the residue (325 mg) is chromatographically purified over silicagel eluting with hexane to ethyl ether/EtOH 90/10 and again with C-18 reversed phase column silica from MERCK, using water to acetonitrile/MeOH as eluents with a gradient from 0% to 100%. 94 mg of pure title compound are thus obtained (36 % yield).
Intermediate 17. trans[{3-[5-({[(2R){[tert-butyl(dimethyl)silyl]oxy}(8-hydroxyoxo-1,2- oquinolinyl)ethyl]amino}methyl)oxo-2,3-dihydro-1H-benzimidazol pyl}(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate 85 mg (0.15 mmol) of trans[[3-(5-formyloxo-2,3-dihydro-1H-benzimidazol yl)propyl](methyl) amino] cyclohexyl hydroxy(dithienyl)acetate mediate 16) and 80 mg (0.20 mmol) of 5-((1R)amino{[tert-butyl(dimethyl)-silyl]oxy}ethyl) hydroxyquinolin-2(1H)-one acetate (prepared according to preparation 8 from US20060035931) are dissolved in 2 ml MeOH and 1 ml THF. After adding 0.04 ml (0.23 mmol) of diisopropylethylamine and 100 mg (0.47 mmol) of sodium triacetoxyborohydride the mixture is d overnight under argon atmosphere at rt.
After adding 100 mg more of sodium triacetoxyborohydride the stirring is prosecuted for 48 hr. After concentrating in vacuo the residue is partitioned in ethyl acetate/4% aqueous sodium en carbonate solution. A yellowish solid is filtered, ved in chloroform and washed with 4 % NaHCO3. The combined organic phases are dried and concentrated. The residue is chromatographically purified over silicagel eluting with chloroform/EtOH/Et3N (100/0/0.1 to 0/100/0.1). 96 mg of 71 % pure title compound are obtained (51 % yield) and used per se in the next tic step.
EXAMPLE 2. trans[{3-[5-({[(2R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolin yl)ethyl]amino}methyl)oxo-2,3-dihydro-1H-benzimidazolyl]propyl} (methyl)amino]cyclohexyl hydroxy(dithienyl)acetate dihydrofluoride. 95 mg (0.12 mmol) of 71% pure trans[{3-[5-({[(2R){[tert-butyl(dimethyl)silyl]oxy} (8-hydroxyoxo-1,2-dihydroquinolinyl)ethyl]amino}methyl)oxo-2,3-dihydro-1H- benzimidazolyl]propyl}(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate (Intermediate 17) are dissolved in 2 ml THF. 0.05 ml (0.31 mmol) of triethylamine trihydrofluoride are added and the system stirred overnight at room temperature. The supernatant is discarded and the residue is washed with 2x10 additional ml of THF and the supernatant is again discarded. Acetonitrile (5 ml) is added to the residue and the solid is stirred for 2 hr, aged ght, filtered and washed with acetonitrile. The residue is chromatographically purified with C-18 reversed phase column silica from MERCK, using water to acetonitrile/MeOH as eluents with a gradient from 0% to 100%. 31.8 mg of pure title compound are thus obtained (51 % yield).
LRMS (m/z): 758 (M+1)+. 1H NMR (400 MHz, DMSO-d 6) δ ppm: 1.35 (m. 6H); 1.61-1.77 (b.s. 5H); 1.85-1.97 (b.s. 2H); 2.12 (s. 3H); 2.32-2.45 (b.s. 4H); 2.68-2.74 (b.s. 2H); 3.72-3.86 (c.s. 3H); 4.62-4.73 (b.s. 1H); 5.06-5.14 (b.s. 1H); 6.47 (d. J=12 Hz 1H); 6.90 (d. J=6Hz 1H); 6.95-7.09 (c.s. 8H); 7.23-7.30 (b.s. 1H); 7.47 (d. J=6Hz 1H); 8.06 (d. J=12 Hz 1H); .26-10.49 (b.s. 1H); 10.80-10.88 (b.s. 1H).
Intermediate 18. 1-(3-hydroxypropyl)-1H-1,2,3-benzotriazolecarbonitrile 100 mg (0.52 mmol) of 3-amino[(3-hydroxypropyl)amino]benzonitrile (Intermediate 12) are suspended in 0.5 ml of 5N aqueous HCl. After cooling ally with an ice/water bath, a on of 54.12 mg (0.78 mmol) of sodium nitrite in 0.4 ml water is added dropwise with ng. After 3.5 hr excess water is added and the solid is extracted with dichloromethane, washed with water, dried and concentrated to give 104 mg of pure title compound (96 % .
Intermediate 19. 1-(3-hydroxypropyl)-1H-1,2,3-benzotriazolecarbaldehyde A mixture of 500 mg (2.47 mmol) of 1-(3-hydroxypropyl)-1H-1,2,3-benzotriazole carbonitrile (Intermediate 18) and 550 mg of Ni-Al alloy 1:1 in 5.55 ml of 75 % formic acid in water is stirred at 90ºC for 2.5 hr. After filtration and evaporation 10 ml of 2N NaOH and 10 ml of EtOH are added to the residue and the system is stirred at rt for 1.5 hr. The pH is made 6-7 by on of 2N HCl and the system is extracted thoroughly with ethyl acetate. After washing with water, drying and concentrating, 0.35 g of 80 % pure title compound (55 % .
Intermediate 20. 1-(3-bromopropyl)-1H-1,2,3-benzotriazolecarbaldehyde 200 mg (0.975 mmol) of 1-(3-bromopropyl)-1H-1,2,3-benzotriazolecarbaldehyde (Intermediate 19) are dissolved in 10.5 ml of dichloromethane. 388 mg (1.17 mmol) of carbon tetrabromide are added and the solution cooled externally with an ice/water bath. 307 mg (1.17 mmol) of triphenylphosphine are slowly added and the system is stirred for 20 min with external cooling and 2 hr at rt. After addition of 0.5 more equivalents of both carbon tetrabromide and triphenylphosphine and onal stirring for 10 min with the external cooling and 1 hr at rt the solvents are eliminated in vacuo and the residue is chromatographically purified over silicagel eluting with /ethyl ether (100/0 to 0/100). 195 mg of pure title compound are obtained (74 % yield).
Intermediate 21. 4-[[3-(5-formyl-1H-1,2,3-benzotriazolyl)propyl](methyl)amino]cyclohexyl hydroxy(dithienyl)acetate A mixture of 152.56 mg (0.57 mmol) of 1-(3-bromopropyl)-1H-1,2,3-benzotriazole carbaldehyde (Intermediate 20), 200 mg (0.57 mmol) of trans(methylamino) cyclohexyl hydroxy(dithienyl)acetate (Intermediate 5) and 0.138 ml 0.80 mmol) of diisopropylethylamine in 25 ml acetonitrile was stirred under argon at 75ºC for 17 hr and at 90ºC for 24 hr. After concentration in vacuo, the e is tographically purified over silicagel eluting with form/EtOH (100/0 to 90/10) to give 157 mg of pure title compound (51 % yield).
Intermediate 22. trans[{3-[5-({[(2R){[tert-butyl(dimethyl)silyl]oxy}(8-hydroxyoxo-1,2- dihydroquinolinyl)ethyl]amino}methyl)-1H-1,2,3-benzotriazolyl]propyl} (methyl)amino]cyclohexyl hydroxy(dithienyl)acetate 132 mg (0.245 mmol) of trans[[3-(5-formyl-1H-1,2,3-benzotriazol yl)propyl](methyl)amino]cyclohexyl hydroxy(dithienyl)acetate (Intermediate 21) and 106.3 mg (0.269 mmol) of 5-((1R)amino{[tert-butyl(dimethyl)-silyl]oxy}ethyl) hydroxyquinolin-2(1H)-one acetate (prepared according to preparation 8 from US20060035931) are dissolved in 1.6 ml MeOH and 0.8 ml THF. After adding 0.05 ml (0.29 mmol) of diisopropylethylamine and 76.9 mg (0.36 mmol) of sodium triacetoxyborohydride the mixture is stirred overnight under argon atmosphere at rt.
After successive on of 230 additional mg (1.08 mmol) of reducing agent, ng for 3 hr and 76.9 mg (0.36 mmol) more and ng for 2 hr the ts are eliminated in vacuo and the residue (0.57 g) is stirred with form, filtered and the solid discarded. The filtrate is concentrated and partitioned between 50 ml of ethyl acetate and 10 ml of 4% solution of sodium hydrogen carbonate. The organic solution is washed again with NaHCO3 solution, dried and concentrated to give 210 mg of 91 % pure title compound (yield 91%) that is used per se in the next synthetic step.
EXAMPLE 3. trans[{3-[5-({[(2R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolin yl)ethyl]amino}methyl)-1H-1,2,3-benzotriazolyl]propyl}(methyl)amino] cyclohexyl hydroxy(dithienyl)acetate dihydrofluoride. 205 mg (0.218 mmol) of 91% pure trans[{3-[5-({[(2R){[tert-butyl(dimethyl) oxy}(8-hydroxyoxo-1,2-dihydroquinolinyl)ethyl]amino} methyl)-1H-1,2,3- benzotriazolyl]propyl}(methyl)amino]cyclohexyl hydroxy(dithienyl) acetate (Intermediate 22) are dissolved in 2 ml THF. 0.145 ml (0.89 mmol) of triethylamine trihydrofluoride are added and the system stirred overnight at room temperature. The supernatant is discarded and the residue is washed with 2x3 additional ml of THF and the atant is again discarded. Acetonitrile (4 ml) is added to the residue and the solid is stirred for 30 min, ed and washed with more acetonitrile. After drying overnight at 40ºC 164 mg of pure title compound are thus obtained (96 % yield).
LRMS (m/z): 743 (M+1)+. 1H NMR (400 MHz, DMSO-d 6) δ ppm: 1.32 (m. 5H); 1.59-1.69 (b.s. 3H); 1.84-1.94 (b.s. 2H); 2.01 (m. 2H); 2.11 (s. 3H); 2.26-2.40 (c.s. 4H); 2.60-2.75 (c.s. 2H); 3.90 (s. 2H); 4.34-4.42 (b.s. 1H); 4.67 (m. 4H); 5.04-5.11 (m. 1H); 5.28-5.46 (b.s. 1H); 6.40 (d. J=12 Hz 1H); 6.86-6.93 (c.s. 1H); 6.94-7.00 (c.s. 2H); 7.03-7.10 (c.s. 4H); 7.19- 7.34 (b.s. 1H); 7.44-7.48 (m. 2H); 7.49-7.54 (m. 1H); 7.74-7.80 (m. 1H); 7.92 (s. 1H); 8.10 (d. J=12 Hz 1H); 10.10-10.51 (b.s. 1H).
Intermediate 23. 1-(3-bromopropyl)-1H-indolecarbaldehyde 0.70 g (30.31 mmol) of 60 % sodium hydride suspension are added to 14 ml of ous DMF and a solution of 2.40 g (16.53 mmol) of 1H-indolecarbaldehyde in ml of DMF added dropwise. After 45 min of stirring at room temperature the solution is cooled externally with an ice/water bath and a solution of 2.52 ml (5.01 g; 24.80 mmol) of 1,3-dibromopropane in 6 ml of DMF added dropwise. The solution is stirred at room temperature for 2 hr before adding 10 ml of water and 10 ml of 2N HCl. The suspension is extracted thrice with ethyl ether, washed with water, dried and concentrated in vacuo. The residue is chromatographically ed (hexane to hexane/EtAcO 4:1) to give 1.4 g of the pure title compound (33 % yield).
Intermediate 24. trans[[3-(5-formyl-1H-indolyl)propyl](methyl)amino]cyclohexyl hydroxy(di thienyl)acetate A mixture of 1.27 g (4.78 mmol) of 1-(3-bromopropyl)-1H-indolecarbaldehyde (intermediate 23), 1.40 g (3.98 mmol) of trans(methylamino)cyclohexyl hydroxy(di thienyl)acetate (intermediate 5) and 0.77 ml (0.56 g; 5,5 mmol) of triethylamine in 6 ml MeCN and 6 ml THF is stirred at 90ºC overnight under argon. After concentrating in vacuo the residue is chromatographically purified eluting with Cl3CH to Cl3CH/MeOH 95:5 to give 1.6 g (75 % yield) of pure title compound.
Intermediate 25. trans[{3-[5-({[(2R){[tert-butyl(dimethyl)silyl]oxy}(8-hydroxyoxo-1,2- oquinolinyl)ethyl]amino}methyl)-1H-indolyl]propyl}(methyl)amino] cyclohexyl y(dithienyl)acetate A mixture of 190 mg (0.35 mmol) of trans[[3-(5-formyl-1H-indol yl)propyl](methyl)amino]cyclohexyl hydroxy(dithienyl)acetate (intermediate 24), 174. 59 mg (0.44 mmol) of 5-((1R)amino{[tert-butyl(dimethyl)-silyl]oxy}ethyl) hydroxyquinolin-2(1H)-one acetate (prepared ing to preparation 8 from US20060035931), 0.077 ml (0.44 mmol) of diisopropilethylamine and 243.8 mg (1.15 mmol) of sodium triacetoxyborohydride in 2 ml of MeOH and 1 ml THF is stirred under argon atmosphere for 2.5 hr at room temperature. After adding 25 ml of 4% aqueous solution of sodium hydrogen carbonate the system is extracted thrice with ethyl acetate and the organic on washed thoroughly with 4% aqueous sodium hydrogen ate. After dryiyng and concentrating, the residue is chromatographically purified over silicagel eluting with chloroform/EtOH (100/0 to 90/10). 177 mg of 94 % pure title compound are ed (55 % yield).
EXAMPLE 4. trans[{3-[5-({[(2R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolin yl]amino}methyl)-1H-indolyl]propyl}(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate dihydrofluoride. 170 mg (0.20 mmol) of 91% pure trans[{3-[5-({[(2R){[tert-butyl(dimethyl)silyl]oxy}- 2-(8-hydroxyoxo-1,2-dihydroquinolinyl)ethyl]amino} methyl)-1H-1,2,3- benzotriazolyl]propyl}(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate (Intermediate 22) are dissolved in 7 ml THF. 0.08 ml (0.78 mmol) of triethylamine trihydrofluoride are added and the system stirred overnight at room temperature. The supernatant is discarded and the residue is washed with 2x3 additional ml of THF and the supernatant is again discarded. Acetonitrile (4 ml) is added to the residue and the solid is stirred for 30 min, ed and washed with more acetonitrile. After drying overnight at rt 146 mg of 98 % pure title compound are thus obtained (92 % yield).
LRMS (m/z): 741 (M+1)+. 1H NMR (400 MHz, DMSO-d6) \δ ppm: 1.35 (m. 5H); 1.60-1.73 (b.s. 3H); 1.79-1.95 (m. 5H); 2.00-2.16 (c.s. 4H); .41 (b.s. 2H); 2.66-2.83 (b.s. 3H); 3.53-3.65 (c.s. 1H); 4.00 (s. 2H); 4.15 (m. 2H); 4.66 (m. 1H); 5.17 (m. 1H); 6.40 (b.s. 2H); 6.90 (m. 1H); 6.98 (m. 1H); 7.07 (b.s. 3H); 7.14-7.49 (c.s. 6H); 7.55 (s. 1H); 8.02 (d. J=12 Hz 1H); 9.10-10.70 (b.s. 1H).
Intermediate 26. 4-[(tetrahydro-2H-pyranyloxy)methyl]benzonitrile To a solution of roxymethyl)benzonitrile (1 g, ol) in dry CH2Cl 2 (25 mL) under argon was added PPTs (190 mg, 0.76mmol) and 3,4-dihydro-2H-pyran (0,824mL, 9.01mmol). The reaction was stirred at room temperature under argon for 4h. The reaction mixture was evaporated and the residue treated with water (80 mL) and Et2O (150 mL). The organic layer was separated and the aqueous layer was ted with Et2O (2x 100 mL). The combined organic layers were washed with brine and dried over sodium sulphate. Removal of the solvent under reduced pressure afforded 1.86 g of a less oil. The crude obtained was purified by column tography with n-Hexane (A) and EtOAc (B) as eluents (0% to 25%). The appropriate fractions were collected and the solvent removed afford the title compound (1.53g, 91%) as colourless oil.
LRMS (m/z): 218 (M+1)+.
Intermediate 27.
N'-hydroxy[(tetrahydro-2H-pyranyloxy)methyl]benzenecarboximidamide To a suspension of hydroxylamine hydrochloride (365 mg, 5.25mmol) in EtOH (3 mL) was added Et3N (0.78mL, 5.6mmol) at room temperature under argon. A white precipitate formed. It was stirred at that ature for 40 minutes. Then 4- [(tetrahydro-2H-pyranyloxy)methyl]benzonitrile (Intermediate 26; 0.76g, 3.5mmol) in EtOH (2 mL) was added dropwise; the on mixture became clear. It was stirred at RT overnight. The crude obtained was purified by column chromatography with CH2Cl 2 (A) and CH2Cl 2/MeOH (95:5) (B) as eluents (0% to 80% B). The riate fractions were collected and the solvent removed to afford 1.25 g of sticky oil with some solids. It was dissolved in EtOAc/H2O (1:1, 150 mL). The organic layer was washed again with H2O (50 mL) and brine. It was dried over sodium sulphate, filtered and evaporated to afford the title compound , 95%) as sticky oil.
LRMS (m/z): 251 (M+1)+.
Intermediate 28. -(3-bromopropyl){4-[(tetrahydro-2H-pyranyloxy)methyl]phenyl}-1,2,4- oxadiazole To a solution of N'-hydroxy[(tetrahydro-2H-pyranyloxy)methyl]benzene- carboximidamide (Intermediate 27; 211mg, 0.84mmol) in DCM (3mL) was added DIEA (0.176mL, 1.01mmol). The mixture was cooled to 0ºC and a solution of 4- bromobutanoyl chloride (0.108mL, 0.88mmol) in DCM (1mL) was added se. The mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure and the crude obtained was purified by column chromatography with silica gel, eluting with a mixture of Hexane: ether give the title compound as a solid (198mg, 53%).
LRMS (m/z): 382 (M+1)+ Intermediate 29. trans {methyl[3-(3-{4-[(tetrahydro-2H-pyranyloxy)methyl]phenyl}-1,2,4- oxadiazolyl)propyl]amino}cyclohexyl hydroxy(dithienyl)acetate Obtained as a solid (152mg, 42%) from romopropyl){4-[(tetrahydro-2H-pyran- 2-yloxy)methyl]phenyl}-1,2,4-oxadiazole (Intermediate 28; 195mg, 0.51mmol), trans (methylamino)cyclohexyl hydroxy(dithienyl)acetate (Intermediate 5; 209mg, 0.51mmol) and Et3N (0.178mL, 1.02mmol) following the mental procedure as described for Intermediate 9 and the crude obtained was ed by column chromatography with silica gel, eluting with a mixture of Chloroform: Ethanol.
LRMS (m/z): 652 (M+1)+ Intermediate 30. trans [(3-{3-[4-(hydroxymethyl)phenyl]-1,2,4-oxadiazol yl}propyl)(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate To a solution of trans {methyl[3-(3-{4-[(tetrahydro-2H-pyranyloxy)methyl]phenyl}- 1,2,4-oxadiazolyl)propyl]amino}cyclohexyl hydroxy(dithienyl)acetate (Intermediate 29; 147mg, 0.21mmol) in anh tetrahydrofurane (3.5mL) was added hydrochloric acid (1M, 0.627mL). The e was stirred overnight at room temperature. A solution of saturated bicarbonate was added into the mixture and then extracted with ethyl acetate. The organics layers were combined, washed with brine, dried, filtered and the organic solvent was removed under reduced pressure. The crude obtained was purified by column chromatography with silica gel, eluting with a mixture of Chloroform: Ethanol to give the title compound (89mg, 75%) LRMS (m/z): 568 (M+1)+ Intermediate 31. trans -[3-(4-formylphenyl)-1,2,4-oxadiazol yl]propyl}(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate To a on of trans [(3-{3-[4-(hydroxymethyl)phenyl]-1,2,4-oxadiazol yl}propyl)(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate (Intermediate 30; 78mg, 0.14mmol) in CHCl3 (2mL, amylene stabilized) was added portion wise manganese oxide ,1.52mmol). The on mixture was stirred at 45 ºC for 4h.
The cooled on mixture was filtered through a syringe filtered, washed with more CHCl 3 (20 mL) and the solvent was d under reduced pressure to afford the title compound (78mg, 98%) as a light-brown oil. The nd was used in the next step without further purification.
LRMS (m/z): 566 (M+1)+ Intermediate 32. trans [(3-{3-[4-({[(2 R){[tert-butyl(dimethyl)silyl]oxy}(8-hydroxyoxo-1,2- dihydroquinolinyl)ethyl]amino}methyl)phenyl]-1,2,4-oxadiazol yl}propyl)(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate Obtained as a off-white solid (35mg, 29%) from trans [{3-[3-(4-formylphenyl)-1,2,4- oxadiazolyl]propyl}(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate (74mg, 0.13mmol), 5-((1R)amino{[tert-butyl(dimethyl)-silyl]oxy}ethyl)hydroxyquinolin- 2(1H)-one acetate (prepared ing to preparation 8 from US20060035931; 62mg, 0.16mmol), DIEA (28µL, 0.16mmol) and sodium triacetoxyborohydride (62mg, 0.28mmol) following the procedure as described for Intermediate 10 and the crude obtained was purified by C-18 reversed phase column silica, using water to acetonitrile/MeOH as eluents with a gradient from 0% to 100%.
LRMS (m/z): 885 (M+1)+ EXAMPLE 5. trans [(3-{3-[4-({[(2 R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolin yl)ethyl]amino}methyl)phenyl]-1,2,4-oxadiazol yl}propyl)(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate dihydrofluoride ed as a white solid (28mg, 85%) from trans [(3-{3-[4-({[(2 [tertbutyl (dimethyl)silyl]oxy}(8-hydroxyoxo-1,2-dihydroquinolinyl)ethyl]amino}- methyl)phenyl]-1,2,4-oxadiazolyl}propyl)(methyl)amino]cyclohexyl hydroxy(di thienyl)acetate (35mg, 0.04mmol) and triethylamine rofluoride (30µL, 0.19mmol) following the experimental procedure as described for Example 1.
LRMS (m/z): 770 (M+1)+ 1H NMR (300 MHz, dmso) δ 8.13 (d, J = 10.1 Hz, 1H), 7.94 (d, J = 8.2 Hz, 2H), 7.49 (dd, J = 17.2, 6.5 Hz, 3H), 7.25 (s, 1H), 7.07 (d, J = 8.3 Hz, 3H), 7.02 – 6.85 (m, 3H), 6.47 (d, J = 10.0 Hz, 1H), 5.12 (bs, 1H), 4.67 (bs, 1H), 3.88 (s, 2H), 2.98 (bs, 2H), 2.72 (bs, 2H), 2.44 – 2.30 (m, 2H), 2.15 (s, 3H), 1.91 (bs, 4H), 1.69 (bs, 2H), 1.36 (bs, 4H).
Intermediate 33. ethyl [4-(hydroxymethyl)phenoxy]acetate A solution of 4-(hydroxymethyl)phenol (400mg, 3.19mmol) in CH3CN (4 mL) was placed in a sealed tube, then potassium carbonate (550mg, 3.98mmol) and ethyl bromoacetate (0.365mL, 3.23mmol) were added and purged with argon. The reaction mixture was stirred at reflux (90 ºC) for 20h. The cooled reaction mixture was filtered through sintered glass (pore nº 4) and the solvent removed to obtain light-yellow oil.
The crude was purified by column tography with nHexane and Et2O as eluents (0% to 100% B in 20 column volumes and 100% for 10 CV, 18 mL/min). The riate fractions were collected and the solvent d to afford the title compound (446mg, 62%) as colourless solid.
LRMS (m/z): 211 (M+1)+ Intermediate 34. tert -butyl methyl(2-oxoethyl)carbamate To an oled solution of tert-butyl 2-hydroxyethyl(methyl)carbamate (300mg, 1.71mmol)) in dry CH2Cl 2 (8.5mL) under argon was added portion wise Dess-Martin periodinane (762mg, 1.8mmol). Once finished the addition, the reaction e was stirred at room temperature for 3h. The mixture was poured into ted solutions of NaHCO 3 (50 mL) and Na2S2O3 (50 mL) and more CH2Cl 2 (100 mL). It was well-stirred at room temperature for 30 s. The organic phase was separated and washed with sat. aq. NaHCO3 (1x 20 mL). It was dried over magnesium sulphate and concentrated to afford the title compound (370 mg, 98%) as colourless oil together with a yellow solid, which was used in the next step without further purification. 1H NMR (300 MHz, cdcl3) δ 9.61 (s, 1H), 3.98 (d, J = 33.9 Hz, 2H), 2.94 (t, J = .8 Hz, 3H), 1.46 (dd, J = 8.2, 6.3 Hz, 9H).
Intermediate 35. trans [{2-[(tert-butoxycarbonyl)(methyl)amino]ethyl}(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate To a solution of tert -butyl (2-oxoethyl)carbamate in DCE (3 mL) under argon was added trans (methylamino)cyclohexyl hydroxy(dithienyl)acetate (Intermediate 5; 150mg, 0.43mmol) and NaBH(OAc)3 (136mg, 0.64mmol). The reaction mixture was stirred at room temperature under argon for 3h. The solvent was d under reduced pressure and the residue poured into sat. aq. NaHCO3 (20 mL). It was extracted with EtOAc (2x50 mL), the combined organic layers were dried over sodium te and the solvent removed to afford 290 mg of brown oil. The sample was purified by column chromatography with CH2Cl 2 and EtOH (95:5) as eluents (0% to 100%). The riate fractions were collected and the solvent removed to afford the title compound (203mg, 92%) as brownish oil.
LRMS (m/z): 509 (M+1)+ Intermediate 36. trans {methyl[2-(methylamino)ethyl]amino}cyclohexyl hydroxy(di thienyl)acetate To a solution of trans [{2-[( tert -butoxycarbonyl)(methyl)amino]ethyl}(methyl)amino]- cyclohexyl hydroxy(dithienyl)acetate (198mg, 0.39mmol) in THF (6.5 mL) under argon was added 1M aq. HCl (1.17 mL) and the mixture was stirred at RT for 18h.
More 1M HCl (0.8 mL, 2 eq.) was added and the on mixture was stirred at 70 ºC for 4 hours. The reaction mixture was ed with sat. aq. NaHCO3 (20 mL). It was extracted with EtOAc (3x50 mL), the combined organic layers were dried over sodium sulphate and the solvent removed to afford brown oil. The crude material was injected into a C18 silica column. The gradient used was H2O and acetonitrile/MeOH (1:1). The appropriate fractions were collected and all the solvents evaporated under reduced pressure to afford the title compound (90 mg, 54%) as light-brown oil.
LRMS (m/z): 409 (M+1)+ ediate 37. trans [{2-[{[4- (hydroxymethyl)phenoxy]acetyl}(methyl)amino]ethyl}(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate trans {methyl[2-(methylamino)ethyl]amino}cyclohexyl hydroxy(dithienyl)acetate (Intermediate 36; 85mg, 0.21mmol) and ethyl [4-(hydroxymethyl)phenoxy]acetate mediate 33; 65mg, 0.31mmol) were dissolved in EtOH (0.65 mL) and heated in a PLS at 75 ºC for 48h. More Intermediate 33 (15 mg, 0.3 eq) and MgSO4 (50 mg) were added and the on mixture was stirred at 75 ºC for another 50 h. The sample was purified by column with CHCl3 and EtOH as eluents (0% to 100% B). The appropriate fractions were collected and the solvent removed to afford crude of 18 mg of blue oil. It was repurified with CH2Cl 2 and CH2Cl 2/MeOH (9:1) as s (0% to 100% B). The appropriate fractions were collected and the solvent removed to give the title compound (10 mg; 7.6%) as a sticky solid.
LRMS (m/z): 573 (M+1)+ Intermediate 38. trans -[[(4- phenoxy)acetyl](methyl)amino]ethyl}(methyl)amino]cyclohexyl hydroxy(di- 2-thienyl)acetate Obtained as an oil (27mg, 66%) from trans [{2-[{[4-(hydroxymethyl)phenoxy]-acetyl}- (methyl)amino]ethyl}(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate (Intermediate 37; 40mg, 0.07mmol) and ese oxide (61mg, 0.7mmol) following the experimental procedure as descried for Intermediate 31 and the crude obtained was used in the next step without further purification.
LRMS (m/z): 571 (M+1)+ Intermediate 39. trans [{2-[{[4-({[(2 R){[tert-butyl(dimethyl)silyl]oxy}(8-hydroxyoxo-1,2- dihydroquinolin yl)ethyl]amino}methyl)phenoxy]acetyl}(methyl)amino]ethyl}(methyl)amino]cycloh exyl hydroxy(dithienyl)acetate Obtained as a yellow foam (81mg, 66%) from trans[{2-[[(4-formylphenoxy)- acetyl](methyl)amino]ethyl}(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate mediate 38; 73mg, 0.13mmol), 5-((1R)amino{[tert-butyl(dimethyl)- silyl]oxy}ethyl)hydroxyquinolin-2(1H)-one acetate (prepared according to preparation 8 from US20060035931; 56mg, 0.14mmol), DIEA (29µL, 0.17mmol) and sodium triacetoxyborohydride (81mg, 0.38mmol) ing the procedure as described for Intermediate 10 and the crude obtained was purified over silica gel eluting with Chloroform/Methanol (100/0 to 0/100).
LRMS (m/z): 890 (M+1)+ EXAMPLE 6. trans [{2-[{[4-({[(2 ydroxy(8-hydroxyoxo-1,2-dihydroquinolin yl]amino}methyl)phenoxy]acetyl}(methyl)amino]ethyl}(methyl)amino]cycloh exyl hydroxy(dithienyl)acetate dihydrofluoride Obtained as a white solid (90mg, 72%) from trans [{2-[{[4-({[(2 R){[tertbutyl (dimethyl)silyl]oxy}(8-hydroxyoxo-1,2-dihydroquinolin yl)ethyl]amino}methyl)phenoxy]acetyl}(methyl)amino]ethyl}(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate (Intermediate 39; 135mg, 0.15mmol) and triethylamine trihydrofluoride (97µL, 0.60mmol) following the experimental procedure as bed for Example 1.
LRMS (m/z): 775 (M+1)+ 1H NMR (300 MHz, dmso) δ 8.14 (d, J = 10.0 Hz, 1H), 7.50 (d, J = 5.0 Hz, 1H), 7.29 (d, J = 8.1 Hz, 2H), 7.14 – 7.05 (m, 3H), 7.05-6.99 (m, 2H), 6.95 (d, J = 8.1 Hz, 2H), 6.89 (d, J = 8.5 Hz, 2H), 6.53 (d, J = 9.8 Hz, 1H), 5.16 (s, 1H), 4.83 (d, J = 20.7 Hz, 2H), 4.72 (s, 1H), 3.82 (bs, 2H), 2.86 (bs, 2H), 2.77 (s 3H), 2.50 (s, 3H) , 2.23 (d, J = 18.1 Hz, 2H), 1.94 (bs, 2H), 1.74 (bs, 2H), 1.39 (bs, 2H), 1.08 (bs, 4H).
Intermediate 40. 2-{[ tert -butyl(dimethyl)silyl]oxy}ethyl)-1H-indolyl]propanoic acid To a solution of 3-(1H-indolyl)propanoic acid (5g, 0.026mol) in DMF (20mL) was added at 0ºC sodium hydride (2.11g, 0.088mol), the mixture was stirred some minutes at 0ºC and (2-bromoethoxy)(tert-butyl)dimethylsilane (5.67mL, 0.026mol) was added.
The on mixture was stirred overnight at room temperature. The crude mixture was poured into a sodium sulphate saturate solution and extracted with ethyl acetate. The solvent was removed under reduced re and the crude obtained was purified over silica gel eluting with hexane:ether (100/0 to 0/100) to obtain the title compound (4g, 43%).
LRMS (m/z): 348 (M+1)+ Intermediate 41. 3-[1-(2-{[ tert -butyl(dimethyl)silyl]oxy}ethyl)-1H-indolyl]propanol To a solution of lithium aluminium hydride (0.44g, 0.011mol) in diethyl ether (10mL) was added dropwise at 0ºC solution of 3-[1-(2-{[tert -butyl(dimethyl)silyl]oxy}ethyl)-1H- indolyl]propanoic acid (Intermediate 40; 2g, 0.011mol) in ethyl ether (10mL). The on mixture was stirred at room temperature for 45 minutes. ted sodium bicarbonate was added into the mixture at 0ºC. The organic phase was extracted and the solvent was removed under reduced pressure giving the title compound (3.2g, 83%), which was used in the next step without further purification.
LRMS (m/z): 334 (M+1)+ Intermediate 42. 3-[1-(2-{[ tert -butyl(dimethyl)silyl]oxy}ethyl)-1H-indolyl]propyl methanesulfonate To a on of 3-[1-(2-{[tert -butyl(dimethyl)silyl]oxy}ethyl)-1H-indolyl]propanol (Intermediate 41; 3.2g, 0.009mol) in CH2Cl 2 (25mL) was added at -40ºC methanesulfonyl bromide L, 0.011mol) and triethylamine (1.74mL, 0.012mol).
The reaction e was stirred for 5 minutes. More CH2Cl 2 was added into the mixture and the c layer was washed with water. The solvent was removed under reduced pressure giving the title compound (3.5g, 88%), which was used in the next step without further purification.
LRMS (m/z): 412 (M+1)+ Intermediate 43. 1-(2-{[ tert -butyl(dimethyl)silyl]oxy}ethyl)(3-iodopropyl)-1H-indole To a solution of 3-[1-(2-{[tert -butyl(dimethyl)silyl]oxy}ethyl)-1H-indolyl]propyl methanesulfonate (Intermediate 42; 3.5g, 8.5mmol) in ketone (20mL) was added sodium iodide (2.55g, 17mmol). The reaction mixture was stirred overnight at 50ºC.
The crude reaction was filtered and the t was removed under d pressure.
The crude obtained was ed over silica gel eluting with hexane:ether (100/0 to 0/100) to obtain the title compound (2.7g, 71%).
LRMS (m/z): 444 (M+1)+ Intermediate 44. trans [{3-[1-(2-{[ tert -butyl(dimethyl)silyl]oxy}ethyl)-1H-indol yl]propyl}(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate ed as an oil (750mg, 70%) from 1-(2-{[tert -butyl(dimethyl)silyl]oxy}ethyl)(3- opyl)-1H-indole (Intermediate 43; 630mg, 1.42mmol), trans (methylamino)cyclohexyl hydroxy(dithienyl)acetate (Intermediate 5; 450mg, 1.28mmol) and Et3N (0.2mL, ol) following the experimental procedure as described for Intermediate 9 and the crude obtained was used in the next step without further purification.
LRMS (m/z): 668 (M+1)+ Intermediate 45. trans [{3-[1-(2-hydroxyethyl)-1H-indolyl]propyl}(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate To a solution of trans [{3-[1-(2-{[ tert -butyl(dimethyl)silyl]oxy}ethyl)-1H-indol yl]propyl}(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate (Intermediate 44; 19g, 2.85mmol) in THF (20mL) was added hydrochloric acid (8.55mL, 1M). The reaction mixture was stirred overnight at room temperature. Ethyl Acetate was poured into the mixture and the organic layer was washed with water and sodium bicarbonate, dried, filtered and the t was removed under reduced pressure. The crude obtained was purified over silica gel g with chloroform:ethanol (100/0 to 0/100) to obtain the title compound (940mg, 59%).
LRMS (m/z): 553 (M+1)+ Intermediate 46. trans thyl{3-[1-(2-{[(4-methylphenyl)sulfonyl]oxy}ethyl)-1H-indol yl]propyl}amino)cyclohexyl hydroxy(dithienyl)acetate To a solution of trans [{3-[1-(2-hydroxyethyl)-1H-indol yl]propyl}(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate (Intermediate 45; 140mg, 0.25mmol) in CH2Cl 2 (10mL) was added triethylamine (46µL, ol) and dimethylaminopyridine (31mg, 0.25mmol). The reaction mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure and the crude obtained was purified over silica gel eluting with ethyl ether to obtain the title nd (110mg, 61%).
LRMS (m/z): 707 (M+1)+ Intermediate 47. tran 3-[1-(2-{[(2 R){[tert-butyl(dimethyl)silyl]oxy}(8-hydroxyoxo-1,2- dihydroquinolinyl)ethyl]amino}ethyl)-1H-indol pyl}(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate To a solution of trans (methyl{3-[1-(2-{[(4-methylphenyl)sulfonyl]oxy}ethyl)-1H-indol- 3-yl]propyl}amino)cyclohexyl hydroxy(dithienyl)acetate (Intermediate 46; 310mg, 0.44mmol) in N,N-dimethylacetamide anhydrous (1.5mL) was added 5-((1R)amino- 1-{[tert-butyl(dimethyl)-silyl]oxy}ethyl)hydroxyquinolin-2(1H)-one free base (prepared according to preparation 8 from US20060035931; 146mg, 0.44mmol) and sodium bicarbonate (73mg, 0.87mmol). The reaction mixture was stirred overnight at 70ºC.
Water was poured into the mixture and the itate was filtered. The crude was purified over silica gel eluting with chloroform / ethanol to obtain the title compound as a solid (20mg, 5%).
LRMS (m/z): 870 (M+1)+ EXAMPLE 7. trans [{3-[1-(2-{[(2 R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolin yl)ethyl]amino}ethyl)-1H-indolyl]propyl}(methyl)amino]cyclohexyl hydroxy(di- 2-thienyl)acetate dihydrofluoride Obtained as a white solid (11mg, 63%) from tran s[{3-[1-(2-{[(2 R){[tertbutyl hyl)silyl]oxy}(8-hydroxyoxo-1,2-dihydroquinolinyl)ethyl]amino}ethyl)- 1H-indolyl]propyl}(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate (Intermediate 47; 20mg, 0.02mmol) and ylamine trihydrofluoride (15µL, 0.09mmol) following the mental procedure as described for Example 1.
LRMS (m/z): 755 (M+1)+ 1H NMR (600 MHz, dmso) δ 10.46 (s, 1H), 8.26 (bs, 2H), 7.59 – 7.38 (m, 4H), 7.31 ), 7.19 – 6.84 (m, 6H), 6.49 (t, J = 17.6 Hz, 1H), 5.34 (s, 1H), 4.71 (bs, 1H), 4.45 (bs, 2H), 3.24 (bs, 2H), 2.98 (dd, J = 57.9, 20.5 Hz, 5H), 2.65 (d, J = 35.8 Hz, 3H), 2.10 – 1.80 (m, 4H), 1.53 (bs, 4H), 1.46 – 1.33 (m, 4H).
Intermediate 48. trans [{2-[( tert -butoxycarbonyl)amino]ethyl}(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate Obtained as a solid (281mg, 40%) from tert -butyl 2-bromoethylcarbamate (385mg, 1.72mmol), trans (methylamino)cyclohexyl hydroxy(dithienyl)acetate (Intermediate ; 500mg, 1.42mmol) and Et3N (0.3mL, 2.15mmol) following the experimental procedure as described for Intermediate 9 and the crude ed was purified over silica gel eluting with CH2Cl 2:EtOH.
LRMS (m/z): 495 (M+1)+ Intermediate 49. trans [(2-aminoethyl)(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate To a solution of trans [{2-[( tert ycarbonyl)amino]ethyl}(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate (Intermediate 48; 281mg, 0.57mmol) in dioxane (3.5mL) was added hydrochloric acid (4M in dioxane, 1.5mL). The on mixture was stirred overnight at room temperature. The crude reaction was washed with sodium bicarbonate and the crude was extracted with THF. The solvent was removed under reduced pressure giving the title compound (266mg, 95%), which was used in the next step without further purification.
LRMS (m/z): 395 (M+1)+ Intermediate 50. [4-(hydroxymethyl)phenoxy]acetic acid To a solution of trans [(2-aminoethyl)(methyl)amino]cyclohexyl hydroxy(di l)acetate (312mg, 1.48mmol) in THF (12 mL) and water (8 mL) was added a solution of lithium hydroxide (109mg, 4.46mmol) in water (4 mL). It was d at room temperature for 2h. The THF was removed under vacuum and the aqueous solution was acidified with 5N HCl until pH=2. It was extracted with EtOAc (3x20 mL). The combined organic layers were washed with brine (1x20 mL), dried over sodium sulphate and the t evaporated to afford the title nd (248mg, 89%) as a white solid, which was used in the next step without further purification.
LRMS (m/z): 183 (M+1)+ Intermediate 51. trans [[2-({[4- (hydroxymethyl)phenoxy]acetyl}amino)ethyl](methyl)amino]cyclohexyl hydroxy(dithienyl)acetate To a solution of [4-(hydroxymethyl)phenoxy]acetic acid (Intermediate 50; 99mg, 0.54mmol) in DMF (4.5mL) was added trans [(2- thyl)(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate (Intermediate 49; 215mg, 0.54mmol), HBTU , 0.83mmol) and DIEA (0.38mL, 2.19mmol). The reaction mixture was stirred overnight at room ature. The solvent was removed and the crude was partitioned between ethyl acetate and sodium bicarbonate 4%. The organic layer was washed with water, brine, dried, filtered and the solvent was removed to give crude, which was purified over silica gel eluting with CHCl 3:Hexane to give the title compound (152mg, 47%) LRMS (m/z): 559 (M+1)+ Intermediate 52. trans [(2-{[(4-formylphenoxy)acetyl]amino}ethyl)(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate Obtained as a solid (130mg, 85%) from trans [[2-({[4- (hydroxymethyl)phenoxy]acetyl}amino)ethyl](methyl)amino]cyclohexyl hydroxy(di thienyl)acetate mediate 51; 152mg, 0.27mmol) and manganese oxide (236mg, ol) following the experimental procedure as described for ediate 31 and the crude obtained was used in the next step without further purification.
LRMS (m/z): 557 (M+1)+ Intermediate 53. trans [[2-({[4-({[(2 R){[ tert -butyl(dimethyl)silyl]oxy}(8-hydroxyoxo-1,2- dihydroquinolin yl)ethyl]amino}methyl)phenoxy]acetyl}amino)ethyl](methyl)amino]cyclohexyl hydroxy(dithienyl)acetate Obtained as a yellow foam , 86%) from trans [(2-{[(4- formylphenoxy)acetyl]amino}ethyl)(methyl)amino]cyclohexyl hydroxy(dithienyl)- acetate (Intermediate 52; 130mg, 0.23mmol), 5-((1R)amino{[tert-butyl(dimethyl)- silyl]oxy}ethyl)hydroxyquinolin-2(1H)-one acetate (prepared according to preparation 8 from US20060035931; 99mg, ol), DIEA (53µL, l) and sodium triacetoxyborohydride (148mg, 0.7mmol) following the procedure as described for Intermediate 10 and the crude obtained was purified over silica gel eluting with Chloroform/Methanol (100/0 to 0/100).
LRMS (m/z): 876 (M+1)+ EXAMPLE 8. trans [[2-({[4-({[(2 R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolin yl)ethyl]amino}methyl)phenoxy]acetyl}amino)ethyl](methyl)amino]cyclohexyl y(dithienyl)acetate dihydrofluoride Obtained as a white solid (89mg, 57%) from trans [[2-({[4-({[(2 R){[ tert - butyl(dimethyl)silyl]oxy}(8-hydroxyoxo-1,2-dihydroquinolinyl)ethyl]amino}- methyl)phenoxy]acetyl}amino)ethyl](methyl)amino]cyclohexyl hydroxy(dithienyl)- acetate (Intermediate 53; 176mg, 0.2mmol) and triethylamine trihydrofluoride (131µL, 0.8mmol) following the experimental procedure as described for Example 1.
LRMS (m/z): 761 (M+1)+ 1H NMR (300 MHz, dmso) δ 8.15 (d, J = 9.9 Hz, 1H), 7.87 (bs, 1H), 7.50 (d, J = .1 Hz, 1H), 7.31 (d, J = 8.3 Hz, 2H), 7.14 – 7.06 (m, 4H), 7.05 – 6.99 (m, 2H), 6.94 (dd, J = 8.2, 4.0 Hz, 2H), 6.53 (d, J = 9.8 Hz, 1H), 5.14 (bs, 1H), 4.71 (bs, 1H), 4.48 (bs, 2H), 3.79 (bs, 2H), 2.73 (bs, 2H), 2.48 (s, 3H), 2.43 – 2.29 (m, 2H), 2.19 (bs, 2H), 1.93 (s, 3H), 1.37 (bs, 4H), 1.08 (d, J = 6.1 Hz, 2H). ediate 54. -chlorocyanomethoxybenzoic acid To a on of ochloromethoxybenzoic acid (4g, 0.019mol) in water (60mL) was added hydrochloric acid (35%, 0.63mL) and the e was stirred vigorously and cooled to 5ºC. Then a solution of sodium nitrite (1.92g, 0.027mol) in water (6 mL) was added dropwise. The mixture was stirred for some minutes and then a previously formed solution of copper cyanide (2.32g, 0.026mol) and sodium e (3.65g, ol) in water (20mL) was added dropwise maintaining a low temperature.
Once the addition was finished the reaction mixture was stirred 1 hour at room temperature. The pH of the aqueous phase was adjusted to 3 and ethyl acetate was added into the mixture and the organic layer was washed with water, dried, filtered and the solvent was removed under reduced pressure giving the title compound (2.93g, 62%).
LRMS (m/z): 212 (M+1)+ Intermediate 55. 2-chloro(hydroxymethyl)methoxybenzonitrile To a solution of 5-chlorocyanomethoxybenzoic acid (Intermediate 54; 2.93g, ol) in anh THF (50mL) was added n wise at 0ºC borane-methyl sulphide complex (2M in THF, 2.63mL, 0.027mol). The reaction mixture was stirred 3 hours at room temperature. 5.5mL of water was added into the mixture and with ethyl the crude was extracted. The solvent was removed under reduced pressure and the crude obtained was purified over silica gel eluting with Chloroform/Methanol (100/0 to 0/100) to give the title compound as a solid (2.13g, 77%) LRMS (m/z): 198 (M+1)+ Intermediate 56. 2-chloromethoxy[(tetrahydro-2H-pyranyloxy)methyl]benzonitrile To a solution of 2-chloro(hydroxymethyl)methoxybenzonitrile mediate 55; 800mg, 4.05mmol) in dichloromethane/THF (28mL/12mL) was added under nitrogen atmosphere 3,4-dihydro-2H-pyran (0.444mL, 4.86mmol) and pyridinium p-toluene sulfonate (100mg, 0.4mmol). The reaction mixture was stirred for 48 hours at room temperature. The solvent was removed under reduced pressure and the crude obtained was partitioned between ether and water. The organic layer was dried, filtered and the solvent removed giving a crude which was purified over silica gel eluting with Chloroform/Hexane (100/0 to 0/100) to give the title compound an oil (1.1g, 98%) LRMS (m/z): 282 (M+1)+ Intermediate 57. 2-chloro-N'-hydroxymethoxy[(tetrahydro-2H-pyran yloxy)methyl]benzenecarboximidamide To a solution of Hydroxylamine hydrochloride (1.28g, 0.018mol) in ethanol (10mL) was added Et3N L, 0.019mol). The reaction mixture was stirred at 0ºC and then a solution of 2-chloromethoxy[(tetrahydro-2H-pyranyloxy)methyl]benzonitrile (Intermediate 56; 1.1g, 4.11mmol) in ethanol (20mL) was added. The e was stirred for 5 hours at 65ºC. The t was removed under d re and the crude obtained was purified over silica gel eluting with Chloroform/Hexane (100/0 to 0/100) to give the title compound oil (796mg, 60%) LRMS (m/z): 315 (M+1)+ Intermediate 58. -(3-bromopropyl){2-chloromethoxy[(tetrahydro-2H-pyran yloxy)methyl]phenyl}-1,2,4-oxadiazole To a solution of 2-chloro-N'-hydroxymethoxy[(tetrahydro-2H-pyran yloxy)methyl]benzenecarboximidamide (Intermediate 57; 796mg, 2.53mmol) and DIEA (551µL, 3.15mmol) in dichloromethane (18mL) was added dropwise 4-bromobutanoyl chloride (324µL, 2.8mmol) in dichloromethane (3mL). The reaction e was stirred hours at room temperature. The mixture was diluted with dichloromethane and the organic layer was washed with sodium bicarbonate and brine. The solvent was removed under d pressure giving an oil, which was used to cyclize without further manipulation. The crude ed was dissolved in toluene and refluxed for 2 hours. The solvent was removed under reduced pressure and the crude obtained was purified over silica gel g with Ethyl acetate/Hexane (100/0 to 0/100) to give the title compound an oil (487mg, 37%) LRMS (m/z): 446 (M+1)+ Intermediate 59. trans [[3-(3-{2-chloromethoxy[(tetrahydro-2H-pyran yloxy)methyl]phenyl}-1,2,4-oxadiazolyl)propyl](methyl)amino]cyclohexyl hydroxy(dithienyl)acetate Obtained as an oil (585mg, 84%) from 5-(3-bromopropyl){2-chloromethoxy [(tetrahydro-2H-pyranyloxy)methyl]phenyl}-1,2,4-oxadiazole (Intermediate 58; 486mg, 0.95mmol), trans (methylamino)cyclohexyl hydroxy(dithienyl)acetate (Intermediate 5; 386mg, 1.1mmol) and DIEA (0.38mL, 2.18mmol) following the experimental procedure as described for Intermediate 9 and the crude obtained was purified over silica gel eluting with CH2Cl 2:EtOH.
LRMS (m/z): 717 (M+1)+ Intermediate 60. trans [(3-{3-[2-chloro(hydroxymethyl)methoxyphenyl]-1,2,4-oxadiazol yl}propyl)(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate Obtained as a yellow oil (378mg, 74%) from trans [[3-(3-{2-chloromethoxy ahydro-2H-pyranyloxy)methyl]phenyl}-1,2,4-oxadiazolyl)propyl](methyl)- amino]cyclohexyl hydroxy(dithienyl)acetate (Intermediate 59; 579mg, 0.81mmol) and hydrochloric acid (1M, 2.43mL) following the experimental procedure as described for Intermediate 30 and the crude obtained was purified over silica gel eluting with CHCl ne.
LRMS (m/z): 633 (M+1)+ Intermediate 61. trans [{3-[3-(2-chloroformylmethoxyphenyl)-1,2,4-oxadiazol yl]propyl}(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate Obtained as an oil (326mg, 78%) from trans [(3-{3-[2-chloro(hydroxymethyl) methoxyphenyl]-1,2,4-oxadiazolyl}propyl)(methyl)amino]cyclohexyl hydroxy(di thienyl)acetate (Intermediate 60; 377mg, l) and manganese oxide , ol) ing the mental procedure as described for Intermediate 31 and the crude obtained was used in the next step without further purification.
LRMS (m/z): 631 (M+1)+ Intermediate 62. trans [(3-{3-[4-({[(2 R){[ tert -butyl(dimethyl)silyl]oxy}(8-hydroxyoxo-1,2- oquinolinyl)ethyl]amino}methyl)chloromethoxyphenyl]-1,2,4- oxadiazolyl}propyl)(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate Obtained as a yellow foam (373mg, 76%) from trans -[3-(2-chloroformyl yphenyl)-1,2,4-oxadiazolyl]propyl}(methyl)amino]cyclohexyl hydroxy(di l)acetate (Intermediate 61; 320mg, ol), 5-((1R)amino{[tertbutyl (dimethyl)-silyl]oxy}ethyl)hydroxyquinolin-2(1H)-one acetate (prepared according to preparation 8 from US20060035931; 220mg, 0.56mmol), DIEA (115µL, 0.66mmol) and sodium triacetoxyborohydride (350mg, 1.65mmol) following the procedure as described for Intermediate 10 and the crude obtained was purified over silica gel eluting with Chloroform/Methanol (100/0 to 0/100).
LRMS (m/z): 949 (M+1)+ EXAMPLE 9. trans [(3-{3-[2-chloro({[(2 R)hydroxy(8-hydroxyoxo-1,2- dihydroquinolinyl)ethyl]amino}methyl)methoxyphenyl]-1,2,4-oxadiazol yl}propyl)(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate dihydrofluoride Obtained as a white solid (279mg, 82%) from trans -{3-[4-({[(2 R){[ tert - butyl(dimethyl)silyl]oxy}(8-hydroxyoxo-1,2-dihydroquinolinyl)ethyl]amino}- methyl)chloromethoxyphenyl]-1,2,4-oxadiazolyl}propyl)(methyl)-amino]- cyclohexyl hydroxy(dithienyl)acetate (Intermediate 62; 367mg, 0.39mmol) and triethylamine trihydrofluoride (252µL, 1.55mmol) following the experimental procedure as described for Example 1.
LRMS (m/z): 835 (M+1)+ 1H NMR (300 MHz, dmso) δ 8.15 (d, J = 10.0 Hz, 1H), 7.54 (s, 1H), 7.46 (dd, J = .1, 1.3 Hz, 1H), 7.36 (s, 1H), 7.25 (s, 1H), 7.11 – 7.01 (m, 3H), 7.00 – 6.88 (m, 3H), 6.48 (d, J = 9.9 Hz, 1H), 5.12 – 5.03 (m, 1H), 4.67 (bs, 1H), 3.80 (s, 3H), 3.01 (t, J = 7.2 Hz, 2H), 2.82 – 2.63 (m, 2H), 2.41 (bs, 1H), 2.16 (s, 3H), 1.98 – 1.83 (m, 5H), 1.70 (s, 2H), 1.35 (s, 4H), 1.04 (d, J = 6.1 Hz, 3H).
Intermediate 63. methyl rohydroxymethoxybenzoate To solution of 4-aminochloromethoxybenzoic acid (10g, 0.048mol) in water (50mL) was added HBF4 (48% in water, 16.2mL, 0.12mol) and acetyl chloride (2.24mL, 0.031mol) and the mixture was stirred for 1 hour at room temperature. The mixture was cooled to 0ºC to add dropwise sodium nitrite , 0.054mol) in water (30mL). The reaction was allowed to stirrer at 0ºC for 30 minutes. Then the solid was ed and it was treated with Acid Acetic (500mL). The mixture was heated at 100ºC for 1 hour. The mixture was cooled and it was stand without further manipulation overnight. The solvent was removed under reduced pressure and the crude obtained was partitioned between Ethyl acetate and Brine. The organic layer was dried, filtered and the solvent was removed under reduced pressure. The crude was treated with sodium hydroxide ) for 90 minutes at room temperature and overnight at 45ºC.
The crude was extracted with dichloromethane and purified over silica gel eluting with romethane/Ethanol (100/0 to 0/100) to give the title compound as a foam (1.1g, %) LRMS (m/z): 217 (M+1)+ Intermediate 64. ro(hydroxymethyl)methoxyphenol To a solution of methyl 5-chlorohydroxymethoxybenzoate (Intermediate 63; 1.1g, .08mmol) in THF (30mL) was added dropwise at 0ºC lithium aluminium hydride (1M in THF, 9.65mL). The reaction mixture was d 10 minutes at 0ºC , 1 hour at room temperature and 30 minutes at 65ºC. The mixture was cooled at 0ºC and a saturated solution of L-Tartrate (100mL) was added cautiously. Then Ethyl acetate was added and the mixture was stirred for 1 hour at room ature. The c layer was separated, dried, filtered and the solvent was removed under reduced pressure to give a crude, which was purified over silica gel eluting with Chloroform/Ethanol (100/0 to 0/100) to give the title compound as a foam (460mg, 450%) LRMS (m/z): 189 (M+1)+ Intermediate 65. ethyl [2-chloro(hydroxymethyl)methoxyphenoxy]acetate To a solution of 2-chloro(hydroxymethyl)methoxyphenol mediate 64; 459mg, 2.43mmol) in acetonitrile (5 mL) was added ethyl bromoacetate (0.26mL, 2.43mmol) and potassium carbonate (420mg, 3.04mmol) in a sealed tub. The mixture was stirred 2 hours at 90ºC. The solid was filtrated, washed with acetonitrile and the solvent of the filtrate was removed under reduced pressure giving the title compound as a brown oil (640mg, 85%), which was used in the next step without further purification.
LRMS (m/z): 275 (M+1)+ Intermediate 66. [2-chloro(hydroxymethyl)methoxyphenoxy]acetic acid To a solution of ethyl [2-chloro(hydroxymethyl)methoxyphenoxy]acetate (Intermediate 65; 640mg, ol) in THF (20mL) was added water (20mL) and lithium hydroxide (391mg, 9.32mmol). The reaction mixture was stirred for 1 hour at room temperature. The t was removed under d pressure and the s phase was acidified until acid pH and then extracted with ethyl acetate. The organic layer was washed with brine, dried, filtered and the solvent was removed under reduced pressure to give the title nd as a red solid (550mg, 95%), which was used in the next step without further purification.
LRMS (m/z): 247 (M+1)+ Intermediate 67. trans [{2-[{[2-chloro(hydroxymethyl) methoxyphenoxy]acetyl}(methyl)amino]ethyl}(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate Obtained the title compound (400mg, 64%) from [2-chloro(hydroxymethyl) methoxyphenoxy]acetic acid (Intermediate 66; 230mg, ol), trans {methyl[2- (methylamino)ethyl]amino}cyclohexyl hydroxy(dithienyl)acetate (Intermediate 36; 376mg, 0.92mmol), HBTU (350mg, 0.92mmol) and DIEA (0.64mL, 3.69mmol) following the experimental procedure as described for Intermediate 51 and the crude obtained was purified over silica gel eluting with Chloroform/Hexane (100/0 to 0/100).
LRMS (m/z): 638 (M+1)+ Intermediate 68. trans [{2-[[(2-chloroformyl methoxyphenoxy)acetyl](methyl)amino]ethyl}(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate Obtained as an oil (390mg, 90%) from trans [{2-[{[2-chloro(hydroxymethyl) methoxyphenoxy]acetyl}(methyl)amino]ethyl}(methyl)amino]cyclohexyl y(di thienyl)acetate (Intermediate 67; 400mg, 0.63mmol) and manganese oxide (545mg, 6.27mmol) following the experimental ure as described for Intermediate 31 and the crude obtained was used in the next step without further purification.
LRMS (m/z): 636 (M+1)+ Intermediate 69. trans [{2-[{[4-({[(2 R){[tert-butyl(dimethyl)silyl]oxy}(8-hydroxyoxo-1,2- dihydroquinolinyl)ethyl]amino}methyl)chloro methoxyphenoxy]acetyl}(methyl)amino]ethyl}(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate ed as a foam (306mg, 52%) from trans [{2-[[(2-chloroformyl yphenoxy)acetyl](methyl)amino]ethyl}(methyl)amino]cyclohexyl hydroxy(di thienyl)acetate (Intermediate 68; 390mg, 0.61mmol), 5-((1R)amino{[tertbutyl (dimethyl)-silyl]oxy}ethyl)hydroxyquinolin-2(1H)-one acetate red according to preparation 8 from US20060035931; 226mg, 0.68mmol), DIEA (139µL, 0.8mmol) and sodium triacetoxyborohydride , 1.84mmol) following the procedure as described for Intermediate 10 and the crude obtained was purified over silica gel eluting with Chloroform/Methanol (100/0 to 0/100).
LRMS (m/z): 954 (M+1)+ EXAMPLE 10. 4-[{2-[{[2-chloro({[(2 R)hydroxy(8-hydroxyoxo-1,2- dihydroquinolinyl)ethyl]amino}methyl) methoxyphenoxy]acetyl}(methyl)amino]ethyl}(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate ofluoride Obtained as a white solid (170mg, 64%) from trans [{2-[{[4-({[(2 R){[tertbutyl (dimethyl)silyl]oxy}(8-hydroxyoxo-1,2-dihydroquinolin yl)ethyl]amino}methyl)chloromethoxyphenoxy]acetyl}-(methyl)amino]ethyl}- (methyl)-amino]-cyclohexyl y(dithienyl)acetate (Intermediate 69; 300mg, 0.31mmol) and triethylamine trihydrofluoride (205µL, 1.26mmol) following the experimental procedure as described for Example 1.
LRMS (m/z): 840 (M+1)+ 1H NMR (300 MHz, dmso) δ 8.12 (d, J = 9.8 Hz, 1H), 7.46 (d, J = 5.1 Hz, 1H), 7.30 (d, J = 3.0 Hz, 1H), 7.26 (s, 1H), 7.11 – 7.01 (m, 3H), 7.01 – 6.86 (m, 3H), 6.63 (d, J = 4.4 Hz, 1H), 6.49 (d, J = 9.6 Hz, 1H), 5.08 (s, 1H), 4.95 (d, J = 8.6 Hz, 2H), 3.73 (d, J = 2.7 Hz, 3H), 3.69 (bs, 2H), 3.03 (s, 2H), 2.85 (bs, 2H), 2.69 (s, 3H), 2.45 (bs, 2H), 2.41 – 2.29 (m, 2H), 1.88 (s, 3H), 1.35-1.3 (m, 4H), 1.25 – 1.02 (m, 4H).
Intermediate 70. 2-oxo-2,3-dihydro-1,3-benzothiazolecarbaldehyde Obtained as a white solid (240 mg of 97% purity by HPLC, 99% yield) from 6-bromo oxo-2,3-dihydro-1,3-benzothiazole (302 mg, 1.31 mmol), methylmagnesium bromide (0.48 mL of a 3M solution in Et2O, 1.44 mmol), tert-butyllithium (3.0 mL of a 1.7 M solution in Hexanes, 5.10 mmol) and DMF (0.6 mL, 7.7 mmol) following the procedure described in Step 2 of Example 16 from patent WO02/50070.
LRMS (m/z): 180 .
Intermediate 71. 3-(3-hydroxypropyl)oxo-2,3-dihydro-1,3-benzothiazolecarbaldehyde 2-oxo-2,3-dihydro-1,3-benzothiazolecarbaldehyde (120 mg, 0.67 mmol), 3- bromopropanol (85 µL, 0.94 mmol), potassium carbonate (278 mg, 2.01 mmol) and ium iodide (55 mg, 0.33 mmol) were ded in acetonitrile (2 mL) and the whole mixture was heated at 65 ºC for 48h. Then, the solids were filtered off and washed with acetonitrile and the resulting filtrate was evaporated to dryness to afford the title compound as a solid (204 mg of 77% purity by HPLC, 99% yield) which was used without further purification.
LRMS (m/z): 238 (M+1)+.
Intermediate 72. 3-(6-formyloxo-1,3-benzothiazol-3(2 H)-yl)propyl methanesulfonate To a solution of 3-(3-hydroxypropyl)oxo-2,3-dihydro-1,3-benzothiazole carbaldehyde (Intermediate 71, 158 mg, 0.67 mmol) in CH2Cl 2 (5 mL) was added Et3N (0.11 mL, 0.80 mmol) and the mixture was cooled to 0 ºC. To this on, methanesulfonyl chloride was added dropwise (57 µL, 0.74 mmol) and the mixture was maintained at 0 ºC for 90 min. CH2Cl 2 and 4% aqueous sodium bicarbonate solution (10 mL) were added to the reaction e and stirred for 10 min. The two layers were separated and the organic phase was washed with water and brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to give the title compound as a colourless oil (243 mg, 99% yield) which was used without further purification.
LRMS (m/z): 316 .
Intermediate 73. trans [[3-(6-formyloxo-1,3-benzothiazol-3(2 H)- yl)propyl](methyl)amino]cyclohexyl hydroxy(dithienyl)acetate To a on of ormyloxo-1,3-benzothiazol-3(2H)-yl)propyl methanesulfonate (Intermediate 72, 210 mg, 0.67 mmol) in DMF (2 mL) was added trans (methylamino)cyclohexyl hydroxy(dithienyl)acetate (Intermediate 5, 234 mg, 0.67 mmol), sodium iodide (250 mg, 1.67 mmol) and DIEA (174 µL, 1.00 mmol) and the mixture was stirred at 60 ºC for 3 hours. The reaction mixture was evaporated to dryness, the solid residue was re-suspended in a CH2Cl 2/Hexanes mixture (20 mL of a 1/1 mixture) and the suspension was filtered through Celite®. The solvent was removed under reduced pressure and the resulting brownish residue was purified by column chromatography over silica gel eluting with a mixture of CH2Cl 2/EtOH (gradient from 0 to 10% of EtOH) to provide the title compound as a yellow oil (231 mg, 55% yield (90% purity from HPLC)).
LRMS (m/z): 571 .
Intermediate 74. trans [{3-[6-({[(2 R){[ tert -butyl(dimethyl)silyl]oxy}(8-hydroxyoxo-1,2- dihydroquinolinyl)ethyl]amino}methyl)oxo-1,3-benzothiazol-3(2 H)- pyl}(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate Obtained as a pale yellow solid (2104 mg, 59% yield) from trans [[3-(6-formyloxo- 1,3-benzothiazol-3(2 H)-yl)propyl](methyl)amino]cyclohexyl hydroxy(dithienyl)acetate (Intermediate 73, 230 mg, 0.40 mmol), 5-((1R)amino{[ tert -butyl(dimethyl)- silyl]oxy}ethyl)hydroxyquinolin-2(1 H)-one acetate (prepared according to preparation 8 from US20060035931, 148 mg, 0.44 mmol) and sodium toxyborohydride (270 mg, 1.27 mmol) following the experimental procedure described for the synthesis of Intermediate 10. The crude obtained was purified by column chromatography over silica gel, eluting with a mixture of CHCl3:EtOH (from 0 to 50% of EtOH).
LRMS (m/z): 890 (M+1)+.
EXAMPLE 11. trans -[6-({[(2 R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolin yl)ethyl]amino}methyl)oxo-1,3-benzothiazol-3(2 H)- yl]propyl}(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate dihydrofluoride Obtained as a pale yellow solid (149 mg, 81% yield) from trans [{3-[6-({[(2 R){[ tert - butyl(dimethyl)silyl]oxy}(8-hydroxyoxo-1,2-dihydroquinolin yl)ethyl]amino}methyl)oxo-1,3-benzothiazol-3(2 H)- yl]propyl}(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate (Intermediate 74, 200 mg, 0.22 mmol) and triethylamine trihydrofluoride (150 µL, 0.92 mmol) ing the mental procedure described for the synthesis of Example 1.
LRMS (m/z): 775 (M+1)+. 1H NMR (300 MHz, dmso) δ 8.11 (d, J = 10.0 Hz, 1H), 7.60 (s, 1H), 7.46 (dt, J = 3.8, 1.9 Hz, 1H), 7.31 (dt, J = 18.2, 9.1 Hz, 2H), 7.10 – 7.02 (m, 3H), 7.00 – 6.94 (m, 3H), 6.90 (d, J = 8.1 Hz, 1H), 6.45 (d, J = 9.9 Hz, 1H), 5.11 (bs, 1H), 4.68 (bs, 1H), 3.93 (bs, 3H), 3.84 (s, 2H), 2.72 (d, J = 7.0 Hz, 2H), 2.44 (s, 2H), 2.14 (s, 3H), 1.91 (s, 2H), 1.72 (dd, J = 15.0, 7.1 Hz, 4H), 1.37 (dd, J = 19.6, 10.5 Hz, 4H).
Intermediate 75. methyl ohydroxybenzoate 4-aminohydroxybenzoic acid ( 5.0 g, 32.6 mmol) was added dropwise to a 0 ºC solution of an HCl 1.25 M solution in 00 mL) and MeOH (100 mL). After 5 min of final addition the mixture was allowed to warm up to room temperature and stirred overnight. HPLC monitoring of the on showed remaining starting material and the mixture was stirred at ambient temperature for 48 hours. The solvent was then removed under reduced pressure and the residue was treated with saturated aqueous bicarbonate solution and the aqueous phase was ted with AcOEt (2 x ). The combined organic extracts were washed with brine, dried over anhydrous sodium te, filtered and concentrated to dryness obtaining the title compound (5.37 g, 97% yield) as a crystalline solid.
LRMS (m/z): 168 (M+1)+.
Intermediate 76. methyl 2-oxo-2,3-dihydro-1,3-benzoxazolecarboxylate To a solution of methyl 4-aminohydroxybenzoate (Intermediate 75, 1.06 g, 6.34 mmol) in THF (13.5 mL) was added carbonyl diimidazole (1.88 g, 11.6 mmol) and the reaction mixture was heated to reflux temperature for 1 day. After that time, the t was removed and the residue was partitioned between CH2Cl 2 and 1N aqueous HCl solution. The organic phase was washed with 1N aqueous HCl solution (2x) and water, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to provide the title compound as white solid (870 mg of a 79% purity, 56% yield). The crude was used in the next step without any further purification.
LRMS (m/z): 194 (M+1)+.
Intermediate 77. 6-(hydroxymethyl)-1,3-benzoxazol-2(3 H)-one To a on of methyl 2-oxo-2,3-dihydro-1,3-benzoxazolecarboxylate (865 mg of 79% purity, 3.51 mmol) in THF (15 mL) was added, under argon atmosphere and at 0 ºC, lithium aluminium hydride (400 mg, 10.5 mmol) in portions in order to maintain the internal ature below 5 ºC. After the last addition, the thick suspension was allowed to warm up to room ature and stirred for 1.5 hours. Then, water was added (0.4 mL) dropwise followed by addition of 4N sodium hydroxide (0.4 mL) and water (1.2 mL). The mixture was filtered and the solid residue was washed with EtOH.
The ethanolic phase was trated to dryness. The brown solid obtained was purified by reverse phase column chromatography over C18 modified silica gel eluting with water:MeOH (from 0 to 100% of MeOH) to give a pure fraction of the title compound (148 mg, 26% yield).
LRMS (m/z): 166 (M+1)+.
Intermediate 78. 6-({[ tert -butyl(diphenyl)silyl]oxy}methyl)-1,3-benzoxazol-2(3 H)-one To a solution of roxymethyl)-1,3-benzoxazol-2(3H)-one (Intermediate 77, 330 mg, 2.0 mmol) in DMF (10 mL) was added imidazole (203 mg, 2.98 mmol) and the reaction was cooled to 0 ºC before tert -butylchlorodiphenylsilane (0.52 mL, 2.0 mmol) was added dropwise. Upon addition, the reaction was d to warm up to room temperature and ng was maintained for 16 hours. Water and CH2Cl 2 (40 mL each) were added to the reaction mixture and the phases were ted. The aqueous phase was extracted with CH2Cl 2 (2 x 50 mL) and the resulting organic extracts were washed with water (2 x 50 mL) and brine (50 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced re. The brown oil obtained was purified by column chromatography over silica gel eluting with Hexane:Et 2O (from 0 to 100% of Et2O) to afford the title compound as a beige solid (437 mg, 54% yield).
LRMS (m/z): 404 (M+1)+.
Intermediate 79. 6-({[ tert -butyl(diphenyl)silyl]oxy}methyl)(2-hydroxyethyl)-1,3-benzoxazol-2(3 H)- To a solution of 6-({[tert -butyl(diphenyl)silyl]oxy}methyl)-1,3-benzoxazol-2(3 H)-one (Intermediate 78, 218 mg, 0.54 mmol) in DMF (2 mL) were added potassium carbonate (232 mg, 1.68 mmol) and 2-bromoethanol (60 µL, 0.85 mmol) and the reaction mixture was placed in a sealed vessel at 120 ºC over a period of 4 hours. CH2Cl 2 was added to the mixture and the solids were filtered off and washed with CH2Cl 2. The resulting filtrate was washed with water and brine and the organic phase was filtered through a Phase Separator membrane to remove remaining water. The crude oil was purified by column chromatography over silica gel using Hexane:Et2O as eluent (from 0 to 100% of Et 2O) to give the title compound as a white solid (107 mg, 44% yield).
LRMS (m/z): 448 (M+1)+. ediate 80. 2-[6-({[ tert (diphenyl)silyl]oxy}methyl)oxo-1,3-benzoxazol-3(2 H)-yl]ethyl methanesulfonate Obtained as a less oil (139 mg of 90% purity by HPLC, 99% yield) from 6-({[tert - butyl(diphenyl)silyl]oxy}methyl)(2-hydroxyethyl)-1,3-benzoxazol-2(3 H)-one (Intermediate 79, 107 mg, 0.24 mmol), Et3N (50 µL, 0.34 mmol) and methanesulfonyl chloride (26 µL, 0.34 mmol) ing the experimental procedure described for the synthesis of Intermediate 72. The crude was used for the next step without further purification.
LRMS (m/z): 526 (M+1)+. ediate 81. trans [{2-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)oxo-1,3-benzoxazol-3(2 H)- yl]ethyl}(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate Obtained as a solid (92 mg of 88% purity by HPLC, 44% yield) from 2-[6-({[ tert - butyl(diphenyl)silyl]oxy}methyl)oxo-1,3-benzoxazol-3(2 H)-yl]ethyl methanesulfonate (Intermediate 80, 139 mg, 0.24 mmol), trans (methylamino)cyclohexyl hydroxy(di thienyl)acetate (Intermediate 5, 95 mg, 0.27 mmol), sodium iodide (75 mg, 0.50 mmol) and DIEA (65 µL, 0.37 mmol) following the experimental procedure described for the synthesis of Intermediate 73. The crude was purified by column chromatography over silica gel eluting with Hexane:Et2O (from 0 to 100% of Et2O).
LRMS (m/z): 781 (M+1)+.
Intermediate 82. trans [{2-[6-(hydroxymethyl)oxo-1,3-benzoxazol-3(2 H)- yl]ethyl}(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate To a solution of trans [{2-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)oxo-1,3- azol-3(2 H)-yl]ethyl}(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate (Intermediate 81, 92 mg of 88% purity by HPLC, 0.10 mmol) in THF (1 mL) was added triethylamine trihydrofluoride (55 µL, 0.342 mmol) and the final solution was stirred at ambient temperature overnight. Saturated aqueous sodium bicarbonate and CHCl3 were added and the phases separated. The s phase was extracted with CHCl3 (2 x 15 mL) and the combined organic extracts were filtered through a Phase tor membrane and concentrated under reduced re. The solid residue was purified by column chromatography over silica gel eluting with CH2Cl 2:EtOH (from 0 to 10% EtOH) to give the title compound as a colourless foam (40 mg, 70% yield).
LRMS (m/z): 543 (M+1)+.
Intermediate 83. trans [[2-(6-formyloxo-1,3-benzoxazol-3(2 H)- yl)ethyl](methyl)amino]cyclohexyl y(dithienyl)acetate To a solution of trans [{2-[6-(hydroxymethyl)oxo-1,3-benzoxazol-3(2 H)- yl]ethyl}(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate (Intermediate 82, 40 mg, 0.07 mmol) in CH2Cl 2 (1 mL) was added Dess-Martin inane reagent (45 mg, 0.11 mmol) and the mixture was stirred for 40 min. Saturated aqueous solutions of sodium bicarbonate and sodium thiosulfate were added (0.5 mL each) and stirring was maintained for 10 more min. The phases were separated and the aqueous phase was extracted with CH2Cl 2 (2 x 5 mL). The combined organic extracts were filtered through a Phase Separator membrane and concentrated to s to afford the title compound (63 mg of 60% purity by HPLC, 100% yield) as a yellow oil. The crude oil was used as this without any r purification.
LRMS (m/z): 541 (M+1)+.
Intermediate 84. trans [{2-[6-({[(2 [ tert -butyl(dimethyl)silyl]oxy}(8-hydroxyoxo-1,2- dihydroquinolinyl)ethyl]amino}methyl)oxo-1,3-benzoxazol-3(2 H)- yl]ethyl}(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate Obtained as a yellow solid (44 mg of a 81% purity by HPLC, 59% yield) from trans [[2-(6-formyloxo-1,3-benzoxazol-3(2 H)-yl)ethyl](methyl)amino]cyclohexyl hydroxy(di- nyl)acetate (Intermediate 83, 63 mg of a 60% purity by HPLC, 0.07 mmol), 5- ((1 mino{[ tert -butyl(dimethyl)-silyl]oxy}ethyl)hydroxyquinolin-2(1 H)-one e (prepared according to preparation 8 from US20060035931, 32 mg, 0.10 mmol) DIEA (21 µL, 0.12 mmol) and sodium triacetoxyborohydride (107 mg, 0.50 mmol) following the experimental procedure described for the synthesis of Intermediate . The crude obtained was purified by column chromatography over silica gel, eluting with a mixture of CHCl3:EtOH (from 0 to 50% of EtOH).
LRMS (m/z): 859 (M+1)+.
EXAMPLE 12. trans [{2-[6-({[(2 R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolin yl)ethyl]amino}methyl)oxo-1,3-benzoxazol-3(2 H)- yl]ethyl}(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate dihydrofluoride Obtained as a pale yellow solid (29 mg, 72% yield) from trans [{2-[6-({[(2 R){[ tert - butyl(dimethyl)silyl]oxy}(8-hydroxyoxo-1,2-dihydroquinolinyl)ethyl]amino}- methyl)oxo-1,3-benzoxazol-3(2 H)-yl]ethyl}(methyl)amino]cyclohexyl hydroxy(di thienyl)acetate (Intermediate 84, 44 mg, 0.05 mmol) and triethylamine trihydrofluoride (40 µL, 0.25 mmol) following the experimental procedure described for the sis of Example 1.
LRMS (m/z): 745 (M+1)+. 1H NMR (300 MHz, dmso) δ 8.13 (d, J = 9.8 Hz, 1H), 7.45 (d, J = 4.4 Hz, 1H), 7.36 (bs, 2H), 7.23 (bs, 2H), 7.05 (bs, 3H), 7.01 – 6.85 (m, 3H), 6.48 (d, J = 10.1 Hz, 1H), .14 (bs, 1H), 4.62 (bs, 1H), 3.86 (d, J = 7.0 Hz, 2H), 2.70 (d, J = 16.0 Hz, 3H), 2.35 (s, 3H), 2.22 (bs, 2H), 1.91 (bs, 2H), 1.81 (bs, 2H), 1.49 (bs, 2H), 1.41 – 1.13 (m, 3H).
Intermediate 85. 3-(4-hydroxybutyl)oxo-2,3-dihydro-1,3-benzoxazolecarbaldehyde Obtained as a solid (120 mg of a 76% purity by HPLC, 35% yield) from 2-oxo-2,3- dihydro-1,3-benzoxazolecarbaldehyde (Intermediate 7, 180 mg, 1.10 mmol), 4- bromobutanol (255 mg, 1.67 mmol), potassium carbonate (460 mg, 3.33 mmol) and potassium iodide (92 mg, 0.55 mmol) following the procedure described for the synthesis of Intermediate 71. The crude residue was purified by column chromatography over silica gel eluting with CH2Cl 2:EtOH (from 0 to 5% of EtOH).
Intermediate 86. 4-(6-formyloxo-1,3-benzoxazol-3(2 butyl methanesulfonate Obtained as a less oil (153 mg of 80% purity by HPLC, 99% yield) from 3-(4- hydroxybutyl)oxo-2,3-dihydro-1,3-benzoxazolecarbaldehyde mediate 85, 120 mg of 76% purity by HPLC, 0.39 mmol), Et3N (145 µL, 1.05 mmol) and methanesulfonyl chloride (64 µL, 0.83 mmol) following the experimental procedure described for the synthesis of Intermediate 72. The crude was used for the next step without further purification.
LRMS (m/z): 314 (M+1)+.
Intermediate 87. trans [[4-(6-formyloxo-1,3-benzoxazol-3(2 H)-yl)butyl](methyl)amino]- cyclohexyl hydroxy(dithienyl)acetate Obtained as a solid (93 mg, 42% yield) from 4-(6-formyloxo-1,3-benzoxazol-3(2 H)- yl)butyl esulfonate (Intermediate 86, 121 mg, 0.39 mmol), trans (methylamino)cyclohexyl hydroxy(dithienyl)acetate (Intermediate 5, 137 mg, 0.39 mmol), sodium iodide (145 mg, 0.97 mmol) and DIEA (105 µL, 0.58 mmol) ing the experimental procedure described for the synthesis of Intermediate 73. The crude was purified by column chromatography over silica gel eluting with CH2Cl 2:MeOH (from 0 to 100% of MeOH).
LRMS (m/z): 569 (M+1)+.
Intermediate 88. trans [{4-[6-({[(2 R){[tert-butyl(dimethyl)silyl]oxy}(8-hydroxyoxo-1,2- dihydroquinolinyl)ethyl]amino}methyl)oxo-1,3-benzoxazol-3(2 H)- yl]butyl}(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate Obtained as a solid (80 mg of 62% purity by HPLC, 35% yield) from trans -(6- formyloxo-1,3-benzoxazol-3(2 H)-yl)butyl](methyl)amino]cyclohexyl hydroxy(di thienyl)acetate mediate 87, 90 mg, 0.16 mmol), 5-((1R)amino{[ tert - butyl(dimethyl)-silyl]oxy}ethyl)hydroxyquinolin-2(1 H)-one acetate (prepared according to preparation 8 from 0035931, 69 mg, 0.17 mmol) and sodium triacetoxyborohydride (135 mg, 0.64 mmol) following the experimental procedure described for the synthesis of Intermediate 10. The crude obtained was purified by column chromatography over silica gel, eluting with a mixture of CHCl 3:EtOH (from 0 to 50% of EtOH).
LRMS (m/z): 887 (M+1)+.
EXAMPLE 13. trans [{4-[6-({[(2 R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolin yl)ethyl]amino}methyl)oxo-1,3-benzoxazol-3(2 H)- yl]butyl}(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate dihydrofluoride Obtained as a pale yellow solid (44 mg, 98% yield) from trans [{4-[6-({[(2 R){[tertbutyl (dimethyl)silyl]oxy}(8-hydroxyoxo-1,2-dihydroquinolinyl)ethyl]amino}- methyl)oxo-1,3-benzoxazol-3(2 H)-yl]butyl}(methyl)amino]cyclohexyl hydroxy(di thienyl)acetate (Intermediate 88, 79 mg of a 62% purity by HPLC, 0.06 mmol) and triethylamine rofluoride (40 µL, 0.25 mmol) following the experimental procedure described for the synthesis of e 1.
LRMS (m/z): 773 (M+1)+. 1H NMR (300 MHz, dmso) δ 8.30 (d, J = 9.9 Hz, 1H), 7.65 (bs, 2H), 7.49 (s, 1H), 7.44 – 7.28 (m, 2H), 7.24 (dd, J = 8.1, 4.6 Hz, 3H), 7.18 – 7.03 (m, 3H), 6.64 (d, J = 9.9 Hz, 1H), 5.32 (s, 1H), 5.29 – 5.18 (m, 1H), 4.85 (s, 1H), 3.97 (d, J = 7.3 Hz, 4H), 2.85 (s, 3H), 2.54 (d, J = 7.1 Hz, 4H), 2.28 (d, J = 5.4 Hz, 2H), 2.08 (bs, 2H), 1.85 (bs, 4H), 1.66 – 1.40 (m, 4H).
Intermediate 89. trans [(3-{5-[({(2 R){[ tert -butyl(dimethyl)silyl]oxy}[3-(formylamino) hydroxyphenyl]ethyl}amino)methyl]oxo-2,3-dihydro-1H-benzimidazol yl}propyl)(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate Obtained as a solid (56 mg of 71% purity by HPLC, 56% yield) from trans [[3-(5- formyloxo-2,3-dihydro-1H-benzimidazolyl)propyl](methyl)amino]cyclohexyl hydroxy(dithienyl)acetate (Intermediate 16, 46 mg, 0.08 mmol), N-[5-[( R)amino (tert -butyldimethylsilyloxy)ethyl]hydroxyphenylformamide acetate (prepared ing to the ation of Example 3 from WO2007127297, 33 mg, 0.09 mmol) and sodium triacetoxyborohydride (605 mg, 0.28 mmol) following the experimental procedure described for the synthesis of Intermediate 10. The crude obtained was purified by column chromatography over silica gel, g with a mixture of CHCl 3:EtOH (from 0 to 50% of EtOH).
LRMS (m/z): 848 (M+1)+.
EXAMPLE 14. trans [(3-{5-[({(2 R)[3-(acetylamino)hydroxyphenyl] hydroxyethyl}amino)methyl]oxo-2,3-dihydro-1H-benzimidazol yl}propyl)(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate dihydrofluoride Obtained as a pale yellow solid from trans [(3-{5-[({(2 [ tert -butyl(dimethyl)- silyl]oxy}[3-(formylamino)hydroxyphenyl]ethyl}amino)methyl]oxo-2,3-dihydro- zimidazolyl}propyl)(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate (56 mg of 71% purity by HPLC, 0.05 mmol) and triethylamine trihydrofluoride (30 µL, 0.19 mmol) following the experimental procedure described for the sis of Example 1.
LRMS (m/z): 734 (M+1)+. 1H NMR (300 MHz, dmso) δ 9.53 (s, 1H), 8.24 (d, J = 6.5 Hz, 1H), 8.00 (s, 1H), 7.47 – 7.36 (m, 2H), 7.22 (bs, 2H), 7.09 – 6.71 (m, 6H), 4.65 (bs, 1H), 4.54 (bs, 1H), 3.74 (d, J = 6.7 Hz, 2H), 2.57 (s, 3H), 2.40-2.3 (m, 3H), 2.07 (bs, 4H), 1.87 (d, J = 4.9 Hz, 2H), 1.67 (bs, 4H), 1.32 b(s, 4H).
Intermediate 90. 3-(3-hydroxypropyl)oxo-2,3-dihydro-1,3-benzoxazolecarbaldehyde Obtained as a solid (191 mg of 85% purity by HPLC, 49% yield) from 2-oxo-2,3- dihydro-1,3-benzoxazolecarbaldehyde (Intermediate 7, 245 mg, 1.50 mmol), 3- bromopropanol (190 µL, 2.11 mmol), potassium carbonate (620 mg, 4.50 mmol) and potassium iodide (125 mg, 0.75 mmol) following the experimental procedure described for the synthesis of Intermediate 71. The crude residue was purified by column chromatography over silica gel eluting with CH2Cl 2:EtOH (from 0 to 10% of EtOH).
LRMS (m/z): 222 (M+1)+.
Intermediate 91. 3-(6-formyloxo-1,3-benzoxazol-3(2 propyl methanesulfonate Obtained as a colourless oil (297 mg of 86% purity by HPLC, 99% yield) from 3-(3- hydroxypropyl)oxo-2,3-dihydro-1,3-benzoxazolecarbaldehyde (Intermediate 90, 190 mg of 85% purity by HPLC, 0.85 mmol), Et3N (145 µL, 1.05 mmol) and methanesulfonyl chloride (75 µL, 0.97 mmol) following the mental procedure described for the synthesis of Intermediate 72. The crude was used for the next step without r cation.
LRMS (m/z): 300 (M+1)+.
Intermediate 92. trans -(6-formyloxo-1,3-benzoxazol-3(2 H)- yl)propyl](methyl)amino]cyclohexyl 9-methyl-9H-xanthenecarboxylate Obtained as a solid (298 mg, 54% yield) from 3-(6-formyloxo-1,3-benzoxazol-3(2 H)- yl)propyl methanesulfonate (Intermediate 91, 297 mg, 0.99 mmol), trans (methylamino)cyclohexyl 9-methyl-9H-xanthenecarboxylate (prepared according to preparation of Intermediate 162 from WO2011141180, 349 mg, 0.99 mmol), sodium iodide (372 mg, 2.48 mmol) and DIEA (260 µL, 1.49 mmol) following the experimental procedure described for the synthesis of Intermediate 73. The crude was purified by column chromatography over silica gel eluting with CH2Cl 2:EtOH (from 0 to 100% of EtOH).
LRMS (m/z): 555 (M+1)+.
Intermediate 93. trans -[6-({[(2 R){[ tert -butyl(dimethyl)silyl]oxy}(8-hydroxyoxo-1,2- dihydroquinolinyl)ethyl]amino}methyl)oxo-1,3-benzoxazol-3(2 H)- yl]propyl}(methyl)amino]cyclohexyl 9-methyl-9H-xanthenecarboxylate Obtained as a solid (110 mg, 44% yield) from trans [[3-(6-formyloxo-1,3- benzoxazol-3(2 H)-yl)propyl](methyl)amino]cyclohexyl 9-methyl-9H-xanthene carboxylate (Intermediate 92, 160 mg, 0.29 mmol), 5-((1R)amino{[ tert - butyl(dimethyl)-silyl]oxy}ethyl)hydroxyquinolin-2(1 H)-one acetate (prepared according to preparation 8 from US20060035931, 135 mg, 0.34 mmol) and sodium triacetoxyborohydride (200 mg, 0.94 mmol) ing the experimental procedure described for the synthesis of Intermediate 10. The crude obtained was purified by column chromatography over silica gel, eluting with a mixture of CHCl 3:CHCl 3/MeOH/NH 4OH (40/4/0.2) (from 0 to 100% of CHCl3/MeOH/NH 4OH (40/4/0.2)).
LRMS (m/z): 874 (M+1)+.
EXAMPLE 15. trans [{3-[6-({[(2 R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolin yl)ethyl]amino}methyl)oxo-1,3-benzoxazol-3(2 H)- yl]propyl}(methyl)amino]cyclohexyl yl-9H-xanthenecarboxylate dihydrofluoride ed as a pale yellow solid from trans [{3-[6-({[(2 R){[ tert -butyl(dimethyl)- silyl]oxy}(8-hydroxyoxo-1,2-dihydroquinolinyl)ethyl]amino}methyl)oxo-1,3- benzoxazol-3(2 H)-yl]propyl}(methyl)amino]cyclohexyl 9-methyl-9H-xanthene ylate (Intermediate 93, 110 mg, 0.13 mmol) and triethylamine trihydrofluoride (80 µL, 0.50 mmol) ing the experimental procedure bed for the synthesis of Example 1.
LRMS (m/z): 759 (M+1)+. 1H NMR (300 MHz, dmso) δ 8.13 (d, J = 9.9 Hz, 1H), 7.40 – 7.23 (m, 4H), 7.20 (s, 1H), 7.13 (bs, 4H), 7.1-7.02(m, 2H), 6.91 (d, J = 8.1 Hz, 2H), 6.47 (d, J = 9.9 Hz, 1H), .13 (bs, 1H), 4.55 (t, J = 10.8 Hz, 1H), 3.87 (s, 2H), 3.77 (t, J = 6.8 Hz, 2H), 2.72 (d, J = 5.8 Hz, 2H), 2.38 (dd, J = 20.3, 14.1 Hz, 2H), 2.27 (bs, 2H), 2.07 (s, 2H), 1.71 (d, J = 16.8 Hz, 4H), 1.55 (d, J = 10.9 Hz, 2H), 1.27 (dd, J = 29.5, 17.5 Hz, 2H), 1.03 (bs, 2H).
Intermediate 94. trans [{3-[6-[({(2 R){[ tert -butyl(dimethyl)silyl]oxy}[3-(formylamino) hydroxyphenyl]ethyl}amino)methyl]oxo-1,3-benzoxazol-3(2 H)- yl]propyl}(methyl)amino]cyclohexyl 9-methyl-9H-xanthenecarboxylate Obtained as a solid (87 mg, 42% yield) from trans [[3-(6-formyloxo-1,3- benzoxazol-3(2 H)-yl)propyl](methyl)amino]cyclohexyl 9-methyl-9H-xanthene carboxylate (Intermediate 92, 135 mg, 0.24 mmol), N-[5-[( R)amino(tert - butyldimethylsilyloxy)ethyl]hydroxyphenylformamide acetate (prepared according to the preparation of Example 3 from WO2007127297, 83 mg, 0.27 mmol) and sodium triacetoxyborohydride (360 mg, 1.70 mmol) following the experimental procedure described for the synthesis of Intermediate 10. The crude obtained was purified by column chromatography over silica gel, eluting with a mixture of CHCl 3:CHCl 3/MeOH/NH 4OH (40/4/0.2) (from 0 to 100% of CHCl3/MeOH/NH 4OH 0.2)).
LRMS (m/z): 850 (M+1)+.
EXAMPLE 16. trans [{3-[6-[({(2 R)[3-(formylamino)hydroxyphenyl] hydroxyethyl}amino)methyl]oxo-1,3-benzoxazol-3(2 H)- yl]propyl}(methyl)amino]cyclohexyl yl-9H-xanthenecarboxylate dihydrofluoride Obtained as a pale yellow solid from trans [{3-[6-[({(2 R){[ tert -butyl(dimethyl)- silyl]oxy}[3-(formylamino)hydroxyphenyl]ethyl}amino)methyl]oxo-1,3- benzoxazol-3(2 H)-yl]propyl}(methyl)amino]cyclohexyl 9-methyl-9H-xanthene carboxylate (Intermediate 94, 87 mg, 0.10 mmol) and triethylamine trihydrofluoride (66 µL, 0.41 mmol) following the experimental procedure bed for the synthesis of Example 1.
LRMS (m/z): 735 (M+1)+. 1H NMR (300 MHz, dmso) δ 9.56 (s, 1H), 8.25 (d, J = 1.9 Hz, 1H), 8.03 (d, J = 1.8 Hz, 1H), 7.38 – 7.22 (m, 2H), 7.19 (bs,3H), 7.16 – 7.07 (m, 4H), 6.86 (dd, J = 8.3, 1.8 Hz, 1H), 6.79 (d, J = 8.2 Hz, 1H), 4.56 (dd, J = 16.4, 8.6 Hz, 1H), 3.78 (dd, J = 16.7, 9.6 Hz, 2H), 2.61 (d, J = 6.0 Hz, 3H), 2.39 (t, J = 6.5 Hz, 2H), 2.25 (bs, 4H), 2.08 (bs, 2H), 1.76 (s, 3H), 1.55 (bs, 2H), 1.25 (bs, 4H), 1.12 – 0.95 (m, 4H).
Intermediate 95. 4-[(3-hydroxypropyl)amino]nitrobenzonitrile To a solution of 4-fluoronitrobenzonitrile (10 g, 0.06 mol) in THF (50 mL) was added in portions, via syringe, 3-aminopropanol (5 mL, 0.07 mol) and the mixture was stirred at room ature. After one hour of reaction the crude mixture was ated to dryness and AcOEt was added (300 mL). The organic layer was washed with aqueous sodium onate (250 mL of a 4% s solution) and the aqueous phase was further extracted with AcOEt (2 x 100 mL). The combined organic extracts were washed with brine, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to give the title compound as an orange solid (13.4 g, 99% yield) which was used in the next step without further purification.
LRMS (m/z): 222 (M+1)+.
Intermediate 96. 3-amino[(3-hydroxypropyl)amino]benzonitrile To a suspension of hydroxypropyl)amino]nitrobenzonitrile (Intermediate 95, 13.4 g, 0.06 mol) in EtOH (500 mL) was added, under argon atmosphere, palladium over carbon (350 mg, 3,3 mmol of a 10% Pd/C) and the mixture was degassed. Then, H2 was added up to an internal pressure of 20 psi, and the final suspension was stirred at room temperature for 2.5 hours. The crude was filtered through a Whatmann glass micro fibre filter and the solvent was removed under reduced pressure to afford the title compound as a brownish solid (11.5 g, 95% yield) which was used in the next step without further purification.
LRMS (m/z): 192 (M+1)+.
Intermediate 97. 1-(3-hydroxypropyl)-1H-1,2,3-benzotriazolecarbonitrile To a vigorously stirred solution of o[(3-hydroxypropyl)amino]benzonitrile (Intermediate 96, 11.5g, 0.06 mol) in aqueous HCl (105 mL of a 5N HCl solution) was added, dropwise an 0 ºC, a solution of sodium nitrite (6.2 g, 0.09 mol) in water (47 mL).
After 3.5 hours of vigorously stirring at 0 ºC, water was added (200 mL) and the reaction mixture extracted with AcOEt (3 x 150 mL). The ed organic extracts were washed with water (3 x 100 mL) and brine, and the resulting organic phase was evaporated to dryness to deliver the title compound as a brownish solid (10.8 g, 86%) which was used without further purification.
LRMS (m/z): 203 (M+1)+.
Intermediate 98. ydroxypropyl)-1H-1,2,3-benzotriazolecarbaldehyde To a solution of 1-(3-hydroxypropyl)-1H-1,2,3-benzotriazolecarbonitrile (Intermediate 97, 9.6 g, 47.5 mmol) in aqueous Formic Acid (106mL of a 75% solution in water) was added Niquel-Aluminium alloy (10.6 g, 0.12 mol). The mixture was stirred overnight at 75ºC. The solids were removed by filtration through Celite® and the solvent was removed under d pressure. The crude obtained was treated with MeOH (415 mL) and ium carbonate was added (49 g, 0.35 mol). After 1h the solution was acidified with 2N HCl until neutral pH and MeOH evaporated under reduced pressure.
The aqueous phase was extracted with CH2Cl 2 (3 x 200 mL) and the ing organic layer washed with water (2 x 50 mL), dried and evaporated under reduced pressure to afford the title compound as a solid (6.05 g, 60% , which was used in the next step without further purification.
LRMS (m/z): 206 (M+1)+.
Intermediate 99. ormyl-1H-1,2,3-benzotriazolyl)propyl methanesulfonate Obtained as a colourless oil (701 mg, 99% yield) from of 1-(3-hydroxypropyl)-1H-1,2,3- benzotriazolecarbaldehyde mediate 98, 500 mg, 2.44 mmol), Et3N (0.41 mL, 2.96 mmol) and methanesulfonyl chloride (0.19 mL, 2.45 mmol) following the experimental procedure described for the synthesis of Intermediate 72. The crude obtained was used without r purification.
LRMS (m/z): 284 (M+1)+.
Intermediate 100. trans -(5-formyl-1H-1,2,3-benzotriazolyl)propyl](methyl)amino]cyclohexyl (2 lopentyl(hydroxy)2-thienylacetate To a solution of trans (methylamino)cyclohexyl (2S)-cyclopentyl(hydroxy)2- thienylacetate (Intermediate 172 from WO2011/141180A1, 318 mg, 0.93 mmol) in DMF (3 mL) was added sodium iodide (355 mg, 2.37 mmol) and DIEA (0.25 mL, 1.44 mmol).
To this suspension a solution of 3-(5-formyl-1H-1,2,3-benzotriazolyl)propyl methanesulfonate (Intermediate 99, 380 mg, 1.17 mmol) in DMF (2 mL) was added and the mixture was stirred at 75 ºC for 7 hours. The reaction mixture was evaporated to s, the solid residue was re-suspended in CHCl3 (30 mL) and the suspension was filtered through Celite®. The solvent was removed under reduced pressure and the resulting yellow solid was purified by column chromatography over silica gel eluting with a mixture of CH2Cl 2/EtOH (gradient from 0 to 100% of EtOH) to provide the title compound as a yellow solid (473 mg (70% purity by HPLC), 68% yield).
LRMS (m/z): 525 (M+1)+.
Intermediate 101. trans [{3-[5-({[(2 [tert-butyl(dimethyl)silyl]oxy}(8-hydroxyoxo-1,2- dihydroquinolinyl)ethyl]amino}methyl)-1H-1,2,3-benzotriazol yl]propyl}(methyl)amino]cyclohexyl yclopentyl(hydroxy)2-thienylacetate Obtained as a solid (144 mg, 35% yield (60% purity by HPLC) from trans [[3-(5- formyl-1H-1,2,3-benzotriazolyl)propyl](methyl)amino]cyclohexyl (2S)- cyclopentyl(hydroxy)2-thienylacetate (Intermediate 100, 221 mg, 0.29 mmol), 5-((1 R)- 2-amino{[tert-butyl(dimethyl)-silyl]oxy}ethyl)hydroxyquinolin-2(1 H)-one acetate (prepared according to preparation 8 from 0035931, 120 mg, 0.30 mmol) and sodium triacetoxyborohydride (560 mg, 2.64 mmol) following the experimental procedure described for the synthesis of Intermediate 10. The crude obtained was purified by column chromatography over silica gel, eluting with a e of hexane:Et 2O:EtOH (from 0 to 100% of Et2O and then from 0 to 100% of EtOH).
LRMS (m/z): 843 (M+1)+.
EXAMPLE 17. trans [{3-[5-({[(2 R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolin yl)ethyl]amino}methyl)-1H-1,2,3-benzotriazol yl]propyl}(methyl)amino]cyclohexyl (2S)-cyclopentyl(hydroxy)2-thienylacetate dihydrofluoride Obtained as a pale yellow solid (80 mg, 92% yield) from trans [{3-[5-({[(2 R){[tertbutyl (dimethyl)silyl]oxy}(8-hydroxyoxo-1,2-dihydroquinolinyl)ethyl]amino}- methyl)-1H-1,2,3-benzotriazolyl]propyl}(methyl)amino]cyclohexyl (2S)- cyclopentyl(hydroxy)2-thienylacetate (Intermediate 101, 144 mg of a 60% purity, 0.1 mmol) and triethylamine trihydrofluoride (65 µL, 0.41 mmol) following the experimental procedure described for the synthesis of e 1.
LRMS (m/z): 729 (M+1)+. 1H NMR (300 MHz, dmso) δ 8.09 (d, J = 10.0 Hz, 1H), 8.03 (s, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.38 (dd, J = 5.1, 1.2 Hz, 1H), 7.07 (bs, 2H), 7.00 – 6.85 (m, 2H), 6.44 (d, J = 10.0 Hz, 1H), 5.95 (bs, 1H), 5.17 (bs, 1H), 4.71 (bs, 2H), 4.56 (bs, 2H), 4.06 (bs, 2H), 2.88 – 2.60 (m, 3H), 2.47 – 2.28 (m, 2H), 2.16 (bs, 2H), 2.06 (bs, 2H), 1.91 (bs, 2H), 1.86 – 1.73 (m, 2H), 1.67 (bs, 4H), 39 (m, 8H).
Intermediate 102. trans [{3-[5-({[(2 R){[tert-butyl(dimethyl)silyl]oxy}(5-hydroxyoxo-3,4- o-2H-1,4-benzoxazinyl)ethyl]amino}methyl)-1H-1,2,3-benzotriazol pyl}(methyl)amino]cyclohexyl yclopentyl(hydroxy)2-thienylacetate Obtained as a solid (97 mg, 47% yield (66% purity by HPLC)) from trans [[3-(5- formyl-1H-1,2,3-benzotriazolyl)propyl](methyl)amino]cyclohexyl yclopentyl- (hydroxy)2-thienylacetate (Intermediate 100, 100 mg, 0.19 mmol), 8-[(R)amino (tert-butyl-dimethyl-silanoxy)-ethylhydroxy-4H-benzo[1,4]oxazinone (prepared according to intermediate 65 from WO2008149110, 60 mg, 0.16 mmol) and sodium triacetoxyborohydride (209 mg, 0.99 mmol) following the experimental procedure described for the synthesis of Intermediate 10. The crude obtained was purified by column chromatography over silica gel, eluting with a mixture of CH2Cl 2:EtOH (from 0 to 50% of EtOH).
LRMS (m/z): 848 (M+1)+.
EXAMPLE 18. trans [{3-[5-({[(2R)hydroxy(5-hydroxyoxo-3,4-dihydro-2H-1,4- benzoxazinyl)ethyl]amino}methyl)-1H-1,2,3-benzotriazol yl]propyl}(methyl)amino]cyclohexyl (2S)-cyclopentyl(hydroxy)2-thienylacetate dihydrofluoride Obtained as a pale yellow solid (47 mg, 81% yield) from trans[{3-[5-({[(2 R){[tertbutyl (dimethyl)silyl]oxy}(5-hydroxyoxo-3,4-dihydro-2H-1,4-benzoxazin yl)ethyl]amino}methyl)-1H-1,2,3-benzotriazolyl]propyl}(methyl)amino]cyclohexyl (2 S)-cyclopentyl(hydroxy)2-thienylacetate (Intermediate 102, 97 mg of a 66% , 0.08 mmol), and triethylamine rofluoride (50 µL, 0.31 mmol) following the experimental procedure described for the synthesis of Example 1.
LRMS (m/z): 729 (M+1)+. 1H NMR (300 MHz, dmso) δ 9.99 (bs, 1H), 7.98 (s, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.55 (s, 1H), 7.38 (d, J = 4.9 Hz, 1H), 7.05 (s, 1H), 6.96 (s, 1H), 6.85 (d, J = 8.5 Hz, 1H), 6.48 (d, J = 8.3 Hz, 1H), 5.96 (s, 1H), 4.93 (bs, 1H), 4.71 (bs 2H), 4.57 (bs, 2H), 4.43 (t, J = 9.0 Hz, 2H), 3.98 (bs, 2H), 2.77 – 2.53 (m, 2H), 2.39 (s, 3H), 2.10 (bs, 2H), 2.02 (bs, 4H), 1.97 – 1.60 (m, 4H), 1.60 – 1.15 (m, 8H), 1.10 (d, J = 6.9 Hz, 2H).
Intermediate 103. 3-(3-{[ tert -butyl(dimethyl)silyl]oxy}propyl)oxo-2,3-dihydro-1,3-benzoxazole dehyde To a solution of 2-oxo-2,3-dihydro-1,3-benzoxazolecarbaldehyde (Intermediate 7, 300 mg, 1.84 mmol) in DMF (10 mL) were added potassium carbonate (633 mg, 4.58 mmol) and (3-bromopropoxy)(tert -butyl)dimethylsilane (0.47 mL, 2.03 mmol), and the resulting e was heated to 75ºC. Upon complete disappearance of starting material (ca 16 hours), the solvent was removed under reduced pressure and the solid residue was treated with CH2Cl 2 and stirred for 5 min. The suspension was ed through Celite® and the solid residue washed with additional CH2Cl 2. The filtrate was concentrated to dryness and the crude was purified by column chromatography over silica gel, eluting with Hexane:Et2O (from 0 to 32% of Et2O) to give the title compound as a white solid (550 mg, 89% .
LRMS (m/z): 336 (M+1)+.
Intermediate 104. 3-(3-{[ tert -butyl(dimethyl)silyl]oxy}propyl)[( E/Z )methoxyvinyl]-1,3- benzoxazol-2(3 H)-one A solution of methoxymethyltriphenylphosphonium chloride (1,2 g, 3.5 mmol) in THF (7 mL) was treated, under argon atmosphere and at 0 ºC, with m hexamethyldisilazide (3.5 mL of a 1M solution in toluene, 3.5 mmol) and the mixture was stirred at this temperature for 30 min. Then, a solution of 3-(3-{[tert - butyl(dimethyl)silyl]oxy}propyl)oxo-2,3-dihydro-1,3-benzoxazolecarbaldehyde (Intermediate 103, 468 mg, 1.4 mmol) in THF (4 mL) was added and stirring was maintained at room temperature for 14 hours. Saturated aqueous ammonium chloride solution and AcOEt were added (30 mL each) and stirring was maintained for 5 min.
Water was added (10 mL), the layers were separated and the aqueous phase was extracted with AcOEt (3 x 40 mL). The resulting organic phase was washed with water and brine (60 mL each), dried over anhydrous sodium sulphate, filtered and evaporated to dryness. The resulting oil was ed by column chromatography over silica gel g with Hexane:Et2O (from 0 to 100% of Et2O) to afford the title compound as a colourless oil (432 mg of a 1:1 E:Z mixture, 85% yield).
LRMS (m/z): 364 (M+1)+.
Intermediate 105. 3-(3-hydroxypropyl)[( E/Z thoxyvinyl]-1,3-benzoxazol-2(3 H)-one To a solution of TBAF (1.15 mL of a 1M solution in THF, 1.15 mmol) glacial AcOH was added se (0.2 mL) and the final mixture was added to a solution of 3-(3-{[ tert - butyl(dimethyl)silyl]oxy}propyl)[( E/Z )methoxyvinyl]-1,3-benzoxazol-2(3 H)-one (Intermediate 104, 378 mg, 1.04 mmol) in THF (1 mL). The on mixture was stirred at room temperature fro 14 hours. ted aqueous ammonium chloride solution (10 mL), water (10 mL) and Et2O (20 mL) were added. The aqueous phase was separated and further extracted with Et2O (4 x 30 mL) and the organic phase was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluting with Hexane:Et 2O (from 0 to 100% of Et2O) to provide the title compound as a colourless oil (228 mg of a 1:1 E/Z mixture, 88% yield) LRMS (m/z): 250 (M+1)+.
Intermediate 106. 3-[6-[( E/Z )methoxyvinyl]oxo-1,3-benzoxazol-3(2 H)-yl]propyl methanesulfonate Obtained as a colourless oil (356 mg of a 1:1 E/Z mixture (92% purity by HPLC), 98% yield) from 3-(3-hydroxypropyl)[(E/Z )methoxyvinyl]-1,3-benzoxazol-2(3 H)-one (Intermediate 105, 254 mg, 1.02 mmol), methanesulfonyl chloride (80 µL, 1.03 mmol) and Et3N (160 µL, 1.15 mmol) following the experimental procedure bed for the synthesis of Intermediate 100.
LRMS (m/z): 328 .
Intermediate 107. trans [{3-[6-[( E/Z )methoxyvinyl]oxo-1,3-benzoxazol-3(2 H)- yl]propyl}(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate Obtained as a brownish oil (500 mg of a 1:1 E/Z mixture (90% purity by HPLC), 86% yield) from trans (methylamino)cyclohexyl hydroxy(dithienyl)acetate (Intermediate , 315 mg, 0.9 mmol), (E/Z )methoxyvinyl]oxo-1,3-benzoxazol-3(2 H)- yl]propyl methanesulfonate (Intermediate 106, 356 mg, 1.0 mmol), sodium iodide (290 mg, 1.93 mmol) and DIEA (0.24 mL, 1.38 mmol). following the experimental ure described for the synthesis of Intermediate 101. The crude was purified by column chromatography over silica gel eluting with a mixture of CH2Cl 2/EtOH ent from 0 to 100% of EtOH).
LRMS (m/z): 583 (M+1)+.
Intermediate 108. trans (methyl{3-[2-oxo(2-oxoethyl)-1,3-benzoxazol-3(2 H)- yl]propyl}amino)cyclohexyl hydroxy(dithienyl)acetate To a solution of trans [{3-[6-[( E/Z )methoxyvinyl]oxo-1,3-benzoxazol-3(2 H)- yl]propyl}(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate (Intermediate 107, 500 mg, 0.86 mmol) in THF (5 mL) was added dropwise a solution of HCl (0.45 mL of a 4M solution in dioxane, 1.8 mmol) and the mixture was stirred for 1hour. Aqueous sodium bicarbonate was added and the aqueous layer was extracted with CH2Cl 2 (3 x 30 mL).
The resulting organic phase was washed with water and brine (30 mL each), dried over ous sodium sulphate, filtered and concentrated under reduced pressure to afford the title compound as a brownish oil (545 mg (90% purity by HPLC, 100% yield). The crude was immediately used without r purification.
LRMS (m/z): 542 (M+18)+, 556 (M+32)+.
Intermediate 109. trans -[6-(2-{[(2 R){[tert-butyl(dimethyl)silyl]oxy}(8-hydroxyoxo-1,2- dihydroquinolinyl)ethyl]amino}ethyl)oxo-1,3-benzoxazol-3(2 H)- yl]propyl}(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate To a solution of trans (methyl{3-[2-oxo(2-oxoethyl)-1,3-benzoxazol-3(2 H)- yl]propyl}amino)cyclohexyl hydroxy(dithienyl)acetate (Intermediate 108, 487 mg, 0.86 mmol) in dichloroethane (8 mL) was added )amino{[tertbutyl (dimethyl)-silyl]oxy}ethyl)hydroxyquinolin-2(1 H)-one acetate (prepared according to preparation 8 from US20060035931, 347 mg, 0.88 mmol). The suspension was d for 10 min and sodium cianoborohydride was added (145 mg, 2.31 mmol). A few drops of MeOH were also added to the reaction mixture and stirring was maintained for 18 hours. Chloroform and ted s sodium bicarbonate solution were added and the phases separated and ing insoluble solid was kept in the flask. The aqueous phase was extracted with chloroform (3 x 50 mL) and the organic layer was dried over ous sodium sulphate, filtered and trated under reduced pressure obtaining a brown solid residue. The insoluble solid was dissolved in MeOH and joined to the solid residue and the mixture was purified initially by column chromatography over silica gel eluting with chloroform:EtOH (from 0 to 100% EtOH) followed by reverse phase column chromatography over C18 modified silica gel eluting with water:MeOH (from 0 to 100% MeOH) to give the title compound as a yellowish solid (170 mg, 22% yield).
LRMS (m/z): 888 (M+1)+.
EXAMPLE 19. trans [{3-[6-(2-{[(2 R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolin yl)ethyl]amino}ethyl)oxo-1,3-benzoxazol-3(2 H)- yl]propyl}(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate dihydrofluoride Obtained as a pale yellow solid (67 mg, 85% yield) from trans [{3-[6-(2-{[(2 R){[tertbutyl (dimethyl)silyl]oxy}(8-hydroxyoxo-1,2-dihydroquinolinyl)ethyl]amino}ethyl)- 2-oxo-1,3-benzoxazol-3(2 H)-yl]propyl}(methyl)amino]cyclohexyl hydroxy(di thienyl)acetate (Intermediate 109, 100 mg of a 70% purity, 0.08 mmol), and triethylamine rofluoride (55 µL, 0.34 mmol) following the experimental procedure described for the synthesis of Example 1.
LRMS (m/z): 812 (M+1)+. 1H NMR (300 MHz, dmso) δ 8.16 (d, J = 10.0 Hz, 1H), 7.45 (dd, J = 5.0, 1.2 Hz, 2H), 7.26 – 7.12 (m, 3H), 7.10 – 7.02 (m, 3H), 7.00 – 6.82 (m, 3H), 6.50 (d, J = 9.9 Hz, 1H), .10 (s, 1H), 4.66 (bs, 2H), 3.81 (bs, 2H), 2.9-2.5 (m, 2H), 2.43 (bs, 2H), 2.11 (s, 3H), 1.90 (bs, 2H), 1.79 (bs, 4H), 1.65 (bs, 4H), 1.35 (bs, 4H).
Intermediate 110. ethyl [4-(2-oxopropyl)phenoxy]acetate 1-(4-hydroxyphenyl)propanone (500 mg, 3.33 mmol), ethyl 2-bromoacetate (0.37 mL, 3.34 mmol) and potassium carbonate (575 mg, 4.16 mmol) were dissolved in itrile (7 mL) in a sealed tube under argon atmosphere. The reaction mixture was heated to 90 ºC for 3.5 hours. The solids were filtered and washed with additional acetonitrile and the filtrate was concentrated under reduced pressure to give the title compound (790 mg, 100% .
LRMS (m/z): 237 (M+1)+. ediate 111. [4-(2-oxopropyl)phenoxy]acetic acid To a solution of ethyl [4-(2-oxopropyl)phenoxy]acetate (Intermediate 110, 786 mg, 3.33 mmol) in THF (24 mL) water was added (12 mL) and the mixture was stirred for 10 min.
Then, lithium hydroxide monohydrate (420 mg, 10.01 mmol) was added and stirring was continued for 3.5 hours at room temperature. THF was evaporated from the reaction mixture and water was added (25 mL). The solution was acidified with 5N HCl until pH 2 was reached and the aqueous phase was extracted with CH2Cl 2 (3 x 30 mL).
The ing organic extract was washed with water and brine, dried over anhydrous sodium te, ed and trated under reduced pressure to give the title compound (392 mg, 57% yield).
LRMS (m/z): 209 .
Intermediate 112. trans {methyl[2-({[4-(2- oxopropyl)phenoxy]acetyl}amino)ethyl]amino}cyclohexyl hydroxy(di thienyl)acetate To a solution of trans [(2-aminoethyl)(methyl)amino]cyclohexyl hydroxy(di l)acetate (Intermediate 49, 266 mg, 0.57 mmol) in DMF (9 mL) were added [4-(2- pyl)phenoxy]acetic acid (Intermediate 111, 131 mg, 0.63 mmol), DIEA (0.4 mL, 2.3 mmol) and HATU (430 mg, 1,13 mmol), and the reaction mixture was stirred at room temperature, under argon atmosphere, for 18 hours. The solvent is removed under reduced pressure and water was added to the solid residue. The aqueous phase was extracted with AcOEt (2x 50 mL) and the combined organic extracts were washed with brine, dried over anhydrous sodium sulphate, filtered and concentrated to dryness.
The residue obtained was purified by column chromatography over silica gel eluting with a mixture of CH2Cl 2:EtOH (from 0 to 10% of EtOH) to provide the title compound (281 mg, 85% yield).
LRMS (m/z): 585 (M+1)+.
Intermediate 113. trans [[2-({[4-(2-{[(2 R){[tert-butyl(dimethyl)silyl]oxy}(8-hydroxyoxo-1,2- dihydroquinolinyl)ethyl]amino}propyl)phenoxy]acetyl}amino)ethyl](methyl)- amino]cyclohexyl hydroxy(dithienyl)acetate Obtained as a solid (137 mg, 32% yield) from trans {methyl[2-({[4-(2- oxopropyl)phenoxy]acetyl}amino)ethyl]amino}cyclohexyl hydroxy(dithienyl)acetate (Intermediate 112, 280 mg, 0.48 mmol), 5-((1R)amino{[tert-butyl(dimethyl)- silyl]oxy}ethyl)hydroxyquinolin-2(1 H)-one acetate (prepared according to preparation 8 from 0035931, 205 mg, 0.52 mmol) and sodium triacetoxyborohydride (325 mg, 1.53 mmol) following the experimental procedure bed for the synthesis of Intermediate 10 using only MeOH as solvent (4 mL). The crude obtained was purified by column chromatography over silica gel, eluting with a mixture of CH2Cl 2:EtOH (from 0 to 90% of EtOH).
LRMS (m/z): 843 (M+1)+.
EXAMPLE 20. trans -({2-[4-(2-{[(2 R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolin yl)ethyl]amino}propyl)phenoxy]acetyl}amino)ethyl]amino}cyclohexyl hydroxy(di- 2-thienyl)acetate dihydrofluoride Obtained as a pale yellow solid (967 mg, 78% yield) from trans [[2-({[4-(2-{[(2 R) {[tert-butyl(dimethyl)silyl]oxy}(8-hydroxyoxo-1,2-dihydroquinolinyl)ethyl]- amino}propyl)phenoxy]acetyl}amino)ethyl](methyl)amino]cyclohexyl hydroxy(di thienyl)acetate (Intermediate 113, 135 mg, 0.15 mmol), and triethylamine trihydrofluoride (60 µL, 0.38 mmol) following the mental procedure described for the synthesis of Example 1.
LRMS (m/z): 812 (M+1)+. 1H NMR (300 MHz, cd3od) δ 8.33 (t, J = 9.9 Hz, 1H), 7.35 (bs, 2H), 7.32 – 7.15 (m, 2H), 7.10 (bs, 3H), 6.99 (d, J = 23.2 Hz, 4H), 6.67 (d, J = 9.9 Hz, 1H), 5.37 (bs, 1H), 4.83 (bs, 2H), 4.52 (bs, 2H), 3.59 (bs, 2H), 3.48 (bs, 2H), 3.27 – 2.99 (m, 5H), 2.80 – 2.59 (m, 3H), 2.06 (bs, 4H), 1.69 – 1.39 (m, 4H), 1.33 – 1.14 (m, 2H).
E 21. trans [{3-[5-({[(2 R)hydroxy(4-hydroxyoxo-2,3-dihydro-1,3-benzothiazol- 7-yl)ethyl]amino}methyl)-1H-1,2,3-benzotriazolyl]propyl}(methyl)amino]- cyclohexyl (2S)-cyclopentyl(hydroxy)2-thienylacetate Obtained as a colourless foam (8 mg, 6% yield) from trans [{3-[5-({[(2 R){[tertbutyl (dimethyl)silyl]oxy}(8-hydroxyoxo-1,2-dihydroquinolin yl)ethyl]amino}methyl)-1H-1,2,3-benzotriazolyl]propyl}(methyl)amino]cyclohexyl (2 S)-cyclopentyl(hydroxy)2-thienylacetate (Intermediate 101, 151 mg of a 70% purity, 0.2 mmol), 7-[(1R)aminohydroxyethyl]hydroxy-3H-benzothiazolone, acetate salt (prepared ing to step d of Example 1 from patent WO2009/098448, 49 mg, 0.17 mmol) and sodium triacetoxyborohydride (68 mg, 0.32 mmol) following the experimental procedure bed for the synthesis of Intermediate 113. The reaction mixture was purified by e phase column chromatography over C18 modified silica gel eluting with water:MeOH (from 0 to 100% MeOH) LRMS (m/z): 729 (M+1)+. 1H NMR (300 MHz, dmso) δ 7.90 (s, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.37 (s, 1H), 7.05 (s, 1H), 6.95 (d, J = 3.8 Hz, 1H), 6.86 (d, J = 8.2 Hz, 1H), 6.69 (d, J = 8.4 Hz, 1H), 5.91 (bs, 1H), 5.44 (bs, 2H), 4.62 (bs, 3H), 4.57 (bs, 2H), 3.87 (bs, 1H), 2.68 (bs, 2H), 2.37 (s, 3H), 2.12 (bs, 2H), 1.96 (bs, 3H), 1.78 (bs, 1H), 1.59 (bs, 2H), 1.31 (bs, 12H).
Biological tests Test 1: Human Adrenergic ß1 and ß2 Receptor Binding Assays The study of binding to human adrenergic beta1 and beta2 receptors was performed using commercial membranes prepared from Sf9 cells where they are overexpressed (Perkin Elmer). The membrane suspensions (16 µg/well for beta1 and 5µg/well for beta2) in assay buffer (75mM Tris/HCl with 12.5mM MgCl2 and 2mM EDTA pH=7.4) were incubated with 0.14 or 0.6 nM of 3H-CGP12177 ham) for beta 1 and beta 2 receptors respectively in a final volume of 250 µl, in GFC Multiscreen 96 well plates (Millipore) previously d with assay buffer containing 0.3 % PEI (Sigma). Non specific binding was measured in the presence of 1µM propanolol. Incubation was maintained for 60 minutes at room ature and with gentle g. The binding ons were terminated by filtration and washing with 2.5 volumes of Tris/HCl 50mM pH=7.4. The affinity of each test nd to the receptor was determined by using ten different concentrations ran in duplicate. IC50s were calculated using Activity Base software from IDBS and the four parameters-log equation.
Test 2: Human Muscarinic M1, M2, M3, M4 and M5 receptors binding assays The study of binding to human muscarinic M1, M2, M3, M4 and M5 receptors was performed using cial membranes (Perkin Elmer) prepared from CHO-K1 cells.
Radioligand binding experiments were conducted in 96 polypropylene well plates in a total volume of 200 µl. All reagents were dissolved in assay binding buffer (PBS with calcium and magnesium, , except compounds that were ved in DMSO 100%. Non-specific binding (NSB) was measured in the presence of 1 µM atropine. [3H]-NMS was used as the radioligand at a tration of 1 nM for M2, M3 and M5 and 0.3 nM for M1 and M4. [3H]-NMS and antagonists were incubated with membranes that express human muscarinic receptors M1, M2, M3, M4 and M5 at concentrations of 8.1, 10, 4.9, 4.5 and 4.9 µg/well, respectively.
After an incubation period of two hours with gentle shaking, 150 µl of the reaction mix were transferred to 96 GF/C filter plates (Millipore), usly treated with wash buffer (Tris 50 mM ; NaCl 100 mM; pH:7.4), containing 0.05 % PEI (Sigma) during one hour.
Bound and free [3H]-NMS were separated by rapid vacuum filtration in a manifold from Millipore and washed four times with ice cold wash buffer. After drying 30 min, 30 µl of OPTIPHASE Supermix were added to each well and radioactivity quantified using a eta microplate scintillation counter.
The affinity of each test compound to the ors was determined by using ten different trations ran in duplicate. IC50s were calculated using Activity Base software from IDBS and the four parameters-log equation.
Binding IC50, nM Example β2 M3 1 140 0.3 2 120 0.4 4 220 0.6 2.7 0.4 6 34 1.4 8 18 2.2 9 2.2 0.2 5.7 0.4 11 4,2 0.5 1.5 1 16 12 5.9 17 13 0.6 18 1.4 0.4 19 62 0.8 3.1 3.6 PHARMACEUTICAL COMPOSITIONS Compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous ts, or mixtures thereof. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. ave or radio frequency drying may be used for this purpose.
Pharmaceutical compositions according to the present invention comprise the compounds of the invention in association with a pharmaceutically able t or carrier.
As used herein, the term pharmaceutical composition refers to a mixture of one or more of the compounds described herein, or physiologically/pharmaceutically acceptable salts, solvates, N-oxides, isomers, es, rphs or prodrugs thereof, with other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism.
As used herein, a logically/pharmaceutically acceptable diluent or carrier refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered nd.
A pharmaceutically acceptable excipient refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a compound.
The invention further provides ceutical compositions comprising the compounds of the invention in ation with a pharmaceutically acceptable t or carrier together with one or more other therapeutic agents such as the previously described for use in the treatment of a pathological condition or disease associated with both β2 adrenergic or agonist and muscarinic receptor antagonist activities.
The invention is also directed to ceutical compositions of the invention for use in the treatment of a pathological disease or disorder associated with both β2 adrenergic receptor agonist and muscarinic receptor antagonist activities, in particular wherein the pathological disease or disorder is selected from a pulmonary disease, such as asthma or c obstructive pulmonary disease, pre-term labor, glaucoma, a neurological disorder, a c disorder, inflammation, urological disorders such as urinary incontinence and gastrointestinal disorders such as ble bowel syndrome or spastic colitis.
Also described is a method of treatment of a pathological condition or disease associated with both β2 adrenergic receptor agonist and muscarinic receptor antagonist activities in particular wherein the ogical condition or disease is selected from a pulmonary disease, such as asthma or c obstructive pulmonary disease, rm labor, ma, a neurological disorder, a cardiac disorder, inflammation, urological disorders such as urinary incontinence and gastrointestinal disorders such as irritable bowel syndrome or spastic colitis, comprising administering a therapeutically effective amount of a pharmaceutical ition of the invention.
The present invention also provides pharmaceutical compositions which comprise, as an active ingredient, at least a compound of formula (I) or a pharmaceutically acceptable salt, solvate, N-oxide or deuterated derivative thereof in association with a pharmaceutically able ent such as a carrier or diluent. The active ingredient may comprise 0.001% to 99% by weight, preferably 0.01% to 90% by weight, of the composition depending upon the nature of the formulation and whether further dilution is to be made prior to application. Preferably the compositions are made up in a form suitable for oral, inhalation, topical, nasal, , percutaneous or injectable administration.
Pharmaceutical compositions le for the delivery of compounds of the invention and methods for their preparation will be readily apparent to those skilled in the art.
Such itions and methods for their preparation can be found, for example, in Remington: The Science and ce of Pharmacy, 21st Edition, Lippincott Williams & Wilkins, Philadelphia, Pa., 2001.
The pharmaceutically acceptable excipients which are d with the active compound or salts of such compound, to form the compositions of this invention are well-known per se and the actual excipients used depend inter alia on the intended method of administering the compositions. Examples, without limitation, of excipients include m carbonate, m phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
Additional le carriers for formulations of the compounds of the present invention can be found in Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins, Philadelphia, Pa., 2001; or in Handbook of Pharmaceutical Excipients, 6th ed., published by Pharmaceutical Press and American Pharmacists Association, 2009. i) Oral Administration The compounds of the invention may be administered orally (peroral administration; per os (latin)). Oral administration involve swallowing, so that the compound is absorbed from the gut and delivered to the liver via the portal circulation (hepatic first pass metabolism) and finally enters the gastrointestinal (GI) tract.
Compositions for oral stration may take the form of tablets, retard tablets, sublingual tablets, capsules, tion aerosols, inhalation solutions, dry powder tion, or liquid preparations, such as mixtures, solutions, elixirs, syrups or suspensions, all ning the compound of the invention; such preparations may be made by s well-known in the art. The active ient may also be presented as a bolus, electuary or paste.
Where the composition is in the form of a tablet, any pharmaceutical carrier routinely used for ing solid formulations may be used. Examples of such carriers include magnesium stearate, talc, gelatine, acacia, stearic acid, starch, lactose and sucrose.
A tablet may be made by compression or moulding, ally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent.
Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
For tablet dosage forms, ing on dose, the drug may make up from 1 wt% to 80 wt% of the dosage form, more typically from 5 wt% to 60 wt% of the dosage form. In addition to the drug, tablets generally n a disintegrant. Examples of egrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline ose, lower alkyl- substituted hydroxypropyl ose, starch, pregelatinized starch and sodium alginate. Generally, the disintegrant will comprise from 1 wt% to 25 wt%, preferably from 5 wt% to 20 wt% of the dosage form.
Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), ol, xylitol, dextrose, e, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate. Tablets may also optionally include surface active , such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When t, surface active agents are typically in amounts of from 0.2 wt% to 5 wt% of the tablet, and glidants typically from 0.2 wt% to 1 wt% of the tablet. s also generally n lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate. Lubricants generally are present in amounts from 0.25 wt% to 10 wt%, preferably from 0.5 wt% to 3 wt% of the tablet. Other conventional ingredients include anti-oxidants, colorants, flavoring agents, preservatives and tastemasking agents.
Exemplary tablets contain up to about 80 wt% drug, from about 10 wt% to about 90 wt% binder, from about 0 wt% to about 85 wt% diluent, from about 2 wt% to about 10 wt% disintegrant, and from about 0.25 wt% to about 10 wt% lubricant. Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt led, or extruded before tabletting. The final formulation may include one or more layers and may be coated or uncoated; or encapsulated.
The ation of tablets is sed in detail in "Pharmaceutical Dosage Forms: Tablets, Vol. 1 ", by H. Lieberman and L. n, Marcel Dekker, N.Y., 1980.
Where the composition is in the form of a capsule, any routine ulation is suitable, for example using the entioned rs in a hard gelatine capsule.
Where the composition is in the form of a soft gelatine capsule any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, tes or oils, and are incorporated in a soft gelatine capsule.
Solid formulations for oral administration may be formulated to be immediate and/or modified release. Modified release formulations e delayed-, sustained-, pulsed-, lled-, targeted and programmed release.
Liquid ations include suspensions, ons, syrups and elixirs. Such formulations may be used as fillers in soft or hard capsules and typically include a carrier, for example, water, ethanol, polyethylene glycol, ene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. The solutions may be aqueous solutions of a soluble salt or other derivative of the active compound in association with, for e, sucrose to form a syrup. The suspensions may comprise an insoluble active compound of the invention or a pharmaceutically acceptable salt thereof in association with water, together with a suspending agent or flavouring agent. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet. ii) Oral mucosal administration The compounds of the invention can also be stered via the oral mucosal. Within the oral mucosal cavity, delivery of drugs is classified into three categories: (a) sublingual delivery, which is systemic delivery of drugs through the l membranes lining the floor of the mouth, (b) buccal delivery, which is drug stration through the mucosal membranes lining the cheeks (buccal mucosa), and (c) local delivery, which is drug delivery into the oral cavity.
Pharmaceutical products to be administered via the oral mucosal can be designed using mucoadhesive, quick dissolve tablets and solid lozenge formulations, which are formulated with one or more mucoadhesive hesive) polymers (such as hydroxy propyl cellulose, polyvinyl pyrrolidone, sodium carboxymethyl cellulose, hydroxy propyl methyl cellulose, y ethyl cellulose, polyvinyl alcohol, polyisobutylene or polyisoprene); and oral mucosal permeation enhancers (such as butanol, butyric acid, propranolol, sodium lauryl sulphate and ) iii) Inhaled administration The compounds of the invention can also be administered by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder r or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a suitable propellant, such as 1 ,1 ,1 ,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3- heptafluoropropane. For intranasal use, the powder may include a bioadhesive agent, for example, chitosan or cyclodextrin.
Dry powder itions for topical delivery to the lung by inhalation may, for example, be presented in capsules and cartridges of for example gelatine or blisters of for example laminated aluminium foil, for use in an inhaler or insufflator. Formulations lly contain a powder mix for inhalation of the compound of the invention and a suitable powder base (carrier substance) such as lactose or . Use of lactose is preferred. Each capsule or cartridge may generally n between 0.0001-10 mg, more preferably 2 mg of active ingredient or the equivalent amount of a pharmaceutically acceptable salt thereof. Alternatively, the active ingredient (s) may be presented without excipients.
Packaging of the formulation may be le for unit dose or multi-dose delivery. In the case of multi- dose delivery, the formulation can be pre-metered or metered in use. Dry powder inhalers are thus classified into three groups: (a) single dose, (b) multiple unit dose and (c) multi dose devices.
For inhalers of the first type, single doses have been weighed by the manufacturer into small ners, which are mostly hard gelatine capsules. A capsule has to be taken from a separate box or container and inserted into a receptacle area of the inhaler.
Next, the capsule has to be opened or perforated with pins or cutting blades in order to allow part of the atory air stream to pass through the capsule for powder nment or to rge the powder from the capsule through these perforations by means of centrifugal force during tion. After inhalation, the emptied capsule has to be removed from the inhaler again. Mostly, disassembling of the r is necessary for inserting and removing the capsule, which is an operation that can be difficult and burdensome for some patients.
Other drawbacks related to the use of hard gelatine capsules for inhalation powders are (a) poor protection t moisture uptake from the ambient air, (b) problems with opening or perforation after the capsules have been exposed previously to extreme relative humidity, which causes fragmentation or indenture, and (c) possible inhalation of capsule fragments. Moreover, for a number of capsule inhalers, incomplete expulsion has been reported (e. g. Nielsen et al, 1997).
Some capsule inhalers have a magazine from which individual capsules can be transferred to a receiving r, in which perforation and emptying takes place, as described in WO 92/03175. Other capsule inhalers have revolving magazines with capsule chambers that can be brought in line with the air conduit for dose discharge (e. g. WO91/02558 and GB 2242134). They comprise the type of multiple unit dose inhalers er with blister rs, which have a limited number of unit doses in supply on a disk or on a strip.
Blister inhalers provide better moisture tion of the ment than capsule inhalers. Access to the powder is obtained by perforating the cover as well as the blister foil, or by peeling off the cover foil. When a blister strip is used instead of a disk, the number of doses can be increased, but it is inconvenient for the patient to replace an empty strip. ore, such devices are often disposable with the incorporated dose system, including the technique used to transport the strip and open the blister pockets.
Multi-dose rs do not contain pre-measured quantities of the powder formulation.
They consist of a relatively large ner and a dose measuring principle that has to be operated by the patient. The container bears multiple doses that are isolated individually from the bulk of powder by volumetric displacement. Various dose measuring principles exist, including rotatable membranes (Ex. EP0069715) or disks (Ex. GB 2041763; EP 0424790; DE 4239402 and EP 0674533), rotatable cylinders (Ex.
EP 0166294; GB 2165159 and WO 92/09322) and rotatable frustums (Ex. WO 92/00771), all having cavities which have to be filled with powder from the container.
Other multi dose devices have measuring slides (Ex. US 5201308 and WO 97/00703) or measuring plungers with a local or circumferential recess to displace a certain volume of powder from the container to a delivery chamber or an air conduit (Ex. EP 0505321, WO 92/04068 and WO 92/04928), or measuring slides such as the Genuair® (formerly known as Novolizer SD2FL), which is bed the following patent applications Nos: 00703, WO03/000325 and WO2006/008027.
Reproducible dose measuring is one of the major concerns for multi dose inhaler devices.
The powder formulation has to exhibit good and stable flow ties, e filling of the dose measuring cups or cavities is mostly under the influence of the force of gravity.
For reloaded single dose and multiple unit dose rs, the dose measuring accuracy and reproducibility can be guaranteed by the manufacturer. Multi dose inhalers on the other hand, can contain a much higher number of doses, whereas the number of handlings to prime a dose is generally lower.
Because the inspiratory air stream in dose devices is often straight across the dose measuring cavity, and because the massive and rigid dose measuring systems of multi dose inhalers can not be agitated by this inspiratory air stream, the powder mass is simply entrained from the cavity and little de-agglomeration is obtained during discharge.
Consequently, separate disintegration means are necessary. However in practice, they are not always part of the inhaler . Because of the high number of doses in multidose devices, powder adhesion onto the inner walls of the air conduits and the deagglomeration means must be minimized and/or regular cleaning of these parts must be possible, without affecting the residual doses in the device. Some multi dose inhalers have disposable drug containers that can be replaced after the ibed number of doses has been taken (Ex. WO 97/000703). For such semi-permanent multi dose inhalers with disposable drug containers, the ements to prevent drug accumulation are even more strict.
Apart from applications through dry powder inhalers the compositions of the invention can be administered in aerosols which operate via propellant gases or by means of ed atomisers, via which solutions of pharmacologically-active substances can be sprayed under high pressure so that a mist of inhalable les results. The age of these atomisers is that the use of lant gases can be completely dispensed with. Such atomiser is the at® which is described, for example, in PCT Patent Applications Nos. W0 91/14468 and WO 97/12687, reference here is being made to the contents thereof.
Spray compositions for topical delivery to the lung by inhalation may for example be formulated as aqueous solutions or suspensions or as aerosols red from pressurised packs, such as a metered dose inhaler, with the use of a suitable liquefied propellant. l compositions suitable for inhalation can be either a suspension or a solution and generally contain the active ingredient (s) and a suitable propellant such as a fluorocarbon or hydrogen-containing chlorofluorocarbon or mixtures thereof, particularly hydrofluoroalkanes, e. g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetra-fluoroethane, especially 1,1, 1, 2-tetrafluoroethane, 1,1, 1,2, 3,3, 3- heptafluoro-n-propane or a e thereof. Carbon dioxide or other suitable gas may also be used as propellant.
The aerosol composition may be excipient free or may optionally contain additional formulation excipients well known in the art such as surfactants (eg oleic acid or lecithin) and cosolvens (eg ethanol). rised formulations will lly be retained in a canister (eg an aluminium canister) closed with a valve (eg a metering valve) and fitted into an actuator provided with a mouthpiece.
Medicaments for administration by inhalation desirably have a controlled particle size.
The optimum particle size for inhalation into the bronchial system is usually 1-10 µm, preferably 2-5 µm. Particles having a size above 20 µm are generally too large when inhaled to reach the small airways. To achieve these particle sizes the particles of the active ingredient as produced may be size reduced by conventional means eg by micronisation. The desired fraction may be separated out by air classification or sieving. ably, the particles will be crystalline. ing high dose reproducibility with micronised s is difficult because of their poor flowability and extreme agglomeration tendency. To improve the efficiency of dry powder compositions, the particles should be large while in the inhaler, but small when discharged into the respiratory tract. Thus, an excipient such as lactose or e is generally employed. The le size of the excipient will usually be much r than the inhaled medicament within the present ion. When the excipient is lactose it will typically be present as milled lactose, preferably crystalline alpha lactose monohydrate.
Pressurized aerosol compositions will generally be filled into canisters fitted with a valve, especially a metering valve. Canisters may optionally be coated with a plastics material e. g. a fluorocarbon polymer as bed in WO96/32150. Canisters will be fitted into an actuator adapted for buccal delivery. iv) Nasal mucosal administration The compounds of the invention may also be administered via the nasal mucosal.
Typical itions for nasal mucosa administration are lly applied by a metering, atomizing spray pump and are in the form of a solution or suspension in an inert vehicle such as water optionally in combination with tional excipients such as buffers, anti-microbials, tonicity modifying agents and viscosity modifying agents. v) Parenteral Administration The compounds of the ion may also be administered directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, uscular and subcutaneous. Suitable devices for parenteral administration include needle (including eedle) ors, needle-free injectors and infusion techniques.
Parenteral formulations are lly aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile nonaqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
The ation of parenteral formulations under sterile conditions, for example, by lyophilization, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art. The lity of compounds of the ion used in the ation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.
Formulations for parenteral administration may be formulated to be immediate and/or modified release. ed release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Thus compounds of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug-coated stents and PGLA microspheres. vi) Topical Administration The compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, ons, creams, ointments, dusting powders, dressings, foams, films, skin s, , implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used. Typical carriers include l, water, mineral oil, liquid petrolatum, white petrolatum, in, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated; see, for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999). Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free injection.
Formulations for l administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. vii) Rectal/lntravaginal Administration Compounds of the ion may be stered rectally or vaginally, for example, in the form of a suppository, y, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as riate. Formulations for rectal/vaginal administration may be ated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, -, controlled-, targeted and programmed release. viii) Ocular Administration Compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronized suspension or solution in isotonic, pH- adjusted, sterile saline. Other formulations suitable for ocular and aural administration include ointments, biodegradable {e.g. absorbable gel sponges, collagen) and nonbiodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. A polymer such as crossed-linked polyacrylic acid, nylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl ose, or a heteropolysaccharide r, for example, gelan gum, may be orated together with a preservative, such as benzalkonium chloride. Such ations may also be delivered by horesis.
Formulations for ocular/aural administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted, or programmed release. ix) Other logies Compounds of the invention may be combined with soluble macromolecular es, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.
The amount of the active compound administered will be ent on the subject being treated, the severity of the disorder or ion, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. However, an effective dosage is lly in the range of 0.01-3000 µg, more preferably 0.5-1000 µg of active ingredient or the equivalent amount of a pharmaceutically acceptable salt thereof per day. Daily dosage may be administered in one or more treatments, ably from 1 to 4 treatments, per day.
The pharmaceutical formulations may conveniently be presented in unit dosage form and may be prepared by any of the s well known in the art of pharmacy.
Preferably the composition is in unit dosage form, for example a tablet, capsule or d aerosol dose, so that the patient may administer a single dose.
The active substance compositions ing to the ion are preferably stered in the form of compositions for inhalation delivered with the help of inhalers, especially dry powder inhalers; however, any other form of nasal, topical, parenteral or oral application is possible. Here, the application of inhaled compositions es one of the preferred application form, especially in the therapy of ctive lung diseases or for the treatment of asthma.
COMBINATIONS The compounds of the invention can also be used in combination with other drugs known to be effective in the treatment of the diseases or the disorders indicated above.
For example the compounds of the present invention can be combined with a corticosteroid and/or with a PDE4 inhibitor.
Accordingly, another embodiment of the invention is a combination product comprising (i) a compound of the invention as defined previously, and (ii) another compound, selected from a corticosteroid and a PDE4 inhibitor, for simultaneous, separate or sequential use in the treatment of the human or animal body.
A preferred embodiment of the invention is a combination product as defined before for the treatment or prevention of ogical conditions, es and disorders associated with both β2 adrenergic receptor agonist and muscarinic receptor antagonist activities in particular wherein the pathological condition or disease is ed from from a pulmonary disease, such as asthma or c obstructive pulmonary disease, pre-term labor, glaucoma, a neurological er, a cardiac disorder, inflammation, urological disorders such as urinary incontinence and gastrointestinal disorders such as irritable bowel syndrome or spastic colitis; as well as a method for treating a subject ted with a pathological condition or disease associated with both β2 adrenergic receptor agonist and muscarinic receptor antagonist ties, in particular wherein the pathological condition or disease is selected from a pulmonary disease, such as asthma or chronic obstructive pulmonary disease, pre-term labor, glaucoma, a neurological disorder, a cardiac disorder, inflammation, urological disorders such as urinary inence and gastrointestinal disorders such as irritable bowel syndrome or spastic colitis; preferably asthma and c obstructive pulmonary disease, which comprises administering to said subject an ive amount of a combination product as defined before.
As indicated above, the compounds or pharmaceutically acceptable salts, solvates, N- oxides, isomers, es, polymorphs or prodrugs thereof, according to the ion may also be used in combination with another therapeutically active agent, for example a corticosteroid and/or with a PDE4 inhibitor.
The amount of each active which is ed to achieve a therapeutic effect will, of course, vary with the particular active, the route of administration, the subject under ent, and the particular disease or disorder being treated.
The active ingredients may be administered from 1 to 6 times a day, sufficient to exhibit the desired activity. Preferably, the active ingredients are administered once or twice a day, most preferably once a day.
Examples of suitable corticosteroids and glucocorticoids that can be combined with the compounds of the invention are solone, methylprednisolone, dexamethasone, dexamethasone acetate, dexamethasone cipecilate, naflocort, deflazacort, halopredone acetate, budesonide, beclomethasone dipropionate, hydrocortisone, triamcinolone acetonide, fluocinolone acetonide, nonide, clocortolone pivalate, methylprednisolone aceponate, dexamethasone oate, ane, hydrocortisone aceponate, prednicarbate, alclometasone dipropionate, halometasone, methylprednisolone suleptanate, mometasone, mometasone furoate, rimexolone, prednisolone farnesylate, ciclesonide, butixocort propionate, RS-85095, CGP-13774, GW-250495, deltacortisone, NO-Prednisolone, NO-Budesonide, dnol dicloacetate, QAE-397, 7beta-OH-EPIA, RPR-106541, deprodone propionate, fluticasone, fluticasone propionate, fluticasone furoate, halobetasol propionate, ednol etabonate, betamethasone butyrate propionate, flunisolide, prednisone, thasone sodium phosphate, triamcinolone, betamethasone 17-valerate, thasone, betamethasone dipropionate, 21-Chloro-11beta-hydroxy-17alpha-[2- (methylsulfanyl)acetoxy]pregnene-3,20-dione, desisobutyrylciclesonide, hydrocortisone acetate, hydrocortisone sodium succinate, prednisolone sodium phosphate and hydrocortisone probutate, prednisolone sodium metasulfobenzoate and clobetasol propionate.
Examples of suitable PDE4 inhibitors that can be combined with the compounds of the present invention are benafentrine dimaleate, etazolate, denbufylline, rolipram, cipamfylline, zardaverine, arofylline, filaminast, tipelukast, tofimilast, piclamilast, tolafentrine, mesopram, drotaverine hydrochloride, lirimilast, roflumilast, last, oglemilast, apremilast, last, revamilast, ronomilast, (R)-(+)[2-(3- Cyclopentyloxymethoxyphenyl)phenylethyl]pyridine (CDP-840), N-(3,5-Dichloro- 4-pyridinyl)[1-(4-fluorobenzyl)hydroxy-1H-indolyl]oxoacetamide (GSK- 842470), 9-(2-Fluorobenzyl)-N6-methyl(trifluoromethyl)adenine (NCS-613), N-(3,5- Dichloropyridinyl)methoxyquinolinecarboxamide (D-4418), 3-[3- (Cyclopentyloxy)methoxybenzyl](ethylamino)isopropyl-3H-purine hydrochloride (V-11294A), 6-[3-(N,N-Dimethylcarbamoyl)phenylsulfonyl](3-methoxyphenylamino)- 8-methylquinolinecarboxamide hydrochloride (GSK-256066), 4-[6,7-Diethoxy-2,3- bis(hydroxymethyl)naphthalenyl](2-methoxyethyl)pyridin-2(1H)-one (T-440), (-)- trans[3'-[3-(N-Cyclopropylcarbamoyl)oxo-1,4-dihydro-1,8-naphthyridinyl] fluorobiphenylyl]cyclopropanecarboxylic acid, MK-0873, CDC-801, GSK-356278, TA-7906, CP-80633, 4, NIK-616, GPD-1116, D4396, UK-500001, BLX-914, 2- carbomethoxycyano(3-cyclopropylmethoxydifluroromethoxyphenyl) cyclohexan1-one, cis [4-cyano(3-cyclopropylmethoxydifluoromethoxyphenyl) cyclohexanol, 3-(Cyclopentyloxy)methoxyphenyl]-3(S)-(3-methylbenzyl) piperidinone 55903), 26 (Eur Respir J 2003, pl. 45): Abst 2557) and the compounds d in the PCT patent applications number WO 03/097613, , , , , and .
Particularly preferred combination products according to the invention comprise a compound of the present invention and a therapeutically effective amount of one or more additional therapeutic agents selected from the group consisting of mometasone furoate, ciclesonide, budesonide, asone propionate, fluticasone furoate, betamethasone valerate, clobetasol propionate, rolipram, roflumilast, last, cilomilast, arofylline, last and tetomilast.
Thus, in one aspect of the invention, the combination product comprises a nd of the present invention and a corticosteroid. Particularly preferred corticosteroids are those selected from the group consisting of mometasone furoate, ciclesonide, budesonide, fluticasone furoate, fluticasone propionate, betamethasone valerate and clobetasol propionate.
In a still other aspect of the ion, the combination product comprises a compound of the present invention and a PDE4 inhibitor. Particularly preferred PDE4 inhibitors are those selected from the group consisting of rolipram, roflumilast, oglemilast, cilomilast and the compounds claimed in the PCT patent applications number WO 03/097613, , , , , and WO 2010/069504. The combination product may r comprise a corticosteroid selected from the group ting of mometasone furoate, ciclesonide, budesonide, asone furoate and fluticasone nate.
The compounds of the t ion and the combinations of the invention may be used in the treatment of respiratory, skin and inflammatory diseases, wherein the use of a dual both β2 adrenergic or t and antimuscarinic receptor nist is expected to have a beneficial effect, for example a pulmonary disease, such as asthma or chronic obstructive pulmonary disease, pre-term labor, ma, a neurological disorder, a cardiac disorder, inflammation, urological disorders such as urinary incontinence and gastrointestinal disorders such as irritable bowel syndrome or spastic colitis; preferably asthma and chronic obstructive pulmonary disease.
The active compounds in the combination product may be administered together in the same pharmaceutical composition or in different compositions intended for separate, simultaneous, concomitant or sequential administration by the same or a different route.
It is contemplated that all active agents would be administered at the same time, or very close in time. Alternatively, one or two actives could be administered in the morning and the other (s) later in the day. Or in another scenario, one or two actives could be stered twice daily and the other (s) once daily, either at the same time as one of the twice-a-day dosing occurred, or separately. Preferably at least two, and more preferably all, of the actives would be administered er at the same time.
Preferably, at least two, and more preferably all actives would be administered as an admixture.
FORMULTION EXAMPLE Formulation Example 1 (Oral suspension) Ingredient Amount Active Compound 3 mg Citric acid 0,5 g Sodium chloride 2,0 g Methyl paraben 0,1 g Granulated sugar 25 g Sorbitol (70% solution) 11 g Veegum K 1,0 g Flavoring 0,02 g Dye 0,5 mg Distilled water q.s. to 100 mL ation Example 2 (Hard gelatine capsule for oral administration) Ingredient Amount Active Compound 1 mg Lactose 150 mg Magnesium stearate 3 mg Formulation Example 3 (Gelatin cartridge for inhalation) Ingredient Amount Active Compound (micronized) 0,2 mg Lactose 25 mg Formulation Example 4 (Formulation for inhalation with a DPI) Ingredient Amount Active Compound (micronized) 15 mg Lactose 3000 mg ation Example 5 lation for a MDI) Ingredient Amount Active Compound (micronized) 10 g 1,1,1,2,3,3,3-heptafluoro-n-propane q.s. to 200 ml

Claims (9)

Claims
1. A compound of formula (I), or pharmaceutically acceptable salts or N-oxides or solvates or deuterated derivatives thereof: A1 L1 N B G O A2 R3 wherein • R1 and R2 independently are selected from the group consisting of a hydrogen atom and a linear or ed C1-4 alkyl group, • R3 ents a group of formula: R5 R4 R4 ∗ i) ∗ or ii) Q wherein: o R4 represents a hydrogen atom, a hydroxy group, a ymethyl group or a linear or branched C1-4 alkyl group, o R5 represents a saturated or unsaturated C3-8 lkyl group, a C5-6 aryl group, a 5- to 6- membered heteroaryl group containing at least one heteroatom ed from N, S, and O; a (C1-4 alkyl)-(C5-6 aryl) group,a (C1-4 alkyl)-(C3-8 cycloalkyl) group or a (C1-4 alkyl)-(5- to 6- membered heteroaryl group containing at least one heteroatom selected from N, S, and O) group, which groups independently are optionally substituted with one or more substituents Ra, o R6 represents a C5-6 aryl group, a 5- to 6- membered heteroaryl group containing at least one heteroatom selected from N, S, and O, a saturated or unsaturated C3-8 cycloalkyl group, a C1-8 alkyl group, a C2-8 alkenyl group, a C2-8 alkynyl group, a (C1-4 alkyl)-(C5-6 aryl) group, a (C1-4 alkyl)-(C3-8 cycloalkyl) group or a (C1-4 alkyl)-(5- to 6- ed heteroaryl group containing at least one heteroatom ed from N, S, and O) group, which groups independently are optionally substituted with one or more substituents Rb, o Ra and Rb independently represent a halogen atom, a hydroxy group, a C1-4 alkyl group, a C1-4 alkoxy group, -SH, a C1-4 alkylthio group, a nitro group, a cyano group, -CO2R’, -NR’R’’, -C(O)NR’R’’, -N(R’’’)C(O)-R’, -N(R’’’)- C(O)NR’R’’, whererin R’, R’’ and R’’’ each ndently represents a hydrogen atom or a C1-4 alkyl group, or R’ and R’’ together with the nitrogen atom to which they are attached from a 3 to 6 membered heterocyclic ring. o Q represents a direct bond, –CH2-, -CH2-CH 2-, -O-, -O-CH2-, -S-, -S-CH2-, or –CH=CH-, o * represents the point of attachment of R3 to the remainder of the molecule of formula (I), • A1 and A2 ndently are selected from the group consisting of C1-10 alkylene group, C2-10 alkenylene group and C2-10 alkynylene group, wherein said groups are optionally substituted with one or more substituents selected from a n atom, a hydroxy group, a linear or branched C1-4 alkyl group, a linear or branched C1-4 alkoxy group, a C5-6 aryl group and a C3-7 cycloalkyl group, • L1 is selected from a direct bond, -O-, -NRc-, -S-, -S(O)-, -SO2-, O)-, - (CO)NR c-, –NRc(CO)(CH –O(CH2)q(CO)NR c-, 2)qO-, –NRc(CH 2)qO-, – O(CH c-, d-, 2)qNR –NRc(CO)NR -C(O)-, -C(O)O-, -OC(O)-, -S(O)2NR c-, -NR cS(O) cS(O) d-, –C(O)NRcS(O) cC(O)-, n Rc 2-, -NR 2NR 2- and –S(O)2NR and Rd are independently selected form a hydrogen atom and a linear or branched C1-4 alkyl group and q has a value of 0, 1 or 2, • G is selected from the group ting of a C3-10 mono- or bicyclic cycloalkyl group, a C5-C14 mono- or ic aryl group, a 3- to 14-membered saturated or unsaturated mono- or ic heterocyclyl group having one or more heteroatoms selected from N, S and O, a 5- to 14-membered mono- or bicyclic heteroaryl group having one or more heteroatoms selected from N, S and O and a ic ring system consisting of two monocyclic ring systems which are linked between each other by a nt bond wherein said monocyclic ring systems are independently selected from a C3-8 cycloalkyl group, a C5-C6 aryl group, a 3 to 8-membered saturated or unsaturated heterocyclyl group having one or more heteroatoms selected from N, S and O and a 5- to 6-membered heteroaryl group having one or more heteroatoms selected from N, S and O, wherein the cyclic groups ndently are optionally substituted with one or more substituents selected from a halogen atom, a C1-4 alkyl group, a C1-4 alkoxy group, a carboxy, group, a cyano group, a nitro group, a hydroxy group, an oxo group, a trifluoromethyl group and a trifluoromethoxy group, • B is a moiety having a beta2-adrenergic binding activity, and represents a group of formula (IB): Ar ∗ Formula (IB) wherein: o R7 is selected from the group consisting of a hydrogen atom, a linear or branched C1-4 alkyl group and a linear or branched C1-4 alkoxy group,Ar is selected from the group consisting of a C3-10 saturated or unsaturated, mono- or bicyclic cycloalkyl group, a C5-C14 mono- or bicyclic aryl group, a 3- to 14-membered saturated or unsaturated mono- or bicyclic heterocyclyl group having one or more heteroatoms selected from N, S and O, a 5- to 14-membered mono- or bicyclic heteroaryl group having one or more heteroatoms selected from N, S and O and wherein the cyclic groups independently are ally substituted with one or more substituents selected from a n atom, a cyano group, a nitro group, a oxo group, a y group, a C1-4 alkyl group, a C1-4 alkoxy group, - CF3, –OCF3, -NReRf, -(CH2)p-OH, -NRe(CO)Rf, -NRe-SO2-Rg, -SO2NReRf, Rh, and –NRe(CH2)(0-2)-Ri, wherein p has a value of 0, 1 or 2 and wherein: o Re and Rf ndently represent a hydrogen atom or a linear or branched C1-4 alkyl group, o Rg is selected from the group ting of a linear or branched C1-4 alkyl group, a C6-5 aryl group, a saturated or unsaturated C3-8 cycloalkyl, wherein the cyclic groups independently are optionally substituted with one or more substituents selected from halogen atom, a C1-4 alkyl group and a C1-4 alkoxy group, o Rh is selected from a hydrogen atom,-NReRf and a C5-6 aryl group which is optionally substituted with one or more substituents selected from a C1-4 alkyl group and a C1-4 alkoxy group, o Ri is ed from the group ting of a C5-6 aryl group, C3-8 cycloalkyl group and a 3 to 8 membered saturated or unsaturated heterocyclyl group, which groups independently are optionally substituted with one or more substituents ed from an n atom, a C1-4 alkyl group and a C1-4 alkoxy group. with the proviso that when G is a phenyl group, L1 is not one of the group selected from a direct bond, -O-, -NHC(O)-, -C(O)NH- and –NH(CO)O- group. 2. A compound according to claim 1, wherein G is selected from the group consisting of a C5-C6 aryl group, 8 to 10-membered saturated or unsaturated bicyclic heterocyclyl group having one or more atoms selected from N, S and O, a 8- to 10- membered bicyclic heteroaryl group having one or more heteroatoms selected from N, S and O and a C5-C6 aryl group linked to a ring system selected from a C5-6 aryl group, a C3-7 lkyl group and a 5- to 6-membered heteroaryl group having two or three heteroatoms selected from N, S and O, wherein the cyclic groups independently are optionally substituted with one or more substituents selected from a halogen atom, a C1-4 alkyl group, a C1-4 alkoxy group, a cyano group, a nitro group, a hydroxy group and oxo group. 3. A compound according to claim 1 or claim 2, wherein G is selected from a phenyl group, 9- to 10-membered unsaturated bicyclic heterocyclyl group having one or more heteroatoms selected from N, S and O, a 9 to 10-membered bicyclic heteroaryl group having one or more heteroatoms selected from N, S and O and a C5-C6 aryl group linked to a ring system selected from a C5-6 aryl group and a 5- to 6-membered heteroaryl group having two or three heteroatoms selected from N, S and O, wherein the cyclic groups independently are ally substituted with one or two substituents selected from a halogen atom, a methyl group, a y group, a cyano group, a hydroxy group and an oxo group. 4. A compound according to any one of claims 1 to 3, wherein L1 is ed from the group ting of direct bond, -NRc-, -S-, -SO2-, -C(O)-, -, -S(O)2NR c-, -NR cS(O) c(CO)(CH c-, -NRc(CO)NR d- and -CONRcS(O) 2-, –NR 2)O-, –O(CH2)(CO)NR 2-, wherein Rc and Rd independently are selected from a hydrogen atom and a methyl group. 5. A compound according to any one of claims 1 to 4, wherein L1 is selected from a direct bond, -NH-, -S-, -SO2-, -C(O)-, -NRc(CO)NR d- and –O(CH c- group.
2. (CO)NR 6. A compound ing to claim 5, wherein L1 is selected from a direct bond, -NH-, - SO2-, -NH(CO)NH- and –O(CH2)(CO)NRc-. 7. A compound according to claim 6, wherein L1 is ed from a direct bond and – O(CH2)(CO)NRc- group. 8. A compound according to any one of claims 1 to 7, wherein -G-L1- has the following W or Z Lx Formula (Iwa) Formula (Iwb) wherein - V, W and Z are independently selected from a –N-, -C-, -S-, -O- and –C (O)- - Lx represents a 5- to 6- membered heteroaryl group having at least one atom selected from N, S and O, or Lx represents a -CO-NRc-, wherein Rc represents a hydrogen atom or a methyl group. - * represents the point of attachment with A 2 and - • represents the point of attachment with A1. 9. A compound according to claim 8, wherein -G-L1- has the following formula (Iwa): Formula (Iwa) wherein V, W and Z are as defined in claim 5, preferably Z is a nitrogen atom, V represents a nitrogen atom, an oxygen atom, a carbon atom or a sulphur atom and W represents a nitrogen atom, a carbon atom or a carbonyl atom. 10. A compound according to claim 9, wherein G-L1 has the following formula (Iwaa): Formula (Iwaa) wherein V and W are as defined in any one of claims 8 or 9. 11. A compound according to any one of claims 1 to 10, having the ing formula (IA): V R2 N N O A1 A2 R3 a (IA) wherein R1, R2, R3, A1, A2, V, W and B are as defined in any one of claims 1 to 10. 12. A compound according to any one of claims 1 to 11, wherein A1 and A2 independently represent a C1-6 alkylene group optionally substituted with one or more substituents selected from a C1-2 alkyl group, a C1-2 alkoxy group and a phenyl group. 13. A compound according to claim 12, wherein A1 and A2 independently represent a C1-6 alkylene group substituted with one or two substituents selected from a methyl group and a methoxy group. 14. A compound according to claim 13, wherein A1 and A2 independently represent a C1-6 alkylene Group substituted with one or two substituents which are methyl group(s). 15. A compound according to claim 1, n, in the formula of (IB), Ar represents a group of formula Ga O Gb N HO Y (R) T r X O Rj O (c) (d) wherein • Ga and Gb independently are selected from a nitrogen atom and a carbon atom, • r has a value of 0, 1, 2 or 3 and • R is seleted from the group consisting of a halogen atom, a amino group, a cyano group, a nitro group, an oxo group, a y group, a C1-4 alkyl group, a C1-4 alkoxy group, -CF3, –OCF3, -(CH2)p-OH, -NH(CO)H, -NH-SO2-Rg, -SO2NH2, -OC(O)H, -(4-methyl)phenyl, –O(CO)-N(CH
3. 2, -OC(O)NH2 and – NH(CH2)(1-2)-Ri, group, wherein p is as defined in claim 10 and Rg and Ri independently are selected from a phenyl group optionally substituted with a substituent selected from a methyl group or a methoxy group. • Rj ents a halogen atom, • T is ed from the group consisting of –CH2- and –NH-, • Both X and Y represent a hydrogen atom or X together with Y form the group – CH2-CH2-, -CH=CH-, -CH2-O- or –S-, wherein in the case of -CH2-O- the methylene group is bound to the carbonyl group holding X and the oxygen atom is bound to the carbon atom in the phenyl ring holding Y, 16. A compound according to claim 15, wherein Ar represents a compound of formula (a) or (b) or HO Y (R)r T X wherein: • Both Ga and Gb represent a carbon atom, • R is seleted from the group consisting of a halogen atom, an amino group, a cyano group, a nitro group, -(CH2)p-OH, )H, -NH-SO2-CH3, -SO2NH2, - OC(O)H, –O(CO)-(4-methyl)phenyl, –O(CO)-N(CH3)2, -OC(O)NH2 and -CF3 group, wherein p has a value of 0, 1 or 2, • T represents –NH- group, • Both X and Y represent a hydrogen atom or X together with Y form the group – CH=CH-, -CH2-CH2-, -CH2-O- or –S-, wherein in the case of -CH2-O- the methylene group is bound to the carbon atom in the amido tuent holding X and the oxygen atom is bound to the carbon atom in the phenyl ring holding 17. A compound according to claim 15, wherein Ar is selected from the group consisting of 3-bromoisoxazolyl, 3,4-dihydroxyphenyl, 4-hydroxy (methylsulfonamido)phenyl, 3,4-bis(4-methylbenzoyloxy)phenyl, 3,5- bis(dimethylcarbamoyloxy)phenyl, (5-hydroxyhydroxymethyl)pyridyl, (4-amino- 3,5-dichloro)phenyl, 4-hydroxyphenyl, oxy(2-hydroxyethyl)phenyl, oxy- 3-(hydroxymethyl)phenyl, [4-aminochloro(trifluoromethyl)]phenyl, (3-formamido hydroxy)phenyl, 8-hydroxyoxo-1,2-dihydroquinolinyl, 8-hydroxyoxo-1,2,3,4- tetrahydroquinolinyl, 5-hydroxyoxo-3,4-dihydro-2H-benzo[b][1,4]oxazinyl and
4. 4-hydroxyoxo-2,3-dihydrobenzo[d]thiazolyl. 18. A compound according to claim 17, wherein Ar is selected from the group ting of 4-hydroxy(hydroxymethyl)phenyl, (3-formamidohydroxy)phenyl, 8- hydroxyoxo-1,2-dihydroquinolinyl, 8-hydroxyoxo-1,2,3,4-tetrahydroquinolinyl and 5-hydroxyoxo-3,4-dihydro-2H-benzo[b][1,4]oxazinyl. 19. A nd according to claims 16, wherein Ar represents a compound of formula (b) wherein T, X and Y are as defined in claim 16. 20. A nd according to any one of claims 1 to 19, having the following formula (IC): OH O N O nG L1 m N R8 R9 R10 HO Y HN X Formula (IC) • R3 represents a group of formula: R5 R4 R4 ∗ i) ∗ or ii) Q wherein: o R4 represents a hydrogen atom, a hydroxy group, a ymethyl group or a linear or branched C1-4 alkyl group, o R5 and R6 independently represent a C5-6 aryl group, a 5 to 6 membered heteroaryl group containing at least one heteroatom selected from N, S, and O; a (C1-4 alkyl)-(C5-6 aryl) group or a C3-8 cycloalkyl group, o Q ents a direct bond or a –CH2-, -CH2-CH2-, -O-, -O-CH2-, -S-, -SCH2- , or –CH=CH-, o * represents the point of attachment of R3 to the remainder of the molecule of formula (I), • Both X and Y represent a hydrogen atom or X together with Y form the group – CH=CH-, -CH2-CH2-, -CH2-O- or –S-, n in the case of -CH2-O- the methylene group is bound to the carbon atom in the amido substituent holding X and the oxygen atom is bound to the carbon atom in the phenyl ring holding Y • n has a value of 0, 1 or 2, • m has a value of 2, 3 or 4, • R8, R9 and R10 independently represent a hydrogen atom or a linear or branched C1-4 alkyl group, • -G-L1- represents a group of formula: W or ∗ Z Lx Formula (Iwa) Formula (Iwb) wherein - V, W and Z are independently selected from a –N-, -C-, -S-, -O- and –C (O)-, - Lx represents a 5- to 6- membered heteroaryl group having at least one heteroatom selected from N, S and O, or Lx represents a –O-CH2-CO-NRd-, wherein Rd represents a hydrogen atom or a methyl group. - * represents the point of attachement with the moiety containing the cycl ohexyl group and - • represents the point of attachement with the moiety containing the aminoethylphenol , 21. A nd according to claim 20, wherein in formula (Iwb), Lx represents a 5- to 6- ed heteroaryl group having at least one heteroatom selected from N, S and 22. A compound according to claim 21, wherein Lx represents a pyridyl, an oxadiazolyl, an imidazolyl or a thiazolyl group. 23. A compound according to claim 22, wherein Lx represents an oxadiazolyl group. 24. A compound according to claim 20 having the following formula (ID): H R3 N V O n W R8 R9 O HO Y N HN X N Formula (ID) wherein: • V, W, X, Y, R8, R9, R10, n and m are as defined in claim 20, • R3 ents a group of formula: R5 R4 R4 ∗ i) ∗ or ii) Q wherein: o R4 ents a hydrogen atom, a hydroxy group, a hydroxymethyl group or a linear or ed C1-4 alkyl group, o R5 and R6 independently represents a l group, a phenyl group, a benzyl group or a C4-6 cycloalkyl group, o Q represents a direct bond or an oxygen atom, o * represents the point of attachment of R3 to the remainder of the molecule of formula (I), 25. A compound ng to claim 20 to 24, wherein X together with Y form the group -CH=CH- or –CH2-O-. 26. A compound according to claim 25, wherein X together with Y forms the group – CH=CH-. 27. A compound according to any one of claims 20 to 26, wherein W represents a nitrogen atom or a yl group. 28. A compound according to claim 27, wherein W represents a nitrogen atom. 29. A compound according to any one of claims 20 to 27 wherein V represents a nitrogen atom, an oxygen atom or a sulphur atom. 30. A compound according to claim 29, wherein V is a nitrogen atom or an oxygen atom. 31. A compound according to any one of claims 20 to 29 wherein V ents a nitrogen atom or an oxygen atom while W represents a carbonyl group. 32. A compound according to any one of claims 20 to 29 wherein both V and W represent a nitrogen atom. 33. A compound according to any one of claims 20 to 32 wherein n has a value 0 and/or m has a value of 3. 34. A compound according to any one of claims 20 to 33, wherein R10 ents a hydrogen atom or a methyl group and/or R8 and R9 independently represent a hygrogen atom or a methyl group. 35. A compound ing to claim 34, wherein R10 ents a methyl group and/or both R8 and R9 represent a hydrogen atom. 36. A compound according to any one of claims 20 to 33, wherein R3 represents a group of formula i) wherein: • R4 represents a hydrogen atom, a methyl group or a hydroxy group, • R5 and R6 independently represent a thienyl group, a cyclopentyl group or a benzyl group. 37. A compound according to claim 36, wherein R4 represents a hydroxy group. 38. A compound according to claim 36 or claim 37, n R5 and R6 are thienyl groups. 39. A compound according to claim 20 wherein -G-L1- represents a group of formula: N Lx Formula (Iwa) Formula (Iwb) wherein o V is selected from –N-, -C-, -S- and -O-, o W is selected from –N-, -C-, and –C(O)-, o Lx represents an oxadiazolyl group or –O-CH2-CO-NRc-, wherein Rc represents a hydrogen atom or a methyl group. o * ents the point of attachment with the moiety containing the cyclohexyl group and o • represents the point of attachment with the moiety containing the aminoethylphenol fragment, - R 8 and R9 independently are selected from a hydrogen atom and a methyl group, - R 10 represents a methyl group, - n has a value of 0 or 1, - m has a value of 2, 3 or 4, - Both X and Y represents a hydrogen atom or X together with Y form –CH=CH-, -CH2-O-, or –S- group, - R 3 represents a group of formula: R5 R4 R4 ∗ i) ∗ or ii) Q wherein: o R4 represents a methyl group or a hydroxy group, o R5 and R6 ndently represents a thienyl group, a phenyl group, benzyl group or a cyclopentyl group, o Q represents a direct bond or an oxygen atom, o * represents the point of attachment of R3 to the remainder of the molecule of formula (I). 40. A compound according to claim 39 wherein -G-L1- represents a group of formula (Iwaa): Formula (Iwaa) wherein o W represents a nitrogen atom or a carbonyl group, o V represents a nitrogen or an oxygen atom, - Both R 8 and R9 represents a hydrogen atom, - X together with Y form -, - R 4 represents a hydroxy group and 3 represents a group of formula i) wherein R both R5 and R6 represent a l group. 41. A compound ing to claim 1 which is one of 4-[{3-[6-({[(2R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolinyl)ethyl] amino}methyl)oxo-1,3-benzoxazol-3(2H)-yl]propyl}(methyl)amino]-cyclohexyl hydroxy(dithienyl)acetate, dihydrofluoride, trans[{3-[5-({[(2R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolin yl)ethyl]amino}methyl)oxo-2,3-dihydro-1H-benzimidazolyl]propyl} (methyl)amino]cyclohexyl hydroxy(dithienyl)acetate dihydrofluoride, Trans[{3-[5-({[(2R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolin yl)ethyl]amino}methyl)-1H-1,2,3-benzotriazolyl]propyl}(methyl)amino] cyclohexylhydroxy(dithienyl)acetate dihydrofluoride, Trans[{3-[5-({[(2R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolin yl]amino}methyl)-1H-indolyl]propyl}(methyl)amino]cyclohexylhydroxy (di thienyl)acetate dihydrofluoride, Trans[{3-[5-({[(2R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolin yl)ethyl]amino}methyl)-1H-benzimidazolyl]propyl}(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate, Trans[{3-[5-({[(2R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolinyl) ethyl]amino}methyl)-1H-indazolyl]propyl}(methyl)amino]cyclohexylhydroxy(di thienyl)acetate, Trans[{3-[6-({[(2R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolin yl)ethyl]amino}methyl)oxo-1,3-benzothiazol-3(2H)-yl]propyl}(methyl)amino] cyclohexyl hydroxy(dithienyl)acetate, Trans[(3-{5-[({(2R)[3-(formylamino)hydroxyphenyl]- 2- hydroxyethyl}amino)methyl]-1H-1,2,3-benzotriazolyl}propyl)(methyl)amino] cyclohexyl y(dithienyl)acetate, Trans[{3-[5-({[(2R)hydroxy(4-hydroxyoxo-2,3-dihydro-1,3-benzothiazol- 7-yl)ethyl]amino}methyl)-1H-1,2,3-benzotriazolyl]propyl}(methyl) amino]cyclohexyl hydroxy(dithienyl)acetate, Trans[{3-[6-(2-{[(2R)hydroxy(8-hydroxymethylene-1,2-dihydroquinolin yl)ethyl]amino}ethyl)oxo-1,3-benzoxazol-3(2H)-yl]propyl}(methyl)amino] cyclohexyl hydroxy(dithienyl)acetate, Trans[{2-[6-({[(2R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolin yl)ethyl]amino}methyl)oxo-1,3-benzoxazol-3(2H)-yl]ethyl}(methyl)amino] cyclohexylhydroxy(dithienyl)acetate, Trans[{4-[6-({[(2R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolin yl)ethyl]amino}methyl)oxo-1,3-benzoxazol-3(2H)-yl]butyl}(methyl)amino] cyclohexylhydroxy(dithienyl)acetate, Trans[{3-[5-({[(2R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolin yl]amino}methyl)-1H-1,2,3-benzotriazolyl]propyl}(methyl)amino] cyclohexylcyclopentyl(hydroxy)2-thienylacetate, Trans[{3-[6-({[(2R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolin yl)ethyl]amino}methyl)oxo-1,3-benzoxazol-3(2H)-yl]propyl}(methyl)amino] cyclohexylmethyl-9H-xanthenecarboxylate, Trans[{3-[6-({[(2R)hydroxy(5-hydroxyoxo-3,4-dihydro-2H-1,4- benzoxazinyl)ethyl]amino}methyl)- 2-oxo-1,3-benzothiazol-3(2H)-yl]propyl} l)amino]cyclohexyl y(dithienyl)acetate, Trans[(2-{5-[({(2R)[3-(formylamino)hydroxyphenyl]hydroxyethyl} amino)methyl]-1H-indolyl}ethyl)(methyl)amino]cyclohexyl 9H-fluorene carboxylate, Trans[(3-{5-[({(2R)[3-(formylamino)hydroxyphenyl]hydroxyethyl} amino)methyl]-1H-indolyl}propyl)(methyl)amino]cyclohexyl 2-hydroxyphenyl (2-thienyl)propanoate, Trans[{3-[5-(2-{[(2R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolin yl)ethyl]amino}methylpropyl)oxo-2,3-dihydro-1H-benzimidazolyl]propyl} (methyl)amino]cyclohexyl 2,2-diphenylpropanoate, Trans[{2-[5-(2-{[(2R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolinyl) ethyl]amino}methylpropyl)-1H-indazolyl]ethyl}(methyl)amino]cyclohexyl 2- phenyl(2-thienyl)propanoate, Trans[{3-[6-(2-{[(2R)hydroxy(8-hydroxymethylene-1,2-dihydroquinolin yl]amino}propyl)oxo-1,3-benzoxazol-3(2H)-yl]propyl}(methyl)amino] cyclohexyl hydroxy(dithienyl)acetate, Trans[(3-{3-[4-({[(2R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolin yl)ethyl]amino}methyl)phenyl]-1,2,4-oxadiazolyl}propyl)(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate, Trans[{2-[{[4-({[(2R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolin yl)ethyl]amino}methyl)phenoxy]acetyl}(methyl)amino]ethyl}(methyl)amino]cyclohexy l y(dithienyl)acetate, Trans[[2-({[4-({[(2R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolin yl)ethyl]amino}methyl)phenoxy]acetyl}amino)ethyl](methyl)amino]cyclohexyl hydroxy(dithienyl)acetate, Trans[(3-{3-[2-chloro({[(2R)hydroxy(8-hydroxyoxo-1,2- dihydroquinolinyl)ethyl]amino}methyl)methoxyphenyl]-1,2,4-oxadiazol yl}propyl)(methyl)amino]cyclohexyl hydroxy(dithienyl)acetate, and Trans[{2-[{[2-chloro({[(2R)hydroxy(8-hydroxyoxo-1,2-dihydroquinolin-
5. 5-yl)ethyl]amino}methyl)methoxyphenoxy]acetyl}(methyl)amino]ethyl}(methyl) amino]cyclohexyl hydroxy(dithienyl)acetate, or ceutically able salts or N-oxides or solvates or deuterated derivative thereof: 42. A compound according to claim 41 which is Trans[{3-[5-({[(2R)hydroxy(8- hydroxyoxo-1,2-dihydroquinolinyl)ethyl]amino}methyl)-1H-1,2,3-benzotriazol yl]propyl}(methyl)amino] cyclohexylhydroxy(dithienyl)acetate dihydrofluoride, or pharmaceutically acceptable salts or N-oxides or solvates or deuterated derivative thereof. 43. A compound according to any one of claims 1 to 42 for use in the treatment of a human or animal body by therapy. 44. A compound ing to any one of claims 1 to 42 for use in the treatment of a ogical condition or disease associated with β2 rgic receptor agonist and M3 muscarinic receptor antagonist activities. 45. A compound for use according to claim 44, wherein the condition or disease is preferably selected from ary diseases, pre-labor, glaucoma, neurological disorders, cardiac disorders, inflammation and gastrointestinal disorders. 4
6. A compound according to claim 45, wherein the pulmonary disease is asthma and or chronic obstructive pulmonary disease. 4
7. A pharmaceutical ition comprising a compound as defined in any one of claims 1 to 42 in association with a pharmaceutically acceptable diluent or carrier. 4
8. Use of a compound as defined in any one of claims 1 to 42, in the manufacture of a medicament for use in the treatment of pulmonary diseases, pre-labor, glaucoma, neurological disorders, cardiac disorders, inflammation and gastrointestinal ers. 4
9. Use according to claim 48, wherein the pulmonary disease is asthma or chronic obstructive ary disease. 50. A combination t comprising (i) a compound ing to any one of claims 1 to 42; and (ii) another compound selected from a corticosteroid and a PDE4 inhibitor, for simultaneous, separate or sequential use in the treatment of the human or animal body. 51. A compound of formula (I), as claimed in any one of claims 1 to 44, substantially as herein described with reference to any example thereof. 52. A pharmaceutical ition as claimed in claim 47, substantially as herein described with reference to any example thereof. 53. Use as claimed in claim 48 or 49, substantially as herein described with reference to any example f. 54. A combination product as claimed in claim 50, substantially as herein described with reference to any example thereof.
NZ624784A 2011-11-11 2012-11-09 New cyclohexylamine derivatives having ?2 adrenergic agonist and m3 muscarinic antagonist activities NZ624784B2 (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
EP11382344.7A EP2592078A1 (en) 2011-11-11 2011-11-11 New cyclohexylamine derivatives having beta2 adrenergic agonist and M3 muscarinic antagonist activities
EP11382344.7 2011-11-11
US201161563907P 2011-11-28 2011-11-28
US61/563,907 2011-11-28
PCT/EP2012/072309 WO2013068552A1 (en) 2011-11-11 2012-11-09 NEW CYCLOHEXYLAMINE DERIVATIVES HAVING β2 ADRENERGIC AGONIST AND M3 MUSCARINIC ANTAGONIST ACTIVITIES

Publications (2)

Publication Number Publication Date
NZ624784A NZ624784A (en) 2015-06-26
NZ624784B2 true NZ624784B2 (en) 2015-09-29

Family

ID=

Similar Documents

Publication Publication Date Title
AU2012333986B2 (en) New cyclohexylamine derivatives having beta2 adrenergic agonist and M3 muscarinic antagonist activities
CA2849872A1 (en) New cyclohexylamine derivatives having .beta.2 adrenergic agonist and m3 muscarinic antagonist activities
ES2613355T3 (en) New cyclohexylamine derivatives with beta2-adrenergic agonist activity and muscarinic m3 antagonist
US10005771B2 (en) Bicyclic derivatives having β2 adrenergic agonist and M3 muscarinic antagonist activities
KR20150096732A (en) New cyclohexyl and quinuclidinyl carbamate derivatives having beta2 adrenergic agonist and m3 muscarinic antagonist activity
NZ624784B2 (en) New cyclohexylamine derivatives having ?2 adrenergic agonist and m3 muscarinic antagonist activities
HK1197241B (en) New cyclohexylamine derivatives having beta2 adrenergic agonist and m3 muscarinic antagonist activities