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NZ716244B2 - Quinoline derivative - Google Patents
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NZ716244B2 - Quinoline derivative - Google Patents

Quinoline derivative Download PDF

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Publication number
NZ716244B2
NZ716244B2 NZ716244A NZ71624414A NZ716244B2 NZ 716244 B2 NZ716244 B2 NZ 716244B2 NZ 716244 A NZ716244 A NZ 716244A NZ 71624414 A NZ71624414 A NZ 71624414A NZ 716244 B2 NZ716244 B2 NZ 716244B2
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New Zealand
Prior art keywords
group
oxy
pyridinyl
cancer
ethyl acetate
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NZ716244A
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NZ716244A (en
Inventor
Takayuki Inukai
Jun Takeuchi
Tomoko Yasuhiro
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Ono Pharmaceutical Co Ltd
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Priority claimed from PCT/JP2014/069419 external-priority patent/WO2015012298A1/en
Publication of NZ716244A publication Critical patent/NZ716244A/en
Publication of NZ716244B2 publication Critical patent/NZ716244B2/en

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    • 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
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/16—Emollients or protectives, e.g. against radiation
    • A—HUMAN NECESSITIES
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    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • 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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • 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
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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 to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • 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
    • 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
    • C07D401/14—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 three or more hetero rings

Abstract

compound represented by general formula (I) (I) has a strong Axl inhibiting activity by introducing a distinctive bicyclic structure in which a saturated carbocyclic ring is fused to a pyridone ring, and thus may be used as a therapeutic agent for Axl related diseases such as acute myeloid leukemia, melanoma, breast cancer, pancreatic cancer, cancer such as glioma, kidney disease, immune system disease, and circulatory system disease. emia, melanoma, breast cancer, pancreatic cancer, cancer such as glioma, kidney disease, immune system disease, and circulatory system disease.

Description

[Description] [Title of Invention] QUINOLINE DERIVATIVE [Technical Field] The present invention relates to a compound represented by general formula (I): (wherein all of the symbols have the same meanings as given below), a salt thereof, a solvate thereof, an N—oxide thereof, or a prodrug thereof nafter, also abbreviated as the compound ofthe present ion).
[Background Art] Axl (also known as: UFO, ARK, Tyro7) is a receptor tyrosine kinase belonging to a TAM family (Axl, Mer and Tyro3) cloned from tumor cells. Gas6 h—arrest—specific protein 6) cloned as a gene specifically expressed at the time of cell proliferation arrest is known as a ligand for Axl. Axl activated by binding of Gas6 transfers a signal via phosphorylation. Since the signal activates an Erkl/Z pathway a PI3K/Akt y, the activation of Axl is known to be involved in pathologic ions of cancers, immune system diseases, circulatory system diseases, and the like (see, Non—Patent Literature 1).
In particular, the relation n Axl and various types of cancers is well known. For example, it is known that the expression of Axl is involved in metastasis and prognosis of breast cancer (see, Non-Patent Literature 2), and that Axl is involved in the pathologic conditions of acute myeloid ia (AML) (see Non-Patent Literature 3). Therefore, it is considered that compounds which inhibit the activation of Axl are useful for treatment of various type of cancers, immune system diseases, and circulatory system diseases.
By the way, as prior art of the compound of the present invention, a compound represented by l formula (A): /A" N\R9A 2A R1A R \ \llB: R3A \ A R" (Al (wherein AA represents C-R10A and N; BA 1A represents C-R1 and N; DA represents heterocycles of the following general formulae, and the like.
R12A \N R131 —<\ I N R1" \ \N/N\R1¢A (wherein R‘ A, R4 A, and R8 8 A are independently -H, F, -Cl, Br, ~I, -OH, ~NH2, -OCH3 A and R3 A 8 A A , —OC2 H5 , or the like; R2 are independently —R8 or the like; R5 and R6 A may be the same as each other or ent from each other, and represent -H, , -c1, -Br, -1, -CN, ~N02, -CH3, or the like; R7 A, R8 A, R10 A, and R1 ‘A may be the same as each other or ent from each other, and represent —H, —F, —Cl, -Br, -1, -CN, -N02 the like; R9A represents —H or the like; R12A I , -CH3 , or represents -CN, phenyl, or the like; R13A represents -H, -F, (:1, -Br, ~I, ~CN, -N02, -CH3, or the like; R14A represents -H, -F, -Cl, —Br, -I, ~N02, -CN, or the like (where the definitions of the groups are excerpted)) is known to be an Axl inhibitor (see, Non-Patent Literature 1).
Furthermore, a compound represented by general formula (B): Rue R35 XB'NYO R'bB I K? \ YB 0 0 Ras D3 R38 \WBR1aB RbB NJJ (wherein EB and GB are independently a hydrogen atom, a Cl—6 alkyl group optionally substituted with one to six R19 B, a C6—ll aryl group optionally substituted with one to six R19B or the like; XB represents N or C-R4B; YB "3 represents N or C-Rl ; DB represents -O—, ~S—, —NH— or the like; WB represents CH or N; RaB , RbB RCB , , RdB , R183, R1 CB Rl "3 and R4 B , independently ent a hydrogen atom, -OR1 10 B , or the like; R19B represents a halogen atom, -CN, or the like; and Rl ""3 represents a hydrogen atom, a C1—6 alkyl group optionally substituted with one to six R12 9 B (where the definitions of the groups are ted)) is known to be an Axl inhibitor (see Patent Literature 2). ‘ On the other hand, a compound having a quinoline on and represented by the following general formula (C): 0 N ON \ o H3C0 H360 N is known to have an ASKI inhibitory activity, and be an agent for preventing and/or treating amyotrophic lateral sclerosis (ALS) (see Patent Literature 3).
Furthermore, a compound represented by general formula (D): RD—XD—wD—YD—Rw (D) (wherein RD represents K, N/J or the like; TD represents phenyl or the like; ZD ents N or CR7 D ; WD represents a substituted or unsubstituted phenyl, substituted or tituted 6-membered nitrogen-containing heteroaryl or the like; XD represents 0, S, S(=O), or the like; YD D C(=O)-(CR3 D R4 D)p represents -NRa ~ or the like; R"D represents, a hydrogen atom, an alkyl group, or the like; and R1 represents 0 TDD xN/Rbo "\N’Rbo JZD'JP , " Furthermore, a compound represented by general formula (E): R4IE o R1E R45 RZE N/ R‘E (wherein R1 E, R2E and R4E independently represent H, F, Cl, Br, I, CN, ORl OE, C1—C12 alkyl, or the like; LE ents a C3—C12 carbon ring, C6~C20 aryl, or the like; R5E 3 E, -C(=YE)R1°ER13 E, ~NR1°EC(=YE)R13E, represents )R1 or the like; Rl OE represents H, Cl—C12 alkyl, a C3—Cl2 carbon ring, a C2—C20 heterocycle, or the like; R13E represents H, C1—C6 alkyl, or the like; and YB represents 0 or S (where the definitions of the groups are excerpted)) is known to be a c-Met inhibitor (see Patent Literature 5).
However, any of the prior art literatures r mention nor suggest that a quinoline derivative as a compound of the present invention, having a bicyclic structure in which a saturated carbon ring is fused to a ne ring, ented by the following structural formula.
(Rem has a significant Axl inhibitory activity.
[Prior art Literatures] [Patent Literatures] [00 l 0] [Patent Literature 1] WO2012/028332 [Patent Literature 2] W02013/074633 [Patent Literature 3] W02012/011548 [Patent Literature 4] W02006/l 16713 [Patent Literature 5] WO2007/146824 [Non-Patent Literatures] [00 1 1] [Non-Patent Literature 1] Clinical Science, Vol. 122, p. 361-368, 2012 [Non-Patent Literature 2] Proceedings of the national academy of sciences of the United States ofAmerica, Vol. 107, No. 3, p. 1124—1129, 2010 [Non—Patent Literature 3] Blood, Vol. 121, p. 2064-2073, 2013 [Summary of Invention] [Technical Problem] A problem to be solved by the present invention is to find a compound having an Axl inhibitory activity, which is useful for treatment of cancer such as AML, and to provide the nd as pharmaceuticals whose side effects are reduced. ion to Problem] [001 3] In order to solve the above-mentioned problem, the inventors of the present invention have keenly studied to find a compound strongly inhibiting Axl. As a result, surprisingly, the inventors have found that a bicyclic ure, in which a saturated carbon ring is fused to a pyridone ring, represented by the following structural formula: es the Axl tory activity, and have completed the present invention.
That is to say, the present invention relates to: a compound represented by general formula (I) wherein R1 represents (1) a C1–8 alkyl group ally tuted with one to five R1 1 , (2) a C3–7 carbon ring optionally substituted with one to five R1 2 , or (3) a 4- to 7-membered heterocycle optionally substituted with one to five R1 3 , wherein when the C1–8 alkyl group represented by R1 is a branched alkyl group, the C1–3 alkyl group branched from the same carbon atom, together with the carbon atom bound o, optionally forms a saturated C3–7 carbon ring, R2 represents (1) a C1–4 alkyl group, (2) a halogen atom, (3) a C1–4 haloalkyl group, (4) an oxo group, (5) an -OR21 group, or (6) an =NR22 group, R3 represents (1) a C1–4 alkyl group, (2) a halogen atom, or (3) a C1–4 haloalkyl group, R4 represents (1) a C1–4 alkoxy group, (2) a C1–4 haloalkyl group, (3) an -OR41 group, (4) a C1–4 alkyl group, (5) a C2–4 alkenyloxy group, or (6) a C2–4 alkynyloxy group, R5 represents (1) a hydrogen atom, (2) a C1–4 alkyl group, (3) a halogen atom, (4) a C1–4 haloalkyl group, or (5) an -OR21 group, R1 1 represents (1) an -OR101 group, (2) an SO2 R1 0 2 group, (3) an NR1 0 3 R1 0 4 group, or (4) a C3–7 carbon ring optionally tuted with one to three halogen atoms, R1 2 represents (1) a C1–8 alkyl group optionally substituted with a yl group, or (2) a halogen atom, R1 3 represents (1) a C1–8 alkyl group optionally substituted with a hydroxyl group, or (2) a halogen atom, R2 1 represents (1) a hydrogen atom, or (2) a C1–4 alkyl group, R2 2 represents (1) a hydroxyl group, or (2) C1–4 alkoxy group, R4 1 represents (1) a hydrogen atom; (2) a C1–8 alkyl group substituted with one to two substituents selected from the group consisting of (a) 5- to 7-membered cyclic group optionally tuted with one to two substituents selected from the group consisting of (i) a C1–4 alkyl group, (ii) a C1–4 haloalkyl group, and (iii) a halogen atom, (b) NR4 0 1 R4 0 2 , (c) a hydroxyl group, and (d) an SO2 R4 0 3 group; (3) a C2–8 alkenyl group substituted with one to two substituents selected from the group consisting of (a) 5- to 7-membered cyclic group ally substituted with one to two substituents selected from the group consisting of (i) a C1–4 alkyl group, (ii) a C1–4 haloalkyl group, and (iii) a halogen atom, (b) NR4 0 1 R4 0 2 , (c) a hydroxyl group, and (d) an SO2 R4 0 3 group; or (4) a C2–8 alkynyl group substituted with one to two substituents selected from the group consisting of (a) 5- to 7-membered cyclic group optionally substituted with one to two substituents ed from the group consisting of (i) a C1–4 alkyl group, (ii) a C1–4 haloalkyl group, and (iii) a halogen atom, (b) NR4 0 1 R4 0 2 , (c) a yl group, and (d) an SO2 R4 0 3 group, R1 0 1 represents (1) a hydrogen atom, or (2) a C1–4 alkyl group, R1 0 2 ents (1) a hydrogen atom, or (2) a C1–4 alkyl group, R1 0 3 and R1 0 4 each independently represents (1) a hydrogen atom, or (2) a C1–4 alkyl group, R4 0 1 and R4 0 2 each independently represents (1) a hydrogen atom, or (2) a C1–4 alkyl group, R4 0 3 represents (1) a hydrogen atom, or (2) a C1–4 alkyl group, A represents (1) CH, or (2) a en atom, L represents (1) -O-, (2) -NH-, (3) -C(O)-, (4) -CR6 R7 -, (5) -S-, (6) -S(O)-, or (7) -S(O)2 -, R6 and R7 each independently represents (1) a hydrogen atom, (2) a halogen atom, (3) a C1–4 alkyl group, (4) a hydroxyl group, or (5) NH2, ring1 represents benzene or pyridine, represents a single bond or a double bond, m is an integer from 0 to 5, n is an r from 0 to 5, p is an integer from 0 to 2, q is an integer from 0 to 4, when m is two or more, a plurality of R2 may be the same as or different from each other, and when two of R2 represent a C1–3 alkyl group and are on the same carbon atom, the R2, together with a carbon atom bound thereto, may form a saturated C3–7 carbon ring, when n is two or more, a plurality of R3 may be the same as or different from each other, and when q is two or more, a ity of R4 may be the same as or different from each other, a salt thereof, a solvate thereof, or an N-oxide thereof, the compound according to the above-mentioned [1], n m is one or more, and one of two R2 is necessarily an oxo group, the compound according to any one of the above-mentioned [1] to [2], wherein L is (1) -O-, (2) -NH-, or (3) -C(O)-, the compound according the above-mentioned [1], which is represented by general formula (I-1) wherein R2 - 1 represents (1) a C1–4 alkyl group, (2) a halogen atom, (3) a C1–4 haloalkyl group, (4) an -OR21 group, or (5) an =NR22 group, m-1 is an integer from 0 to 4, L1 is (1) -O-, (2) -NH-, or (3) -C(O)-, 1 represents benzene or pyridine, when m-1 is two or more, a plurality of R2-1 may be the same as or different from each other, and when two of R2-1 represent a C1–3 alkyl group and are on the same carbon atom, the R2-1, together with a carbon atom bound thereto, may form a saturated C3–7 carbon ring, and other symbols have the same meanings as defined in the above-mentioned [1], the compound according to any one of the above-mentioned [1] to [4], which is: N-{5-[(6,7-dimethoxyquinolinyl)oxy]pyridinyl}-2,5-dioxophenyl-1,2,5,6,7,8-h exahydroquinolinecarboxamide, (2) N-{5-[(6,7-dimethoxyquinolinyl)oxy]pyridinyl}-7,7-dimethyl-2,5-dioxophenyl -1,2,5,6,7,8-hexahydroquinolinecarboxamide, (3) N-{5-[(6,7-dimethoxyquinolinyl)oxy]pyridinyl}(2,2-dimethylpropyl)-2,5-dioxo -1,2,5,6,7,8-hexahydroquinolinecarboxamide, (4) N-[5-({7-[3-(4-morpholinyl)propoxy]quinolinyl}oxy)pyridinyl]-2,5-dioxophen yl-1,2,5,6,7,8-hexahydroquinolinecarboxamide, (5) N-{4-[(6,7-dimethoxyquinolinyl)oxy]fluorophenyl}-2,5-dioxophenyl-1,2,5,6,7, 8-hexahydroquinolinecarboxamide, (6) N-{4-[(6,7-dimethoxyquinolinyl)oxy]phenyl}-2,5-dioxophenyl-1,2,5,6,7,8-hexahy droquinolinecarboxamide, (7) (6,7-dimethoxyquinolinyl)oxy]pyridinyl}(4-fluorophenyl)-2,5-dioxo-1,2 ,5,6,7,8-hexahydroquinolinecarboxamide, (8) (6,7-dimethoxyquinolinyl)oxy]pyridinyl}(3-fluorophenyl)-2,5-dioxo-1,2 ,5,6,7,8-hexahydroquinolinecarboxamide, (9) N-{5-[(6,7-dimethoxyquinolinyl)oxy]pyridinyl}(2-fluorophenyl)-2,5-dioxo-1,2 ,5,6,7,8-hexahydroquinolinecarboxamide, (10) N-{5-[(6,7-dimethoxyquinazolinyl)oxy]pyridinyl}-2,5-dioxophenyl-1,2,5,6,7,8 -hexahydroquinolinecarboxamide, (11) N-{5-[(6,7-dimethoxyquinazolinyl)oxy]pyridinyl}(4-fluorophenyl)-2,5-dioxo-1 ,2,5,6,7,8-hexahydroquinolinecarboxamide, (12) N-{5-[(6,7-dimethoxyquinolinyl)oxy]pyridinyl}[(2S)hydroxymethylbu tanyl]-2,5-dioxo-1,2,5,6,7,8-hexahydroquinolinecarboxamide, (13) N-{4-[(6,7-dimethoxyquinolinyl)oxy]fluorophenyl}(3-fluorophenyl)-2,5-dioxo -1,2,5,6,7,8-hexahydroquinolinecarboxamide, (14) N-{5-[(6,7-dimethoxyquinolinyl)oxy]pyridinyl}-6,6-dimethyl-2,5-dioxophenyl -1,2,5,6,7,8-hexahydroquinolinecarboxamide, (15) N-[5-({6-methoxy[3-(4-morpholinyl)propoxy]quinolinyl}oxy)pyridinyl]-2,5-di oxophenyl-1,2,5,6,7,8-hexahydroquinolinecarboxamide, (16) N-(5-{[7-(3-hydroxymethylbutoxy)methoxyquinolinyl]oxy}pyridinyl)-2,5-d ioxophenyl-1,2,5,6,7,8-hexahydroquinolinecarboxamide, or (17) N-[5-({6-methoxy[3-(1-pyrrolidinyl)propoxy]quinolinyl}oxy)pyridinyl]-2,5-di oxophenyl-1,2,5,6,7,8-hexahydroquinolinecarboxamide, A compound which is N-{5-[(6,7-dimethoxyquinolinyl)oxy]pyridinyl}-2,5-dioxophenyl-1,2,5,6,7,8-h exahydroquinolinecarboxamide, a salt thereof, a solvate thereof, or an N-oxide thereof. a pharmaceutical composition containing a compound represented by general formula (I) as defined in the above-mentioned [1], a salt thereof, a solvate thereof, or an N-oxide thereof, the pharmaceutical composition according to the above-mentioned [7], which is an Axl inhibitor, the pharmaceutical composition according to the above-mentioned [7], which is an agent for preventing and/or ng an Axl-related disease, the ceutical ition according to the above-mentioned [9], wherein the Axl-related diseases includes cancer, kidney diseases, immune system diseases, or circulatory system diseases, the pharmaceutical composition according to the above-mentioned [10], wherein the cancer is acute myeloid leukemia, chronic d leukemia, acute tic leukemia, melanoma, breast cancer, pancreatic cancer, glioma, esophageal adenocarcinoma, large intestine cancer, renal cell oma, thyroid cancer, non-small cell lung cancer, prostate cancer, stomach cancer, liver cancer, uveal malignant melanoma, ovarian cancer, endometrial cancer, lymphoma, head and neck , or sarcoma, the pharmaceutical composition according to the above-mentioned [7], which is a metastasis suppressing agent for cancer cells, use of a compound represented by general formula (I), a salt thereof, a solvate thereof, or an N-oxide f as defined in the mentioned [1], in the manufacture of an agent for preventing and/or treating an Axl-related disease. the use according to [13], wherein the Axl-related e includes a cancer, a kidney disease, an immune system disease, or a circulatory system disease. the use ing to [14], wherein the cancer is acute myeloid leukemia, c myeloid leukemia, acute lymphatic leukemia, melanoma, breast cancer, pancreatic cancer, glioma, geal adenocarcinoma, large intestine , renal cell carcinoma, thyroid cancer, non-small cell lung cancer, prostate cancer, stomach cancer, liver cancer, (followed by page 11a) uveal malignant melanoma, ovarian cancer, endometrial cancer, lymphoma, head and neck cancer, or sarcoma. the use according to [13], wherein the agent is a metastasis suppressing agent for cancer cells.
[Effects of Invention] A compound of the present invention has a strong Axl inhibitory activity, has an lective inhibitory activity to a specific kinase, and has d CYP inhibitory [FOLLOWED BY PAGE 12] effect, and therefore is useful as a eutic drug for acute myeloid leukemia or the like, has less side effect and has little concern about drug interaction. iption ofEmbodiments] The present invention will be described in detail hereinafter.
In the present invention, a halogen atom denotes a e atom, a chlorine atom, a bromine atom, and an iodine atom.
In the present invention, the C1—8 alkyl group includes a straight or branched Cl-S alkyl group. Examples thereof e methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, isobutyl, sec-butyl, tert~butyl, and an isomer f.
In the present invention, the C1-4 alkyl group includes a ht or branched Cl~4 alkyl group. Examples thereof include methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec—butyl, and tert—butyl.
In the present invention, the Cl—3 alkyl group includes a straight or branched C1-3 alkyl group. Examples f include a methyl group, an ethyl group, a propyl group, and an isopropyl.
In the present invention, the Cl—4 haloalkyl group denotes, for example, a fluoromethyl group, a chloromethyl group, a bromomethyl group, an iodomethyl group, a difluoromethyl group, a trifluoromethyl group, a l-fluoroethyl group, a 2-fluoroethyl group, a roethyl group, a pentafluoroethyl group, a l-fluoropropyl group, a 2-chloropropyl group, a 3—fluoropropyl group, a 3—chloropropy1' group, a 4,4,4-trifluorobutyl group, and a 4~bromobutyl group.
In the present invention, the C28 alkenyl group denotes, for example, a vinyl group, a propenyl group, a butenyl group, a pentenyl group, a hexenyl group, a heptenyl group, and a octenyl group, and an isomer f, and the like.
In the present invention, the C2—8 alkynyl group denotes, for example, an ethynyl group, a propynyl group, a l group, a .pentynyl group, a hexynyl group, a heptynyl group, an octynyl group, and an isomer thereof.
In the present invention, examples of the Cl—4 alkoxy group include a methoxy group, an ethoxy group, a y group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, or a tert-butoxy group.
In the present invention, the (32—4 alkenyloxy group s, for example, xy, propenyloxy, loxy, and an isomer thereof.
In the present invention, the C2~4 alkynyloxy group denotes, for example, ethynyloxy, propynyloxy, butynyloxy, and an isomer thereof.
In the present invention, the C3—7 carbon ring denotes a C3—7 monocyclic carbon ring, and a carbon ring which may be partially or completely saturated, and examples thereof include cyclopropane, utane, cyclopentane, cyclohexane, cycloheptane, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclobutadiene, cyclopentadiene, cyclohexadiene, cycloheptadiene, or benzene ring.
In the present invention, the C5—7 carbon ring denotes a C5—7 monocyclic carbon ring, and a carbon ring which may be partially or completely saturated, and examples thereof e entane, cyclohexane, cycloheptane, cyclopentene, cyclohexene, cycloheptene, entadiene, cyclohexadiene, cycloheptadiene, or benzene ring.
In the present invention, examples of the saturated C3~7 carbon ring include cyclopropane, cyclobutane, cyclopentane, cyclohexane, and cycloheptane.
In the present invention, the 4- to ered heterocycle s 4- to 7~membered monocyclic heterocycle, which includes one to five heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, and a part or all of which is saturated. Example thereof include azetidine, pyrroline, idine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, lidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydroazepine, tetrahydroazepine, roazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, oxetan, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrooxepine, tetrahydrooxepine, perhydrooxepine, thietane, dihydrothiophene, tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydrothiepin, ydrothiepin, perhydrothiepin, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, ydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole iazolidine), dihydrofiirazan, tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole, (oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine, ooxazepine, tetrahydrooxazepine, rooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine, perhydrooxadiazepine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine), dihydrothiazine, tetrahydrotbjazine, dihydrothiadiazine, tetrahydrothiadiazine, dihydrothiazepine, tetrahydrothiazepine, perhydrothiazepine, othiadiazepin, tetrahydrothiadiazepin, perhydrothiadiazepin, morpholine, thiomorpholine, oxathiane, dioxolane, dioxane, dithiolane, dithiane, pyrrole= ole, triazole, tetrazole, le, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepin, thiophene, thiopyran, thiepin, oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, azine, thiazepine, or thiadiazepin ring.
In the present invention, the 5— to 7-membered cyclic group denotes C5—7 carbon ring and 5- to 7-membered heterocycle. Herein, the C5—7 carbon ring has the same meaning as defined above, the 5- to 7-membered heterocycle es 5- to 7-membered unsaturated heterocycle and 5- to 7—membered ted cycle. es of 5~ to 7—membered heterocycle include pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, zine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrooxepine, tetrahydrooxepine, perhydrooxepine, dihydrothiophene, tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydrothiepin, tetrahydrothiepin, perhydrothiepin, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), othiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan, ooxadiazole, tetrahydrooxadiazole, (oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine, dihydrooxazepine, tetrahydrooxazepine, perhydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine; rooxadiazepine, dihydrothiadiazole, ydrothiadiazole (thiadiazolidine), dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine, dihydrothiazepine, tetrahydrothiazepine, perhydrothiazepine, dihydrothiadiazepin, tetrahydrothiadiazepin, perhydrothiadiazepin, morpholine, rpholine, oxathiane, dioxolane, dioxane, dithiolane, dithiane, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepin, thiophene, thiopyran, thiepin, oxazole, isoxazole, thiazole, isothiazole, n, oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine, or azepin ring.
In the present invention, the bered cyclic group denotes C6 carbon ring and 6-membered heterocycle. Examples thereof include cyclohexane, cyclohexene, cyclohexadiene, benzene, pyridine, pyrazine, dine, pyridazine, pyran, thiopyran, oxazine, oxadiazine, thiazine, azine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydropyran, tetrahydropyran, dihydrothiopyran, ydrothiopyran, dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine, dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine, ydrothiadiazine, morpholine, thiomorpholine, oxathiane, dioxane, and dithiane ring.
In the present invention, "when the C1—8 alkyl group ented by R1 is a branched alkyl group, the Cl—3 alkyl group branched from the same carbon atom optionally forms a saturated C3—7 carbon ring together" denotes that in a partial structure of the following general formula (1): (Ram (wherein all of the symbols have the same meanings as defined above), for example, when R1 is a branched alkyl chain as represented in the above-mentioned l formula, the alkyl chain branched from the same carbon atom, together with the carbon atom bound thereto, forms a saturated carbon ring, as shown in the following general formula: (wherein all ofthe s have the same meanings as defined above).
In the present invention, "when two of R2 represent a C1—3 alkyl group and are on the same carbon atom, the R2, together with a carbon atom bound thereto, may form a saturated C3—7 carbon ring" denotes that in a partial structure of the following general formula (I): (wherein all of the s have the same meanings as defined above), for example, when R2 is an alkyl group as represented in the above-mentioned general formula are on the same carbon atom, the R2, together with a carbon atom bound thereto, forms a ted carbon ring, as shown in the following general formula: (wherein all of the symbols have the same meanings as defined above).
In the t invention, "when two of R2"1 represent a C1—3 alkyl group and are on the same carbon atom, the R24, together with a carbon atom bound thereto, form a saturated C3—7 carbon ring" has the same definition as that for R2 in the phrase: "when two of R2 represent a C1—3 alkyl group and are on the same carbon atom, the R2, together with a carbon atom bound thereto, may form a saturated C3—7 carbon ring." In the present invention, it is preferable that m is one or more, and one of R2 is necessarily an oxo group. [003 6] In the present invention, it is preferable that A is CH.
In the present invention, it is preferable that R4 is a C14 alkoxy group or an —OR41 group. [003 8] In the present invention, it is preferable that L is —O-, ~NH—, or -C(O)-.
In the present invention, ringl is preferably a 6-membered cyclic group, and more ably benzene or pyridine.
In the present ion, it is preferable that the compound represented by general formula (I) is a compound represented by general formula (1—1): in all of the symbols have the same gs as defined .
In the present invention, it is preferable that two g anns in the ringl and ringl-l are bound to a para position.
In the present invention, in general a (1-1), A is preferably CH, and R4 is preferably a C1—4 alkoxy group or an -OR41 group.
In the present invention, preferable compounds preferably include the compounds described in Examples, and the following (1) to ( 17) are more preferable: N— { 5— [(6,7-dimethoxyquinolinyl)oxy] pyridinyl } -2,5 ~dioxo—l-phenyl—1,2,5,6,7,8—h exahydro-3—quinolinecarboxamide, (2)N- { 5-[(6,7—dimethoxy—4-quinolinyl)oxy] -2~pyridinyl } -7,7-dimethyl-2,5-dioxo- l -phe nyl-l ,2,5,6,7, 8—hexahydro-3 —quinolinecarboxamide, (3 )N-{5~[(6,7—dimethoxyquinolinyl)oxy]—2—pyridinyl}—1-(2,2-dimethylpropyl)-2,5~di 0x0— 1 ,2,5,6,7,8-hexahydro—3 -quinolinecarboxamide, (4) N~[5-({7-[3 -(4-morpholinyl)propoxy]—4—quinolinyl } oxy)—2-pyridinyl] -2,5-dioxo~l -phen yl- l ,2,5,6,7,8-hexahydro—3 -quinolinecarb0xamide, (5) N—{4—[(6,7~dimethoxy—4-quinolinyl)oxy]fluorophenyl}—2,5—dioxo- l -phenyl-l ,2,5 ,6,7, 8—hexahydro~3-quinolinecarboxamide, (6) N—{4-[(6,7-dimethoxy—4-quinolinyl)oxy]phenyl}-2,5-dioxo-1—phenyl-l,2,5 ,6,7,8-hexahy droquinolinecarboxamide, (7) N—{5—[(6,7—dimethoxy-4—quinolinyl)oxy]pyridinyl}-1—(4-fluorophenyl)-2,5-dioxo-1 ,2 ,5,6,7,8-hexahydro-3 -quinolinecarboxamide, (8) N— { 5-[(6,7-dimethoxyquinolinyl)oxy]pyridinyl}- l -(3 -fluorophenyl)-2,5-dioxo- 1 ,2 ,5 ,6,7,8~hexahydro-3 -quinolinecarboxamide, (9) N— { 5—[(6,7—dimethoxyquinolinyl)oxy]—2—pyridinyl}-1~(2-fluorophenyl)—2,5—dioxo— 1 ,2 ,5,6,7,8—hexahydro—3-quinolinecarboxamide, (10) N— {5—[(6,7-dimethoxy—4~quinazolinyl)oxy]—2—pyridinyl} -2,5—dioxo- l-phenyl- 1 ,2,5,6,7,8 ~hexahydro—3—quinolinecarboxamide, (11) N— { 5 — [(6,7—dimethoxyquinazolinyl)oxy]pyridinyl} - l -(4-fluorophenyl)-2,5-dioxo—l ,2,5,6,7,8—hexahydro~3 —quinolinecarboxamide, (12) N— { 5-[(6,7—dimethoxy-4—quinolinyl)oxy]pyridinyl}[(ZS)-l -hydroxymethy1~2-b utanyl]—2,5-dioxo—1,2,5,6,7,8-hexahydroquinolinecarboxamide, (13) N— {4-[(6,7—dimethoxy~4-quinolinyl)oxy] -3 -fluoropheny1}—l -(3 -fluoropheny1)-2,5-dioxo -1 ,2,5 ,6,7, 8—hexahydro-3~quinolinecarboxamide, (14) N— { 5—[(6,7—dimethoxy—4-quinolinyl)oxy]~2—pyridinyl } -6,6-dimethyl-2,5-dioxopheny1 ,6,7,8-hexahydro—3—quinolinecarboxamide, (15) N—[S-({6-methoxy-7~[3—(4-morpholinyl)propoxy]quinolinyl}oxy)pyridinyl]-2,5-di 0x0- 1 l- 1 ,2,5,6,7,8—hexahydro—3 -quinolinecarboxamide, (16) N-(5- { [7—(3~hydroxy-3 -methylbutoxy)methoxyquinolinyl]oxy}~2-pyridinyl)-2,5-d ioxophenyl-1,2,5,6,7,8-hexahydro-3—quinolinecarboxamide, (l 7) N—[5-({6-methoxy~7-[3 -(1-pyrrolidinyl)propoxy]~4—quinolinyl}oxy)pyridinyl]-2,5-di 0x0— 1 -phenyl-l ,2,5,6,7,8—hexahydro—3 —quinolinecarboxamide.
[Isomer] In the present invention, unless specifically directed, all of the isomers are included. For example, an alkyl group includes straight chain and ed chain groups. In addition, all of geometrical isomers of double bonds, rings, and fiised rings (E-, Z—, cis-, trans-isomers), optical isomers by the presence of an asymmetric carbon atom (R-, er, oc~, Iii-configurations, enantiomers, reomers), l active isomers having optical rotation property (D, L, d, l-isomers), polar isomers according to chromatographic separation (more polar isomer, less polar ), brium compound, rotamers, mixtures thereof at any rate, and racemic mixtures are included in the present invention. Furthermore, the present invention also encompasses all isomers by tautomers.
Furthermore, the optical isomer of the present ion is not only limited to an l isomer having purity of 100%, but also may include other optical isomers having purity of less than 50%.
In the present ion, unless otherwise noted, as apparent to a person skilled in the art, a symbol: ' represents binding toward the back side of the plane of the paper (that is to say, the oc—configuration), represents binding toward the front side of the plane of the paper (that is to say, the B-configuration), and represents oc—configuration, guration or an arbitrary mixture thereof.
The compound represented by general formula (I) is converted into a corresponding salt by the well~known method. A salt is preferably a water—soluble salt. Examples of a le salt include salts of an alkali metal (potassium, sodium, and the like), salts of an alkaline earth metal (calcium, magnesium, and the like), ammonium salts, or salts of a pharmaceutically acceptable c amine (tetramethylammonium, triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, dine, monoethanolamine, diethanolamine, tris(hydroxymethyl)aminomethane, lysine, arginine, N-methyl-D-glucamine, and the like), acid addition salts (inorganic acid salts (hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, and the like), c acid salts (acetate, trifluoro acetate, lactate, tartrate, oxalate, fumarate, e, benzoate, citrate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionate, glucuronate, gluconate, and the like).
The compound represented by l formula (I) and a salt thereof can be also converted into a solvate. It is preferable that the solvate is xic and water—soluble.
Examples of a suitable solvate include solvates with water, or an alcoholic solvent (for example, ethanol).
The N—oxide of the compound ented by l formula (1) denotes compounds represented by general formula (I) in which a nitrogen atom is oxidized.
Furthermore, the N-oxide of the compound represented by general formula (I) may be salts of alkali (earth) metal salt, ammonium salt, organic amine salt, and acid addition salt mentioned above.
The prodrug of the compound represented by general formula (1) denotes a compound which is converted to a nd represented by general formula (I) by a reaction with an enzyme, stomach acid, and the like, in a living body. Prodrugs of the compound represented by l formula (I) include: compounds in which the hydroxyl group is ed, alkylated, phosphorylated, or borated, when the compounds represented by general formula (I) have a hydroxyl group (for example, the compounds represented by general formula (I) in which the hydroxyl group is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, or dimethylaminomethylcarbonylated); and compounds in which the carboxyl group is esterified or amidated (for example, compounds represented by general formula (I) in which the carboxyl group is made into ethyl ester, isopropyl ester, phenyl ester, carboxymethyl ester, dimethylaminomethyl ester, pivaloyloxymethyl ester, carbonyloxyethyl ester, phthalidyl ester, (5—methyloxo-l,3-dioxolenyl)methyl ester, cyclohexyloxycarbonylethyl ester, methylamide, and the like). These nds can be produced by well—known methods. Furthermore, the g of the compound ented by general formula (I) may be e or non-hydrate. Furthermore, the prodrug of the compound represented by general formula (I) may be a compound which is changed into the compound represented by general a (I) under the physiological condition, as described in opment of Medicaments", vol.7 "Molecular Design", p.163-198, published by Hirokawa Shoten in 1990. In addition, the compound ented by general formula (I) may be labeled with an isotope thereof (for example, 2 H, 3 H, 1 l 13C,14C,13N,15N,150,17O,180,358,18F,36C1,1231,1251,andthelike).
[Process for producing nd of the present invention] The compound of the present invention can be produced by the well-known methods, for example, the method described in Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition (Richard C.
Larock, John Wiley & Sons Inc, 1999), or methods described in Examples, or the like, with appropriate modification and in combination thereof.
A compound represented eral formula (I) wherein LIS an oxygen atom, and R2IS an OX0 group, thatIS, a compound represented by general formula (I-A): / / A (LA) (R4)q \ \NJ in all of the s have the same meanings as defined above) can be produced by the process represented by the following on process schemes 1 and 2: Reaction process scheme 1 x‘xZ:. (R3)no:./XZ(R3)I1(Rah; NHZ (ll) (Rt)q :NJ _____,, (Rm—r :Njh—‘t / / (R4)~— Reaction 1 f (Nb) Reaction 2 q (3) \N in each of XI and X2 ndently represents a halogen atom, X1 and X2 be the same as or different from each other, and the other symbols have the same meanings as defined above). , In the reaction process scheme 1, the reaction 1 can be carried out by subjecting a compound represented by general formula (a) and a compound represented by general formula (II) to the aromatic nucleophilic substitution reaction. The aromatic nucleophilic substitution reaction is well known, and is carried out, for example, in an organic solvent (chlorobenzene, N,N-dimethyl sulfoxidc, N,N-dimethyl acetamide, N,N—dimethylformamide, chloroform, dichloromethane, diethyi ether, ydrofuran, methyl t-butyl ether, and the like), in the presence or e of a catalyst (4-dimethy1aminopyridine (DMAP) and the like), and in the presence or absence of a base m hydride, triethylamine, cesium carbonate, and the like), at 0 to 200°C.
In the reaction process scheme 1, the reaction 2 is carried out by ng a compound represented by general formula (b) in an organic solvent (tetrahydrofuran, and the like), in the presence of a palladium catalyst (tris(dibenzylideneacetone)dipalladium(0) chloroform complex, and the like), in the presence of a base (lithium bis(trimethylsilyl)amide (LHMDS), pottasium bis(trimethylsilyl)amide (KHMDS), sodium bis(trimethylsilyl)amide (NaHMDS), and the like), a phosphine compound (2-dicyclohexylphosphino-2’,6’—dimethoxybiphenyl (S-Phos), rt—butylp‘hosphine (P(t—Bu)3), and the like) at 0 to 100°C, and then reacting by adding inorganic acid (hydrochloric acid, hydrobromic acid, hydroiodic acid, ic acid, phosphoric acid, nitric acid, and the like) at 0 to 150°C.
Alternatively, the production method for aryl amine bed in Organic Letters, Vol 3, No. 17, p.2729-2732, 2001 can be employed.
Reaction process scheme 2 RSI R5 H2N_R1 00") \ )9 o l (IV) Rd’ CN Reaction 3 Rd’0 0 Reaction 4 o ’9 (Rah _._, / / (l-A) (R4)q__ Reactions \ \NJ (wherein Rd represents a C1-4 alkyl group, and the other symbols have the same meanings as defined above).
In the reaction process scheme 2, the reaction 3 is carried out by a reaction of compound represented by general formula (d) and a compound represented by general formula (III). The reaction is well known, and, for example, can be d out at 0 to 100°C in an organic solvent (N,N—dimethyl formamide and the like), in the presence of a base (tert-butoxy potassium and the like).
In the reaction process scheme 2, the reaction 4 can be carried out by subjecting a nd represented by general formula (e) and a compound represented by general formula (IV) to on reaction. The reaction is well known, and, for example, can be carried out by reacting at 0 to 100°C in an alcohol solvent (methanol, ethanol, and the like).
In the reaction s scheme 2, the reaction 5 can be d out by using and subjecting the nd represented by general formula (c) and the compound ented by general formula (1) to an amidation reaction. The amidation reaction is well known, and examples thereof include: (1) a method using an acid halide, (2) a method using a mixed acid anhydride, and (3) a method using a condensing agent.
These methods are specifically described below: (1) The method using an acid halide is carried out, for example, by reacting a ylic acid with an acid halogenating agent (oxalyl chloride, thionyl chloride, and the like) in an organic solvent (chloroform, dichlcromethane, diethyl ether, tetrahydrofuran, and the like) at —20°C to reflux temperature, and then reacting the obtained acid halide in the presence of a base (pyridine, ylamine, dimethylaniline, dimethylaminopyridine, diisopropylethylamine, and the like) in amine and an organic solvent (chloroform, dichloromethane, diethyl ether, tetrahydrofuran, and the like) at 0 to 40°C. Additionally, the method can be also carried out by reacting the obtained acid halide with an amine at 0 to 40°C by using an alkaline aqueous solution (sodium bicarbonate water or sodium hydroxide solution, and the like) in an organic solvent (dioxane, tetrahydrofuran, and the like). (2) The method using a mixed acid ide is carried out, for example, by reacting ylic acid with an acid halide (pivaloyl chloride, tosyl chloride, mesyl chloride, and the like) or an acid derivative (ethyl formate, isobutyl chloroformate, and the like) in the presence of a base (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropylethylamine, and the like) in an organic solvent (chloroform, dichloromethane, diethyl ether, tetrahydrofuran, and the like) or in the absence of any solvent at 0 to 40°C, and then reacting the obtained mixed acid anhydride with amine in an organic solvent oform, dichloromethane, diethyl ether, tetrahydrcfuran, and the like) at 0 to 40°C. (3) The method using a condensing agent is carried out, for example, by reacting a carboxylic acid with an amine in an organic solvent (chloroform, dichloromethane, dimethyl formamide, diethyl ether, tetrahydrofuran, and the like) or in the absence of any solvent at 0 to 40°C in the presence or absence of a base (diisopropylethylamine (DIPEA), pyridine, ylamine, dimethylaniline, dimethylaminopyridine, and the like), using a condensing agent Aza—1—benzotriazolyl)—N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), (l ,3 ~dicyclohexylcarbodiimide (DCC), 1—ethy1-3—[3—(dimethylamino)propyl]carbodiimide (EDC), l l '-carbony1diimidazole (CD1), 2-chloro-l-methylpyridiniumiodine, l-propylphosphonic acid cyclic ide (PPA), and the like) and using, or not using, oxybenztriazole (HOBt).
These reactiOns (l), (2), and (3) are desirably carried out under an inert gas (argon, nitrogen, etc.) atmosphere in anhydrous conditions.
Furthermore, the compound ented by general formula (c) can be also ed by the reaction process scheme 3. on process scheme 3 3 (Rah) (R)n OHA‘Noz2 o'noz (V) A (R4)q ——————) \ \/Nf (R4)q Reactionl \/\/NJ Reaction6 (Rm :/./(R3NH2:Nj (a)' (by (wherein all of the symbols have the same meanings as defined above).
In the reaction process scheme 3, a compound ented by general formula (b)’ can be produced by the same method as in the above-mentioned reaction 1 using a compound represented by general formula (a)’ and the compound represented by general formula (V).
In the on process scheme 3, the reaction 6 can be carried out by subjecting the compound represented by general formula (b)’ to a ion reaction of the nitro group. The reduction reaction of a nitro group is well known, and can be carried out by, for e, the following method. (1) The reduction reaction is carried out in, for example, a solvent [ethers (tetrahydrofiiran, dioxane, dirnethoxyethane, diethyl ether, etc), alcohols (methanol, l, and the like), benzenes (benzene, toluene, and the like), s (acetone, methyl ethyl ketone, and the like), nitriles (acetonitrile, and the like), amides (dimethylformamide, and the like), water, ethyl acetate, acetic acid or a mixture solvent oftwo or more thereof] in the presence of a hydrogeneration catalyst (palladium—carbon, palladium black, palladium, palladium hydroxide, platinum dioxide, platinum-carbon, nickel, Raney-nickel, ruthenium chloride, etc), in the presence or absence of acids (hydrochloric acid, sulfuric acid, hypochlorous acid, boric acid, tetrafluoroboric acid, acetic acid, p-toluenesulfonic acid, oxalic acid, trifluoroacetic acid, formic acid, and the like), at normal pressure or reduced pressure under a hydrogen atmosphere, in the presence of formic acid ammonium or in the ce of hydrazine, at 0 to 200°C. (2) The reaction is carried out, for example, in a water—miscible solvent (ethanol, methanol, tetrahydrofuran, etc.) in the presence or absence of an acid (hydrochloric acid, hydrobromic acid, ammonium chloride, acetic acid, ammonium e, etc.) using a metal reagent (zinc, iron, tin, tin chloride, iron de, samarium, indium, sodium borohydride~Nickel chloride, etc.) at 0 to 150°C.
In the reaction process schemes 1 to 3, when a compound represented by each general formula includes a protective group, a ection reaction can be carried out if necessary. The deprotection reaction of the protective group is known, and can be d out by the methods mentioned below. Examples thereof include: (1) deprotection reactions by alkaline hydrolysis, (2) ection reaction in acidic conditions, (3) ection reaction by hydrogenolysis, (4) deprotection on of a silyl group, (5) deprotection reaction using metal, (6) deprotection on using a metal complex, and the like.
These s are specifically described: ( 1) The deprotection reaction by alkaline hydrolysis ion is carried out, for example, in an organic t (for e, methanol, tetrahydrofuran, dioxane, etc.) with hydroxide of alkaline metal (for e, sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), hydroxide of alkaline earth metal (for example, barium hydroxide, calcium hydroxide, and the like), or carbonate (for example, sodium carbonate or potassium carbonate, and the like), or an aqueous solution thereof or a mixture thereof at 0 to 40°C. (2) The deprotection reaction in acidic conditions is carried out, for example, in an organic solvent (for example, dichloromethane, chloroform, dioxane, ethyl acetate, methanol, isopropyl alcohol, tetrahydrofuran, anisole, etc.), organic acid (for example, acetic acid, trifluoroacetic acid, methanesulfonic acid, p-tosyl acid, etc.), or inorganic acid (for example, hloric acid, sulfuric acid, etc.), or a mixture thereof (for example, hydrogen bromide/acetic acid, etc.) in the presence or absence of 2,2,2- trifluoroethanol at O to 100°C. (3) The deprotection reaction by enolysis is carried out, for example, in a solvent (for example, ethers (tetrahydrofuran, e, dimethoxyethane, diethyl ether, etc.), alcohols (for example, methanol, ethanol, and the like), benzenes (for example, benzene, toluene, etc.), ketones (for example, acetone, methyl ethyl ketone, and the like), nitriles (for example, acetonitrile, and the like), amides (for example, N,N-dimethylformamide, and the like), water, ethyl acetate, acetic acid, or a mixture of two or more thereof, etc.) in the presence of a catalyst (for e, palladium-carbon, palladium black, palladium hydroxide—carbon, platinum oxide, Raney nickel, etc.) under en atmosphere at normal pressure or elevated pressure, or in the presence of ammonium formate at 0 to 200°C. (4) The deprotection reaction of a silyl group is d out, for example, in a water-miscible organic solvent (for example, ydrofuran, acetonitrile, and the like), by using tetrabutylammonium e at 0 to 40°C. The reaction is also carried out, for example, in organic acid (for example, acetic acid, trifluoroacetic acid, methanesulfonic acid, p-tosyl acid, etc.), or in inorganic acid (for example, hydrochloric acid , sulfuric acid, and the like) or a mixture thereof (for example, en bromide/acetic acid, and the like) at —1 0 to 100°C. (5) The deprotection reaction using a metal is carried out, for example, in an acidic solvent (for example, acetic acid, a buffer of pH 4.2 to 7.2, a mixed on of the solution and an organic solvent such as tetrahydrofuran, etc.) in the presence of powder zinc, if necessary, with an ultrasonic wave applied at 0 to 40°C. '[0073] (6) The deprotection reaction using a metal complex is carried out, for example, in an c solvent (for example, dichloromethane, N,N—dimethylformamide, tetrahydrofuran, ethyl e, acetonitrile, dioxane, ethanol, etc), water or a mixed solvent thereof in the presence of a trap reagent (for example, yltin hydride, triethylsilane, ne, morpholine, diethylamine, pyrrolidine, etc.), an organic acid (for example, acetic acid, formic acid, 2—ethylhexanic acid, etc.) and/or in the ce of an organic acid salt (for example, sodium 2-ethylhexanate, potassium 2-ethylhexanate, and the like) in the presence or absence of a phosphine reagent (for example, triphenylphosphine, and the like) using a metal x (for example, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium (II), ium acetate (II), chlorotris(triphenylphosphine)rhodium (I), etc.) at 0 to 40°C.
In addition to the above—mentioned methods, the deprotection reaction can be carried out by the method described in for e, T. W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1999.
Examples of a protective group for a hydroxyl group include a methyl group, a trityl group, a methoxymethyl (MOM) group, a l-ethoxyethyl (EB) group, a methoxyethoxymethyl (MEM) group, a ahydropyranyl (THP) group, a trimethylsilyl (TMS) group, a triethylsilyl (TBS) group, a t-butyldimethylsilyl (TBDMS) group, a t—butyldiphenylsilyl (TBDPS) group, an acetyl (Ac) group, a pivaloyl group, a benzoyl group, a benzyl (Bn) group, a p—methoxybenzyl group, an allyloxycarbonyl (Alloc) group, a 2,2,2~trichloroethoxycarbonyl (Troc) group, and the like.
Examples of a protective group for an amino group include a benzyloxycarbonyl group, a t-butoxycarbonyl group, an allyloxycarbonyl (Alloc) group, a 1-methyl-l-(4-biphenyl)ethoxycarbonyl (Bpoc) group, a trifluoroacetyl group, a 9-fluororenylmethoxycarbonyl group, a benzyl (Bn) group, a p—methoxybenzyl group, a benzyloxymethyl (BOM) group, a 2-(trimethylsi1yl)ethoxymethyl (SEM) group, and the like.
The protective groups for a hydroxyl group and an amino group are not particularly limited to the above-described groups, and groups are included, in addition to the above-mentioned groups, as long as the groups can be detached easily and selectively. For example, those described in Protective Groups in Organic Synthesis (T. W. Greene, John Wiley & Sons Inc, 1999) may be used.
In each on in the present specification, compounds used as starting raw material, for example, the nd ented by general formula (a), (a)’, (d), (II), (III), (IV) or (V) is well known or can be ed by well-known s.
In each reaction in the present specification, as apparent to the skilled persons in the art, the reactions involving heating can be carried out using a water bath, an oil bath, a sand bath or a microwave.
In each reaction in the present specification, a supported reagent which is supported on a high molecular polymer (e.g., polystyrene, polyacrylamide, polypropylene, polyethylene glycol, etc.) may be appropriately used.
In each reaction in the present cation, the reaction products can be purified by tional purification methods, for example, by distillation at normal or d pressure, by high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, ion-exchange resin, scavenger resin, or column chromatography, washing, recrystallization, or the like. The purification may be done after action or after several reactions.
[Toxicity] The toxicity of the compound of the present invention is sufficiently low, and the compound can be safely used as pharmaceuticals.
[Application to pharmaceuticals] Since the compound of the present invention has an Axl inhibitory activity, it can be used as an agent for preventing and/or treating an AXl-related disease in mammals, especially in human.
In the present invention, examples of the Axl-related diseases include cancer, kidney es, immune system e, and atory system disease.
In the present invention, the cancer includes acute myeloid leukemia, chronic myeloid leukemia, acute lymphatic leukemia, melanoma, breast , pancreatic , glioma, esophageal adenocarcinoma, large intestine cancer, renal cell carcinoma, thyroid cancer, non-small cell lung cancer, prostate cancer, stomach cancer, liver cancer, uveal malignant melanoma, ovarian cancer, endometrial cancer, ma, head and neck cancer, and sarcoma.
In the present invention, examples of the kidney diseases include glomerular nephritis, chronic nephritis, IgA nephritis, sequential dary) nephritis, nephrosis tis, acute renal failure, chronic renal failure, diabetic nephropathy, gouty nephropathy, interstitial nephritis, and pyelitis.
In the present invention, examples of the immune system disease include psoriasis, and toid arthritis.
In the present invention, examples of the circulatory system disease include atherosclerosis and thrombosis.
Furthermore, since the compound of the present invention has an Axl tory activity, it can be used as a metastasis ssing agent to cancer cell.
The compound of the present invention may be administered as a combination drug in combination with other drugs in order to accomplish the following purposes: 1) to supplement and/or enhance the preventive and/or therapeutic effect of the compound; 2) to improve the kinetics, improvement of absorption, and reduction of the dose of the nd; and/or 3) to eliminate the side effects of the compound.
A combination drug of the compound of the present invention and other drugs may be administered in the form of a compounding agent including these components mixed into one formulation, or may be administered in separate formulations.
Administration as separate formulations includes simultaneous administration and administration at ent times. In the administration at different times, the compound of the present invention may be administered before the other drug.
Alternatively, the other drug may be stered before the compound of the present invention. The method for the administration of these drugs may be the same as each other or different from each other.
Diseases on which the preventive and/or therapeutic effect of the above—mentioned combination drug works are not particularly d but may be those in which the preventive and/or therapeutic effect of the nd of the present invention is mented and/or enhanced.
The other drugs for supplementing and/or enhancing the preventive and/or therapeutic effect of the compound of the present invention t cancer include, for example, alkylating agents, antimetabolites, anticancer otics, plant alkaloids, hormones, platinum compounds, anti-CD20 antibodies, anti-CD52 antibodies, D-l antibodies, G—CSF formulations, acute promyelocytic ia differentiation-inducing agents, kinase tors, topoisomerase inhibitors, aromatase inhibitors, and other anticancer drugs.
The other drug for supplementing and/or enhancing the preventive and/or therapeutic effect of the nd of the t invention against kidney diseases include, for example, steroids, immunosuppressants, angiotensin II antagonistic drugs, angiotensin-converting enzyme inhibitors, antiplatelet drugs, and anticoagulant drugs.
The other drugs for supplementing and/or enhancing the preventive and/or therapeutic effect of the compound of the present invention against immune system diseases include, for example, immunosuppressants, steroid, disease-modifying anti-rheumatic drugs, prostaglandins, prostaglandin synthase inhibitors, phosphodiesterase inhibitors, metalloprotease inhibitors, anti-cytokine protein formulations such as anti—TNF—o: formulations, anti-IL-l formulations, and anti-IL-6 formulation, cytokine inhibitors, and nonsteroidal anti-inflammatory agents.
The other drugs for supplementing and/or enhancing the tive and/or therapeutic effect of the compound of the present invention against circulatory system diseases include antiplatelet drugs, angiotensin II antagonistic drugs, angiotensin—converting enzyme inhibitors, A reductase inhibitors, and thiazolidine derivatives.
Examples of the alkylating agents e nitrogen mustard N-oxide hydrochloride, cyclophosphamide, ifosfamide, melphalan, thiotepa, carboquone, busulfan, nimustine hydrochloride, dacarbazine, ranimustine, carmustine, chlorambucil, bendamustine, and mechlorethamine.
Examples of the antimetabolites include methotrexate, mercaptopurine, 6-mercaptopurine riboside, fluorouracil, tegafur, tegafur uracil, carmofur, ridine, cytarabine, enocitabine, tegafur gimestat otastat potassium, abine hydrochloride, cytarabine ocfosfate, procarbazine hydrochloride, and hydroxycarbamide.
Examples of the anticancer antibiotics include actinomycin D, mitomycin C, daunorubicin hydrochloride, doxorubicin hydrochloride, bicin hydrochloride, neocarzinostatin, pirarubicin hydrochloride, epirubicin (hydrochloride), idarubicin hydrochloride, mycin A3, bleomycin (hydrochloride), peplomycin sulfate, therarubicin, zinostatin stimalamer, gemtuzumab ozogamicin, and the like.
Examples of the plant formulations include Vinblastine sulfate, vincristine sulfate, vindesine e, irinotecan hydrochloride, etoposide, flutamide, Vinorelbine tartrate, docetaxel e, paclitaxel, and the like.
Examples of the hormones include estramustine phosphate sodium, mepitiostane, epitiostanol, lin acetate, trol (diethylstilbestrol phosphate), fen citrate, fene citrate, fadrozole hydrochloride hydrate, medroxyprogesterone acetate, bicalutamide, leuprorelin acetate, anastrozole, aminoglutethimide, androgen bicalutamide, fulvestrant, and thelike.
Examples of the platinum nds include carboplatin, cisplatin, nedaplatin, and oxaliplatin, and the like.
Examples of the D20 antibodies include rituximab, ibritumomab, ibritumomab tiuxetan, and ocrelizumab.
Examples ofthe anti—CD52 antibodies include alemtuzumab.
Examples of the anti-PD-l antibodies include nivolumab, and lizumab.
Examples of the G—CSF formulation include rastim, filgrastim, lenograstim, and rastim.
Examples of the differentiation-inducing agent for acute promyelocytic leukemia include tamibarotene, tretinoin, and arsenic trioxide formulations.
Examples of the kinase inhibitors include EGFR inhibitors including erlotinib hydrochloride, gefitinib, cetuximab, and panitumumab; HER2 inhibitors including nib and zumab; BCR-ABL inhibitors including imatinib, dasatinib, and nilotinib; inase inhibitors including sunitinib, vandetanib, crizotinib, and sorafenib.
Examples of the topoisomerase inhibitor include topotecan, teniposide, irinotecan, and sobuzoxane.
Examples of the ase inhibitor include tane.
Examples of the other anticancer agents include L—asparaginase, octreotide acetate, porfimer sodium, mitoxantrone acetate, aceglatone, ubenimex, eribulin mesilate, cladribine, krestin, bexarotene, denileukin Vdiftitox, temozolomide, nelarabine, fludarabine, bevacizumab, pemetrexed, pentostatin, bortezomib, lenalidomide, and calcium folinate.
Examples of the immunosuppressant include azathioprine, ascomycin, everolimus, salazosulfapyridine, cyclosporine, cyclophosphamide, sirolimus, tacrolimus, amine, methotrexate, and mide.
Examples of the steroid include amcinonide, hydrocortisone sodium succinate, solone sodium succinate, methylprednisolone sodium succinate, ciclesonide, difluprednate, betarnethasone propionate, dexamethasone, deflazacort, triamcinolone, triamcinolone acetonide, halcinonide, dexamethasone palmitate, hydrocortisone, flumetasone pivalate, prednisolone butylacetate, budesonide, prasterone sulfate, mometasone e, fluocinonide, fluocinolone acetonide, ycortide, flunisolide, prednisolone, alclometasone propionate, clobetasol nate, dexamethasone propionate, deprodone propionate, fluticasone propionate, etasone propionate, betamethasone, prednisolone, methylpredm'solone suleptanate, methylprednisolone sodium ate, thasone sodium phosphate, hydrocortisone sodium phosphate, prednisolone sodium phosphate, diflucortolone valerate, dexamethasone valerate, betamethasone valerate, prednisolone valerate acetate, cortisone acetate, diflorasone acetate, dexamethasone acetate, triamcinolone acetate, paramethason acetate, halopredone acetate, fludrocortisone acetate, prednisolone acetate, methylprednisolone acetate, clobetasone butyrate, hydrocortisone butyrate, hydrocortisone butyrate propionate, and betamethasone butyrate propionate.
Examples of the angiotensin II antagonistic drug include losartan, candesartan, tan, irbesartan, olmesartan, telmisartan, and the like.
Examples of the angiotensin—converting enzyme tor e alacepril, imidapril hydrochloride, quinapril hloride, temocapril hydrochloride, delapril hydrochloride, benazepril hydrochloride, captopril, trandolapril, perindopril erbumine, ril maleate, lisinopril, and the like.
Examples of the antiplatelet drugs include dipyridamole, and dilazep hydrochloride h ydrate.
Examples of the anticoagulant drugs include warfarin and heparin.
Examples of the disease—modifying anti-rheumatic drugs include D-penicillamine, actarit, auranofin, salazosulfapyridine, hydroxychloroquine, bucillamine, methotrexate, leflunomide, arit sodium, aurothioglucose, and sodium aurothiomalate.
Examples of the prostaglandins (hereinafter, iated as "PG") include PGEl formulations (examples: alprostadil alfadex, alprostadil, and the like), PGIZ formulations (example: beraprost sodium, and the like), PG receptor ts, and PG receptor antagonists. Examples of the PG receptor include PGE receptors (EPl, EPZ, EP3, and EP4), PGD ors (DP, and CRTH2), PGF receptors (FP), PGIZ receptors (IP), and TX receptors (TP).
Examples of the prostaglandin se inhibitor e salazosulfapyridine, mesalazine, olsalazine, 4-aminosalicylic acid, JTE—522, auranofin, carprofen, diphenpyramide, flunoxaprofen, flurbiprofen, indometacin, ofen, lornoxicam, loxoprofen, cam, oxaprozin, mide, naproxen, piroxicam, piroxicam cinnamate, zaltoprofen, and pranoprofen.
Examples of the phosphodiesterase inhibitor include rolipram, cilomilast, Bayl9~8004, NIK—616, roflumilast (BY-217), cipamfylline (BRL-61063), atizoram (GP-80633), ONO—6126, SCH—35 1591, YM-976, V—11294A, 787, D-4396, and IC—485.
Examples of the anti-TNF-oc formulation include anti-TNF-a antibodies, soluble TNF-OL receptor, anti—TNF-oc receptor antibodies, and soluble TNF-oc binding protein, and particularly infliximab and etanercept.
Examples of the anti—IL—l formulation e anti-IL-l antibodies, soluble IL-1 receptor, L-lRa antibodies and/or anti-IL-l receptor antibodies and particularly anakinra.
Examples of the anti-IL-6 formulation include anti—IL—l antibodies, soluble lL-6 receptor, and L-6 receptor antibodies, and ularly tocilizumab. es ofthe cytokine inhibitor include suplatast tosylate, T—614, SR—31747, and sonatimod.
Examples of the HMG—COA reductase inhibitor include atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.
Examples of the thiazolidine tive include pioglitazone, ciglitazone, rosiglitazone, and troglitazone.
Furthermore, the combination drugs to be combined with a compound of the present invention es not only ones discovered to date, but also ones that may be discovered in the future.
The nd of the present invention is usually administered systemically or locally, by oral or parenteral administration. Examples of oral agents e liquid medicines for internal use (for example, elixirs, syrups, pharrnaceutically acceptable water-based agents, suspensions, and emulsions), and solid medicine for internal (for example, tablets (including sublingual tablets and orally disintegrating tablets), pills, capsules (including hard capsules, soft capsules, gelatin capsules, and microcapsules), powders, granules, and lozenges). Examples of parenteral agents e liquid medicines (for example, injection agents (subcutaneous injection agents, intravenous injection agents, uscular injection agents, intraperitoneal injection agents, and drip agents, and the like), eye drops (for example, s eye drops (aqueous eye drops, aqueous eye drop sions, Viscous eye drops, and solubilized eye drops, etc), and nonaqueous eye drops (for example, nonaqueous eye drops and nonaqueous eye drop suspensions), and the like), agents for external use (for example, ointments (ophthalmic nts, and the like», and ear drops, and the like. These formulations may be controlled release agents such as rapid e formulations, sustained release formulations, and the like. These formulations can be produced by well-known methods, for example, by the methods described in The Japanese Pharmacopoeia.
Liquid medicines for internal use as the oral agent can be produced by, for example, dissolving or suspending an active ingredient in a generally used t (for example, purified water, l, or mixture liquid thereof, or the like). The liquid medicine may include a wetting agent, a suspension agent, a sweetening agent, a flavoring material, an aromatic substance, a vative, a buffer agent, and the like. [0131} Solid medicines for internal use as the oral agent are formulated by, for example, mixing the active ingredient with, for example, a vehicle (for example, lactose, mannitol, glucose, microcrystalline cellulose, starch, and the like), a binder (for example, hydroxypropyl cellulose, polyvinylpyrrolidone, magnesium metasilicate aluminate, and the like), a disintegrant (for example, sodium carboxymethylcellulose, and the like), lubricant (for example, magnesium stearate, and the like), a stabilizer, a dissolution adjuvant (for e, ic acid, aspartic acid, and the like), and the like, and ating according to standard methods. As necessary, coating may be carried out with a coating agent (for example, sugar, gelatin, hydroxypropyl cellulose, hydroxypropyl methyl ose phthalate, and the like), and coating of two or more layers may be employed.
Agents for al use as parenteral agents are produced by well—known methods or generally used iptions. For example, an ointment may be produced by incorporation or melting of an active ingredient into base material. The ointment base material is selected from well-known material or generally used material. For example, a single al or a mixture of two or more of materials are selected from higher fatty acids and higher fatty acid esters (for example, adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipate esters, myristate esters, palmitate esters, stearate , oleate esters, and the like), waxes (for example, beeswax, spermaceti, ceresin, and the like), surfactants (for example, polyoxyethylene alkyl ether phosphate esters, and the like), higher alcohols (for example, l, l alcohol, etostearyl alcohol, and the like), silicone oils (for example, dimethylpolysiloxane, and the like), hydrocarbons (for example, hilic petrolatum, white petrolatum, purified lanolin, liquid paraffin, and the like), glycols (for example, ethylene , diethylene glycol, propylene glycol, polyethylene glycol, macrogol, and the like), plant oils (for example, oastor oil, olive oil, sesame oil, turpentine oil, and the like), animal oils (for example, mink oil, egg yolk oil, squalane, squalene, and the like), water, absorption promoters, and anti-irritants. rmore, a humectant, preservative, stabilizer, antioxidant, fragrance, and the like, may be included.
The injection agents as parenteral agents include solutions, suspensions, emulsions and solid injection agents to be dissolved or suspended in a solvent before use. The injection agent is used by, for example, dissolving, ding or emulsifying an active ingredient in a solvent. Examples of the solvent include distilled water for injection, logical saline, vegetable oils, alcohols such as propylene glycol, polyethylene glycol, ethanol, and mixtures thereof. Furthermore, the injection agent may contain a stabilizer, a dissolution aid (glutamic acid, aspartic acid, and Polysorbate 80 (registered trademark), etc.), a ding agent, an emulsifying agent, a soothing agent, a buffer, a preservative, and the like. Such an injection agent is produced by sterilizing at the final step or employing an aseptic process. Furthermore, it is also possible to employ an aseptic solid product such as a freeze-dried product produced and sterilized or dissolved in aseptic distilled water for injection or other solvent before use.
When the compound of the present invention or combination agents of the nd of the present ion and other agents are used for the above-mentioned purposes, they are usually administered systemically or y, y by oral or parenteral administration. The doses to be administered are different depending upon ages, body weights, symptoms, therapeutic effects, administration method, treatment time, and the like. The doses per adult person are generally from 1 ng to 1000 mg per dose, once or several times per day, by oral administration, from 0.1 rig to 100 mg per dose, once or several times per day, by eral administration, or continuous administration 1 to 24 hours per day intravenously. Needless to say, as ned above, the doses to be used vary dependent upon various conditions. Therefore, doses lower than the ranges specified above may be sufficient in some cases, and doses higher than the ranges specified above are needed in some cases. les] Hereinafter, the present invention is described in detail with reference to es mentioned below, but the present invention is not limited thereto.
Solvents given in parentheses shown in chromatographic separation and TLC each indicate the eluting solvent or the developing solvent used, and the ratio is expressed in ratio by volume. The description "NH silica" denotes that CHROMATOREX NH TLC PLATE (catalog No.; 3800003) manufactured by FUJI SILYSIA AL LTD. is used; and "DNH silica" denotes that CHROMATOREX NH TLC PLATE (catalog No.; 3800403) ctured by FUJI SILYSIA AL LTD. is used; LC-MS/ELSD was carried out in the following conditions: {Columnz Waters ACQUITY C13 (particle diameter: 1.7 x 106; column length: x 2.1 mm ID); flow rate: 1.0 mL/min; column temperature: 40°C; mobile phase (A): 0.1 % formic acid aqueous solution; mobile phase (B): 0.1 % formic acid-acetonitrile solution; gradient (rate of mobile phase (A) : mobile phase (8)): [0 min] 95:5; [0.1 min] 95:5; [1.2 min] 5:95; [1.4 min] 5:95; [1.41 min] 95:5; [1.5 min] 95:5; detector: UV (PDA), ELSD, MS} The description in a parenthesis in the NMR data shows a solvent used for measurement.
Name of the compounds used in this specification are named by using ACD/Name (registered trademark) manufactured by Advanced Chemistry Development Inc, which is a computer program for naming nds according to the regulation of IUPAC, or named according to the naming method of IUPAC.
Example 1 4-[(6—chloro-3—pyridinyl)oxy]-6,7-dimethoxy quinoline Under the stream of nitrogen, a solution of 4-chloro—6,7-dimethoxy quinoline (1.00 g) (CAS registration No.: 56-9) in chlorobenzene (9 mL), 6-chloropyridineol (0.65 g), and triethyl amine (11.3 mL) were placed in a 100-mL four—necked flask, and the mixture was stirred at a bath temperature (140°C) for five days. The resulting solution was left to cool to room temperature, water and ethyl acetate were added thereto, and the solution was separated. The water layer was extracted again with ethyl acetate, and the combined organic layer was washed with saturated saline solution, and dried over anhydrous sodium sulfate. The t was distilled off under reduced re. The resulting residue was d by silica gel column chromatography (hexane : ethyl acetate = 1:8) to obtain the title compound (1.16 g) having the following physical property values.
TLC: Rf 0.22 (hexane : ethyl acetate = 1:3); 1H—NMR ds) : 8 8.52, 8.48, 7.87 - 7.85, 7.66, 7.49, 7.43, 6.65, 3.95, 3.93.
Example 2: -[(6,7-dimethoxyquinolinyl)oxy]~2-pyridinamine Under the stream of nitrogen, a on of the compound (1.15 g) produced in Example 1 in tetrahydrofuran (THF) (18 mL), 1.0 mol/L lithium bis(trimethylsilyl)amide (LHDMS) (5.45 mL), ibenzylideneacetone)dipalladium(0) chloroform complex (0.19 g), and 2—dicyclohexylphosphino~2’,6’—dimethoxybiphenyl (0.15 g) were placed in a 200~mL four—necked flask, and the mixture was stirred at a bath temperature (80°C) for 16.5 hours. Furthermore, 6 mol/L hloric acid (10 mL) was added thereto, and the mixture was stirred at a bath temperature (80°C) for two hours. The mixture was left to cool to room temperature, then a sodium hydrogen onate aqueous solution and ethyl acetate were added, and the ing solution was separated. The water layer was extracted again with ethyl acetate, and the combined organic layer was washed with a saturated saline solution, and then dried over anhydrous sodium sulfate. The solvent was led off under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate ——> ethyl acetate : methanol = 9:1) to obtain the title compound (0.80 g) having the following physical property values.
TLC: Rf 0.51 (ethyl acetate : methanol = 4:1); 1H-NMR (DMSO-d6 ): 8 8.45, 7.89, 7.51, 7.38 - 7.36, 6.56, 6.42, 6.05, 3.94.
Example 3: ethyl 2,5—dioxo-5,6,7,8-tetrahydro-2H—chromenecarboxylate 1,3-cyclohexanedione (CAS registration No.: 5049) (13.25g) was dissolved in N,N—dimethyl formamide (DMF) (200 mL) at room temperature, and tert-butoxy potassium (13.26 g) and ethyl (E)oyanoethoxypropenoate (CAS registration No.: 943) (20.00 g) were added o. The mixture was stirred for 21 hours.
The reaction solution was diluted with ethyl acetate, 2 mol/L hydrochloric acid aqueous on was added thereto, and the e was stirred. Ethyl acetate and water were further added, and the organic layer was extracted. The extract was washed with a saturated saline solution, then dried over anhydrous sodium sulfate, and the solvent distilled off under reduced pressure to obtain the title compound (23.62 g) having the following physical property values.
TLC: Rf0.35 (hexane : ethyl acetate = 1:1); lH—NMR (CDC13 ): 8 1.37, 2.19, 2.61, 2.92, 4.36, 8.63.
Example 4: 2,5-dioxophenyl - l ,2,5,6,7,8-hexahydroquinoline carboxylic acid The compound (10.00 g) produced in Example 3 was dissolved in ethanol (200 mL) at room temperature, aniline (3.94 g) was added thereto, and the mixture was stirred for six hours. Solids itated from the reaction on were collected by filtration through Kiriyama funnel, and washed with ethanol. The obtained residue was dried under reduced pressure at 60°C. The title compound (4.01 g) having the following physical property values was obtained.
TLC: Rf0.37 (dichloromethane : ol = 9:1); 1I-I-NMR ): 8 2.11, 2.60, 7.25, 7.63, 9.21. e 5: N—{5-[(6,7-dimethoxyquinoliny1)oxy]pyridinyl}—2,5-dioxo—1—pheny1—1,2,5,6,7,8—h exahydroquinolinecarboxamide The nd (105 mg) produced in Example 4 and O-(7-azabenzotriazolyl)-N,N,N’,N’-tetramethyl uronium hexafluorophosphate (HATU) (192 mg) were dissolved in DMF ‘(2 mL) at room temperature, diisopropylethylamine (DIPEA) (0.17 mL) and the compound (100 mg) produced in Example 2 were added thereto, and the mixture was d for 21 hours. The solvent was led ofi under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane : ethyl acetate = 30:70 —> 0:100 —> ethyl acetate : methanol = 70:30) to obtain the title compound (116 mg) having the following physical property values.
TLC: Rf 0.76 (ethyl acetate : methanol = 5:1); 1H-NMR (CDClg): 5 2.13, 2.60, 4.05, 6.44, 7.25, 7.42, 7.53, 7.63, 8.22, 8.48, 8.51, 9.32, 11.93.
Examples 5(1) to 5(54) The following Example compounds were obtained by the procedure having the same e as in Example 5 using the compound produced in Example 2 and correSponding ylic acid derivatives in place of the compound produced in Example 4. e 5(1): N-{5~[(6,7-dimethoxy—4—quinolinyl)oxy]pyridinyl}—7,7—dimethyl-2,5—dioxophenyl — 1 ,2, 5 ,6,7,8-hexahydro—3 —quinolinecarboxamide we’ / H‘c\o \N TLC: Rf 0.75 (ethyl acetate : methanol = 5:1); IH—NMR (CDCl3): 5 1.06, 2.43, 2.48, 4.05, 6.45, 7.25, 7.43, 7.54, 7.55-7.65, 8.22, 8.48, 8.51, 9.32, 11.92.
Example 5(2): N— { 5 - [(6,7—dimethoxy—4—quinolinyl)oxy] —2—pyridiny1} -2 ’,5 ’ -dioxo- 1 ’ -phenyl-2’ ,5 ’ ,6’ ,8 ’ -tetrahydro-l ’H-spiro propane- 1 ,7’ -quinoline]-3 ’ —carboxamide TLC: Rf 0.69 (ethyl acetate : methanol = 5:1); 1H—NMR (CDC13 ): 5 0.39, 0.54, 2.41, 2.48, 4.05, 6.45, 7.22, 7.43, 7.53, 7.55-7.62, 8.22, 8.49, 8.51, 9.36, 11.92.
(Byproduct) N— { 5- dimethoxyquinoliny1)oxy]—2-pyridinyl}-8 ’ —hydroxy—2 ’ ,5 ’ -di0X0-l ’-pheny 1-2 ’ ,5 ’ ,6’,8’ -tetrahydro-1’H—spiro[cyclopropane-1,7’-quinoline]-3 "-carboxamide TLC: Rf0.68 (ethyl e : methanol = 5:1); 1H—NMR (CDC13 ): 8 0.44, 0.61, 1.89, 3.39, 3.45, 4.10, 4.14, 6.76, 7.19, 7.47, 7.58-7.65, 7.86, 8.25, 8.63, 9.27, 12.05.
Example 5(3): N—{5—[(6,7~dimethoxy—4—quinolinyl)oxy]~2-pyridinyl}ethyl-2,5—dioxo-l ,2,5,6,7,8-hex ahydro—3—quinolinecarboxamide (LC—MS/ELSD): (retention time: 0.70 min); 1H—NMR (CDCl3 ): 5 1.41-1.46, 2.25-2.29, 2.62-2.65, .11, 4.06, 4.26-4.30, 6.45-6.47, 7.43, 7.55, 7.55-7.60, 8.29—8.31,8.50-8.53, 9.21, 12.23.
Example 5(4): N—{S—[(6,7-dimethoxyquinolinyl)oxy]—2—pyridinyl}— l -(4-fluorobenzyl)-2,5-dioxo- 1 ,2 ,5,6,7,8—hexahydroquinolinecarboxamide (LC-MS/ELSD): (retention time: 0.80 min); 1H-NMR (CDC13 ): 5 2.14-2.20, 2.58—2.63, 2.96—3.01, 4.06, 5.50, 6.45-6.47, .10, 7.26-7.37, 7.43, 7.55, 7.57—7.61, 8.29-8.30, 8.50—8.54, 9.29, 12.10.
Example 5(5): (6,7~dimethoxy—4—quinolinyl)oxy]~2—pyridinyl}—2,5—dioxo—1—(tetrahydro-2H-pyra n—4-yl)-l,2,5,6,7,8~hexahydroquinolinecarboxamide (LC-MSIELSD): (retention time: 0.67 min); 1 H—NMR (CDC13 ): 8 2.20-2.30, 2.60-2.64, 3.00-3.30, 3.45-3.55, 4.06, 4.15-4.20 4.40-4.60, 6.45647, 7.44, 7.55—7.61, 8.30—8.31, 8.49-8.52, 9.20, 12.17.
Example 5(6): N- { 5- [(6,7-dimethoxy—4-quinolinyl)oxy]pyridinyl} (2,2-dimethylpropyl)-2,5-dioxo -1 ,2,5 ,6,7,8-hexahydro-3 -quinolinecarboxamide / T" "x": \ o o H3C\o \N TLC: Rf 0.54 (ethyl acetate : methanol = 9:1); 1H—NMR (CDC13): 5 0.99, 2.09, 2.56, 3.19, 3.94, 4.25, 6.54, 7.40, 7.53, 7.86, 8.39, 8.48, 8.89, 12.19.
Example 5(7): (6,7-dimethoxy—4-quinolinyl)oxy]pyridinyl}—1-(4-fluorophenyl)-2,5-dioxo-1 ,2 ,5,6,7,8-hexahydro—3—quinolinecarboxamide Hac’o / H c° \0 \N TLC: Rf0.59 (dichloromethane : methanol = 9:1); 1I-I-NMR (CDC13 ): 6 2.13, 2.60, 4.05, 6.44, 7.24 * 7.35, 7.43, 7.54, 7.57, 8.23, 8.50, 9.32, 11.88. [0 149] Example 5(8): N-{5—[(6,7-dimethoxy-4—quinolinyl)oxy]—2—pyridiny1}—6,6—dimethyl—2,5-dioxo-l -phenyl —1 ,2,5,6,7,8-hexahydro—3 -quinolinecarboxamide TLC: Rf0.51 (dichloromethane : ol = 10:1); IH-NMR (CDC13 ): 6 1.13, 1.80-1.90, 2.40-2.60, 3.92, 3.94, 6.53-6.55, 7.40, 7.50-7.53, 7.57-7.66, 7.84-7.88, 8.34—8.36, 8.40-8.43, 8.47-8.49, 8.99, 11.98.
Example 5(9): N—{5—[(6,7—dimethoxyquinolinyl)oxy]~2—pyridiny1}-1—isobutyl-2,5-dioxo-1,2,5,6,7,8- hexahydro—3-quinolinecarboxamide TLC: Rf0.50 (ethyl acetate : methanol = 19:1); 1H-NMR d5): 8 0.94, 2.05-2.25, 2.49-2.65, 3.15-3.24, 3.93, 4.13, 6.54, 7.04, 7.53, 7.86, 8.38-8.45, 8.48, 8.89, 12.24.
Example 5(10): N»{5-[(6,7-dimethoxy—4—quinoliny1)oxy]~2-pyridinyl}-1—[(2R)— 1 -hydroxy~3-methy1—2-b ]~2,5—dioxo—1 ,2,5,6,7,8—hexahydro-3 ~quinolinecarboxamide TLC: Rf 0.20 (ethyl acetate, NH silica); lH—NMR (CDC13 ): 8 0.70, 1.11, 2.13, 2.41, 2.87-2.99, 3.35, 4.02, 4.07, 4.19, 4.88D 6.17, 7.19, 7.53, 7.86, 8.17, 8.37, 8.58, 8.61, 12.18.
Example 501): N— {5— [(6,7-dimethoxyquinoliny1)oxy]~2-pyridiny1 } — 1 —[(2S)hydroxy—3-methylb utanyl]-2,5-dioxo-1,2,5,6,7,8-hexahydro—3~quinolinecarboxamide H’c‘o \N TLC: Rf 0.20 (ethyl acetate, NH silica); IH-NMR (CDC13 ): 8 0.70, 1.11, 2.13, 2.41, 2.87-2.99, 3.35, 4.02, 4.07, 4.19, 4.88, 6.17, 7.19, 7.53, 7.86, 8.17, 8.37, 8.58, 8.61, 12.18.
Example 5(12): N— { 5—[(6,7—dimethoxy-4~quinolinyl)oxy]—2-pyridinyl } (3-fluorophenyl)-2,5-diox0~ 1 ,2 ,5,6,7,8—hexahydro-3—quinolinecarboxamide H,c’° / H"(kc \N TLC: Rf0.56 (ethyl e : methanol = 9: 1); 1H—NMR (CDC13 ): 8 2.13, 2.60, 4.05, 6.44, 7.07, 7.32, 7.43, 7.54, 7.59, 8.23, 8.49, 9.32, 11.85.
Example 5(13): N- {5 - [(6,7—dimethoxyquinolinyl)oxy]-2~pyridiny1 }-l -[1 —(hydroxymethyl)cyclobutyl] -2,5-dioxo-1 ,7,8—hexahydroquinolinecarboxamide TLC: Rf 0.15 (ethyl acetate, NH silica); 1I—l-NMR (CDC13 ): 8 1.81-1.95, 2.16-2.29, 2.40-2.75, 2.83—3.01, 3.45, 4.05, 4.06, 4.18, 4.48, 6.41, 7.39, 7.55, 7.61, 8.28, 8.46, 8.54, 9.08, 11.99.
Example 5(14): N—{5—[(6,7-dimethoxy—4—quino1inyl)oxy]—2—pyridinyl}—l~[(1R)~1—(4—fluorophenyl)ethyl] ioxo- 1 ,2,5,6,7,8-hexahydro-3 linecarboxamide TLC: Rf 0.5 l (ethyl acetate); lH-NMR (CDC13 ): 5 2.00—2.20, 2.45-3.07, 4.05, 4.06, 6.45, 7.03-7.12, 7.18-7.23, 7.43, 7.55, 7.58, 8.28, 8.50, 8.51, 9.23, 12.07.
Example 5(15): N— { 5-[(6,7-dimethoxy—4-quinolinyl)oxy]~2—pyridinyl}-1 -[(1 S)(4—fluorophenyl)ethyl]- 2,5-dioxo—l ,2,5,6,7,8-hexahydro—3-quinolinecarboxamide TLC: Rf 0.50 (ethyl acetate, NH silica); 1H—NMR (CDC13 ): 6 2.00-2.20, 2.45-3.07, 4.05, 4.06, 6.45, 7.03-7.12, 7.18-7.23, 7.43, 7.55, 7.58, 8.28, 8.50, 8.51, 9.23, 12.07.
Example 5( 16): N-{5-[(6,7-dimethoxyquinolinyl)oxy]pyridinyl}—1 —(2-fluorophenyl)-2,5~dioxo-1 ,2 ,5,6,7,8-hexahydro-3~qumolinecarboxamide TLC: Rf0.52 (ethyl acetate : methanol = 9:1); 1H~NMR (CDC13 ): 5 2.15, 2.63, 4.05, 6.44, 7.26 — 7.61, 8.22, 8.49, 9.33, 11.85.
Example 5(17): N— { 5 - [(6,7—dimethoxy-4—quinolinyl)oxy] —2—pyridinyl} ~2 ’ ,5 ’ -dioxo—1 ’ -phenyl-2’,5 ’,6’ ,8’ —tetrahydro-1 ’ H-spiro[cyclobutane—1,7’ -quinoline]—3 ’-earboxamide TLC: Rf 0.71 (ethyl acetate : ol = 5: 1); 1H—NMR (CDC13 ): 5 1.78-1.93, 2.64, 2.73, 2.93, 3.02, 4.05, 6.45, 7.24, 7.42, 7.53-7.67, 8.22, 8.49, 9.29, 11.92. [01 59] e 5(18): N— {5- [(6,7-dimethoxy-4—quinolinyl)oxy]pyridinyl } ~2,5-dioxo-l - [(1 S)-1—phenylethyl] —1,2,5,6,7,8—hexahydro—3~quinolinecarboxamide TLC: Rf 0.69 (ethyl acetate : methanol = 5:1); 1H—NMR (CDC13 ): 8 2.01, 2.55, 2.95, 4.05, 4.06, 6.44, 7.19, 7.29-7.43, 7.55, 7.57, 8.28, 8.49—8.53, 9.25, 12.13. e 5(19): 1 —cyclopropyl-N—{5-[(6,7-dirnethoxy—4~quinolinyl)oxy]—2-pyridinyl } ~2,5-dioxo- 1,2,5 ,6, 7,8-hexahydro—3~quinolinecarboxamide (LC-MS/ELSD): (retention time: 0.69 min); MASS (ESI, Pos.): 527(M+H)+.
Example 5(20): 1-(1 propyl-2—hydroxyethyl)~N—{5-[(6,7-dimethoxyquinolinyl)oxy] ~2—pyridinyl }—2,5-dioxo-1,2,5,6,7,8-hexahydroquinolinecarboxamide (LC—MS/ELSD): (retention time: 0.71 min); MASS (1381, Pos.): 571(M+H)+. [01 62] Example 5(21): N- {5-[(6,7-dimethoxy~4-quinolinyl)oxy]—2-pyridinyl}[2-(methylsulfonyl)—1-phenylet hyl] —2,5-dioxo-l ,2,5,6,7,8-hexahydro—3 -quinolinecarboxamide TLC: Rf0.67 (ethyl acetate : methanol = 5:1); lH-NMR (CDC13 ): 8 2.20-2.80, 3.14, 3.92, 3.93, 4.61, 6.29, 6.49, 7.33, 7.39, 7.50, 7.83, 8.34, 8.45, 8.92, 11.80. [01 63] Example 5(22): N—{5—[(6,7-dimethoxy—4~quinolinyl)oxy]~2-pyridinyl} ~2,5-dioxo— 1 —(3 —pentanyl)- 1 ,2,5 xahydro—3—quinolinecarboxamide (LC~MS/ELSD): (retention time: 0.80 min); MASS (ESL Pos.): 557(M+H)+.
Example 5(23): N— {5 —[(6,7—dimethoxy—4—quinolinyl)oxy] -2—pyridinyl} — 1 ~(2-hydroxy—2-methylpropyl)-2, S-dioxo—l ,2,5,6,7,8—hexahydro-3—quinolinecarboxamide (LC—MS/ELSD): tion time: 0.66 min); MASS (1381, Pos.): 559(M+H)+.
Example 5(24): N- {5- [(6,7-dimethoxyquinoliny1)oxy]pyridiny1 } — 1 -(l-hydroxy-3 -methylbutanyl )~2,5-dioxo-l,2,5,6,7,8-hexahydro-3 -quinolinecarboxamide (LC—MS/ELSD): (retention time: 0.71 min); MASS (ESI, Pos.): 573(M+H)+. [01 66] Example 5(25): 1-cyclobutyl-N~{5-[(6,7-dimethoxy—4-quinolinyl)oxy]—2~pyridinyl}-2,5-dioxo-1,2,5,6,7, 8-hexahydr0-3~quinolinecarboxamide (LC—MS/ELSD): (retention time: 0.74 min); MASS (ESL Pos.): 541(M+H)+.
Example 5(26): N-{5—[(6,7-dimethoxy~4-quinolinyl)oxy]pyridinyl}-l-[1~(4-fluorophenyl)ethyl]-2,5—d ioxo-1,2,5,6,7,8-hexahydro—3-quinolinecarboxamide (LC-MS/ELSD): (retention time: 0.80 min); MASS (ESL Pos.): 609 (M+H)+. e 5(27): N—{5-[(6,7-dimethoxy—4—quinolinyl)oxy]~2—pyridinyl}—2,5-dioxo(3—pyridinyl)—1,2,5,6 ,7,8—hexahydro—3«quinolinecarboxamide (LC-MS/ELSD): (retention time: 0.63 min); MASS (ESI, Pos.): 564(M+H)+. e 5(28): N—{5—[(6,7—dimethoxy—4~quinoliny1)oxy]~2—pyridinyl}— 1 - [2-(dimethylamino)ethyl]-2,5- dioxo~1,2,5,6,7,8*hexahydro—3-quinolinecarboxamide (LC—VIS/ELSD): tion time: 0.51 min); MASS (1381, Pos.): 558(M+H)+.
Example 5(29): (6,7-dimethoxy—4—quinoliny1)oxy]pyridinyl}- 1 —(2-methoxymethylpropyl) ,S—dioxo—l,2,5,6,7,8-hexahydro-3—quinolinecarboxamide TLC: Rf0.65 (dichloromethane : methanol = 9:1); lH—NMR (CDC13 ): 8 1.19-1.35, 2.18, 2.62, 2.81, 3.16, 3.83, 4.06, 4.07, 4.99, 6.45, 7.27, 7.44, 7.56, 7.59, 8.31, 8.51, 8.54, 9.23, 12.24.
Example 5(30): N-{5-[(6,7—dimethoxyquinolinyl)oxy]pyridinyl}—1~(3-hydroxy—3-methylbutanyl )—2,5-dioxo-l,2,5,6,7,8—hexahydro-3—quinolinecarboxamide (LC-MS/ELSD): (retention time: 0.70 min); MASS (ESI, 1303.): 573 (M+H')+. [0 1 72] e 5(31): N-{5—[(6,7-dimethoxyquinolinyl)oxy]~2—pyridinyl}—1-(3-oxetanyl)-2,5-dioxo—l ,2,5,6, 7,8—hexahydro-3~quinolinecarboxamide (LC-MS/ELSD): (retention time: 0.68 min); MASS (ESI, Pos.): 543 (M+H)+. [01 73] Example 5(32): 1~(4,4—difluorocyclohexyl)7N-{5-[(6,7-dimethoxy—4—quinolinyl)oxy]pyridinyl}-2,5-di oxo-l,2,5,6,7,8—hexahydro-3~quinolinecarboxamide (LC—MS/ELSD): (retention time: 0.80 min); MASS (ESL Pos.): 605(M+H)+.
[O l 74] Example 5(33): N-{S—[(6,7—dimethoxy—4-quinolinyl)oxy] -2—pyridinyl}~1 -(1-methyl-lH-pyrazoleyl)—2 ,S-dioxo—l ,2,5,6,7,8~hexahydro-3—quinolineoarboxamide (LC-MS/ELSD): (retention time: 0.63 min); MASS (ESI, Pos.): H)+.
Example 5(34): 1 opropylmethyl)—N— { 5—[(6,7-dimethoxy—4—quinolinyl)oxy]"2—pyridinyl } ~2,5-dioxo -l ,2,5,6,7,8—hexahydro—3 -quinolinecarboxamide (LC«MS/ELSD): (retention time: 0.75 min); MASS (ESL Pos.): 541 (M+H)+. e 5(35): N-{5-[(6,7-dimethoxy—4—quinolinyl)oxy]-2—pyridinyl} — l -(3-methyl—2—butany1)—2,5-diox o-l ,2,5 ,6,7,8-hexahydro-3 —quinolinecarboxamide (LC-MS/ELSD): (retention time: 0.82 min); MASS (ESI, Pos.): 557 (M+H)+.
Example 5(36): N-{5-[(6,7—dimethoxyquinolinyl)oxy]pyridinyl}hexyl—2,5-dioxo-l ,2,5,6,7,8-he xahydroquinolinecarboxamide (LC—MS/ELSD): (retention time: 0.88 min); MASS (ESI, Pos.): 571 (M+H)+. [0 1 78] e 5(3 7): l -[(1 S)-1 hexylethyl]-N- {5-[(6,7-dimethoxy-4~quinolinyl)oxy]~2-pyridinyl}~2,5-d ioxo-1 ,2,5,6,7,8—hexahydro—3-quinolineca:rboxamide (LC-MS/ELSD): (retention time: 0.92 min); MASS (ESI, Pos.): 597 (M+H)+. [01 79] Example 5(3 8): N—{5—[(6,7-dimethoxy—4-quinolinyl)oxy]~2-pyridinyl}-2,5-dioxo—1~(3-phenylpropyl)—1,2 ,5,6,7,8-hexahydro—3 linecarboxamide (LC—MS/ELSD): (retention time: 0.85 min); MASS (ESI, Pos.): 605 (M+H)+. [01 80] Example 5(39): l—[(l S)— l —cyclopropylethyl]-N—{5—[(6,7~dimethoxy—4-quinolinyl)oxy] -2—pyridinyl}-2,5- dioxo- l ,2,5,6,7,8—hexahydro-3 -quinolinecarboxamide (LC~MS/ELSD): (retention time: 0.79 min); MASS (ESI, Pos.): 555 (M+H)+.
Example 5(40): 1 -[(1R)cyclopropylethyl] ~N— { 5—[(6,7—dimethoxy—4-quinoliny1)oxy}~2-pyridinyl}~2,5 dioxo-1,2,5,6,7,8~hexahydroquinolinecarboxamide (LC—MS/ELSD): (retention time: 0.80 min); MASS (ESI, Pos.): 555 (M+H)+.
Example 5(41): N—{5-[(6,7-dimethoxy—4—quinolinyl)oxy]~2—pyridinyl}~1-(4—methy1phenyl)-2,5-dioxo-1, 2,5,6,7,8-hexahydro-3—quinolinecarboxamide TLC: Rf0.66 (ethyl acetate : ol = 9:1); lH—NMR (CDClg): 5 2.10, 2.48, 2.60, 4.05, 6.44, 7.13, 7.42, 7.53, 7.56, 8.21, 8.49, 8.50, 9.31, 11.94.
Example 5(42): 1 -(4-chlorophenyl)—N- { 5 -[(6,7-dimethoxy—4-quinolinyl)oxy]pyridinyl}~2,5-dioxo-1,2 ,5,6,7,8-hexahydroquinolinecarboxamide TLC: Rf 0.60 (ethyl acetate : methanol = 9:1); lH~NMR (CDC13 ): 5 2.13, 2.60, 4.05, 6.45, 7.22, 7.42, 7.53, 7.57, 7.61, 8.23, 8.48 8.50, 9.31, 11.85. e 5(43): -difluorophenyl)-N-{5-[(6,7—dimethoxy~4—quinolinyl)oxy]pyridinyl}-2,5-diox0 —1,2,5,6,7,8-hexahydro~3—quinolinccarb0xamide TLC: Rf0.33 (ethyl acetate); IH—NMR (CDCl3)Z 5 2.17, 2.62, 4.06, 6.44, 7.14, 7.31, 7.43, 7.54, 7.57, 8.24, 8.509 9.33, 11.79.
Example 5(44): 1—(2~chlorophenyl)—N—{5—[(6,7—dimethoxyquinolinyl)0xy]~2-pyridinyl}~2,5-di0xo-1,2 ,8—hexahydro—3—quinolinecarboxamide TLC: Rf0.29 (ethyl acetate); 1H—NMR (CDCl3)! 5 2.14, 2.54, 2.64, 4.05, 6.44, 7.34, 7.43, 7.55, 7.57, 7.69, 8.23, 8.49, 8.51, 9.35, 11.85.
Example 5(45): N—{5-[(6,7-dimeth0xy—4—quinolinyl)oxy]-2»pyridinyl} (2-methylphenyl)-2,5-dioxo- 1 2,5,6,7,8~hexahydro-3—quinolinecarboxamide TLC: Rf0.36 (ethyl acetate); 1I—l-NMR (CDC13 ): 8 2.08-2.15, 2.36, 2.58-2.65, 4.05, 6.44, 7.15, 7.43-7.59, 8.23, 8.48-8.52, 9.35, 11.97.
Example 5(46): N—{ 5- [(6,7-dimethoxy—4—quinolinyl)oxy]~2-pyridinyl} — 1 - [( 1 R)—2~hydroxy— l —phenylethyl ]~2,5-dioxo- 1 ,2,5,6,7,8—hexahydro-3 ~quinolinecarboxamide TLC: Rf0.15 (ethyl acetate, NH silica); lH—NMR (CDC13 ): 8 2.14, 2.48, 3.04, 3.30, 4.04, 4.05, 4.51, 5.11, 6.22, 7.19 - 7.42, 7.53, 7.73, 8.16, 8.40, 8.51, 8.86, 11.89. e 5(47): N- { 5 - [(6,7-dimethoxyquinolinyl)oxy]pyridinyl} [(1 S)hydroxy- l -plleny1ethyl ]—2,5-dioxo-l,2,5,6,7,8-hexahydro-3 -quinolinecarboxamide TLC: Rf 0.51 (ethyl acetate : methanol = 10:1); 1H—NMR ): 5 .25, 2.30270, 2.97-3.16, 3.16—3.40, 4.05, 4.06, 4.45-4.60, 4.88-5.19, 5.67-6.15, 6.26, 7.16-7.42, 7.53, 7.72, 8.18, 8.43, 8.52, 8.94, 11.90.
Example 5(48): N— { 7-dimethoxyquino1inyl)oxy]—2-pyridinyl } —2,5-dioxo[( 1 R)-1 - phenylethyl]-l,2,5,6,7,8—hexahydroquinolinecarboxamide TLC: Rf 0.5 1 (ethyl acetate); 1H-NMR (CDC13 ): 5 1.99-2.10, 2.40-2.70, 2.91, 4.06, 6.45, 7.21, 7.30-7.43, 7.55, 7.58, 8.29, 8.52, 9.26, 12.14.
Example 5(49): N— { 5~[(6,7—dimethoxyquinolinyl)oxy] pyridinyl}-1 - [(ZS)-3 —methy1~2-butanyl]-2,5- dioxo-1,2,5,6,7,8—hexahydroquinolinecarboxamide TLC: Rf0.51 (ethyl acetate : methanol = 10:1) 1H-NMR (CDC13 ): 8 0.74, 1.07, 1.70, 2.10-2.40, 2.48-2.73, 2.95-3.15, 3.96, 4.06, 4.07, 6.45, 7.43, 7.52-7.64, 8.31, 8.47-8.56, 9.21, 12.27.
Example 5(50): 1 ~(3~chlorophenyl)~N—{5-[(6,7~dimethoxy-4—quino1inyl)oxy]pyridinyl} -2,5-dioxo-1 ,2 ,5,6,7,8—hexahydro—3~quinolinecarboxamide TLC: Rf0.72 (ethyl acetate : methanol = 19:1); 1 H-NMR (DMSO~d6 ): 5 1.98—2.07, 2.48-2.60, 3.93, 6.54, 7.40, 7.45—7.51, 7.67769, 7.90, 8.36, 8.41, 8.48, 8.97, 11.89.
Example 5(51): N— { 5~[(6,7—dimethoxy-4—quinolinyl)oxy]~2—pyridinyl} — 1 —(3~methylpheny1)—2,5—dioxo- 1 2,5,6,7,8-hexahydro—3-quinolinecarboxamide TLC: Rf0.38 (ethyl acetate : methanol = 19: 1); 1I-I-NMR (DMSO-de )2 8 1.89-2.04, .62, .94, 6.54, 7.10-7.56, 7.86, 8.35, 8.42, 8.47-8.49, 8.97, 11.97.
Example 5(52): N- { 5- [(6,7-dimethoxyquinolinyl)oxy]—2-pyridinyl } [(2R)-3 ~methy1—2-butanyl]-2,5- dioxo-1,2,5,6,7,8—hexahydroquinolinecarboxamide TLC: Rf 0.48 (ethyl acetate : methanol = 10:1); 1H—NMR (CDC13 ): 5 0.74, 1.07, 1.70, 2.10-2.38, 2.49—2.75, 2.93—3.15, 3.88-4.02, 4.06 4.07, 6.45, 7.43, 7.52-7.63, 8.31, 8.46-8.58, 9.21, 12.27.
Example 5(53): .
N— {5 -[(6,7-dimethoxy-4—quinolinyl)oxy] pyridinyl } — 1 ~ [1 —(2—hydroxy—2—Inethylpropy1) -1H—pyrazole—4—yl]-2,5-dioxo- 1 ,2,5,6,7,8-hexahydro-3 -quinolinecarboxamide TLC: Rf 0.15 (ethyl acetate, NH silica); lH—NMR (CDC13): 5 1.27, 2.14, 2.59, 2.73, 3.20, 4.05, 4.18, 6.44, 7.43, 7.53, 7.54, 7.70, 8.24, 8.49, 8.51, 9.28, 11.88.
Example 5(54): N- {5-[(6,7-dimethoxyquinoliny1)oxy]pyridinyl }-2,5—dioxophenyl-2,5,6,7,8,9-h exahydro-1H—cyclohepta[b]piperidinecarboxamide TLC: Rf0.32 (ethyl acetate); 1H-NMR (CDC13 ): 5 1.80, 1.91, 2.71, 2.77, 4.05, 6.45, 7.25, 7.43, 7.53-7.66, 8.21, 8.48, 8.50, 1.99.
Example 6: 1 -(4—fluorophenyl)—N— { 5- thoxyquinolinyl)oxy]pyridinyl}-2,5-dioxo-1 ,2,5,6 ,7,8—hexahydro-3«quinolinecarboxamide The title compound having the following physical property values was obtained by the procedure having the same purpose as in Example 1 —> Example 2-—> Example 3 —> Example 4 —> Example 5, using 4-chloromethoxy quinoline (CAS ration No.: 37—8) in place of 4-chloro-6,7-dimethoxy quinoline.
TLC: Rf 0.73 (ethyl acetate : methanol = 19:1); 1 H-NMR (CDC13 ): 5 1.92-2.09, 2.40-2.70, 3.93, 6.54, 7.29, 7.41-7.60, 7.87, 8.21, 8.36, 8.41, 8.61, 8.97, 11.94.
Example 6(1) to 6(3 8) The following Example compounds were obtained by the procedure having the same purpose as in Example 6, using 4-chloro-7—methoxy quinoline or a corresponding quinoline derivative in place of it and the compound ed in Example 4 or a corresponding carboxylic acid derivative in place of it.
Example 6(1): N-{5—[(7—methoxy—4-quinolinyl)oxy]~2-pyridiny1}-2,5~dioxophenyl—1,2,5,6,7,8-hexa hydro—3—quinolinecarboxamide TLC: Rf0.30 (ethyl e, NH silica); 1H—NMR (DMSO—ds): 8 1.98, 2.45—2.57, 3.92, 6.52, 7.28, 7.40, 7.44, 7.46, 7.57-7.67, 7.85, 8.20, 8.35, 8.40, 8.60, 8.97, 11.95.
Example 6(2): N-{5—[(6—methoxy—4~quinoliny1)oxy]—2—pyridiny1}-2,5—dioxo~l-phenyl-l,2,5,6,7,8—hexa hydro—3—quinoIinecarboxamide (LC—MS/ELSD): (retention time: 0.77 min); lH—NMR (CDC13)I 5 2.05—2.20, 2.51—2.68, 3.97, 6.52, 7.25-7.26, .29, 7.41, 7.54-7.67, 8.00, 8.22, 8.50, 8.55, 9.33, 11.93.
Example 6(3): 1 — [(ZS)-l ~hydroxymethylbutanyl]-N— { 5—[(7—methoxy—4~quinolinyl)oxy]pyridin —dioxo-1,2,5,6,7,8—hexahydro—3-quinolinecarboxamide TLC: Rf0.71 (ethyl acetate : methanol = 5:1); 1H—NMR (CDC13): 8 0.72, 1.12, 2.18, 2.48, 2.92-3.02, 3.31, 3.95, 4.04, 4.17, 4.77, .23, 6.23, 7.21, 7.78, 8.21, 8.24, 8.51, 8.55, 8.77, 12.16.
Example 6(4): 1 - [(2R)- 1 xymethy1~2-butanyl]—N— { 5 -[(7—methoxy—4-quinoliny1)oxy] pyridin yl}-2,5-dioxo-1,2,5,6,7,8-hexahydroquinolinecarboxamide TLC: Rf 0.71 (ethyl e : methanol = 5:1); 1H—NMR (CDC13): 8 0.72, 1.12, 2.18, 2.48, 2.92-3.02, 3.31, 3.95, 4.04, 4.17, 4.77, .23, 6.23, 7.21, 7.78, 8.21, 8.24, 8.51, 8.55, 8.77, 12.16.
Example 6(5): 1 -(3-fluorophenyl)—N- {5—[(7-methoxyquinolinyl)oxy] -2—pyridinyl} -2,5-diox0-l ,2,5,6 ,7,8—hexahydro-3—quinolinecarboxamide TLC: Rf 0.43 (ethyl acetate : methanol = 19:1); lH—NMR (CDC13): 5 1.93-2.08, .65, 3.93, 6.54, 7.27-7.55, 7.65-7.76, 7.87, 8.21, 8.34-8.47, 8.62, 8.98, 11.91.
Example 6(6): oxo— 1 -phenyl~N-(5- { [7—(trifluoromethyl)~4-quinolinyl]0xy} ~2-pyridinyl)—1 ,2,5,6,7 ahydroquinolinecarboxamide (LC—MS/ELSD): (retention time: 1.06 min); 1H—NMR (DMSO-ds ): 5 2.00, 2.52-2.55, 6.88, 7.46-7.48, 7.58-7.66, 7.93-7.96, 8.40—8.44, 8.46, 8.57, 8.85, 8.99, 11.99.
Example 6(7): 1 —cyclobutyl-N-{5 -[(7-methoxy—4-quinolinyl)oxy]~2-pyridiny1}-2,5-dioxo-1,2,5,6,7,8-h exahydroquinolinecarboxamide TLC: Rf0.69 (ethyl e : methanol == 19:1); 1H-NMR (DMSO—de): 5 1.70—1.90, 1.95-2.10, 2.35—2.60, 2.73-2.89, 3.04-3.15, 3.94, 4.89—5.03, 6.55, 7.30, 7.42, 7.88, 8.22, 8.40, 8.42, 8.62, 8.83, 12.16.
Example 6(8): 1 ~(2,2-dimethylpropy1)~N— {5—[(7-methoxyquinolinyl)oxy] —2~pyridinyl}-2,5—dioxo- 2,5,6,7,8-hexahydroquinolinecarboxamide TLC: Rf 0.65 (ethyl acetate : methanol = 19:1); 1H—NMR (DMSO-d5)2 8 0.99, 2.00-2.16, 2.48—2.65, 3.15-3.22, 3.94, 4.12-4.38, 6.55, 7.30, 7.42, 7.88, 8.22, 8.39, 8.42, 8.62, 8.90, 12.20.
Example 6(9): N-{S-[(7-methoxyquinolinyl)oxy]~2—pyridinyl} -6,6—dimethyl—2,5 ~dioxo—l l-1 ,2 ,5,6,7,8-hexahydroquinolinecarboxamide TLC: Rf 0.55 (ethyl e : methanol = 19:1); 1H—NMR (DMSO—d5 ): 8 1.13, 1.80-1.90, 2.34-2.56, 3.92, 6.54, 7.29, 7.41, 7.48-7.68, 7.87, 8.20, 8.35, 8.41, 8.61, 8.99, 11.98.
Example 6(10): 1 ~(4—chlorophenyl)-N— { 5-[(7-methoxyquinolinyl)oxy]—2—pyridinyl} —2,5-dioxo- 1 ,2,5,6 ,7,8-hexahydro-3—quin01inecarboxamide TLC: Rf 0.52 (ethyl acetate : methanol = 19:1); lH—NMR (DMSO-ds): 5 1.91—2.04, 2.37—2.60, 3.93, 6.54, 7.29, 7.41, 7.52, 7.72, 7.88, 8.20, 8.34, 8.41, 8.61, 8.97, 11.91.
Example 6(11): N—{5~[(7~methoxy—4-quinolinyl)oxy]pyridiny1}—1—(4—methylphenyl)-2,5~dioxo- 1 ,2,5 , 6,7,8—hexahydro-3—quinolinecarboxamide TLC: Rf0.41 (ethyl acetate : ol = 19:1); IH—NMR (DMSO—d5 )2 5 1.91-2.03, 2.42, 2.40-2.60, 3.93, 6.54, 7.26-7.46, 7.87, 8.20, 8.36, 8.41, 8.61, 8.96, 11.97. e 6(12): 1-(4,4—difluorocyclohexyl)-N-{5-[(7-methoxyquinoliny1)oxy]~2-pyridiny1}—2,5-dioxo -1,2,5,6,7,8-hexahydroquinolinecarboxamide TLC: Rf0.50 (ethyl acetate, NH silica); IH—NMR )Z 5 1.81, 2.25, 2.31, 2.62, 3.08, 3.30, 3.98, 4.10, 6.43, 7.25, 7.42, 7.57, 8.24, 8.30, 8.51, 8.61, 9.19, 12.08.
Example 6(13): 1 —(cyclopropy1methy1)—N—{5—[(7-methoxy—4—quinolinyl)oxy] —2—pyridiny1 } —2,5-dioxo- 1 ,2 ,5,6,7,8-hexahydroquinolinecarb0xamide TLC: Rf 0.55 (ethyl acetate, NH silica); 1H—NMR (CDC13 ): 8 0.62, 1.15, 2.26, 2.64, 3.15, 3.98, 4.20, 6.43, 7.23, 7.42, 7.57, 8.23, 8.29, 8.51, 8.61, 9.22, 12.23.
Example 6(14): 1 - [(1 R)cyclopropylethyl] -N—{5— th0xy-4—quinoliny1)ox'y]—2-pyridinyl}—2,5—diox 0-1 ,2,5,6,7,8-hexahydro-3 -quinolinecarboxamide TLC: Rf 0.55 (ethyl acetate, NH silica); IH-NMR (CDC13): 5 0.06, 0.30, 0.56, 0.77, 1.80, 2.24, 2.60, 2.89, 3.43, 3.98, 6.44, 7.22, 7.43, 7.56, 8.23, 8.30, 8.51, 8.61, 9.20, 12.29.
Example 6(15): 1 - [( 1 S)-1~cyclopropylethyl]—N~{5-[(7-methoxyquinolinyl)oxy]pyridinyl}-2,5-diox o-l,2,5,6,7,8—hexahydro-3—quinolinecarboxarnide TLC: Rf0.55 (ethyl acetate, NH ); 1H—NMR (CDC13 ): 5 0.06, 0.30, 0.56, 0.77, 1.80, 2.24, 2.60, 2.89, 3.43, 3.98, 6.44, 7.22, 7.43, 7.56, 8.23, 8.30, 8.51, 8.61, 9.20, 12.29. e 6(16): 1 —(4-fluorophenyl)-N—{5- [(6-methoxy—4—quinolinyl)oxy] ~2-pyridinyl}~2,5—dioxo-l ,2,5 ,6 ,7,8-hexahydro—3-quinolinecarboxamide TLC: Rf0.69 (ethyl acetate : methanol = 5:1); 1H—NMR (CDC13 ): 5 2.13, 2.60, 3.97, 6.52, 7.29—7.35, 7.41, 7.55-7.60, 8.00, 8.23, 8.49, 8.54, 9.32, 11.88.
Example 6(17): 1-isobuty1—N—{5-[(7-methoxyquinolinyl)oxy]pyridinyl}—2,5-dioxo- l ,2,5,6,7,8-hex ahydro-3—quinolinecarboxamide TLC: Rf0.34 (ethyl acetate : methanol = 19:1); 1H—NMR (DMSO—ds):8 0.94, 2.08—2.20, 2.40-2.60, 3.12-3.26, 3.94, 4.12, 6.55, 7.30, 7.42, 7.88, 8.22, 8.39, 8.41, 8.62, 8.90, 12.24.
Example 6(18): N— {5* [(7—methoxy—4-quinolinyl)oxy]~2—pyridinyl}-2’ ,5 ’ —dioxo-1 ’-phenyl-2’ ,5’ ,6’ ,8 ’ -tetr ahydro—l ’H—spiro[cyclobutane-l ,7’-quinoline]-3 ’-carboxamide TLC: Rf 0.56 (ethyl acetate : ol = 19:1); lH—NMR (DMSO—ds): 8 1.65—1.91, 2.63—2.74, 3.93, 7.29, 7.45, .53, 7.58~7.71, 7.87, 8.20, 8.36, 8.41, 8.61, 8.94, 11.94.
Example 6(19): 1 -(2,4-difluorophenyl)—N— {5-[(7~methoxy—4~quinolinyl)oxy]—2—pyridinyl}-2,5~dioxo- 1 ,2 ,5,6,7,8-hexahydro~3—quinolinecarboxamide TLC: Rf0.51 (ethyl acetate); lH—NMR (CDC13 ): 8 2.16, 2.62, 3.97, 6.42, 7.10—7.33, 7.42, 7.56, 8.21-8.24, 8.49, 8.60, 9.33, 11.79.
Example 6(20): 1-(2-ch10rophenyl)-N- { 5 -[(7-n1ethoxyquinoliny1)oxy]~2-pyridiny1} -2,5-dioxo- 1 ,2,5,6 ,7,8-hexahydroquinolinecarboxamide TLC: Rf0.40 (ethyl acetate); lH—NMR (CDC13 ): 6 2.14, 2.55, 2.63, 3.97, 6.41, 7.23, 7.35, 7.42, 7.53—7.58, 7.68, 8.21, 8.23, 8.49, 8.60, 9.34, 11.84.
Example 6(21): N—{5-[(7-methoxy-4—quinolinyl)oxy]pyridiny1}—1-(2—methylpheny1)—2,5-di0xo—1 ,2,5 , 6,7,8—hexahydroquinolinecarboxamide TLC: Rf0.44 (ethyl acetate); 1H-NMR (CDC13 ): 5 2.15-2.20, 2.35, 2.58-2.67, 3.97, 6.41, 7.15, 7.24, 7.41-7.49, 7.56, 8.21, 8.23, 8.49, 8.60, 9.34, 11.96.
Example 6(22): 1 -[1 -(hydroxymethyl)cyclobutyl]-N- { 5—[(6-methoxy-4—quinolinyl)oxy]—2-pyridinyl} ~2,5 ~dioxo-1,2,5,6,7,8-hexahydro-3—quinolinecarboxamide TLC: Rf0.15 (ethyl acetate, NH silica); 1H-NMR ): 8 1.87, 2.18, 2.40, 2.62, 2.94, 3.44, 3.98, 4.10, 4.18, 4.50, 6.46, 7.38, 7.58, 7.62, 7.92, 8.28, 8.49, 8.57, 9.02, 12.02. e 6(23): 1~[1-(hydroxymethyl)cyclobutyl]—N—{5-[(7-methoxy—4-quinolinyl)oxy]—2-pyridiny1}-2,5 —dioxo—1,2,5,6,7,8—hexahydroquinolinecarboxamide TLC: Rf0.15 (ethyl e, NH silica); lH—NMR (CDC13): 5 1.95, 2.21, 2.38-2.69, 2.95, 3.42, 3.68, 3.97, 4.15, 4.46, 6.40, 7.23, 7.39, 7.61, 8.24, 8.28, 8.53, 8.58, 9.10,]199.
Example 6(24): N— { 5— [(6—methoxyquin01iny1)oxy]~2-pyridiny1}~ 1 -(2—methy1pheny1)—2,5-dioxo-1 ,2,5 6,7,8—hexahydro—3-quinolinecarboxamide TLC: Rf0.25 (ethyl acetate, NH silica); 1H-NMR (CDC13 )2 5 2.12, 2.26, 2.60, 3.97, 6.51, 7.15, 7.40-7.49, 7.58, 8.00, 8.23, 8.49, 8.55, 9.34, 11.98.
Example 6(25): 1—(2-chlor0phenyl)—N— { 5 -[(6—methoxy—4-quinolinyl)oxy]pyridinyl}~2,5-diox0-1,2,5,6 ,7,8-hexahydroquinolinecarboxamide TLC: Rf 0.25 (ethyl acetate, NH silica); 1H—NMR (CDC13 ): 5 2.15, 2.57, 2.63, 3.97, 6.51, .61, 7.68, 8.00, 8.23, 8.50, 8.55, 9.34, 11.86.
Example 6(26): 1 —(2,4-difluorophenyl)—N— {5-[(6-methoxy-4—quinolinyl)0xy] pyridinyl}—2,5—dioxo— 1 ,2 ,5,6,7,8~hexahydro~3-quinolinecarboxamide TLC: Rf0.25 (ethyl acetate, NH silica); 1H-NMR (CDCI3)! 6 2.18, 2.62, 3.97, 6.51, 7.18, 7.21-7.40, 7.41, 7.57, 8.01, 8.24, 8.50, 8.55, 9.32, 11.79.
Example 6(27): 1—[(1 S)—1-cyclopropylethyl]-N—{5-[(6-methoxy—4-quinolinyl)oxy]pyridinyl}-2,5-diox o~l,2,5,6,7,8—hexahydroquinolinecarboxamide TLC: Rf 0.60 (ethyl acetate : methanol = 10:1); 1H—NMR (CDCl3 ): 5 0.03-0.13, 0.20-0.40, .67, .89, 1.81, 2.09-2.42, 2.47-2.72, 2.89, 3.31-3.52, 3.98, 6.53, 7.42, .64, 8.00, 8.31, 8.53, 8.56, 9.21, 12.30.
Example 6(28): 1 -[(1 S)—2-hydroxy~l -phenylethyl]—N- { 5—[(7—methoxy—4-quinolinyl)oxy]—2~pyridiny1} -2, -dioxo-1 ,2,5,6,7,8~hexahydro—3-quinolinecarboxamide TLC: Rf0.54 (ethyl acetate : methanol = 10:1); 1 H—NMR (CDC13 ): 8 2.07229, 2.36-2.68, 2.97—3.16, 3.17-3.43, 3.96, 4.45—4.62, 4.95623, 5.68~6.05, 6.22, 7.12-7.43, 7.72, 8.17, 8.23, 8.47—8.56, 8.86, 11.90.
Example 6(29): 1 - [(1 R)—1-(4~fluorophenyl)ethyl]—N—{5-[(7—methoxy—4-quinolinyl)oxy]-2—pyridinyl} -2,5 -dioxo-1,2,5,6,7,8-hexahydro—3—quinolinecarboxamide TLC: Rf0.58 (ethyl acetate); lH-NMR (CDC13 ): 8 2.00, 2.05, 2.40—2.80, 2.96, 3.98, 6.43, 7.08, 7.18-7.29, 7.42, 7.58, 8.24, 8.28, 8.51, 8.61, 9.25, 12.07.
Example 6(30): N-{ 5-[(7-methoxy—4«quinolinyl)oxy]—2~pyridinyl}-2,5—dioxo-1 —[(1R) phenylethyl]-l,2,5,6,7,8-hexahydroquinolinecarboxamide TLC: Rf 0.58 (ethyl acetate); lH—NMR (CDCl3): 8 1.99-2.10, 2.40-2.70, 2.90, 3.98, 6.43, 7.22, 7.27—7.43, 7.59, 8.24, 8.28, 8.52, 8.61, 9.26, 12.13.
Example 6(31): 1 —(2-fluorophenyl)—N—{5—[(6-methoxyqui11olinyl)oxy]-2—pyridiny1}-2,5-dioxo-l,2,5,6 ,7,8-hexahydro—3-quinolinecarboxamide TLC: Rf0.60 (ethyl acetate : methanol = 10:1); lH-NMR (CDC13 ): 5 2.06-2.25, 2.63, 3.97, 6.52, 7.42, 7.51-7.67, 7.99, 8.23, 8.50, 8.55, 9.33, 11.85. e 6(32): 1-(3 phenyl)-N- { 5- [(6-methoxy—4-quinolinyl)oxy]~2-pyfidinyl} -2,5-dioxo-l ,2,5,6 ,7,8—hexahydroquinolinecarboxamide TLC: Rf0.66 (ethyl e : methanol = 10:1); 1H-NMR (CDC13 ): 8 2.04-2.26, 2.53-2.70, 3.97, 6.52, 6.99-7.14, 7.27-7.36, 7.37-7.44, 7.52-7.68, 7.99, 8.23, 8.49, 8.55, 9.32, 11.85.
Example 6(33): N-{5—[(7~methoxyn4—quinolinyl)oxy]pyridinyl}—1-[(2S)methy1—2—butanyl]-2,5—dio x0-1,2,5,6,7,8-hexahydro—3—quinolinecarboxamide TLC: Rf 0.57 (ethyl acetate : methanol = 10: 1); 1H—NMR (CDC13 ): 8 0.74, 1.07, 1.70, 2.10-2.34, 2.45-2.76, .14, 3.86—3.96, 3.98, 6.42, 7.21—7.25, 7.43, 7.58, 8.24, 8.30, 8.52, 8.61, 9.21, 12.27. [023 1] Example 6(34): 1 —(2—fluorophenyl)-N~ {5- [(7-methoxy—4—quinolinyl)oxy]-2—pyridinyl}~2,5—dioxo- 1 ,2,5,6 ,7,8—hexahydro-3~quinolinecarboxamide TLC: Rf0.35 (ethyl e : methanol = 19:1); lH-NMR (DMSO-ds): 8 1.96—2.18, 2.30-2.60, 3.93, 6.54, 7.29, 7.41, 7.44-7.72, 7.88, 8.21, 8.36, 8.41, 8.61,9.00,11.81.
Example 6(35): N-{5-[(7-methoxy-4—quinolinyl)oxy]-2—pyridinyl}(3-methylphenyl)—2,5-dioxo—1,2,5, 6,7,8—hexahydro~3—quinolinecarboxamide TLC: Rf 0.50 (ethyl acetate : methanol = 19:1); 1H-NMR (DMSO-ds): 8 .05, 2.40, 2.45-2.60, 3.93, 6.54, 7.22-7.55, 7.87, 8.21, 8.36, 8.42, 8.62, 8.97, 11.97.
Example 6(3 6): l -(3 ophenyl)-N— { 5—[(7—methoxy-4~quinolinyl)oxy] pyridiny1}-2,5-dioxo- 1 ,2,5,6 ,7,8-hexahydro—3—quinolinecarboxamide TLC: Rf 0.74 (ethyl acetate : methanol = 19:1); 1H—NMR (DMSO~d6 )2 5 1.98-2.07, 2.45-2.60, 3.93, 6.54, 7.29, 7.41, 7.46-7.51, 7.66—7.69, 7.87, 8.20, 8.36, 8.41, 8.61, 8.97, 11.89.
Example 6(37): N-{5-[(7-methoxyquinoliny1)oxy]pyridinyl}—1-[(2R)—3—methyl-2—butanyl]-2,5~dio xo-l ,7,8~hexahydroquinolinecarboxamide TLC: Rf0.55 (ethyl acetate : methanol = 10:1); lH-NMR (CDC13 ): 8 0.74, 1.07, 1.70, .38, 2.47—2.74, 2.95-3.20, 3.90-3.95, 3.98, 6.43, 7.20-7.25, 7.43, 7.58, 8.24, 8.30, 8.52, 8.61, 9.21, 12.26.
Example 6(3 8): 1 —[1 -(2—hydroxy—2—methylpropyl)— 1 H-pyrazole—4-yl]—N— { 5-[(7-methoxy—4—quinolinyl)ox y] -2—pyridinyl}-2,5 -dioxo-1 ,2,5,6,7,8-hexahydro-3 ~quinolinecarboxamide TLC: Rf 0.15 (ethyl acetate, NH silica); 1H—NMR (CDC13 ): 8 1.28, 2.14, 2.62, 2.75, 3.10, 3.97, 4.18, 6.41, 7.22, 7.42, 7.52-7.60, 7.70, 8.21, 8.23, 8.48, 8.60, 9.27, 11.87.
Example 7: tert—butyl N—[S—[(6,7—dimethoxy—4—quinazolinyl)amino]pyridyl]carbamate 4—chloro-6,7—dimethoxyquinazoline (CAS registration No.: 137901) (450 mg) and tert-butyl (5-aminopyridin-2—yl)carbamate (420 mg) were dissolved in N,N—dimethyl acetamide (DMA) (20 mL) at room temperature. 4 mol/L hydrochloric acid - dioxane (0.5 mL) was added thereto at 50°C, and the mixture was stirred.
Thereafter, the resulting solution was heated to 80°C and stirred for three hours. The resulting solution was left to cool to room ature, methyl tert-butyl ether (MTBE) was added to the reaction on, solids precipitated from the reaction solution were collected by filtration through Kiriyama funnel, and washed with MTBE. The resulting residue was dried under reduced pressure at 60°C. The title compound (821 mg) having the ing physical property values was obtained.
TLC: Rf 0.45 (ethyl acetate : methanol = 5:1); 1H—NMR(DMSO-d6): 5 1.49, 4.00, 7.34, 7.88, 8.05, 8.32, 8.56, 8.84, 10.02, 11.54.
Example 8: N5-(6,7-dimeth0xy—4~quinazolinyl)pyridine~2,5—diamine The compound (800 mg) produced in Example 7 was dissolved in dichlorornethane (10 mL) at room temperature, trifluoroacetic acid (0.3 mL) was added thereto, and the mixture was stirred at room temperature for six hours. The reaction solution was diluted with ethyl acetate, and saturated sodium bicarbonate water added to the reaction on and stirred. Ethyl acetate and water were further added, and the c layer was extracted. THF and water were added to the water layer, and the organic layer was extracted. The organic layer was collected, washed with a saturated saline solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Ethyl acetate and hexane were added to the resulting residue, followed by stirring at room temperature. The solid was washed with ether in a slurry form. The residue collected by filtration through ma fimnel was dried under reduced pressure at 60°C to obtain the title compound (598 mg) having the following physical property values.
TLC: Rf 0.16 (ethyl acetate : methanol = 5:1); 1H-NMR (DMSO-d6 ): 5 3.91, 5.83, 6.49, 7.12, 7.65, 7.82, 8.09, 8.30, 9.36. e 9: N-{5—{(6,7-dimethoxy—4-quinazolinyl)amino]-2—pyridinyl} -2,5—dioxo-1 -phenyl—1 ,2,5 ,6, 7,8-hexahydroquinolinecarboxamide The nd produced in Example 4 (76 mg) and HATU (154 mg) were ved in DMF (1 mL) at room ature. To the resulting solution, DIPEA (0.14 mL) and the compound produced in Example 8 (80 mg) were added, and the mixture was stirred for 18 hours. The reaction solution was diluted with ethyl acetate, and saturated sodium bicarbonate water was added and stirred. Ethyl acetate and water were fiirther added, and the organic layer was extracted. The organic layer was washed with a saturated saline solution, dried over anhydrous sodium sulfate, and the solvent was led off under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane : ethyl acetate = 30:70 —-+ 0:100 —> ethyl acetate : ol = 70:30) to obtain the title compound (57 mg) having the following physical property values.
TLC: Rf0.59 (ethyl acetate : methanol = 5:1); 1H—NMR (CD03); 6 2.10, 2.58, 4.04, 7.04, 7.13, 7.25, 7.59, 8.20, 8.41, 8.50, 8.64, 9.30, 11.82. es 9(1) to 9(4) The following Example compounds were obtained by the procedure having the same purpose as in Example 7 ——> Example 8 «Example 9, using 4~chloro-6,7-dimethoxyquinazoline or a corresponding quinoline tive in place of it, tert-butyl (5-aminopyridinyl)carbamate or a ponding amine derivative in place of it, and the compound produced in Example 4.
Example 9(1): N~{5-[(6,7-dimethoxyquinolinyl)amino]pyridinyl}-2,5—dioxophenyl~1,2,5,6,7,8 ydro—3«quinolinecarboxamide trifluoroacetate TLC: Rf 0.21 (dichloromethane : methanol = 1 0:1); lH—NMR (DMSO-d5)1 5 1.86—2.14, 2.49—2.62, 3.98, 4.02, 6.75, 7.35-7.40, 7.41-7.52, 7.53—7.73, 7.94—8.07, 8.36-8.56, 8.99, 10.42, 12.03, 14.00.
Example 9(2): N—{4-[(6,7-dimethoxy—4—quinolinyl)amino]pheny1}-2,5-dioxo-l—phenyl-1 ,2,5,6,7,8-hexa hydro-3~quinolinecarboxamide (LC—MS/ELSD): (retention time: 0.75 min); II—I—NMR (CD3 OD): 8 2.04-2.13, 2.56—2.64, 4.01, 4.02, 6.82, 7.24, .42, 7.59-7.67, 7.69, 7.75-7.79, 8.19, 9.17.
Example 9(3): (7-methoxy-4—quinolinyl)amino]pyridinyl}-2,5-dioxophenyl—l,2,5,6,7,8-he xahydro—3—quinolinecarboxamide TLC: Rf 0.63 (ethyl acetate : methanol : ammonia water = 9:1:0.5); IH—NMR (DMSO-d6 ): 8 1.90-2.05, 2.40-2.60, 3.89, 6.70, 7.18, 7.25, 7.42-7.50, 7.54-7.68, 7.86, .40, 8.97, 8.99, 11.85.
Example 9(4): N—{4—[(6,7—dimethoxy—4-quinazolinyl)amino]phenyl}-2,5-dioxophenyl—l ,2,5,6,7,8-he xahydro-3—quinolinecarboxamide (LC—MS/ELSD): (retention time: 0.79 min); lH-NMR (CD3 OD): 5 1.94-2.07, 2.50258, 3.94, 3.96, 7.18, 7.43-7.51, 7.57—7.68, 7.75, 7.87, 8.50, 8.95, 9.69, 11.48.
Example 10: -[(E)—{ nzyloxy)phenyl]imino)methyl] -2,2—dimethyl- 1 ,3-dioxane-4,6-dione 3-benzyloxyaniline (25 g), m’s acid (22 g), ethyl orthoformate (22 g), and ethanol (25 mL) were placed in a 200-mL eggplant flask. The mixture was heated and refluxed for 80 min, and left to cool to room temperature. Then, the precipitated powder was collected by filtration. The powder was washed with l (50 mL) and dried to obtain the title compound (43 g) having the following al property values.
TLC: Rf0.48 (hexane : ethyl acetate = 2: 1); 1H—NMR (DMSO—d6 ): 8 1.66, 5.15, 6.88, 7.11, 7.30 - 7.45, 8.60, 11.2.
Example 11: 7—(benzyloxy)~4(lH)—quinolinone The compound produced in Example 10 (42 g) and 1,2-dichlorobenzene (420 mL) were placed in a l L—eggplant flask. The mixture was heated and refluxed for 5.5 hours, and left to cool to room temperature. Then, the precipitated powder was collected by ion. The powder was washed with methanol (84 mL) and dried to obtain the title compound (18 g) having the following physical property values.
TLC: Rf 0.60 (ethyl acetate :methanol = 9:1); 1 H—NMR (DMSO-d5)1 8 5.19, 5.92, 6.98, 7.32 — 7.43, 7.77, 7.97. {0246] . Example 12: 7-(benzyloxy)chloroquinolinone Under argon atmosphere, the compound produced in Example 11 (17 g), toluene (34 mL) and phosphorus oxychloride (10 g) were placed in a 300-mL eggplant flask. The mixture was heated and refluxed for 2.5 hours, left to cool to 70°C, and diluted with ethyl acetate (135 mL). fter, the mixture was left to cool to room temperature, and was neutralized by 2 mol/L sodium hydroxide aqueous solution. The resulting solution was extracted with ethyl acetate, washed with a saturated saline solution and dried over anhydrous sodium sulfate. y, the solvent was distilled off under reduced pressure to obtain the title compound (18 g) having the following physical property values.
TLC: Rf 0.60 (hexane : ethyl acetate = 2:1); lH-NMR (CDC13 ): 5 5.22, 7.34 - 7.51, 8.13, 8.86. [0.247] Example 13: 7—(benzyloxy)~4—[(6~chlor0pyridinyl)oxy]quinolinone The compound produced in Example 12 (15 g), 6-chloropyridine-3—ol (8.3 g), 4-dimethylaminopyridine (7.5 g), and toluene (75 mL) were placed in a 300-mL eggplant flask. The mixture was heated at 110°C for 6.5 hours, then left to cool to room temperature. Water and ethyl acetate were added thereto, and the resulting solution was ted. The t solution was washed with a saturated saline solution, dried over ous sodium sulfate, and the solvent was distilled off under reduced pressure. Then, the resulting residue was dissolved in a small amount of ethyl acetate, and crystallized by adding methanol to the solution. The precipitates were then collected by filtration to obtain the title compound (15 g) having the following physical property values.
TLC: Rf 0.37 (hexane : ethyl acetate = 1:1); lH—NMR (CDC13 ): 5 5.24, 6.46, 7.31 — 7.52, 8.19, 8.34, 8.65.
Example 14: —{ [7—(benzyloxy)—4-quinolinyl]oxy} —2—pyridinamine Under argon atmosphere, a solution of the compound produced in e (5 g) in THF (25 mL), 1.0 moi/L LHMDS (3.5 mL), tris(dibenzy1ideneacetone) adium(0) chloroform complex (0.63 g), and 2-dicyclohexylphosphino—2’,6’—dimethoxybiphenyl (0.73 g) were placed in a 200~mL neter eggplant flask, and the e was stirred at 70°C. Disappearance of the raw material was confirmed, the resulting product was left to cool to room temperature, then water and ethyl acetate were added, and the solution was separated. After extraction with ethyl acetate, the solution was washed with a saturated saline solution, dried over anhydrous sodium sulfate, and the solvent was led off under reduced pressure. The resulting residue was ded in acetonitrile (100 mL), and 2.0 mol/L hydrochloric acid (10 mL) was added to the suspension, and the mixture was stirred at room temperature for 2.5 hours. 1.0 mol/L sodium hydroxide aqueous on, a ted sodium hydrogen bicarbonate aqueous solution, and ethyl acetate were added, and the solution was separated. The extracted solution was washed with a saturated saline on, dried over anhydrous sodium sulfate, and the solvent was distilled off under d pressure. The resulting residue was purified by silica gel column chromatography (hexane : ethyl acetate = 1:1—90: 1) to obtain the title compound (2.9 g) having the following al ty values.
TLC: Rf0.33 oromethane : ethyl acetate :methanol = 8:4: 1); 1H-NMR (DMSO-dg): 5 5.29, 6.06, 6.41, 6.55, 7.31 - 7.52, 7.88, 8.20, 8.56.
Example 15: N~(5- { [7-(benzyloxy)quinoliny1]oxy}-2—pyridinyl)-2,5—dioxo—1 —pheny1-1 ,2,5 ,6,7,8-he xahydro—3-quinolinecarboxamide The compound produced in Example 14 (800 mg), the compound produced in Example 4 (660 mg), DIPEA (1.2 mL), and DMF (16 mL) were placed in a 30-mL eggplant flask, and finally HATU (1.1 g) was added thereto, followed by stirring at room ature overnight. After disappearance of the raw material was confirmed, water and ethyl acetate were added, and the resulting solution was separated. The resulting solution was ted with ethyl acetate, and then washed with water and a saturated saline solution sequentially in this order, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The resulting residue was dissolved in a small amount of ethyl acetate, and crystallized by adding methanol.
The precipitate was filtered to obtain the title compound (1.2 g) having the following physical property values.
TLC: Rf 0.74 (ethyl acetate :methanol = 9:1); lH-NMR (CDC13 ): 5 2.11, 2.59, 5.23, 6.42, 7.25 - 7.63, 8.20, 8.24, 8.49, 8.59, 9.32, 11.92.
Example 16: N—{5-[(7-hydroxyquinolinyl)oxy]-2—pyridinyl}~2,5-dioxophenyl- l ,2,5 ,6,7,8-hexah ydro—3-quinolinecarboxamide The compound produced in Example 15 (500 mg), 20% palladium hydroxide—carbon (250 mg), ethyl acetate (18 mL), and methanol (2 mL) were placed in a 200-mL eggplant flask. Under en atmosphere, the mixture was stirred at room temperature for four hours, followed by filtration through . The filtrate was distilled off under reduced pressure to obtain the title compound (360 mg) having following physical property values.
TLC: Rf 0.63 (ethyl acetate :methanol = 9:1); 1H—NMR (DMSO-ds): 5 2.00, 2.50, 6.44, 7.19, 7.25, 7.46, 7.60, 7.85, 8.15, 8.34, 8.41, 8.53, 8.97, 10.28, 11.95.
Example 17: {7—[3-(dimethylamino)propoxy]quinolinyl}oxy)—2-pyridiny1]-2,5-dioxo-l-phe nyl—l,2,5,6,7,8—hexahydro—3-quinolinecarboxamide H°c\tl4/V\o/<:<¢j The compound produced in Example 16 (50 mg) was dissolved in THF (1 mL) at room temperature, and ethylamino)—1-propanol (30 mg), l,1‘-azobis(N,N-dimethyl formamide) (50mg), and tributylphosphine (0.071 mL) were added sequentially. The mixture was stirred at 60°C for 20 hours, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane : ethyl acetate = 30:70 —> 0:100 —> ethyl e : methanol = 70:30) to obtain the title compound (22 mg) having the following physical property TLC: Rf 0.75 (ethyl acetate : methanol = 5:1, NH silica); lH-NMR (CDC13): 5 2.11, 2.34, 2.59, 4.19, 6.40, 7.25, 7.40, 7.54, 7.62, 8.20, 8.23, 8.49, 8.59, 9.33, 11.92.
Examples 17(1) to 17(8) The following Example compounds were obtained by the procedure having the same purpose as in Example 16 —> Example 17, using the compound ed in Example 16 and corresponding alcohol derivatives in place of 3-(dimethylamino)—1 -propanol.
Example 17(1): N—(S- { [7-(3-hydroxy-3 -methy1butoxy)~4-quinoliny1]oxy} ~2-pyridinyl)-2,5-dioxophe nyl-l,2,5,6,7,8-hexahydro-3—quinolinecarboxamide TLC: Rf 0.78 (ethyl acetate : methanol = 5:1, NH silica); 1H—NMR (CDC13 ): 8 1.35, 2.09, 2.60, 4.36, 6.41, 7.21, 7.44, 7.55, .65, 8.21, 8.22, 8.49, 8.60, 9.32, 11.92.
Example 17(2): N—[S—({7~[3~(4—morpholinyl)propoxy]quinolinyl}oxy)—2~pyridiny1]2,5-dioxo—1~pheny 1—1 ,2,5,6,7,8-hexahydro—3—quinolinecarboxamide TLC: Rf0.33 (ethyl acetate, DNH silica); lH—NMR (CDC13 ): 8 2.00220, 2.45-2.52, 2.53-2.65, .75, 4.18422, 6.40-6.42, 7.20-7.30, 7.40—7.41, 7.53770, .22, 8.47—8.50, 8.58-8.60, 9.32, 11.92.
Example 17(3): N-[5-({7-[2-(4-morpholiny1)ethoxy]quinoliny1}oxy)pyridiny1]-2,5-dioxo-l-phenyl - 1 ,2,5,6,7,8-hexahydro-3 -quinolinecarboxamide TLC: Rf0.80 (ethyl acetate : methanol = 5:], NH silica); lH—NMR (CDC13 ): 8 2.10, .64, 2.90, 3.76, 4.29, 6.42, 7.22~7.28, 7.40, 7.53765, 8.20, 8.22, 8.49, 8.60, 9.33, 11.92.
Example 17(4): )-1 ~hydroxymethylbutany1]-N- [5—({7-[3 -(4-morpholiny1)propoxy]quinoli nyl} oxy)pyridinyl] -2,5—dioxo-1 ,2,5,6,7,8-hexahydro—3-quinolinecarboxamide TLC: Rf0.18 (ethyl acetate, DNH silica); 1H—NMR (CDC13 ): 5 0.73, 1.13, 1.98-2.11, 2.12-2.26, 2.38—2.63, 2.82-3.08, 3.18-3.41, 3.70-3.79, 3.99—4.08, 4.09427, 4.56-4.79, 6.26, 7.21, 7.26-7.29, 7.74, .27, .59, 8.86, 12.15.
Example 17(5): 1—(2,2-dimethy1propyl)—N—[5-({7-[3-(4—morpholinyl)propoxy]—4—quinolinyl}oxy)-2—pyri dinyl]-2,5~dioxo-1,2,5,6,7,8-hexahydro-3—quinolinecarboxamide TLC: Rf0.41 (ethyl acetate, DNH silica); 1H-NMR (CDC13 ): 6 1.06, 2.01-2.13, 2.14—2.30, 2.44-2.52, 2.53-2.69, 3.01-3.16, 3.67-3.79, 4.21, 6.42, 7.23, 7.42, 7.57, 8.23, 8.29, 8.53, 8.60, 9.22, 12.18.
Example 17(6): 1-(1 ~methy1-1H-pyrazole~4-y1)-N-[5-({7-[3 -(4-morpholiny1)propoxy]~4—quinoliny1}oxy )-2—pyridinyl]—2,5-dioxo-1,2,5,6,7,8—hexahydro-3 -quinolinecarboxamide TLC: Rf 0.50 (ethyl acetate : methanol = 10:1, NH silica); 1H—NMR (CDC13 ): 5 .21, 2.46-2.52, 2.54-2.66, 2.76, 3.69-3.77, 4.03, 4.20, 6.42, 7.22, 7.41, 7.52, 7.53~7.60, 8.17-8.26, 8.48, 8.59, 9.28, 11.90.
Example 17(7): 1-[1-(2—hydroxy—2~methylpropyl)~ 1H—pyrazole-4—yl] -N— [5-({7-[3 -(4-morpholinyl)propo xy]~4-quinoliny1}oxy)—2—pyridinyl]—2,5-dioxo-1,2,5,6,7,8~hexahydroquinolinecarbox amide TLC: Rf 0.50 (ethyl acetate : methanol = 10:1, NH silica); 1 H-NMR (CDC13 ): 6 1.28, .22, .53, 2.54-2.66, 2.69-2.80, 3.20, 3.68-3.78, 4.16-4.25, 6.41, 7.19—7.25, 7.41, 7.52-7.60, 7.69, 8.16-8.26, 8.49, 8.59, 9.28, 11.87.
Example 17(8): 1-[(1R)—1~(4-fluoropheny1)ethyl]—N—[5—({7—[3~(4-morpholiny1)propoxy]quinoliny1}ox y)pyridiny1]-2,5-dioxo—1 ,2,5,6,7,8-hexahydro-3~quinolinecarboxamide TLC: Rf 0.62 (ethyl acetate : ol = 10: 1, NH silica); IH-NMR (CDC13 ): 8 1.93-2.17,2.41-2.64, 2.81-3.13, 3.74, 4.21, 6.42, 7.02-7.13, 7.18-7.26, 7.42, 7.57, 8.23, 8.28, 8.51, 8.60, 9.25, 11.99-12.11.
Example 18: (4-bromophenyl)(6,7-dimethoxy—4-quinazolinyl)methanone At room temperature, 4-chloro-6,7—dimethoxyquinazoline (224 mg), 4-bromobenzaldehyde (221 mg), and methyl imidazolium iodide (74 mg) were placed in a 50—mL eggplant flask, and the mixture was suspended in 1,4—dioxane (3 mL). At room temperature, 60% sodium hydride (52 mg) was added and stirred.
Thereafter, the mixture was heated to 100°C and stirred for one hour. The mixture was left to cool to room temperature, the reaction solution was diluted with ethyl acetate (10 mL), and water was added to the solution (10 mL). The precipitated crystals were collected by filtration to obtain the title compound (196 mg) having the following physical property values.
TLC: Rf0.3l (hexane : ethyl acetate = 1:1); lH—NMR (CDC13 ): 8 3.99, 4.10, 7.42, 7.43, 7.64-7.68, .88 , 9.23.
Example 19: ylpropany1 {4-[(6,7-dimethoxyquinazolinyl)carbonyl]phenyl}carbamate Under argon atmosphere, the nd ed in Example 18 (149 mg), tert-butyl carbamate (51 mg), tris(dibenzylideneacetone)dipalladium - chloroform adduct (21 mg), 4,5-bis(diphenylphosphino)—9,9~dimethylxanthene (35 mg), and cesium carbonate (182 mg) were suspended in 1,4~dioxane (4 mL) in a 50-mL nt flask.
Thereafter, the sion was heated to 100°C, stirred for 12 hours, and then left to cool to room temperature. Water was added thereto, followed by extraction with ethyl acetate. The extracted solution was washed with water and a saturated saline solution, and then dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled off under reduced pressure, followed by purification by silica gel column chromatography (hexane : ethyl acetate = 1:1) to obtain the title compound (145 mg) having the following physical property values.
TLC: Rf 0.17 e : ethyl acetate = 1:1); 1 H-NMR (CDC13 ): 5 1.53, 3.96, 4.09, 6.73, 7.33, 7.40, 7.47—7.51, 7.92-7.96, 9.22.
Example 20: (4-aminophenyl) (6,7-dimethoxy—4-quinazolinyl)methanone hydrochloride The compound produced in Example 19 (41 mg) was suspended was suspended in methanol (0.5 mL) in a 50-mL eggplant flask at room ature. 4 mol/L hydrogen de / ethyl acetate solution (1 mL) was added, and the reaction mixture was stirred at room temperature for one hour, and then concentrated to obtain the title compound (35 mg) having the following physical property values.
TLC: Rf 0.48 (dichloromethane : methanol = 9:1); 1H—NMR (DMSO—d5 ): 8 3.79, 4.01, 6.57 - 6.60, 7.06, 7.46, 7.54 — 7.57 , 9.14.
Example 21: N—{4-[(6,7-dimethoxy-4—quinazolinyl)carbonyl]phenyl} —2,5-dioxopheny1-1 ,2,5,6,7,8— hexahydro-3~quinolinecarboxamide The title compound having the following physical property values was obtained by the procedure having the same purpose as in Example 5 using the compound produced in e 20 and the compound ed in Example 4.
TLC: Rf 0.55 (dichloromethane : ol = 9:1); 1H-NMR (CDC13 ): 8 2.06—2.14, 2.54-2.63, 3.95, 4.11, 7.26-7.29, 7.33, 7.41, 7.61770, 7.82-7.86, 7.94-7.97, 9.23, 9.32, 11.70.
Example 22: 4-[(6,7-dimethoxy-4~quinolyl)oxy]aniline 4-aminophenol (500 mg) was dissolved in dimethyl sulfoxide (DMSO) (5 mL) at room temperature, and 55% sodium hydride (98 mg) was added thereto. Thereafter, 4-chloro-6,7—dimethoxy quinoline (244 mg) was added, and the mixture was stirred at 100°C for three hours. The reaction solution was diluted with ethyl acetate, saturated sodium bicarbonate water was added, and the mixture was d. Furthermore, ethyl acetate and water were added, and the organic layer was extracted. The organic layer was washed with a saturated saline solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The resulting e was washed with methanol to obtain the title compound (442 mg) having the following physical property values.
TLC: Rf0.57 (ethyl acetate); IH-NMR (CDC13 ): 5 3.71, 4.04, 6.41, 6.76, 6.98, 7.39, 7.57, 8.44. e 23: N—{4-[(6,7-dimethoxy-4—quinolinyl)oxy]pheny1} -2,5-dioxopheny1-1 ,2,5,6,7,8—hexahy quinolinecarboxamide u l ,0 N . of) H,c’° / I-I,c\o \N The title compound having the following physical property values was obtained by the procedure having the same purpose as in Example 5, using the nd produced in Example 22 and the compound produced in Example 4.
TLC: Rf 0.72 (ethyl acetate: methanol = 5:1); lH-NMR (CDC13 ): 5 2.11, 2.60, 4.05, 6.49, 7.14, 7.28,7.43, 7.56, 7.61—7.70, 7.80, 8.47, 9.34, 11.46.
Examples 23(1) to 23(3) The following Example compounds were obtained by the procedure having the same purpose as in Example 22 -—> Example 23, using 4-chloro-6,7—dimethoxy quinoline or a ponding quinoline derivative in place of it, 4~aminophenol or a corresponding phenol derivative in place of it.
Example 23(1): 2,5—dioxopheny1-N-[4—(4-quinolinyloxy)phenyl]-1 ,2,5,6,7,8-hexahydroquinolinec arboxamide (LC-MS/ELSD): (retention time: 0.79 min); lH-NMR (CDC13 ): 5 2.05-2.18, 2.53-2.69, 6.56, 7.12~7.20, 7.26-7.34, 7.54-7.85, 8.08, 8.36, 8.66, 9.34, 11.45.
Example 23(2): (6,7-dimethoxyquinolinyl)oxy]methylphenyl}-2,5-dioxo- l-phenyl-l ,2,5,6,7 ,8-hexahydroquinolinecarboxamide TLC: Rf 0.50 (dichloromethane : methanol = 9:1); lH—NMR(CDC13,): 5 2.05-2.15, 2.32, 2.53-2.63, 4.04, 4.05, 6.50, 7.00, 7.06, 7.26-7.30, 7.42, 7.55-7.68, 8.30, 8.48, 9.35, 11.23.
Example 23(3): N-{4-[(6,7-dimethoxy—4-quinolinyl)oxy]~2,6-difluorophenyl}-2,5-dioxo-1~phenyl~l,2,5, 6,7,8-hexahydro-3—quinolinecarboxannde TLC: Rf 0.28 (ethyl acetate); 1H—NMR (CDC13 ): 5 2.06-2.14, 2.55-2.63, 4.03, 4.05, 6.69, 6.78-6.83, 7.26-7.30, 7.41, 7.45, 7.56-7.68, 8.58, 9.32, 10.77.
Example 24: 4-(2-fluoronitrophenoxy)—6,7-dimethoxy quinoline 6,7-dimethoxy quinoline—4-ol (5.0 g), cesium carbonate (1.3 g) and 1,2-difluoronitrobenzene (3.5 mL) were added into DMF (20 mL), and the e was stirred at room temperature for six hours. The reaction solution was diluted with ethyl acetate, and then the c layer was washed with water. The water layer was extracted with ethyl acetate twice, and the combined organic layer was washed with a saturated saline solution, and dried over anhydrous sodium sulfate. The organic layer was concentrated. The resulting residue was purified by silica gel column chromatography e : ethyl acetate = l:l—>0:100) to obtain the title compound (2.3 g) having the following physical property values.
TLC: Rf0.62 (hexane : ethyl acetate = 1:9); - MR (CDC13 ): 5 4.04, 4.07, 6.55, 7.31-7.38, 7.45, 7.47, 8.11-8.26, 819,858.
Example 25: 4—[(6,7-dimethoxy quinoline-4—yl)oxy]-3—fluoroaniline The compound produced in Example 24 (2.1 g) was dissolved in DMF : water = 3:1 (45 mL). Zinc (3.9 g) and ammonium chloride (1.9 mg) were added to the solution, and the solution was stirred at room temperature for one hour. Then the reaction solution was filtered h Celite. Saturated sodium en carbonate aqueous solution was added to the e and solid precipitate was removed by filtration through . Ethyl acetate was added thereto, and the water layer was extracted with ethyl acetate. The combined organic layer was washed with a saturated saline solution, and dried over anhydrous sodium sulfate. The organic layer was trated. The title compound (1.9 g) having the following physical property values was obtained.
TLC: Rf 0.35 (hexane : ethyl acetate = 1:9); 1 H—NMR (DMSO—dg ): 5 3.93, 5.48, 6.38, 6.42-6.48, 6.54, 7.06, 7.37, 7.49, 8.44. e 26: N-{4-[(6,7-dimethoxy—4—quinolinyl)oxy]—3-fluorophenyl} -2,5-dioxo~l -phenyl-1,2,5,6,7, 8~hexahydro-3~quinolinecarboxamide The title compound having the following physical ty values was obtained by the procedure having the same purpose as in Example 5 using the compound produced in Example 25 and the compound produced in Example 4.
TLC: Rf 0.17 (hexane : ethyl acetate = 1:9); lI-I-NMR (CDC13 ): 8 2.06—2.20, 2.54-2.68, 4.06, 6.43, 7.15-7.47, .74, 7.94, 8.48, 9.32, 11.55. [0274} Examples 26(1) to 26(3) The following Example compounds were obtained by the procedure having same e as in e 26, using a carboxylic acid derivative was used in place of the compound produced in Example 4.
Example 26(1): N- {4- [(6,7—dimethoxy-4—quinoliny1)oxy] -3 -fluorophenyl} -l -(2,2-dimethylpropy])—2,5-di oxo-l ,2,5,6,7,8-hexahydro—3-quinolinecarboxamide TLC: Rf 0.36 (ethyl acetate); H—NMR (DMSO-dg ): 5 0.99, 2.00-2.16, 2.54-2.60, 3.11-3 .24, 3.94, 4.28, 6.47, 7.40-7.57, 8.05, 8.47, 8.84, 11.81.
Example 26(2): N- ,7—dimethoxyquinolinyl)oxy] -3—fluorophenyl}-1~(3-fluorophenyl)—2,5-dioxo -1,2,5,6,7,8—hexahydro—3 —quinolinecarboxamide TLC: Rf0.32 (ethyl acetate); lH-NMR (CDC13 ): 5 2.07—2.21, 2512.71, 4.05, 4.06, 6.39-6.45, 7.01-7.13, .23, 7.29-7.40, 7.42, 7.57, 7.60-7.74, 7.85—8.00, 8.48, 9.33, 11.38-11.49.
Example 26(3): N- {4-[(6,7-dimethoxyquinolinyl)oxy] ~3 -fluorophenyl}-2’ ,5 ’ ~dioxo-1 ’-pheny1-2 ’ ,5 ’ ,6 ’ ,8 ’ —tetrahydro-1 ’H—spiro[cyclopropane-1,7’-quinoline]—3 oxamide TLC: Rf 0.33 (ethyl acetate); 1H—NMR (CD013): 5 0.32—0.44, 0.50—0.61, 2.40, 2.48, 4.05, 4.06, 6.42, 7.14-7.25, 7.34-7.40, 7.42, 7.58, 7.59-7.70, 7.93, 8.49, 9.37, 11.54.
Example 27: 4-[(6-chloropyridinyl)oxy]-6,7-dimethoxyquinazoline Under argon atmosphere, DMAP (4.4 g) was added to 4-chloro-6,7-dimethoxyquinazoline (8.0 g) and a DMSO suspension (20 mL) of ropyridineol (4.6 g), heated and stirred at a bath temperature (80°C) for two hours, and left to cool to room temperature. Thereafter, the reaction solution was d with ethyl e, and washed with water and saturated sodium hydrogen carbonate aqueous solution. The organic layer was dried over anhydrous sodium sulfate, and concentrated. The resulting residue was washed with hexane - ethyl acetate (3:1) to obtain the title compound (9.1 g) having the following physical property values.
TLC: Rf 0.16 (hexane : ethyl acetate = 1:1); lH—NMR (DMSO—ds ): 5 3.97, 3.99, 7.41, 7.58, 7.69, 7.97, 8.50, 8.57.
Example 28: -[(6,7—dimethoxy—4-quinazolinyl)oxy]pyridinamine hydrochloride Under argon atmosphere, 1.0 mol/L LHMDS (4.7 mL), tris(dibenzylideneacetone)dipalladium(0) chloroform complex (140 mg), and 2-dicyclohexylphosphino-2’,6’~dimethoxybiphenyl (170 mg) were added to a THF solution (15 mL) of the compound produced in e 27 (1.0 g). The mixture was stirred at a bath temperature (70°C) for four hours. After the reaction on was left to cool to room temperature, and placed into ice water, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was suspended in acetonitrile (30 mL), and 2.0 mol/L hydrochloric acid (10 mL) was added o and stirred at room temperature for 30 min. Precipitates generated in the on solution were collected by filtration to obtain the title compound (591 mg) having the following physical property values.
TLC: Rf0.16 (ethyl acetate : methanol = 10:1); 1H-NMR (DMSO-d6): 8 3.96, 3.99, 4.24, 7.10, 7.42, 7.53, 8.00-8.20, 8.07, 8.20, 8.61.
Example 29: N-{ 5- [(6,7-dimethoxyquinazolinyl)oxy]~2—pyridinyl} -2,5-dioxo—l ~phenyl—1 ,2,5,6,7,8 -hexahydroquinolinecarboxamide The title compound having the following physical property values was obtained by the procedure. having the same purpose as in Example 5 using the compound produced in Example 28 and the compound produced in e 4.
TLC: Rf 0.75 (ethyl e : methanol = 5: 1); 1H—NMR (CDC13 ): 5 2.11, 2.59, 4.07, 7.26, 7.33, 7.54, 7.58-7.69, 8.27, 8.52, 8.61, 9.33, 11.91.
Examples 29(1) to 29(6): The following Example compounds were obtained by the procedure having the same e as in Example 27—> e 28—> Example 29, using corresponding quinoline derivatives in place of 4-chloro~6,7-dimethoxyquinazoline, 6—chloropyridine~3-ol, and the compound produced in Example 4 or corresponding carboxylic acid derivatives in place of it.
Example 29(1): N— { 5—[(7-methoxy—4-quinazolinyl)oxy] -2—pyridinyl}~2,5-dioxo—1-phenyl-1 ,2,5,6,7,8-he xahydro-3~quinolinecarboxamide (LC-MS/ELSD): (retention time: 0.99 min); 1H—NMR (CDC13 ): 5 2.02-2.21, 2.57, 3.99, .25, 7.27-7.29, 7.30-7.33, 7.55-7.69, 8.23, 8.26, 8.51, 8.67, 9.33, 11.89. e 29(2): 1-cyclobutyl-N-{5 - [(6,7-dimethoxy—4-quinazolinyl)oxy]pyridinyl} -2,5-diox0- 1 ,2,5 ,6 ,7,8-hexahydroquinolinecarboxamide TLC: Rf 0.47 (ethyl acetate : methanol = 10:1); 1H~NMR (CDC13 ): 5 1.75-1.95, 1.96—2.10, 2.11-2.25, 2.40—2.54, 2.55-2.65, 2.92-3.16, 4.08, 4.09, 4.74—4.93, 7.34, 7.56, 7.68, 8.36, 8.56, 8.62, 9.16, 12.13.
Example 29(3): N—{5-[(6,7-dimethoxy~4—quinazolinyl)oxy] —2—pyridiny1} — l —(2,2-dimethylpropyl)-2,5-dio xo-l,2,5,6,7,8-hexahydroquinolinecarboxamide TLC: Rf0.44 (ethyl acetate :methanol = 10: 1); 1H—NMR (CDC13): 5 1.06, 2.18-2.27, 2.63, 3.02-3.18, 4.08, 4.09, 7.34, 7.56, 7.69, 8.36, 8.56, 8.61, 9.22, 12.17.
Example 29(4): N—{5-[(6,7-dimethoxy-4—quinazoliny1)oxy]~2—pyridinyl}[(2S)—1-hydroxy—3 -methy1—2- butanyl]-2,5-dioxo-1 ,2,5,6,7,8—hexahydro—3 -quinolinecarboxamide TLC: Rf 0.38 (ethyl e : methanol = 10:1); IH-NMR (CDC13 ): 8 0.74, 1.13, 2.09-2.34, .72, 2.77—3.39,3.90-4.20, 4.07, 4.09, 4.44~4.69, 7.32, 7.55, 7.70, 8.32, 8.53, 8.60, 9.15, 12.07.
Example 29(5): N— { 5-[(6,7-dimethoxyquinazolinyl)oxy]~2-pyridinyl } -1 -(4-fluorophenyl)—2,5-dioxo—1 ,2,5,6,7,8-hexahydro-3—quinolinecarboxamide TLC: Rf0.55 (hexane : ethyl acetate = 1:9, NH silica); lH—NMR (CDC13 ): 8 2.12, 2.56-2.63, 4.07, 7.23-7.35, 7.53, 7.66, 8.26, 8.50, 8.60, 9.30, 11.84.
Example 29(6): , N-{5-[(6,7-dimethoxyquinazolinyl)oxy]pyridinyl}[(2R)hydroxymethyl-2 -butanyl]-2,5-dioxo-1 ,2,5 ,6,7,8-hexahydro-3 linecarboxamide TLC: Rf0.20 (ethyl e, NH silica); 1H—NMR (CDCl3): 5 0.72, 1.11, 2.22, 2.52, 2.94, 3.34, 4.07, 4.08, 4.16, 4.40, 4.72, 7.27, 7.54, 7.72, 8.24, 8.45, 8.56, 8.86, 91.5, 12.14.
Example 30: 4—(2—fluoronitrophenyl)~7-methoxyquinazoline romethoxy—quinazoline (50 mg) and 2—fluoro-4—nitrophenol (60 mg) were added to diphenyl ether (10 mL), and the mixture was stirred at 150°C for hours by using microwave. The reaction solution was cooled, and water was added.
Thereafter, the water layer was extracted with ethyl acetate, and the combined c layer was washed with a saturated saline solution, and then concentrated. The resulting residue was purified by silica gel column chromatography (hexane : ethyl acetate = 10020 —> 0:100) to obtain the title compound (60 mg) having the following physical property values.
MASS (ESI, P08): 286 (M+H)+.
Example 31: 3-fluoro[7-methoxyquinazolineyl)oxy]aniline The title compound having the following al property values was obtained by the procedure having the same purpose as in Example 25, using the compound produced in e 30. 1H-NMR (CDC13 ): 5 3.70, 3.98, 6.49657, 7.06, 7.24~7.30, 8.25, 9.47.
Example 32: N-{3—fluoro-4—[(7-methoxy—4~quinazolinyl)oxy]phenyl}-2,5-dioxophenyl-1 ,2,5,6,7,8 ydroquinolinecarboxamide The title compound having the following physical property values was obtained by the ure having the same purpose as in Example 5, using the compound ed in Example 31 and the compound produced in Example 4.
(LC—MS/ELSD): (retention time: 1.02 min); 1H—NMR (CDC13): 8 2.06-2.20, 2.53-2.68, 3.98, 7.19—7.44, 7.58-7.73, 7.93, 8.25, 8.67, 9.32, 11.51.
Example 33: tert-butyl [4~(quinazolineyloxy)phenyl]carbamate 4—chloro-quinazoline (0.95 g), calcium carbonate (3.5 g), and (4~hydroXy—phenyl)—carbamic acid tert-butyl ester (0.90 g) were added to acetonitrile (10 mL), and the mixture was stirred at 100°C for three hours. Water was added to the on solution, and the water layer was extracted with ethyl acetate. The combined c layer was washed with a saturated saline solution, and then concentrated. The resulting residue was purified by silica gel column chromatography (hexane : ethyl acetate = 100:0 —> 0:100) to obtain the title compound (1.3 g) having the following physical property values. 1 H—NMR (CDC13 ): 8 1.53, 6.63, 7.18—7.20, 7.47, 7.64-7.68, 7.89-7.93, 8.00, 8.37, 8.76.
Example 34: 4-(quinazolineyloxy)aniline hydrochloride 4 mol/L hydrochloric acid-1,4—dioxane on (5 mL) was added to a THF solution (5 mL) of the compound produced in Example 33 (100 mg), and the mixture was stirred at room temperature for three hours. The reaction solution was concentrated to obtain the title compound (81 mg) having the following physical property value.
MASS (ESI, Pos.): 238 (M+H)+. e 35: 2,5—dioxo— l 1~N—[4~(4—quinazolinyloxy)phenyl]- 1 ,2,5 ,6,7,8-hexahydro-3~quinolin ecarboxamide The title compound having the following physical property values was obtained by the procedure having the same purpose as in Example 5, using the compound produced in Example 34 and the compound produced in Example 4.
:(LC—MS/ELSD): tion time: 0.98 min); 1H-NMR (CDC13 ): 5 2.08—2.13, 2.54-2.63, 7.21—7.29, 7.60-7.68, .84, 7.91-7.93, 8.00, 8.37, 8.76, 9.34, 11.43.
Example 36: - { [(3-hydroxymethoxyphenyl)amino]methylene}~2,2—dimethyl—l ,3—dioxane—4,6-dio Under argon atmosphere, a methyl orthoforrnate (50 mL) solution of meldrum’s acid (8.0 g) was heated at 100°C for 5 min, and then 3—hydroxymethoxyaniline (7.0 g) was added to the solution, and the resulting solution was heated and stirred at 105°C for 25 min. The heating was stopped to cool with water, and precipitated powder was collected by filtration, washed with methyl orthoformate and MTBE, and dried under reduced re to obtain the title compound (12.3 g) having the following physical ty values.
TLC: Rf0.25 (hexane : ethyl acetate = 1:1); 1 H—NMR (CDC13): 8 1.75, 3.92, 5.82, 6.73, 6.84-6.88, 8.53, 11.2.
Example 37: ~( { [3-(benzyloxy)—4-methoxyphenyl]amino}methylene)-2,2—dimethyl-1 ,3 -dioxane-4,6- dione Under argon atmosphere, the compound produced in Example 36 (12.0 g) dissolved in DMA (80 mL) at 50°C. The temperature was returned to room temperature. Then, potassium ate (7.35 g) and benzyl bromide (8.75 g) were added thereto. The resulting solution was heated and stirred at 60°C for two hours.
The mixture was left to cool to room ature, and the solvent was concentrated, followed by adding ethyl acetate and water and shaking thereof. Since deposits were precipitated, the deposits were collected by filtration, washed with water and ethyl acetate, and dried under reduced pressure to obtain the title compound (8.0 g) having the following physical property values.
TLC: Rf 0.49 (hexane : ethyl acetate = 1 :1); 1H-NMR (CDC13 ): 8 1.75, 3.90, 5.17, 6.76-6.85, 6.91, 7.30-7.48, 8.48, 11.2.
Example 38: {6—methoxy-7—[3~(4—morpholinyl)propoxy]~4-quinoliny1}oxy)pyridinyl]-2,5-di 0x0- 1 —phenyl—1 ,2,5,6,7,8—hexahydro-3 -quinolinecarboxamide The title compound having the following physical property values was obtained by the procedure having the same purpose as in Example 11 —> Example 12 —> Example 13 —> Example 14 —+ Example 15 —> Example 16 —+ Example 17, using the compound produced in e 37.
TLC: Rf0.20 (ethyl acetate, NH silica); lH-NMR (CDC13 ): 5 2.08-2.19, 2.45-2.64, 3.73, 4.02, 4.27, 6.43, 7.25, 7.43, .65, 8.21, 8.47, 8.49, 9.32, 11.92.
Examples 38(1) to 38(7): The following Example compounds were obtained by the procedure having the same e as in Example 38, using a corresponding compound in place of the compound produced in Example 37.
Example 38(1): N-(5u{ [7-(3-hydroxy—3—methy1butoxy)—6-methoxy—4-quinoliny1]oxy}pyridinyl)-2,5-d ioxopheny1-1,2,5,6,7,8~hexahydro—3—quinolinecarboxamide H, o \N TLC: Rf0.20 (ethyl acetate, NH silica); 1H-NMR (CDC13 ): 5 1.34, 2.07-2.15, 2.56-2.64, 3.28, 4.01, 4.43, 6.45, 7.25, 7.43, 7.53-7.67, 8.21, 8.48, 8.51, 9.33, 11.93.
Example 38(2): N—[S—({6-methoxy~7~[3—(1—piperidiny1)propoxy]~4—quinoliny1}oxy)—2—pyridinyl]-2,5-dio xo~1—pheny1—1,2,5 —hexahydro-3 -quinolinecarboxamide TLC: Rf0.28 (ethyl acetate, NH silica); 1H-NMR (CDC13 ):_ 8 1.42, 1.52-1,64, 2.08-2.15, 2.38—2.45, 2.50—2.63, 4.02, 4.24, 6.42, 7.21—7.28, 7.42, 7.51, .66, 8.21, 8.47, 8.49, 9.32, 11.92.
Example 38(3): N-[5—({6-methoxy-7— [3 —(1-pyrrolidinyl)propoxy]quinolinyl}oxy)pyridinyl]-2,5-di oxo-l-phenyl—1,2,5,6,7,8-hexahydro—3-quinolinecarboxamide TLC: Rf0.25 (ethyl acetate, NH silica); lH—NMR (CDC13 ): 5 1.79, 2.15, 2.56, 2.67, 4.02, 4.27, 6.42, 7.25, 7.42, 7.51, 7.53-7.65, 8.21, 8.47, 8.49, 9.32, 11.92.
Example 38(4): N—[5-({6~methoxy [3 ~(1-piperazinyl)propoxy]-4—quinolinyl}oxy)—2-pyridinyl]-2,5-dio xophenyl—1 ,2,5,6,7,8-hexahydroquinolinecarboxamide TLC: Rf 0.20 (ethyl acetate, NH ); lH-NMR (CD013 ): 8 2.10, 2.55, 2.71, 3.15, 4.01, 4.26, 6.44, 7.26, 7.42, 7.51-7.67, 8.21, 8.49, 9.31,11.92.
Example 38(5): N—(S— { butyn-l —yloxy)—6-methoxyquinolinyl]oxy}—2-pyridinyl)-2,5—di0xo-1 —phe nyl—1,2,5,6,7,8-hexahydro-3~quinolinecarboxamide TLC: Rf 0.56 (ethyl acetate : methanol = 10:1); 1 H—NMR (CDC13 ): 5 1.86, 2.00-2.21, 2.48-2.74, 4.04, 4.90, 6.45, 7.22«7.31, 7.50-7.68, 8.22, 8.45—8.54, 9.33, 11.94.
Example 38(6): N—[S—({6—methoxy—7-[3-(methylsulfony1)propoxy]~4—quinoliny1}oxy)—2-pyridinyl]-2,5-d ioxo- 1 1- 1 ,2,5,6,7,8~hexahydroquinolinecarboxamide TLC: Rf0.16 (ethyl acetate : ol = 10:1, NH silica); ’ H—NMR (CDC13 ): 8 2.02-2.19, 2.40—2.68, 2.99, 3.29-3.40, 4.02, 4.32, 6.45, 7.22-7.29, 7.40, 7.49-7.69, 8.22, 8.44-8.55, 9.33, 11.94.
Example 38(7): N—[S-({6-meth0xy-7—[3-(4-methyl- l -piperazinyl)propoxy]—4-quinolinyl} oxy)—2-pyridin yl]-2,5-dioxophenyl-1 ,2,5,6,7,8-hexahydro-3 linecarboxamide TLC: Rf0.20 (ethyl acetate, NH silica); 1H-NMR (CD013 ): 8 2.13, 2.29, 2.48-2.65, 4.02, 4.25, 6.42, .28, 7.42, 7.51, 7.52-7.67, 8.21, 8.47, 8.49, 9.32, 11.92.
Example 39: N—[5—({7-[(3 -methylbuten—1 y] quinolinyl} oxy)pyridiny1]-2,5-dioxo~ 1 —phe nyl— 1 ,2,5,6,7,8—hexahydro-3 -quinolinecarboxamide Under argon atmosphere, cesium carbonate (94 mg) and 1-bromo-3—methylbutene (140 mg) were added to a DMF solution (15 _mL) of the compound produced in Example 16 (100 mg), and the mixture was stirred at a bath temperature (—10°C) for two hours. An ammonium chloride s solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over anhydrous sodium sulfate, and trated, followed by purification by silica gel column chromatography (hexane : ethyl acetate = 1:4, NH silica) to obtain the title compound (55 mg).
TLC: Rf0.30 (ethyl acetate, NH silica); 1H—NMR (CDC13 )2 8 1.79, 1.82, 2.08-2.17, 2.46-2.63, 4.67, 5.57, 6.39, .26, 7.46, 7.48—7.65, 8.18, 8.22, 8.45, 8.49, 9.29, 11.90.
Example 40: N— — { [(2R)—2,3-dihydroxy~3 ~methylbutyl]oxy} quinolinyl)oxy] -2—pyridinyl} ~2,5 -dioxophenyl-1,2,5,6,7,8-hexahydro—3—quinolinecarboxamide U 00l H:>t§:\o/©:Ij Under argon atmosphere, tert—buthyl alcohol (0.5 mL), water (0.5 mL), AD-mix-B (50 mg), and e sulfonamide (7 mg) were added to a dichloromethane solution (0.5 mL) of the compound produced in Example 39 (20 mg), and the mixture was stirred at room temperature for six hours. A sodium thiosulfate aqueous solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over anhydrous sodium e, and concentrated, followed by purification by silica gel column chromatography (ethyl acetate, NH silica) to obtain the title compound (3 mg).
TLC: RfO. 10 (ethyl e, NH silica); lH—NMR (CDC13 ): 8 1.32, 1.36, 2.11, 2.37, 2.60, 2.87, 3.92, 4.20, 4.32, 6.42, 7.23, 7.43, 7.53—7.66, 8.20, 8.23, 8.48, 8.60, 9.32, 11.93.
Examples 40(1) to 40(6) The following Example compounds were obtained by the procedure having the same purpose as in Example 39 -—> e 40, using a corresponding compound in place of the compound ed in Example 16, 1-bromomethylbutene, and AD-miX-fi or AD-mix-oc.
Example 40(1): N—{5-[(7~{ [(2S)-2,3—dihydroxymethy1buty1]oxy}methoxyquinoIinyl)oxy]-2—pyr idinyl} -2,5-dioxo-1 —pheny1-1 ,2,5 ,6,7,8-hexahydroquinolinecarboxamide TLC: Rf0.41 (ethyl acetate : methanol = 10:1); 1H—NMR (CDC13 ): 5 1.32, 1.36, 1.99-2.19, .68, 3.04, .23, 3.74—3.90, 4.01, 4.21-4.33, 4.37-4.48, 6.45, 7.24-7.29, 7.42, 7.54, 7.54—7.69, 8.18-8.23, 8.46-8.52, 9.32, 11.93.
Example 40(2): N— { 5—[(7— { [(2R)—2,3—dihydroxy~3 —methy1buty1]oxy} —6~methoxyquinolinyl)oxy]py ridinyl}-2,5~dioxo—1—phenyl—1,2,5,6,7,8-hexahydro-3~quinolinecarboxamide TLC: Rf0.48 (dichloromethane : methanol = 9:1); 1H—NMR (CDC13): 3 2, 2.07—2.15, 2.56-2.64, 2.90—3.40, 3.85, 4.01, 4.27, 4.43, 6.45, 7.25-7.29, 7.42, 7.53-7.66, 8.21, 8.48, 8.50, 9.32, 11.93. e 40(3): N—{S-[(7- { [(ZS)—2,3 —dihydroxy-3~methylbutyl]oxy} —6~methoxyquinolinyl)oxy]pyr idinyl}-1—(2,2—dimethy1propyl)—2,5-dioxo—1,2,5,6,7,8—hexahydroquinolinecarboxamid TLC: Rf 0.41 (ethyl acetate :methanol = 10:1); 1H—NMR (CDC13 ): 8 1.06, 1.33, 1.37, 2.11-2.33, 2.55-2.71, 3.04, 3.06-3.15, 3.16-3.24, 3.79—3.91, 4.03, 4.21—4.33, 4.39—4.48, 6.46, 7.43, 7.53-7.61, 8.27-8.33, 8.48-8.56, 9.22, 12.18. [03 11] Example 40(4): .
N— { 5- [(7— { [(2R)-2,3 -dihydroxy~3 -methylbutyl]oxy} methoxyquinolinyl)oxy]~2-py l}—1-(2,2—dimethylpropyl)-2,5-dioxo-1 ,2,5,6,7,8—hexahydro-3 -quinolinecarboxa1ni TLC: Rf0.45 (dichloromethane : ol = 9: 1); 1H—NMR (CDC13 ): 8 1.06, 1.33—1.37, 2.18—2.26, 2.63, .20, 3.87, 4.02, 4.28, 4.44, 6.46, 7.43, 7.55—7.60, 8.30, 8.49-8.55, 9.21, 12.18.
Example 40(5): N— { 5- [(7— { [(2R)—2,3 -dihydroxymethylbutyl]oxy} -6—methoxy—4-quinolinyl)oxy] -2—py ridinyl} —2’ ,5 o-1 ’-phenyl-2 ’ ,5 ’,6 ’ ,8 ’-tetrahydro—1 ’H—spiro[cyclopropane-1 ,7’ -quin oline]‘3 ’~carboxamide TLC: Rf 0.49 (dichloromethane : methanol = 9:1); 1H—NMR (CDC13 ): 5 0.37—0.40, 0.53-0.56, 1.32-1.36, 2.41, 2.48, 2.98, 3.19, 3.85, 4.01, 4.27, 4.43, 6.46, 7.21—7.24, 7.42, 7.54—7.65, 8.22, 8.49-8.52, 9.36, 11.94. [03 13] Example 40(6): N— { 5—[(7- { [(2S)—2,3~dihydroxy—3 -methylbutyl]oxy} —6—methoxy-4—quinolinyl)oxy]pyr idinyl}—1-(3 -fluorophenyl)—2,5 —dioxo-1 ,2,5,6,7,8~hexahydro—3 -quinolinecarboxamide TLC: Rf0.56 (ethyl acetate : methanol = 10:1, DNH silica); lH-NMR (CDC13 ): 5 1.32, 1.36, 2.05—2.22, 2.53—2.71, 2.98-3.09, 3.11-3.26, 3.77-3.92, 4.01, .30, 4.39—4.47, 6.45, 7.00—7.13, 7.28-7.36, 7.42, 7.51-7.69, 8.23, 8.45—8.54, 9.32, 11.86.
Example 41: bis(2-methylpropanyl)(5- { [7-benzyloxy)—6-methoxy—4-quinolinyl] -pyridinyl)i midodicarbonate -{[7—(benzyloxy)methoxy—4—quinolinyl]oxy}pyridinamine (1.6 g) was dissolved in a methy1-3,4,5,6—tetrahydro-2—(1H)-pyrimidinone solution (.15 mL) of di-tert-butyl dicarbonate (CAS registration No.:24424—99—5) (3.95 mL). Triethyl amine (9.37 mL) and DMAP (52 mg) were added to the resulting solution, and solution was stirred at room temperature for five hours. The reaction solution was diluted with hexane : ethyl acetate mixed solution (1 :3), and washed with water.
Then, the organic layer was concentrated, and purified by silica gel column chromatography (hexane : ethyl acetate = 4:1 ——-> 0:1 —»~ ethyl acetate :methanol = 50:1 —> 20:1) to obtain the title compound (2.4 g) having the following al property values.
TLC: Rf0.51 (ethyl acetate); 1H-NMR (CDC13 ): 8 1.49, 4.04, 5.33, 6.45, 7.30-7.43, 7.44-7.62, 8.41, 8.50.
Example 42: bis(2—methyl—2~propany1) {5-[(7—hydroxy-6~methoxy-4~quinoliny1)oxy]pyridiny1}imi dodicarbonate Under argon atmosphere, ethyl acetate (10 mL) and ethanol (30 mL) were added to and dissolved in the nd produced in Example 41 (1. 4g). Palladium hydroxide (20 wt%, 420 mg) was added thereto, and the mixture was stirred under hydrogen atmosphere at room temperature for five hours. Palladium hydroxide was removed through , and the filtrate was concentrated to obtain the title compound (1.2 g).
TLC: Rf 0.49 (ethyl acetate); 1H-NMR (CDC13 ): 8 1.50, 4.08, 6.44, 7.36, .60, 8.42, 8.53. [03 16] Example 43: methyl—2—propany1) [5—( {6-methoxy[(3-methy1-3 —buten- 1 —y1)oxy] -4—quinolinyl} oxy)pyridinyl]imidodicarbonate 3—methylbuten—l-ol (231mg), N,N,N’,N’-tetramethy1 azodicarboxamide (TMAD) (462 mg), and tri—n—butylphosphine (544 mg) were added to a THF suspension (20 mL) of the compound produced in Example 42 (500 mg), and the mixture was stirred at room temperature for three hours. The reaction solution was diluted with ethyl acetate, and concentrated by removing insoluble matters. The resulting residue was purified by silica gel column tography (hexane : ethyl acetate = 3:2 —+ 0:1) to obtain the title compound (570 mg) having the ing physical property values.
TLC: Rf0.52 (hexane : ethyl acetate = 3 :7); 1H~NMR (CDC13): 8 1.49, 1.86, 2.68, 4.03, 4.33, 4.76—4.99, 6.46, 7.35, 7.45, 7.50, 7.55, 8.42, 8.52.
Example 44: bis(2—methy1propanyl){5—[{7—[(3 S)—3,4-dihydroxy~3~methy1butoxy]-6—methoxy~4—qui l}oxy]pyridiny1}imidodicarbonate Dichloromethane : t—butanol : water = 1:1:1 (1.5 mL) was added to and dissolved in the compound produced in Example 43 (170 mg), AD-mix-B (431 mg) and methane sulfonamide (58 mg) were added thereto, and the e was d at room ature overnight. The reaction solution was diluted with ethyl acetate, and washed with water. The organic layer was collected and purified by silica gel column chromatography (hexane : ethyl e = 4:1 —> 0:1—> ethyl acetate : methanol = 9:1) to obtain the title compound (152 mg) having the following physical property values.
TLC: Rf 0.54 (ethyl acetate : methanol = 9:1); 1H-NMR (CDC13 ): 5 1.29, 1.50, 2.06-2.17, 2.19—2.36, 2.90—3.32, 3.45-3.65, 4.02, 4.28-4.51, 6.48, 7.36, 7.45, 7.51, 7.56, 8.42, 8.52.
Example 45: 4-(4— {4—[(6—amino-3 -pyridinyl)oxy]methoxy—7-quinolinyl} oxy)-(2S)—2-methyl~ 1 ,2—b utanediol Trifluoroacetic acid (2 mL) was added to a romethane solution (5 mL) of the compound produced in Example 44 (152 mg). The mixture was stirred at room temperature for two hours. The reaction solution was concentrated, and subjected to azeotrope with e twice. The resulting residue was purified by silica gel column tography (NH silica, ethyl acetate :methanol = 9:l) to obtain the title compound (100 mg) having the following physical property values.
TLC: Rf0.35 oromethane : methanol = 9:1, NH silica); lH~NMR (CDC13 ): 8 1.28, 2.01-2.15, 2.17—2.34, 2.74-2.94, 3.08-3.23, 3.44—3.66, 4.03, 4.26-4.46, 4.52, 6.43, 6.61, 7.31, 7.41, 7.56, 8.03, 8.48. [03 19] Example 46: N—{5— [(7- { [(3 S)—3 ,4—dihydroxy—3 ~methylbutyl] oxy } —6-methoxy-4—quinolinyl)oxy]-2—pyr idinyl} —2,5—dioxo-l -phenyl—1,2,5,6,7,8-hexahydro-3~quinolinecarboxamide /N N l 0);} 0 0 cg, ch’o / HOWO \N The title compound having the following physical property values was obtained by the procedure having the same purpose as in Example 5, using the compound produced in Example 45 and the compound produced in Example 4.
TLC: 0.43 (dichloromethane : ol = 9:1); 1 H-NMR (CDC13 ): 5 1.28, 2.05-2.30, 2.56-2.64, .30, 3.48-3.60, 4.02, 4.31-4.45, 6.45, 7.25-7.28, 7.33, 7.43-7.67, 8.21, 8.48-8.51, 9.32, 11.93. i es 46(1) to 46(3) The following Example compounds were obtained by the procedure having the same purpose as in Example 46, using the compound produced in Example 45, or a compound produced by subjecting the compound produced in Example 43 to the procedure having the same purpose as in Example 44 —+ Example 45 using AD-mix-oc in place of AD-mix-B, and the nd produced in Example 4 or a corresponding carboxylic acid derivative in place of it. e 46(1): N— { 5 ~ [(7- { [(3R)—3 ,4-dihydroxy-3 -methylbutyl]oxy} methoxy—4-quinolinyl)oxy]py ridiny1}-2,5-dioxo-1 -phenyl~1,2,5 ,6,7, 8-hexahydro-3 -quinolinecarboxamide TLC: 0.40 (ethyl acetate :methanol = 10:1); 1H-NMR (CDC13): 8 1.28, 1.97-2.17, 2.18-2.35, 2.52-2.69, 2.74-2.89, 3.13, I 3.40-3.69, 4.02, 4.23-4.52, 6.45, 7.20-7.30, 7.42, 7.53, 7.54-7.70, 8.21, 8.45-8.52, 9.32, 11.93.
Example 46(2): N-{5-[(7- { [(3 S)—3 ,4—dihydroxy—3 ~methylbutyl] oxy}methoxyquinolinyl)oxy]pyr idiny1}-2’,5 o-1 yl—2 ’,5 ",6 ’,8 ’-tetrahydro—1 ’H-spiro [cyclopropane-l ,7’ -quino line] —3 ’—carboxamide TLC: 0.45 (dichloromethane : methanol = 9: 1); 1H—NMR (CDCl3 ): 8 0.37—0.41, 0.53-0.56, 1.28, .30, 2.42, 2.48, .30, 3.48-3.60, 4.02, 4.31-4.45, 6.45, 7.21-7.24, 7.42, 7.48-7.65, 8.21, 8.48-8.51, 9.36, 11.93.
Example 46(3): N- { 5- [(7- { [(3R)-3,4-dihydroxy—3~methylbutyl]oxy} methoxy~4-quinolinyl)oxy]py ridinyl } -2’ ,5 ’ ~dioxo-l ’-phenyl—2’ ,5 ’ ,6’ ,8 "-tetrahydro-l ’H—spiro [cyclopropane-l ,7’ -quin oline]—3’-carboxamide TLC: 0.50 (ethyl acetate : methanol = 10:1, NH silica); 1H—NMR (CDC13): 5 0.33—0.43, 0.50-0.61, 1.28, 1.98—2.14, 2.16-2.33, 2.42, 2.48, 2.73-2.91, 3.08-3.18, 3.42-3.68, 4.02, 4.23-4.51, 6.46, .25, 7.42, 7.54, 7.55-7.66, 8.22, 8.46-8.54, 9.36, 11.94.
Example 47: (5E)—5—(hydroxyimino)—4-methyloxo- 1 l-1 ,2,5,6,7,8~hexahydroquinoline carboxylic acid A pyridine solution (1.0 mL) of the compound produced in Example 4 (142 mg) and hydroxylamine hydrochloride (208 mg) was heated and d for one hour.
The solution was cooled to room temperature. The reaction solution was diluted with ethyl acetate and washed with 1 moi/L hydrochloric acid. The ed organic layer was concentrated to obtain the title compound (151 mg) having the following physical property values.
TLC: Rf 0.42 (dichloromethane : methanol = 9:1); lH~NMR (DMSO‘dé): 8 1.63-1.81, 2.26-2.36, 2.60, 7.38-7.46, 7.51-7.68, 8.90, 11.30, 14.03.
Example 48: N-{(5E)—5—[(6,7-dimethoxy-4—quinolinyl)oxy]—2—pyridiny1}—5—(hydroxyimino)-2—oxo-1— phenyl-1,2,5,6,7,8—hexahydro-3—quinolinecarboxamide The title compound having the following al property values were obtained by the procedure having the same purpose as in Example 5, using the compound produced in Example 47 and the compound produced in e 2.
TLC: 0.15 (ethyl acetate, NH silica); 1I—I-NMR (CDC13 ): 8 1.77-1.94, 2.38, 2.77, 4.05, 6.46, 7.20-7.25, 7.43, 7.50—7.65, 7.99-8.07, 8.22, 8.48, 8.52, 9.33, 12.23.
Example 48(1): N-{5—[(6,7-dimethoxyquinolinyl)oxy]-2—pyridiny1}-(5E)(methoxyimino)-2~oxo-1 — phenyl-l,2,5,6,7,8-hexahydroquinolinecarboxamide The title compound having the following physical property values was obtained by the procedure having the same purpose as in Example 48, using a corresponding ylic acid derivative in place of the compound produced in Example 47 and the compound produced in Example 2.
TLC: 0.18 (ethyl acetate); lH-NMR (CDC13): 5 1.74-1.92, 2.29-2.40, 2.62-2.75, 4.00, 4.05, 6.45, .28, 7.42, 7.50-7.66, 8.20-8.24, 8.46-8.52, 9.36, 12:26.
Example 49: 7—(benzyloxy)~4-(2—fluoronitrophenoxy)—6-methoxyquinoline The title compound having the following physical property values was obtained by the ure having the same e as in Example 24, using 7-benzyloxy—6—methoxy-quinolineol[in place of 6,7-dimethoxy quinoline-4—ol.
TLC: Rf 0.76 e : ethyl acetate = 1:1); 1H-NMR(CDC13): 8 4.03, 5.34, 6.54, 7.28-7.43, 7.45, 7.47-7.55, 8.10-8.15, 8.19, 8.56. e 50: 4—(2—fluoronitrophenoxy)~6-methoxyquinolinol hydrobromate .1 moi/L hydrobromic acid - acetic acid solution (10 mL) was added to the compound produced in Example 49 (1.6 g). The mixture was stirred at room temperature for five hours. MTBE (50 mL) was added to the on solution, and the resulting solution was stirred. Generated precipitates were collected by filtration to obtain the title compound (1.5 g) having the following physical property values. 1H—NMR (CD3 OD): 5 4.14, 7.05, 7.43, 7.76-7.85, 7.86, 8.30-8.38, 8.39-8.46, 8.69.
Example 51: 4-(2—fluoro-4—nitrophenoxy)—6-methoxy—7—[3—(4-morpholinyl)propoxy]quinoline Cesium carbonate (4.0 g) and 4—(3-chloropropyl)morpholine (517 mg) were added to a DMF on (9.8 mL) of the compound produced in Example 50 (1.0 g), and the mixture was stirred at 60°C for 16 hours. The mixture solution was diluted with ethyl acetate, and washed with water. The water layer was ted with ethyl acetate twice. The combined organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (NH silica, hexane : ethyl acetate = 1:1 —> 0:1) to obtain the title compound (600 mg) having the following physical property .
TLC: Rf 0.50 (ethyl acetate, NH silica); 1H—NMR (DMSO—dg): 5 1.90—2.07, 2.32—2.43, 3.25-3.35, 3.48-3.64, 3.92, 4.21, 6.77, 7.45, 7.55-7.67, 8.14-8.25, .50, 8.56.
Example 52: 3~fluoro{(6-methoxy-7—(3-morpholinopropoxy)quinoline-4—yl)oxy} aniline Under argon here, the compound produced in Example 51 (300 mg) dissolved in ethyl acetate : ethanol = 1:1 (30 mL), and palladium hydroxide (20 wt%, 99 mg) was added to the solution, and the argon atmosphere was ed with a en atmosphere. After the solution was stirred at room temperature for eight hours, the reaction solution was filtered through Celite, and the filtrate was concentrated to obtain the title compound (240 mg) having the following physical property values. lH—NMR (CD013 ): 8 2.03-2.23, 2.43-2.53, 2.57, 3.66—3.77, 3.86, 4.03, 4.26, 6.40, 6.45—6.61, 7.03, 7.42, 7.58, 8.46. [033 1] Example 53: N~[3-fluoro—4~({6-methoxy—7-[3-(4-morpholiny1)propoxy]quinolinyl}oxy)phenyl]~2, —dioxo-1—pheny1—1 ,2,5 -hexahydroquinolinecarboxamide The title compound having the following physical property values was obtained by the procedure having the same purpose as in e 5, using the compound produced in Example 52 and the compound produced in Example 2.
TLC: Rf 0.71 (ethyl acetate : methanol = 10:1, NH silica); H—NMR (DMSO—d6 ): 8 1.88-2.07, 2.34-2.41, 2.41-2.46, 2.51-2.57, 3.31-3.37, .64, 3.94, 4.20, 6.42-6.49, 7.39, 7.40—7.53, 7.54-7.71, 8.04, 8.46, 8.95, 11.64.
Example 54: methyl 2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3—carboxylate 2-oxo-1,5,6,7-tetrahydro~cyclopenta[b]pyridine-3~carboxy1ic acid (CAS registration No.: 115122—63—9) (200 mg) was dissolved in methanol (20 mL) at room ature, and concentrated sulfuric acid (0.006 mL) was added to the solution. The mixture was stirred at a bath temperature (70°C) for four hours. The solution was left to cool to room temperature, the t was distilled off under reduced pressure, and a sodium hydrogen bicarbonate aqueous solution and dichloromethane were added thereto, and the solution was separated. The organic layer was washed with a saturated saline solution, and then was dried over anhydrous sodium sulfate, and the t was distilled off under d re to obtain the title compound (155 mg) having the following physical property values.
TLC: Rf0.21 (ethyl e); IH-NMR (CDC13 ): 5 2.13-2.20, 2.80-2.84, 2.97-3.03, 3.91, 8.10.
Example 55: methyl 2-oxo—1~pheny1-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridinecarboxylate The compound ed in Example 54 (140 mg) was dissolved in dichloromethane (7 mL) at room temperature. Phenylboronic acid (220 mg), copper acetate (263 mg), and pyridine (0.234 mL) were added to the solution, and the solution was stirred for 20 hours. The solution was filtered through a glass filter, and the solvent was distilled ofi‘ under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane : ethyl acetate = 8:2 —> ethyl acetate) to obtain the title compound (131 mg) having the following physical property values.
TLC: Rf 0.51 (ethyl acetate); 1H—NMR (CDC13 ): 5 2.02-2.12, .58, 2.83-2.88, 3.88, 7.20~7.23, 7.44-7.53, 8.21.
Example 56: 2-oxo- l —phenyl—2,5 ,6,7~tetrahydro~1H—cyclopenta[b]pyridine-3 ~carboxylic acid The compound produced in Example 55 (120 mg) was dissolved in ol (2 mL) at room temperature. 2 mol/L sodium hydroxide aqueous solution (0.891 mL) was added to the solution, and the solution was stirred for one hour. 2N hloric acid (0.891 mL) and ethyl acetate were added to the reaction solution, and the solution was separated. The organic layer was washed with a saturated saline solution, then was dried over ous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (109 mg) having the following physical property values.
TLC: Rf0.64 (ethyl acetate); 1 H—NMR (CDC13 ): 5 2.09-2.19, 2.63-2.68, 2.92-2.97, 7.25~7.30, 7.52-7.62, 8.51, 14.24.
Example 57: N—{5-[(6,7-dimethoxyquinolinyl)oxy]pyridiny1}oxo—1-pheny1-2,5,6,7- tetrahydro- l H-cyclopenta[b]pyridinecarboxamide NN N 0\g © H‘c\o \N The title compound having the following physical property values was obtained by the procedure having the same purpose as in Example 5, using the compound produced in Example 56 and the compound produced in Example 2.
TLC: Rf 0.65 (ethyl e : methanol = 9:1); 1H—NMR (DMSO—d6): 8 2.03-2.13, 2.60-2.65, .97, 3.97, 3.99, 6.58, 7.45, 7.47— 7.52, 7.57, .68, 7.86-7.90, 8.38, 8.48, 8.53, 8.60, 12.58.
Examples 57(1) to 57(2) The Example compounds each having the following physical ty values were obtained by the procedure having the same purpose as in Example 55 —> Example 56 —> Example 57, using a corresponding derivative in place of the compound produced in Example 54 and the nd produced in e 2.
Example 57(1): N-{5—[(6,7—dimethoxy-4—quinolinyl)oxy]~2—pyridinyl}—2—oxo—1-phenyl-1,2,5,6,7,8— hexahydro—3-quinolinecarboxamide TLC: Rf 0.63 (ethyl acetate, NH silica); 1H-NMR(CDC13): 5 1.71—1.83, 2.20-2.29, 2.68-2.76, 4.05, 6.44, 7.19-7.24, 7.42, 7.46- 7.62, 8.21, 8.44-8.50, 12.51.
Example 57(2): N-{5—[(6,7-dimethoxy-4—quinolinyl)oxy]-2—py1idinyl}-2,5-dioxophenyl-2,5,6,7- tetrahydro— 1 H—cyclopenta[b]piperidine-3~carboxamide TLC: Rf 0.63 (ethyl acetate :methanol = 9:1); lH—NMR (CDCl3): 5 2.68—2.81, 4.05, 6.45, 7.35, 7.43, 7.53, 7.55-7.68, 8.24, 8.49, 8.51, 9.03, 11.91.
Example 58: N— { 5- [(7- {[(4S)-2,2-dimethyl— 1 ,3-dioxolane—4—yl]methoxy} ~6—methoxy-4—quinoliny1)ox y]—2~pyridinyI}-2,5-di0xo— 1 -phenyl-l ,2,5,6,7,8-hexahydro-3—quinolinecarboxamide The title compound having the following physical property values was obtained by the procedure having the same purpose as in Example 17, using the compound ed by subjecting the compound produced in e 37 to procedure having the same purpose as in Example 11 -> Example 12 —> Example 13 —> Example 14 -—> Example 15 —+ Example 16, and (S)-(2,2-dimethyl¥1,3—di0xolane-4—yl)methanol.
TLC: Rf0.60 (ethyl e, NH silica); 1H—NMR (CDC13 ): 8 1.42, 1.50, 2.11, 2.60, 4.01, 4.14-4.29, 4.64, 6.44, 7.42, 7.52-7.65, 8.21, 8.47, 8.50, 9.32, 11.92.
Example 59: N— { 5—[(7—{ 2,3-dihydroxypropyl]oxy} methoxyquinolinyl)oxy]—2-pyridinyl} 2,5-dioxo-l—phenyl-1,2,5,6,7,8—hexahydroquinolinecarboxamide The compound produced in Example 58 (35 mg) was dissolved in THF (1 mL) at room temperature. Methanol (1 mL) and p-toluenesulfonic acid monohydrate (3.0 mg) were added to the solution, and the e was stirred room temperature for 16 hours. The reaction on was d with ethyl acetate, and washed with water and a saturated sodium hydrogen ate aqueous solution. The organic layer was dried over anhydrous sodium sulfate, and then concentrated. The resulting residue was purified by silica gel chromatography (ethyl acetate : methanol = 100:0 —> 70:30) to obtain the title compound (32 mg) having the following physical property values.
TLC: Rf0.55 (ethyl acetate 2 methanol = 5:1, NH silica); 1H—NMR (CDC13)I 8 2.11, 2.56—2.64, 3.89, 4.02, 4.21-4.36, 6.45, 7.25—7.28,7.44, 7.53—7.66, 8.21, 8.48-8.51, 9.32, 11.93.
Examples 59(1) to 59(3) The following-Example nds were obtained by the procedure having the same purpose as in Example 59, using the compound produced in Example 58 or a corresponding compound in place of it.
Example 59(1): N— { 5~ [(7~ { [(2S)—2,3 ~dihydroxypropyl]oxy} ~6—methoxy—4—quinoliny1)oxy]pyridinyl} - 2,5—dioxophenyl—1 ,2,5 ,6,7,8-hexahydroquinolinecarboxamide TLC: Rf0.55 (ethyl acetate : methanol = 5:1, NH silica); lH—NMR (CDCl3): 8 2.11, .64, 3.90, 4.02, 4.21-4.36, 6.44, 7.24-7.29, 7.44, 7.52-7.66, 8.22, .51, 9.33, 11.94.
Example 59(2): N— { 5 - [(7- { [(2 S)—2,3 -dihydroxypropyl]oxy} -6—methoxy—4-quinolinyl)oxy]pyridinyl } 1~(2,2-dimethylpropyl)-2,5-dioxo~1 ,2,5,6,7,8-hexahydroquinolinecarboxamide TLC: Rf0.35 (ethyl acetate, NH ); 1H-NMR (CDC13): 5 1.06, 2.22, 2.63, 3.09, 3.89, 4.02, 4.22, 4.34, 6.44, 7.43, 7.55, 7.58, 8.30, 8.52, 8.54, 9.21, 12.18.
Example 59(3): N-{S-[(7—{[(2R)—2,3~dihydroxypropyl]oxy}~6—methoxy~4-quinolinyl)oxy]pyridinyl}~ 1-(2,2-dimethylpropyl)—2,5—dioxo— 1 ,2,5,6,7,8—hexahydro—3 —quinolinecarboxamide TLC: Rf 0.35 (ethyl e, NH silica); lH—NMR (CDClg): 8 1.06, 2.22, 2.63, 3.09, 3.89, 4.02, 4.22, 4.34, 6.44, 7.43, 7.55, 7.58, 8.30, 8.52, 8.54, 9.21, 12.18.
Example 60: -hydroxy—N-{5-[(7-hydroxy—6—methoxy—4~quinolinyl)oxy] ~2—pyridinyl}~2—oxo~1 ~pheny l-1,2,5,6,7,8-hexahydroquinolinecarboxamide The title compound having the following physical property values was obtained by the procedure having the same purpose as in Example 11 —> Example 12 —> Example 13 —> Example 14 —> Example 15 —> Example 16, using the nd produced in Example 37.
TLC: Rf 0.26 (dichloromethane : methanol = 19:1); 1H-NMR (CDC13 ): 8 1.62-1.93, 2.27, 4.08, 4.85, 6.42, 7.23, 7.52-7.62, 8.21, 8.46, 8.51, 8.80, 12.37.
Example 61: N-{5-[(7—hydroxymethoxy—4-quinolinyl)oxy]-2—pyridinyl}oxophenyl-1,2,5,6,7, 8-hexahydro-3—quinolinecarboxamide The compound produced in Example 60 (300 mg) was dissolved in dichloromethane (5 mL). Triethylsilane (127 mg), and trifluoroacetic acid (0.081 mL) were added to the solution, tially. The solution was stirred at room temperature for 22 hours. The reaction solution was diluted with ethyl acetate, and washed with water and a saturated sodium en carbonate aqueous on. The organic layer was dried over anhydrous sodium sulfate, and then concentrated. The resulting residue was purified by silica gel chromatography (hexane : ethyl acetate = 30:70 —> 0:100) to obtain the title compound (183 mg) having the following physical ty .
TLC: Rf0.77 (ethyl acetate :methanol = 5:1); IH—NMR (CDCI3 ): 8 1.75, 2.23, 2.72, 4.08, 6.42, 7.22, 7.51—7.60, 8.21, 8.44-8.51, 8.49, 12.5 1. e 62: 4-methy1—7,8—dihydro—2H-chrornene—2,5(6H)—dione Ethyl acetoacetate (CAS registration No.:141-97—9) (17.40 g), 1,3—cyclohexanedione (CAS registration No.15049) (10.00 g), DMAP (0.22 g), and pyridine (30 mL) were placed in a 200~mL eggplant flask, and stirred at a bath temperature (140°C) for one day. After the mixture was left to cool to room temperature, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane : ethyl acetate = 4:1) to obtain the title compound (4.50 g) having the following physical property values.
/ELSD): (retention time: 0.81 min); lH—NMR (CDC13 ): 8 2.11, 2.48, 2.57, 2.87, 5.99.
Example 63: 3-bromomethyl—7,8—dihydro-2H—chromene-2,5(6H)~dione N-bromosuccinimide (CAS registration No.: 1285) (2.00 g) was added into a DMF (40 mL) on of the compound produced in Example 62 in a lOO-mL eggplant flask, and the solution was stirred at room temperature for one day. The solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane : ethyl acetate = 9:1) to obtain the title compound (1.16 g) having the following physical property values.
(LC~MS/ELSD): (retention time: 0.76 min); lH—NMR (CDC13 )2 5 2.12, 2.59, 2.69, 2.87.
Example 64: 3-bromomethy1— l ~phenyl~7, dro-2,5(1H,6H)-quinolinedione The compound produced in Example 63 (1.15 g) and aniline (1.25 g) were placed in a 30-mL eggplant flask. The mixture was stirred at a bath temperature (70°C) for 20 hours. 1 mol/L hydrochloric acid was added to the reaction solution.
The reaction on was ted with ethyl acetate, washed with water and a saturated saline solution sequentially in this order, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced re. The resulting residue was purified by silica gel column chromatography (hexane : ethyl acetate = 7:3) to obtain the title compound (1.31 g) having the following physical property values.
(LC—MS/ELSD): (retention time: 1.12 min); H-NMR (CDC13 ): 5 1.96, 2.43, 2.54, 2.79, 7.16-7.20, 7.49-7.58.
Example 65: methyl 4—methy1—2,5—dioxo-1—phenyl-1 ,2,5,6,7,8-hexahydroquinoline carboxylate The compound produced in Example 64 (1.11 g), potassium acetate (0.66 g), DMF (11 mL), and ol (11 mL), and, after degassing, [1 ,1 ’ -bis(diphenylphosphino)ferrocene]palladium(Il)dichloride dichloromethane x (1:1) [PdC12 (dppf); CH2 C12] (0.27 g) were placed in a 200-mL eggplant flask. After replacement with carbon de was carried out, stirring at a bath temperature (70°C) was carried out for 17 hours. 1 mol/L hydrochloric acid was added to the reaction on. The on solution was extracted with ethyl acetate, washed with water and a saturated saline solution in this order, and dried over anhydrous sodium sulfate. The solvent was distilled ofi‘ under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane : ethyl e = 7:3) to obtain the title compound (0.51 g) having the following physical ty values.
(LC-MS/BLSD): tion time: 0.75 min); lH-NMR (CDC13 ): 5 1.97, 2.48, 2.53, 2.56, 3.89, 7.17—7.20, 7.48-7.56.
Example 66: 4—methyl-2,5-dioxo~1 -pheny1-1,2,5,6,7,8-hexahydroquinoline—3 ~carboxylic acid The compound produced in Example 65 (1.85 g) and 5 mol/L hydrochloric acid (19 mL) were placed in a 50-mL eggplant flask. The mixture was stirred at a bath temperature (50°C) for 26 hours. Precipitate was removed by filtration, and the filtrate solvent was distilled off under reduced pressure. The resulting residue was washed in a slurry form with ol and ethyl acetate to obtain the title compound (0.89 g) having the following physical property values.
(LC—MS/ELSD): (retention time: 0.66 min); lH-NMR (CD3 CD): 5 1.97, 2.54, 2.63, 7.29-7.32,7.54-7.63.
Example 67: N—{5—[(6,7—dimethoxy-4—quinolinyl)oxy]pyridiny1}methyl—2,5—dioxo—1 l- 1 ,2 ,8-hexahydro-3~quinolinecarboxamide The title compound having the following physical property values was obtained by the ure having the same purpose as in Example 5, using the compound produced in Example 66 and the compound produced in Example 2.
TLC: Rf0.62 (dichloromethane :methanol = 9: 1); 1H—NMR (CDC13): 5 2.01, 2.53, 2.58, 2.86, 4.05, 6.42, 7.22, 7.42, 7.49-7.61, 8.20, 8.45, 8.50, 9.73.
Example 67(1): N— {4-[(6,7—dimethoxyquinolinyl)oxy]phenyl}methyl-2,5-dioxo— l -phenyl— l ,2,5,6,7 ,8-hexahydro—3-quinolinecarboxamide The title compound having the following physical property values was ed by the procedure having the same purpose as in Example 67, using the compound ed in Example 66 and the compound produced in Example 22.
TLC: Rf 0.48 (ethyl acetate nol = 19:1); lH—NMR (CDC13 )2 5 2.01, 2.52, 2.59, 2.93, 4.04, 6.45, 7.14, 7.23, 7.41, 7.55-7.68, 7.72, 8.47, 9.79. iment Example] Biological Examples are described below. Based- on these experiment s, the effect of the compound of the present invention was verified.
Biological Example 1: Measurement of an Axl inhibitory activity (in vitro test) An Axl enzyme inhibitory activity was measured by using LanthaScreen (registered trademark) system (Invitrogen) based on the attached instruction. The reagents used are shown below.
Reaction buffer solution: a solution containing 50 mmol/L HEPES (pH7.5), 0.01% Brij35, 10 mmol/L MgClz and 1 mmol/L EGTA was prepared by using purified water.
Test substance solution: a solution containing a test compound of 5—fold concentration with respect to the final concentration was prepared by 20-fold diluting a DMSO solution of test compound of each concentration with the reaction buffer solution.
Enzyme solution: a solution containing 400 ng/mL Axl enzyme was prepared by using the reaction bufier solution.
Substrate solution: a solution containing 45 ummol/L ATP and 500 nmmol/L Fluorescein—Poly GT (lnvitrogen) was prepared by using the reaction buffer solution.
Detection solution: a solution containing 20 mM EDTA and 4 nM PY20 rogen) was prepared by using Dilution B rogen).
A 10 mmol/L DMSO solution of the test compound was sed into a l plate , and, furthermore, a 3-fold dilution series was prepared using DMSO. In each well of the 96—well plate for measurement, 5 uL each of the reaction buffer solution containing DMSO was added to a Blank group and a medium group, and uL of the test substance solution was added to the test substance group, respectively.
Next, 10 uL/well of the reaction buffer solution was added to the Blank group, and 10 uL/well each of the enzyme solution was added to the medium group and the test compound group, followed by stirring at room temperature for 10 min. After the completion of stirring, 10 uL each of the substrate solution was added into each well, followed by stirring at room temperature with light shielded for one hour. After the completion of reaction, 25 uL each of the detection solution was added to each well, and stood still at room temperature with light shielded for 30 min. After standing sill, fluorescence intensity at 520 nm and 495 nm at the time of irradiation with exciting light of 340 nm was measured by using Analyst GT (Molecular Devices). The orylation of the artificial substrate was quantified by Time—resolved Fluorescence nce Energy Transfer (TR-FRET). T ratio was calculated by dividing 520 nm fluorescence signal by 495 nm fluorescence signal for each well, and the inhibition rate (%) in the test compound group was calculated based on the following mathematical a.
[Math 1] Inhibition rate (%) = [1 — (TR—FRET ratio of test compound group — A) / (B — A) x 100 A: average value ofTR—FRET ratios of Blank group B: average value ofTR—FRET ratios of medium group Values of 50% inhibition rate (ICSO values) of the test nd were calculated from the tion curve based on the inhibition rate of the test nds in each concentration.
As a result, in the compounds of the t invention, lCSO values of the compound of, for example, Examples 5, 5(1), 5(6), 17(2), and 23(2) were 0.0022 uM, 0.0056 HM, 0.0043 HM, 0.0044 uM, and 0.0011 uM, respectively.
On the other hand, as comparative compounds, the Axl inhibitory activity each of the compound of Example 8 described in Patent Literature 1 (Comparative compound A) and the compound 2 of Example 3 bed in Patent Literature 3 (Comparative compound B), having the following structures, was measured. In both cases, ICSO value was higher than 10 uM.
Q ~ 0 t \" Comparative compound A \ o /° / \0 \N Comparative compound B ical Example 2: Measurement of proliferation suppression rate by using mouse pro-B cell line (Ba/F3 Axl) stably expressing Axl A 0.1 mmol/L DMSO solution of the test compound was dispensed into 96—well plate, and a 3-fold dilution series was ed using DMSO, DMSO solutions of test compounds, having various concentrations, were further SOD-fold diluted with a RPMII64O medium (containing 10% HI—FBS, 1% penicillin) and a diluted solution of the test compound having 500-fold concentration with respect to the final concentration was ed. In each well of the 96-well plate (BD Biosciences) for measurement, 50 pLL of a RPMI medium was added to the Blank group, 50 LL of a RPMI medium containing 0.2% DMSO was added to the medium group, and 50 uL of the diluted solution of the test compound was added to the test compound group, respectively. Ba/F3 Axl was diluted with a medium to have a density of 2X105 cells/mL to prepare a cell suspension. In each well of the l plate for ement, 50 uL each of the RPMI medium was added to the Blank group, and 50 ML each of the cell suspension to the medium group and the test compound group, respectively, and the groups were stood still at 37°C at 5%C02 for 48 hours. After standing still, Relative Light Unit (RLU) was measured by using CELLTITER-GLO (registered trademark) LUMINESCENT CELL VIABILITY ASSAY (Promega). The measurement was carried out according to the ed instruction. To each well, 100 uL each of light-emitting on was added. The plate was stirred at room temperature for 3 min and then stool still at room temperature with light shielded for 10 min, and RLU was measured by using Microplate Reader (SpectraMax MSe, Molecular Devices). The e values of RLU of the Blank group and the medium group were respectively calculated, and the proliferation suppression rate of the test compound group was calculated.
[Math 2] Proliferation suppression rate (%) = {1 — (RLU of test compound group — A) / (B-— A)} x 100 A: average value ofRLU ofBlank group B: average value ofRLU ofmedium group A value of 50% tion rate (IC50 value) of the test compound was calculated from the inhibition curve based on the inhibition rate in each concentration of the test compound.
As a result, in the compounds of the present ion, IC50 values of the compounds of, for example, Examples 5, 5(1), 5(6), 17(2), and 23(2) were 0.0007 uM, 0.0008 uM, 0.0078 1.1M, 0.0012 MM, and 0.0012 uM, respectively.
On the other hand, 1C50 values of the ative compounds A and B, were 0.62 uM and >10 pM, respectively.
Biological e 3: Evaluation of kinase selectivity (in vitro test) Similar to Biological Example 1, values of 50% inhibition rate (ICSO value) with respect to s kinases (KDR, DDR1, FLT4, and ROS) of the test nd were measured.’ The Axl selective inhibitory activity of the test compound with respect to kinases, for example, KDR, was calculated based on the above-mentioned ratio of the ICSO values. The calculated values are shown in the following Table 1.
As the test compound, for the compound of the present invention, the compounds of Examples 5, 5(1), 17(2), and 23(2) were used, and for the comparative compounds, the compound of Example 5 rative compound C) and the compound of Example 92 (Comparative compound D) described in Patent Literature 5, having the following structure, were used. 0 UN o /° / (\NMO \N Comparative compound C [Chem 62] O O O \N /0 / ‘/\N/\/\O \N Comparative compound D [Table 1] KDR [ICSO] / Axl [IC50] about 900 times about 1800 times about 650 times about 520 times about 0.2 times ative compound D about 28 times Results showed that the compound of the present invention had Axl selective inhibition effect on KDR as compared with the comparative compounds. KDR is kinase also referred to as vascular endothelial growth factor receptor 2 (VEGF Receptor 2). It is known that inhibition of KDR may cause a side effect of increasing blood pressure tension, vol. 39, p. 1095-1100, 2002). Therefore, it was suggested that the compounds of the present invention were excellent compounds capable of avoiding the side effect, which was a problem in comparative nds, for example, hypertension. Furthermore, it has been also suggested that the other three types of kinases (DDR1, FLT4, and ROS) might cause side effect to be avoided, from the phenotype of the KO mouse or enic mouse. It became apparent that the compound of the present invention has excellent selectivity to such specific kinases and therefore capable of avoiding side efiect.
Biological Example 4: ement of tory ty of drug—metabolizing enzyme (human CYP2C8 inhibition effect) The reaction was carried out in a 384-well plate. As the positive control substance (CYPZC8: tin), a solution, which had been adjusted with DMSO to have 300 times higher concentration than the final concentration (CYP2C8: 22.5 225 umol/L) and been 75~fold diluted’with purified water containing 2.7% acetonitrile, was prepared (CYP2C8: 0.3 and 3 umol/L). The test compounds were prepared to have a concentration of 0.3 and 3 mol/L with DMSO, and then 75-fold diluted with purified water containing 2.7% acetonitrile to be 4 and 40 . Then, a reaction mixture solution was prepared by addition of a potassium phosphate buffer (pH 7.4), magnesium chloride (5 mol/L), substrate (CYP2C8: Luciferin—ME, 150 nmol/L), and B. ooh—expressed liver microsome CYP2C8 (Cypex, 30 pmol/L) (the numerical values are final concentrations). The reaction was d by addition of 8 nL of this reaction mixture, 4 uL each of the test compound and the positive control solution which had been prepared as bed above, and 4 14L ofNADPH production system solution (5.2 mM NADP, 13.2 mM glucose—6-phosphate, 1.6 U/mL glucose-6—phosphate ogenase) and incubation was carried out at 37°C for 30 min. Thereafter, l6 nL of luciferase solution Was added to stop the on and to allow luciferin to emit light, and the luminescence intensity of the reaction solution was measured. The tion rate is a reduction rate (inhibition rate) of the luminescence ity when compared with the control in which the reaction was carried out by the addition ofDMSO in place of the test compound solution. The inhibition rate was calculated from the following atical formula.
[Math 3] Inhibition rate (%) = 100 — {(luminescence intensity of test compound — ound luminescence ity) / (luminescence intensity of control — background luminescence intensity) x 100} The ICSO value was defined to be < 1 nM when the inhibition rate at l nmol/L was not less than 50%; and > 10 nM when the inhibition rate at 10 umol/L was not more than 50%. The range between the above—mentioned range (not more than 50% at 1 umol/L and not less than 50% at 10 umol/L) was calculated using the following mathematical formula: [Math.4] IC50 = (SO—b) / a wherein a and b are the slope and intercept of the linear regression line: y = ax + b that passes through the two points: the concentration and the inhibition rate at 1 nmol/L and the concentration and the inhibition rate at 10 pmol/L.
The IC50 values of the comparative compounds and compounds of the present invention were measured using the measurement method bed above.
As a , the IC50 value of CYP2C8 was 2.6 uM for the comparative compound E (Example 133 described in Patent Literature 4). On the other hand, for the compound of the present invention, the IC50 values of CYP2C8 were >10 uM in the compounds of, for example, Examples 5, 5(1), 17(2), and 23(2). Therefore, it was shown that the compound of the t invention had less CYP inhibition effect with t to the comparative compound.
[Formulation example] ation e 1 The components indicated below were mixed by a standard method, followed by making the mixture into tablets to obtain 10,000 tablets each containing 10 mg of active ingredient.
N— { 5-[(6,7-dimethoxy—4-quinolinyl)oxy] idinyl} -2,5—dioxo- l ~phenyl-1 ,2,5,6,7, 8—11 exahydro-3—quinolinecarboxarnide . . . 100 g - calcium carboxymethyl cellulose (disintegrant) ...20 g - magnesium stearate (lubricant) ...10 g - microcrystalline cellulose . . .870 g Formulation example 2 The components indicated below were mixed by a standard method, filtered through a dust-removing filter, filled into ampoules so that each ampule ns 5 m1, and thermally sterilized in an autoclave to obtain 10,000 ampoules each containing 20 mg active ingredient.
N—{5-[(6,7-dimethoxyquinolinyl)oxy]pyridinyl}—7,7-dimethyl—2,5—dioxo—1~pheny1 ,6,7,8—hexahydroquinolinecarboxamide . . .200g . mannitol ...ZOg - distilled water ...SOL [Industrial Applicability] A compound of the present invention has a strong Axl inhibitory activity, and therefore, is useful for treatment for Axl-related diseases, for example, cancer, kidney diseases, immune system diseases, and circulatory system diseases.

Claims (17)

1. A compound represented by general formula (1): wherein R1 represents (1) a C1–8 alkyl group optionally substituted with one to five R1 1 , (2) a C3–7 carbon ring optionally substituted with one to five R1 2 , or (3) a 4- to 7-membered heterocycle optionally substituted with one to five R1 3 , wherein when the C1–8 alkyl group represented by R1 is a branched alkyl group, the C1–3 alkyl group branched from the same carbon atom, together with the carbon atom bound thereto, ally forms a saturated C3–7 carbon ring, R2 represents (1) a C1–4 alkyl group, (2) a n atom, (3) a C1–4 haloalkyl group, (4) an oxo group, (5) an -OR21 group, or (6) an =NR22 group, R3 represents (1) a C1–4 alkyl group, (2) a halogen atom, or (3) a C1–4 haloalkyl group, R4 represents (1) a C1–4 alkoxy group, (2) a C1–4 haloalkyl group, (3) an -OR41 group, (4) a C1–4 alkyl group, (5) a C2–4 alkenyloxy group, or (6) a C2–4 alkynyloxy group, R5 represents (1) a en atom, (2) a C1–4 alkyl group, (3) a halogen atom, (4) a C1–4 haloalkyl group, or (5) an -OR21 group, R1 1 ents (1) an -OR101 group, (2) an SO2 R1 0 2 group, (3) an NR1 0 3 R1 0 4 group, or (4) a C3–7 carbon ring optionally substituted with one to three halogen atoms, R1 2 represents (1) a C1–8 alkyl group optionally substituted with a hydroxyl group, or (2) a n atom, R1 3 represents (1) a C1–8 alkyl group optionally substituted with a hydroxyl group, or (2) a halogen atom, R2 1 represents (1) a hydrogen atom, or (2) a C1–4 alkyl group, R2 2 represents (1) a hydroxyl group, or (2) C1–4 alkoxy group, R4 1 represents (1) a hydrogen atom; (2) a C1–8 alkyl group substituted with one to two substituents selected from the group consisting of (a) 5- to 7-membered cyclic group optionally substituted with one to two substituents selected from the group consisting of (i) a C1–4 alkyl group, (ii) a C1–4 haloalkyl group, and (iii) a halogen atom, (b) NR4 0 1 R4 0 2 , (c) a hydroxyl group, and (d) an SO2 R4 0 3 group; (3) a C2–8 alkenyl group tuted with one to two substituents selected from the group consisting of (a) 5- to 7-membered cyclic group optionally substituted with one to two substituents ed from the group consisting of (i) a C1–4 alkyl group, (ii) a C1–4 haloalkyl group, and (iii) a halogen atom, (b) NR4 0 1 R4 0 2 , (c) a hydroxyl group, and (d) an SO2 R4 0 3 group; or (4) a C2–8 alkynyl group substituted with one to two substituents selected from the group consisting of (a) 5- to 7-membered cyclic group optionally substituted with one to two substituents selected from the group consisting of (i) a C1–4 alkyl group, (ii) a C1–4 haloalkyl group, and (iii) a halogen atom, (b) NR4 0 1 R4 0 2 , (c) a hydroxyl group, and (d) an SO2 R4 0 3 group, R1 0 1 represents (1) a hydrogen atom, or (2) a C1–4 alkyl group, R1 0 2 represents (1) a hydrogen atom, or (2) a C1–4 alkyl group, R1 0 3 and R1 0 4 each independently represents (1) a en atom, or (2) a C1–4 alkyl group, R4 0 1 and R4 0 2 each independently ents (1) a hydrogen atom, or (2) a C1–4 alkyl group, R4 0 3 represents (1) a hydrogen atom, or (2) a C1–4 alkyl group, A represents (1) CH, or (2) a nitrogen atom, L represents (1) -O-, (2) -NH-, (3) -C(O)-, (4) -CR6 R7 -, (5) -S-, (6) -S(O)-, or (7) -S(O)2 -, R6 and R7 each ndently represents (1) a hydrogen atom, (2) a halogen atom, (3) a C1–4 alkyl group, (4) a hydroxyl group, or (5) NH2, ring1 represents e or pyridine, represents a single bond or a double bond, m is an integer from 0 to 5, n is an integer from 0 to 5, p is an integer from 0 to 2, q is an integer from 0 to 4, when m is two or more, a plurality of R2 may be the same as or different from each other, and when two of R2 ent a C1–3 alkyl group and are on the same carbon atom, the R2, together with a carbon atom bound thereto, may form a saturated C3–7 carbon ring, when n is 2 or more, a plurality of R3 may be the same as or different from each other, when q is 2 or more, a plurality of R4 may be the same as or ent from each other, a salt f, a solvate thereof, or an N-oxide thereof.
2. The compound according to claim 1, wherein m is one or more, and one of R2 is necessarily an oxo group.
3. The compound according to claim 1 or 2, wherein L is (1) -O-, (2) -NH-, or (3) -C(O)-.
4. The compound according to claim 1, which is represented by general formula (I-1): wherein R2 - 1 represents (1) a C1–4 alkyl group, (2) a halogen atom, (3) a C1–4 haloalkyl group, (4) an -OR21 group, or (5) an =NR22 group, m-1 is an integer from 0 to 4, L1 is (1) -O-, (2) -NH-, or (3) -C(O)-, ring1-1 ents benzene or pyridine, when m-1 is 2 or more, a plurality of R2-1 may be the same as or different from each other, and when two of R2-1 represent a C1–3 alkyl group and are on the same carbon atom, the R2-1, together with a carbon atom bound thereto, may form a saturated C3–7 carbon ring, and other symbols have the same meanings as defined in claim 1.
5. The nd according to any one of claims 1 to 4, which is: (1) N-{5-[(6,7-dimethoxyquinolinyl)oxy]pyridinyl}-2,5-dioxophenyl-1,2,5,6,7,8-h exahydroquinolinecarboxamide, (2) (6,7-dimethoxyquinolinyl)oxy]pyridinyl}-7,7-dimethyl-2,5-dioxophenyl -1,2,5,6,7,8-hexahydroquinolinecarboxamide, (3) N-{5-[(6,7-dimethoxyquinolinyl)oxy]pyridinyl}(2,2-dimethylpropyl)-2,5-dioxo -1,2,5,6,7,8-hexahydroquinolinecarboxamide, (4) N-[5-({7-[3-(4-morpholinyl)propoxy]quinolinyl}oxy)pyridinyl]-2,5-dioxophen yl-1,2,5,6,7,8-hexahydroquinolinecarboxamide, (5) N-{4-[(6,7-dimethoxyquinolinyl)oxy]fluorophenyl}-2,5-dioxophenyl-1,2,5,6,7, 8-hexahydroquinolinecarboxamide, (6) N-{4-[(6,7-dimethoxyquinolinyl)oxy]phenyl}-2,5-dioxophenyl-1,2,5,6,7,8-hexahy droquinolinecarboxamide, (7) N-{5-[(6,7-dimethoxyquinolinyl)oxy]pyridinyl}(4-fluorophenyl)-2,5-dioxo-1,2 ,5,6,7,8-hexahydroquinolinecarboxamide, (8) N-{5-[(6,7-dimethoxyquinolinyl)oxy]pyridinyl}(3-fluorophenyl)-2,5-dioxo-1,2 ,5,6,7,8-hexahydroquinolinecarboxamide, (9) N-{5-[(6,7-dimethoxyquinolinyl)oxy]pyridinyl}(2-fluorophenyl)-2,5-dioxo-1,2 ,5,6,7,8-hexahydroquinolinecarboxamide, (10) N-{5-[(6,7-dimethoxyquinazolinyl)oxy]pyridinyl}-2,5-dioxophenyl-1,2,5,6,7,8 -hexahydroquinolinecarboxamide, (11) N-{5-[(6,7-dimethoxyquinazolinyl)oxy]pyridinyl}(4-fluorophenyl)-2,5-dioxo-1 ,2,5,6,7,8-hexahydroquinolinecarboxamide, (12) N-{5-[(6,7-dimethoxyquinolinyl)oxy]pyridinyl}[(2S)hydroxymethylb utanyl]-2,5-dioxo-1,2,5,6,7,8-hexahydroquinolinecarboxamide, (13) N-{4-[(6,7-dimethoxyquinolinyl)oxy]fluorophenyl}(3-fluorophenyl)-2,5-dioxo ,6,7,8-hexahydroquinolinecarboxamide, (14) N-{5-[(6,7-dimethoxyquinolinyl)oxy]pyridinyl}-6,6-dimethyl-2,5-dioxophenyl -1,2,5,6,7,8-hexahydroquinolinecarboxamide, (15) N-[5-({6-methoxy[3-(4-morpholinyl)propoxy]quinolinyl}oxy)pyridinyl]-2,5-di oxophenyl-1,2,5,6,7,8-hexahydroquinolinecarboxamide, (16) N-(5-{[7-(3-hydroxymethylbutoxy)methoxyquinolinyl]oxy}pyridinyl)-2,5-d ioxophenyl-1,2,5,6,7,8-hexahydroquinolinecarboxamide, or (17) N-[5-({6-methoxy[3-(1-pyrrolidinyl)propoxy]quinolinyl}oxy)pyridinyl]-2,5-di phenyl-1,2,5,6,7,8-hexahydroquinolinecarboxamide.
6. A compound which is N-{5-[(6,7-dimethoxyquinolinyl)oxy]pyridinyl}-2,5-dioxophenyl-1,2,5,6,7,8-h exahydroquinolinecarboxamide, a salt thereof, a solvate thereof, or an N-oxide thereof.
7. A pharmaceutical composition containing a compound represented by general formula (I) as defined in claim 1, a salt thereof, a solvate thereof, or an N-oxide thereof.
8. The pharmaceutical composition ing to claim 7, which is an Axl inhibitor.
9. The pharmaceutical composition according to claim 7, which is an agent for preventing and/or treating an Axl-related disease.
10. The pharmaceutical ition ing to claim 9, wherein the Axl-related disease includes a cancer, a kidney disease, an immune system disease, or a atory system disease.
11. The pharmaceutical composition according to claim 10, wherein the cancer is acute myeloid leukemia, chronic myeloid leukemia, acute lymphatic leukemia, melanoma, breast cancer, atic cancer, glioma, esophageal adenocarcinoma, large intestine cancer, renal cell carcinoma, thyroid cancer, non-small cell lung cancer, te cancer, h cancer, liver cancer, uveal malignant melanoma, ovarian cancer, endometrial cancer, lymphoma, head and neck cancer, or sarcoma.
12. The pharmaceutical composition according to claim 7, which is a metastasis suppressing agent for cancer cells.
13. Use of a compound represented by general formula (I), a salt thereof, a solvate f, or an N-oxide thereof, as defined in claim 1, in the manufacture of an agent for preventing and/or treating an Axl-related disease.
14. The use according to claim 13, wherein the Axl-related e includes a cancer, a kidney disease, an immune system e, or a circulatory system disease.
15. The use according to claim 14, wherein the cancer is acute myeloid leukemia, chronic d leukemia, acute lymphatic leukemia, melanoma, breast cancer, pancreatic cancer, glioma, esophageal adenocarcinoma, large intestine cancer, renal cell carcinoma, d cancer, non-small cell lung cancer, prostate cancer, stomach cancer, liver , uveal malignant melanoma, ovarian cancer, endometrial cancer, lymphoma, head and neck cancer, or sarcoma.
16. The use according to claim 13, wherein the agent is a metastasis suppressing agent for cancer cells.
17. The compound ing to claim 1 or claim 6, substantially as herein described with reference to any one of the Examples thereof.
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