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AU721935B2 - Non-peptide tachykinin receptor antagonists - Google Patents
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AU721935B2 - Non-peptide tachykinin receptor antagonists - Google Patents

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Publication number
AU721935B2
AU721935B2 AU97255/98A AU9725598A AU721935B2 AU 721935 B2 AU721935 B2 AU 721935B2 AU 97255/98 A AU97255/98 A AU 97255/98A AU 9725598 A AU9725598 A AU 9725598A AU 721935 B2 AU721935 B2 AU 721935B2
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compound
indol
amino
acetyl
foam
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AU9725598A (en
Inventor
Sung-Yong Stephen Cho
Thomas Alan Crowell
Bruce Donald Gitter
Philip Arthur Hipskind
James Jeffry Howbert
Joseph Herman Krushinski Jr.
Karen Lynn Lobb
Brian Stephen Muehl
James Arthur Nixon
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Eli Lilly and Co
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Eli Lilly and Co
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Priority claimed from AU10988/95A external-priority patent/AU1098895A/en
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Priority to AU97255/98A priority Critical patent/AU721935B2/en
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    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/42—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/44—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a carbon atom of an unsaturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/77—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/78—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/20—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C07D209/16—Tryptamines
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

S F Ref: 338639D1
AUSTRALIA
PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT 0O S 0
S
g 0* g
ORIGINAL
Name and Address of Applicant: Actual Inventor(s): ge
C
*0 Coog go 0O C Eli Lilly and Company Lilly Corporate Center Indianapolis Indiana 46285 UNITED STATES OF AMERICA Sung-Yong Stephen Cho, Thomas Alan Crowell, Bruce Donald Gitter, Philip Arthur Hipskind, James Jeffry Howbert, Joseph Herman Krushinski Jr., Karen Lynn Lobb, Brian Stephen Muehl and James Arthur Nixon.
C go o g 4*00~6 Address for Service: Spruson Ferguson, Patent Attorneys Level 33 St Martins Tower, 31 Market Street Sydney, New South Wales, 2000, Australia Invention Title: Non-peptide Tachykinin Receptor Antagonists The following statement is a full description of this invention, including the best method of performing it known to me/us:- 5845 1- NON-PEPTIDE TACHYKININ RECEPTOR ANTAGONISTS Tachykinins are a family of peptides which share the common amidated carboxy terminal sequence, Phe-Xaa-Gly-Leu-Met-NH 2 hereinafter referred to as SEQ ID NO:1. Substance P was the first peptide of this family to be isolated, although its purification and the determination of its primary sequence did not occur until the early 1970's. Substance P has the following amino acid sequence, Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH 2 hereinafter referred to as SEQ ID NO:2.
Between 1983 and 1984 several groups reported the isolation of two novel mammalian tachykinins, now *24 termed neurokinin A (also known as substance K, neuromedin L, and neurokinin and neurokinin B (also known as neuromedin K and neurokinin See, J.E. Maggio, Peptides, 6 (Supplement 3):237-243 (1985) for a review of these *discoveries. Neurokinin A has the following amino acid sequence, His-Lys-Thr-Asp-Ser-Phe-Val-Gly-Leu-Met-NH 2 hereinafter referred to as SEQ ID NO:3. The structure of neurokinin B is the amino acid sequence, Asp-Met-His-Asp-Phe-Phe-Val-Gly-Leu-Met-NH 2 hereinafter referred to as SEQ ID NO:4.
Tachykinins are widely distributed in both the central and peripheral nervous systems, are released from 2 nerves, and exert a variety of biological actions, which, in most cases, depend upon activation of specific receptors expressed on the membrane of target cells. Tachykinins are also produced by a number of non-neural tissues.
The mammalian tachykinins substance P, neurokinin A, and neurokinin B act through three major receptor subtypes, denoted as NK-l, NK-2, and NK-3, respectively. These receptors are present in a variety of organs.
0e Substance P is believed i to be 0. involved in the neurotransmission of pain sensations, including the pain associated with migraine headaches and with arthritis. These peptides have also been implicated go in gastrointestinal disorders and diseases of the gastrointestinal tract such as inflammatory bowel disease.
Tachykinins have also been implicated as playing a role in 064,00 numerous other maladies, as discussed infra.
In view of the wide number of clinical maladies associated with an excess of tachykinins, the development O -0 of tachykinin receptor antagonists will serve to control these clinical conditions. The earliest tachykinin receptor antagonists were peptide derivatives. These antagonists proved to be of limited pharmaceutical utility because of their metabolic instability.
Recent publications have described novel classes of non-peptidyl tachykinin receptor antagonists which generally have greater oral bioavailability and metabolic stability than the earlier classes of tachykinin receptor antagonists. Examples of such newer non-peptidyl tachykinin receptor antagonists are found in European Patent Publication 591, 040 Al, published April 6, 1994; Patent Cooperation Treaty publication WO 94/01402, published January 20, 1994; Patent Cooperation Treaty publication WO 94/04494, published March 3, 1994; and Patent Cooperation Treaty publication WO 93/011609, published January 21, 1993.
3 In essence, this invention provides a class of potent non-peptide tachykinin receptor antagonists. By virtue of their non-peptide nature, the compounds of the present invention do not suffer from the shortcomings, in terms of metabolic instability, of known peptide-based tachykinin receptor antagonists.
Summary of the Invention S. 10 This invention encompasses methods for the treatment or prevention of a physiological disorder associated with an excess of tachykinins, which method comprises administering to a mammal in need of said treatment an effective amount of a compound of Formula I
R
8
R
4 R- (CH 2
CH
2 (CH) -R 3 NH R 2
(CH
2 )m
RI
R I 2 wherein m is 0, 1, 2, or 3; n is 0 or 1; o is 0, 1, or 2; p is 0 or 1; 4 R is phenyl, 2- or 3-indolyl, 2- or 3-indolinyl, benzothienyl, benzofuranyl, or naphthyl, which R groups may be substituted with one or two halo, CI-C 3 alkoxy, trifluoromethyl, C I-C 4 alkyl, phenyl-C 1
-C
3 alkoxy, or C I-C 4 alkanoyl groups; R' is trityl, phenyl, diphenylmethyl, phenoxy, phenylthio, piperazinyl, piperidinyl, l)yrr-ohdinyl, mnorpholinyl, indolinyl, indolyl, bcnizothilenyl, hcexamethyleneiminyl, henzofuranyl, tetrahydropyr-idinyl, quinolinyl, i soquinolinyl, phienyl -C 4 alkyl)-, 1pIenIyl-(C 1
-C
4 alkoxy)-, quinolinyl-(C -C 4 alkyl)-, isoquinolinyl-(C 1
-C
4 1 alkyl)-, benizoyl-(C alyl- I,34-tetrahydroisoquinolinyl, or -NI--H any one of which R' groups may be substituted withi halo, CI-C 4 alkyl, C 1
-C
4 a ilkoxy. trifluoromethyl, amino, C -C 4 alkylamino, di(C i-C 4 alky I)aino. Or 2C alkanoylamino; or any one of which R' groups may be substituted withi phlenyl, piperazinyl, ('3-CS cycloalkyl, benzyl, C- 4 alkyl, piperidinyl, pyridinyl, p~yrimlidinyl. 2 -t Is alkanoylan-uno, pyrroldinyl, C 2 -C6' alkanoyl, or C 1
-C
4 alkoxycarbonyl, any one of which groups may be substitu-ted with halo C 1
-C
4 alkyl, C 1
-C
4 alkoxy, trifluoromethyl, amino, C 1
-C
4 alkylarnino, di(C 1
-C
4 alkyl)amino, Or C alkanoylainino, or R' is halo, amino, a leaving group, CI-C 4 alkylamino, or di(CI-C 4 alkyl)am-ino; is pyridyl, anilino-(CI-C 3 alkyl)-, or anilinocarbonyl; R is hydrogen, C 1
-C
4 alkyl, arylsulf'onyl, C 1
-C
4 alkylsulfouyl, carboxy-(Cg-C 3 alkyl)-,
C
1
-C'
3 alkoxycarbonyl-(C 1
-C
3 alkyl)-, or C R wherein "aryl" as used in "arylsulf'onyl" is as herein defined; R is hydrogen, CI-C 4 alkyl, C 1
-C
3 hialoalkyl, phienyl, CI-C 4 alkoxy, CI-C 3 2S h-ydroxyal kyl, amino, CI-C 4 alkylamino, di(C 1
-C
4 alkyl )aniino, or 7 Ci is 0 to 3;
RZ
7 is carboxy, CI-C 4 alkoxycarbonyl,
CI-C
4 alkylcarbonyloxy, amino, C 1
-C
4 al ky lam mno, di(Ci-C 4 alkyl)aniino, CI-C 6 alkoxycarbonylamino, or phIenoxy, phienylthilo, piperazinyl, piperidinyl, pyrrolidinyl, morphiolinlI, i ndol inyl, M indolyl, benzoth-ienyl, benzofuranyl, quinolinyl, isoquinolinyl, phenyl-(C -C 4 alkyl)-, quIinOlin~yl-(C -C 4 alkyl)-, isoquinolinyl-(C 1
-C
4 alkyl)-, benzoyl-CI-C3 alkyl; any one of which R 7 group may be substituted withi halo, trifluoromethyl, C 1
-C
4 alkyl, amino, C 1
-C
4 alkylamino, di(CI-C 4 alkyl)aiyino, Or C 2
-C
4 alkanoylamino; RAL IBVV]021 74.doc:rnjc or any one of which R 7 groups may be substituted with phenyl, piperazinyl,
C
3 -Cs cycloalkyl, benzyl, piperidinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, C2-C 6 alkanoyl, Ci-C 4 alkyl or Ci-C 4 alkoxycarbonyl; any of which groups may be substituted with halo, trifluoromethyl, amino, Ci-C 4 alkoxy, Ci-C 4 alkyl, Ci-C 4 alkylamino, di(Ci-C 4 alkyl)amino, or C 2
-C
4 alkanoylamino; R is hydrogen or Ci-C, alkyl; R' is phenyl, phenyl-(Ci-C 6 alkyl)-, C 3 -Cs cycloalkyl, C 5 -Cs cycloalkcnyl, Ci-C 8 alkyl, naphthyl, C 2 -Cs alkenyl, or hydrogen; i, any one of which groups except hydrogen may be substituted with one or two halo. Ci-C 3 alkoxy, Ci-C3 alkylthio, nitro, trifluoromethyl, or Ci-C 3 alkyl groups; and
R
4 is hydrogen or Ci-C 3 alkyl; with the proviso that if R' is halo, R 3 is phenyl, phenyl-(Ci-C 6 alkyl)-, C 3 -Cs cycloalkyl,
C
5 cycloalkenyl, or naphthyl; 1 or a pharmaceutically acceptable salt thereof.
In another embodiment, this invention encompasses the novel compounds of Formula I and the pharmaceutically acceptable salts, solvates, and prodrugs thereof, as well as pharmaceutical formulations comprising, as an active ingredient, a compound of Formula 1 in combination with a pharmaceutically acceptable carrier, diluent or excipient. This 2n invention also encompasses novel processes for the synthesis of the compounds of Formula The invention provides a method for the treatment or prophylaxis of a physiological disorder associated with an excess of tachykinins in a manmmal, which method comprises administering to said mammal an effective amount of at least one compound according to 5 the invention or of a composition according to the invention.
The invention provides the use of a compound according to the invention for the preparation of a medicament for the treatment or prophylaxis of a physiological disorder in a mammal associated with an excess of tachykinins.
The invention provides a compound according to the invention or a pharmaceutical Slformulation according to the invention when used for the treatment or prophylaxis of a physiological disorder in a mammal associated with an excess of tachykinins.
The invention provides a compound according to the invention or a pharmaceutical formulation according to the invention for use in the treatment or prophylaxis of a physiological disorder in a mammal associated with an excess oftachykinins.
AL
^I I" [II.ABHVV102174.doc.nic 6 The invention provides a medicament whenever manufactured by the use of the In\'ention.
All temperatures stated herein are in degrees Celsius 0 All units of measurement employed herein are in weight units except for liquids which are in volume units.
As used herein, the term "C 1
-C
6 alkyl" refers to straight or branched, monovalent, saturated aliphatic *e '4 4 SOS S 55 S 8 S S. S Sb 0e
S
S
0 0 04
SO
8055
S
0 beje
S
0 to..
8O 00 0 5 450 0 a a 55 S S 5 8 4055 0 *50500 8 R:\L1I3V V'1021I74.doc:njc 7 chains of 1 to 6 carbon atoms and includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, and hexyl. The term
"CI-C
6 alkyl" includes within its definition the term
"C
1
-C
4 alkyl".
"Divalent(C 1
-C
4 )alkyl" represents a straight or branched divalent saturated aliphatic chain having from one to four carbon atoms. Typical divalent(Ci-C4)alkyl groups include methylene, ethylene, propylene, 2 -methylpropylene, 10 butylene and the like.
"Halo" represents chloro, fluoro, bromo or iodo.
"Halo(Ci-C4)alkyl" represents a straight or branched alkyl chain having from one to four carbon atoms with 1, 2 or 3 halogen atoms attached to it. Typical halo(Ci-C 4 )alkyl groups include chloromethyl, 2-bromoethyl, l-chloroisopropyl, 3 -fluoropropyl, 2,3-dibromobutyl, 3chloroisobutyl, iodo-t-butyl, trifluoromethyl and the like.
"Hydroxy(C 1
-C
4 )alkyl" represents a straight or branched alkyl chain having from one to four carbon atoms with hydroxy group attached to it. Typical hydroxy(C 1
-C
4 )alkyl groups include hydroxymethyl, 2hydroxyethyl, 1-hydroxyisopropyl, 2 -hydroxypropyl, 2- 4 W. hydroxybutyl, 3-hydroxyisobutyl, hydroxy-t-butyl and the like.
"CI-C
6 alkylthio" represents a straight or branched alkyl chain having from one to six carbon atoms attached to a sulfur atom. Typical CI-C 6 alkylthio groups include methylthio, ethylthio, propylthio, isopropylthio, butylthio and the like. The term "C 1
-C
6 alkylthio" includes within its definition the term "C 1
-C
4 alkylthio".
The term "C 2
-C
8 alkenyl" as used herein represents a straight or branched, monovalent, unsaturated aliphatic chain having from two to eight carbon atoms.
Typical C 2
-C
6 alkenyl groups include ethenyl (also known as vinyl), 1-methylethenyl, l-methyl-l-propenyl,.1-butenyl, 1- 0 000 4 0 000 00 0 0* #0 *0 0 *0
S
0 00 0 0* 0 0 so.
4 -8hexenyl, 2 -methyl-2-propenyl, 1-propenyl, 2-propenyl, 2butenyl, 2-pentenyl, and the like.
8 cycloalkenyl', represents a hydrocarbon ring structure containing from five to eight carbon atoms and having at least one double bond within that ring, which is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halo, halo (Cl-c4alkyl,
C
1 -c 4 00alkyl,
C
1
-C
4 alkoxy, carboxy, Cl-C 4 alkoxycarbonyl, carbamoyl, N- (Cl-C 4 alkylcarbamoyl, amino, C 1
-C
4 q1 0 alkylamino, di(Cl-C4)alkylarnino or -(CH 2 )a-Rc where a is 1, 3 or 4 and RC is hydroxy, Cl 1
-C
4 alkoxy, carboxy,
C
1
-C
4 alkoxycarbonyl, amino, carbainoyl,
C
1
-C
4 alkylamino or di(Cl-C4alkylamino.
"Cl-C 4 aikylamino" represents a straight or branched alkylamino chain having from one to four carbon atoms attached to an amino group. Typical. Cl-C 4 alkylamino groups include methylamino, ethylamino, propylamino, is opropylamino, butylamino, sec-butylamino and the like.
"Di(Cl 1
C
4 alkyl)amino" represents a straight or .23) branched dialkylamino chain having two alkyl chains, each having independently from one to four carbon atoms attached to a common amino group. Typical di(C1-C4)alkylamino GO groups -include dimethylamino, ethylmethylamino, methylisopropylamino, t-butylisopropylamino, di-t- 4sbutylamino and the like.
"Arylsulfonyl" represents an aryl moiety attached to a sulfonyl group. "Aryl" as used in this term represents a phenyl, naphthyl, heterocycle, or unsaturated heterocycle moiety which is optionally substituted with 1, 2 or 3 substituents independently selected from halo, halo(Cl-c 4 alkyl, C 1
-C
4 alkyl, C 1
-C
4 alkoxy, carboxy,
C
1
-C
4 alkoxycarbonyl, carbamoyl, N- (Cl-C 4 )alkylcarbamoyl, amino,
C
1
-C
4 alkylainino, di(Cl-C4)alkylamino or -(CH 2 )a-Rb where a is 1, 2, 3 or 4; and Rb is hydroxy,
C
1
-C
4 alkoxy, carboxy, cl-c 4 alkoxycarbonyl, amino, carbamoyl, C1-C4.alkylamino or di (C 1
-C
4 )alkylamino.
0 9 The term "heterocycle" represents an unsubstituted or substituted stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic ring which is saturated and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized and including a bicyclic group in which any of the above- *10 defined heterocyclic rings is fused to a benzene-ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which affords a stable structure. The heterocycle is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halo, halo(C 1
-C
4 alkyl, Ci-C 4 alkyl, C 1
-C
4 alkoxy, carboxy, CI-C 4 alkoxycarbonyl, carbamoyl, N-(C1-C4)-alkylcarbamoyl, amino, C 1
-C
4 alkylamino, di(C1-C4)alkylamino or -(CH 2 )a-Rd where a is 1, 2, 3 or 4; and Rd is hydroxy, CI-C 4 alkoxy, carboxy, C-C 4 alkoxycarbonyl, amino, carbamoyl, C 1
-C
4 alkylamino or 10 di(Cl-C 4 )alkylamino.
The term "unsaturated heterocycle" represents an unsubstituted or substituted stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic ring which has one or more double bonds and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quarternized and including a bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The unsaturated heterocyclic ring may be attached at any heteroatom or carbon atom which affords a stable structure. The unsaturated heterocycle is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halo, halo(C 1
-C
4 )alkyl, C 1
-C
4 alkyl, C 1
-C
4 alkoxy, carboxy, C 1
-C
4 alkoxycarbonyl, 10 carbainoyl, N- (Cl-C4)alkylcarbamoyl, amino, C 1
-C
4 alkylamino, di(C1-C4)alkylamino or -(CH 2 )a-Re where a is 1, 2, 3 or 4; and Re is hydroxy,
C
1
-C
4 alkoxy, carboxy, Cl-C 4 alkoxycarbonyl, amino, carbanoyl,
C
1
-C
4 alkylamino or di (Cl-C 4 alkylamino.
Examples of such heterocycles and unsaturated heterocycles include piperidinyl, piperazinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidiny., imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, too oe*t isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, 0benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinylsuif oxide, thiamorpholinylsulfone, oxadiazolyl, triazolyl, tetrahydroquinolinyl, tetrahydrisoquinolinyl, 3 -methylimidazoly., 3-methoxypyridy., 4 -chloroquinolinyl, 2DJ 4 -aminothiazolyl, 8-methylquinolinyl, G-chloroquinoxalinyl, 99 3 -ethylpyridy., 6 -methoxybenzimidazolyl, 4 -hydroxyfuryl, 4-methylisoquinoliniyl, 6 ,8-dibromoquinoiinyl, 4,8-dimethylnaphthyl, 2-methyl-l,2 4 -tetrahydroisoquinolinyl, '~N-methyl-quinolin-2-yl, 2 -t-butoxycarbonyl-,234- 5 isoquinolin-7-yl and the like.
"Cl-C 6 alkoxy" represents a straight or branched alkyl chain having from one to six carbon atoms attached to an oxygen atom. Typical Cl-CE alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy and the like. The term "CI-C 6 alkoxy'l includes within its definition the term "CI-C 4 alkoxy".
"C
2
-C
6 alkanoyll" represents a straight or branched alkyl chain having from one to five carbon atoms attached to a carbonyl moiety. Typical C 2
-C
6 alkanoyl groups include ethanoyl, propanoyl, isopropanoyl, butanoyl, 11 t-butanoyl, pentanoyl, hexanoyl, 3-methylpentanoyl and the like.
"C
1
-C
4 alkoxycarbonyl" represents a straight or branched alkoxy chain having from one to four carbon atoms attached to a carbonyl moiety. Typical C 1
-C
4 alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl and the like.
"C3-C8 cycloalkyl" represents a saturated hydrocarbon ring structure containing from three to eight ~a*.carbon atoms which is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halo, (Cl-C 4 alkyl, C 1
-C
4 alkyl, C 1
-C
4 alkoxy, carboxy, C 1
-C
4 alkokycarbonyl, carbamoyl, N- (Cl-C4)alkylcarbamoyl, amino,
C
1
-C
4 alkylamino, di(Cl-C4)alkylamino or -(CH 2 )a-R where a is 1, 2, 3 or 4 and Rf is hydroxy, C 1
-C
4 alkoxy, carboxy, CI-c 4 alkoxycarbonyl, amino, carbarnoyl, C1i-C 4 alkylamino or di(CI-C4)alkylamino. Typical C 3
-C
8 cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, 3 -methyl-cyclopentyl, 4-ethoxycyclohexyl, 4carboxycycloheptyl, 2-chlorocyclohexyl, cyclobutyl, cyclooctyl, and the like.
The term ,amino-protecting group" as used in the Uspecification refers to substituents of the amino group commonly employed to block or protect the amino functionality while reacting other functional groups on the compound. Examples of such amino -protecting groups include formyl, trityl, phthalimido, trichloroacetyl, chloroacetyl, bromoacetyl, iodoacetyl, and urethane-type blocking groups such as benzyloxycarbonyl, 4 -phenylbenzyloxycarbonyl, 2 -methylbenzyloxycarbonyl, 4 -methoxybenzyloxycarbonyl, 4 -fluorobenzyloxycarbonyl, 4 -chlorobenzyloxycarbonyl, 3 -chlorobenzyloxycarbonyl, 2 -chlorobenzyloxycarbonyl, 2,4 -dichlorobenzyloxycarbonyl, 4 -bromobenzyloxycarbonyl, 3 -bromobenzyloxycarbonyl, 4 -nitrobenzyloxycarbonyl, 4 -cyanobenzyloxycarbonyl, t-butoxycarbonyl, 12 3 4 *4r
I
5 i 7
'S
1,1l-diphenyleth-l-yloxycarbonyl, 1,1l-diphenylprop-lyloxycarbonyl, 2-phenylprop-2-yloxycarbonyl, 2-(p-toluyl)prop-2-yloxycarbonyl, cyclopentanyloxycarbonyl, 1methylcyclopentanyloxycarbonyl, cyclohexanyloxycarbonyl, 1methylcyclohexanyloxycarbonyl, 2methylcyclohexanyloxycarbonyl, 2-(4-toluylsulfonyl)ethoxycarbonyl, 2-(methylsulfonyl)ethoxycarbonyl, S 2-(triphenylphosphino)-ethoxycarbonyl, fluorenylmethoxy- S carbonyl 2-(trimethylsilyl)ethoxycarbonyl, 10 allyloxycarbonyl, 1- (trimethylsilylmethyl)prop--'enyloxycarbonyl, S 4-acetoxybenzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl, cyclopropylmethoxycarbonyl, 4-(decyloxy)benzyloxycarbonyl, isobornyloxycarbonyl, l-piperidyloxycarbonyl and the like; benzoylmethylsulfonyl group, 2-nitrophenylsulfenyl, diphenylphosphine oxide and S like amino-protecting groups. The species of aminoprotecting group employed is usually not critical so long as the derivatized amino group is stable to the condition 20 of subsequent reactions on other positions of the intermediate molecule and can be selectively removed at the
S
appropriate point without disrupting the remainder of the molecule including any other amino-protecting groups.
S Preferred amino-protecting groups are trityl, te-butoxycarbonyl (t-BOC), allyloxycarbonyl and benzyloxycarbonyl. Further examples of groups referred to by the above terms are described by E. Haslam, "Protective Groups in Organic Chemistry", McOmie, ed., 1973), at Chapter 2; and T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis" (1991), at Chapter 7.
The term "carboxy-protecting group" as used in the specification refers to substituents of the carboxy group commonly employed to block or protect the carboxy functionality.while reacting other functional groups on the compound. Examples of such carboxy-protecting groups include methyl, p-nitrobenzyl, p-methylbenzyl, p-methoxy-
S.
S2a 13
S..
S
*5 boO j S 0
S.
0r
S.
S
Sb
S,
OS
benzyl, 3,4-dimethoxybenzyl, 2, 4 -dimethoxybenzyl, 2,4,6trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl, 3,4-methylene-dioxybenzyl, benzhydryl, 4,4'-dimethoxybenzhydryl, 2,2',4,4'-tetramethoxybenzhydryl, t-butyl, t-amyl, trityl, 4-methoxytrityl, 4,4'-dimethoxytrityl, 4,4',4''-trimethoxytrityl, 2-phenylprop-2-yl, trimethylsilyl, t-butyldimethylsilyl, phenacyl, 2,2,2-trichloroethyl, 2-(di(n-butyl)methylsilyl)ethyl, p-toluenesulfonylethyl, 4-nitrobenzylsulfonylethyl, allyl, cinnamyl, 1-(trimethylsilylmethyl)prop-l-en-3-yl and like moieties. Preferred carboxy-protecting groups are allyl, benzyl and t-butyl. Further examples of these groups are found in E. Haslam, supra, at Chapter 5, and T.W. Greene, et al,, suDra, at Chapter The term "leaving group" as used herein refers to a group of atoms that is.displaced from a carbon atom by 6 the attack of a nucleophile in a nucleophilic substitution reaction. The term "leaving group" as used in this document encompasses, but is not limited to, activating 20 groups.
The term "activating group" as used herein refers a leaving group which, when taken with the carbonyl group to which it is attached, is more likely to take part in an acylation reaction than would be the case 2 if the group were not present, as in the free acid. Such activating groups are well-known to those-skilled in the art and may be, for example, succinimidoxy, phthalimidoxy, benzotriazolyloxy, benzenesulfonyloxy, methanesulfonyloxy, toluenesulfonyloxy, azido, or -O-CO-(C 4
-C
7 alkyl).
The compounds used in the method of the present invention have multiple asymmetric centers. As a consequence of these chiral centers, the compounds of the present invention occur as racemates, mixtures of enantiomers and as individual enantiomers, as well as diastereomers and mixtures of diastereomers. All a-~ 055 0rl
'I
14 asymmetric forms, individual isomers and combinations thereof, are within the scope of the present invention.
The terms and are used herein as commonly used in organic chemistry to denote specific configuration of a chiral center. The term (rectus) refers to that configuration of a chiral center with a clockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The term (sinister) refers to that configuration of a chiral center with a counterclockwise oeo relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The priority of groups is based upon their atomic number (in order of decreasing atomic number). A partial list of priorities and a discussion of stereochemistry is contained in "Nomenclature of Organic Compounds: Principles and Practice", Fletcher, et al., eds., 1974) at pages 103-120.
In addition to the system, the older D-L system is also used in this document to denote absolute Sconfiguration, especially with reference to amino acids.
S.
In this system a Fischer projection formula is oriented so that the number 1 carbon of the main chain is at the top.
SThe prefix is used to represent the absolute configuration of the isomer in which the functional (determining) group is on the right side of the carbon atom at the chiral center and that of the isomer in which it is on the left.
As noted supra, this invention includes the pharmaceutically acceptable salts of the compounds defined by Formula I. A compound of this invention can possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of organic and inorganic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
15 The term "pharmaceutically acceptable salt" as used herein, refers to salts of the compounds of the above formula which are substantially non-toxic to living organisms. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a pharmaceutically acceptable mineral or organic acid or an organic or inorganic base.
Such salts are known as acid addition and base addition salts.
.0 Acids commonly employed to.form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
Examples of such pharmaceutically acceptable salts are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, s.m. suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, 26 hexyne-1,6-dioate, benzoate, chlorobenzoate, Smethylbenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, yhydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-l-sulfonate, napththalene-2sulfonate, mandelate and the like. Preferred pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid and methanesulfonic acid.
16 Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like. Such bases useful in preparing the salts of this invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like. The potassium and sodium salt forms are particularly preferred.
1 0 It should be recognized that the particular S counterion forming a part of any salt of this invention is usually not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole.
This invention further encompasses the pharmaceutically acceptable solvates of the compounds of Formulas I. Many of the Formula I compounds can combine with solvents such as water, methanol, ethanol and acetonitrile to form pharmaceutically acceptable solvates such as the corresponding hydrate, methanolate, ethanolate and acetonitrilate.
The especially preferred compounds used in the g methods of this invention are those of Formula I wherein a) R is substituted or unsubstituted 2- or 3indolyl, phenyl, or naphthyl; b) n is 1; c) R 1 is phenyl, substituted phenyl, piperidinyl, substituted piperidinyl, piperazinyl, substituted piperazinyl, pyrrolidinyl, pyridyl, benzoyl, or morpholinyl; d) R 2 is -CO-R 6
C
1
-C
4 alkylsulfonyl, or CI-C 3 alkoxycarbonyl-(C 1
-C
3 alkyl)-; e) R 3 is phenyl, substituted phenyl, C 3 -Cg cycloalkyl, substituted C 3
-C
8 cycloalkyl, naphthyl or substituted naphthyl; and 17 f) R 8 is hydrogen or methyl.
A most preferred group of compounds used in the methods of this invention are those of Formula I wherein
R
is optionally substituted indolyl, R 1 is substituted piperidinyl or substituted piperazinyl, R8 is hydrogen, and
R
2 is acetyl or methylsulfonyl. Another preferred group of compounds used in the methods of this invention are those of Formula I wherein R is naphthyl,
R
1 is optionally substituted phenyl, substituted piperidinyl or substituted 10 piperazinyl, R2 is acetyl or methylsulfonyl, and-R3 is phenyl or substituted phenyl.
The especially preferred compounds of this invention are those of Formula I wherein a) R is substituted or unsubstituted 2- or 3indolyl, phenyl, or naphthyl; b) n is 1; c) R 1 is trityl, phenyl, substituted phenyl, piperidinyl, substituted piperidinyl, piperazinyl, substituted piperazinyl, pyrrolidinyl, pyridyl, benzoyl, or 20 morpholinyl; d) R 2 is -CO-R6, C1-C4 alkylsulfonyl, or C1-C3 alkoxycarbonyl-(CI-C3 alkyl)-; e) R 3 is phenyl, substituted phenyl, C3-Cs cycloalkyl, substituted C3-Cs cycloalkyl, naphthyl or substituted naphthyl; and f) R 8 is hydrogen or methyl.
SThe compounds of the present invention can be prepared by a variety of procedures well known to those of ordinary skill in the art. The particular order of steps required to produce the compounds of Formula I is dependent upon the particular compound being synthesized, the starting compound, and the relative lability of the substituted moieties.
Examples of such protocols are depicted in Schemes I through IV. The coupling of the substituted amine to the compound of Formula II (Method A) can be 18 9 9.9 9 *9 a 9 #9 4 9 I .9 9.
*e s .9« a 4 *e o performed by many means known in the art, the particular methods employed being dependent upon the particular compound of Formula II which is used as the starting material and the type of substituted amine used in the coupling reaction. These coupling reactions frequently employ commonly used coupling reagents such as 1,1-carbonyl diimidazole, dicyclohexylcarbodiimide, diethyl azodicarboxylate, l-hydroxybenzotriazole, alkyl chloroformate and triethylamine, phenyldichlorophosphate, 10 and chlorosulfonyl isocyanate. Examples of these methods are described infra. After deprotection of the amino group, the compounds of Formula III are obtained.
The compound of Formula III is then reduced, S converting the amide into an amine (Method Amides can be reduced to amines using procedures well known in the art. These reductions can be performed using lithium aluminum hydride as well as by use of many other different aluminum-based hydrides. Alternatively, the amides can be reduced by catalytic hydrogenation, though high 20 temperatures and pressures are usually required for this.
Sodium borohydride in combination with other reagents may be used to reduce the amide. Borane complexes, such as a borane dimethylsulfide complex, are especially useful in this reduction reaction.
s25 The next step in Scheme I (Method C) is the selective acylation of the primary amine using standard methods, as typified by Method C. Because of the higher steric demand of the secondary amine, ,the primary amine is readily available for selective substitution.
This acylation can be done using any of a large number of techniques regularly employed by those skilled in organic chemistry. One such reaction scheme is a substitution using an anhydride such as acetic anhydride.
Another reaction scheme often employed to acylate a primary amine employs a carboxylic acid preferably with an activating agent as described for Method A, supra. An 19 amino-de-alkoxylation type of reaction uses esters as a means of acylating the primary amine. Activated esters which are attenuated to provide enhanced selectivity are very efficient acylating agents.
&s 0 We 94 0 @0 *0*00 C. a R 4 R (CH2) fCH-....CO2H R 2 0o 1 1) Coupling Reaction II NH 2) Deproceccion NH 2 I (Method A) N- (CH) 0-
H
R
-(CH
2
NH
I
0=
C\
Ireduction (standard methods) (Method 8)
I
N (CH) 0- R
H
ethods)
NH
2
I
N 3H (Method C) H NI-acylace (standard mT Ce Ce
C
*&ee IN2- acylation. alkylation. or sutonylat ion (many methods) (Method D) N- 3 NH R I
I
wherein: R" is equal to (CH 2 and
R
2 is not hydrogen.
Scheme II
NH
2 H2NN
/C=
C IH N N
H
VII
1) reduction 2)selective protection of terminal primary amine 3) coupling reaction R" 0 BOC uN CH 2 C IH
H
VIII
(Method 2) 0O &0 Deprotect ion (Method P)
H
N
(CH
2 RI
N-(CH)
0
)-R
3
H
NH
reductive aikylatioi (Method 0) R' 0 HN-" ,CH 2 C IH
O=C\
H
N
N2-acylation, alkylation, or sulfonylation (many methods) (Method D) (CH2)n
R
I
N- (CH) 0
R
3 NH R- 0= C 21 Primary amines can also be acylated using amides to perform what is essentially an exchange reaction. This reaction is usually carried out with the salt of the amine.
Boron trifluoride, usually in the form of a boron trifluoride diethyl ether complex, is frequently added to this reaction to complex with the leaving ammonia.
The next procedure is one of substitution of the secondary amine (Method For most of the compounds of Formula I this substitution is one of alkylation, :0 acylation, or sulfonation. This substitution is usually accomplished using well recognized means. Typically, alkylations can be achieved using alkyl halides and the like as well as the well-known reductive alkylation methods as seen in Method G, Scheme II, supra, employing aldehydes **1i or ketones. Many of the acylating reaction protocols discussed supra efficiently acylate the secondary amine as well. Alkyl- and aryl-sulfonyl chlorides can be employed to sulfonate the secondary amine.
S0.. In many instances one of the later steps in the synthesis of the compounds of Formula I is the removal of an amino- or carboxy-protecting group. Such procedures, S which vary, depending upon the type of protecting group employed as well as the relative lability of other moieties on the compound, are described in detail in many standard S references works such as T.W. Greene, et al., Protective Groups in Organic Synthesis (1991).
Schemes II and III depict alternative protocols and strategies for the synthesis of the compounds of Formula I. Many of the individual reactions are similar to those described in Scheme I but the reactions of Schemes II and III are done in a different, but yet well known to those skilled in the art, series of steps.
22 Scheme III 0
NH
2
NH
2 0 N H NH2 Tritylation Reduction Reductive Alkylation (Method H) Tritylation Amide Coupling Reduction (Method J) go 0 4 1 00 6 *r 5* S S 9.
9
RYC
RN
R
NH
Trityl selective acylation (Method K) *5 9 0* 95S 9@ 99 9 .9 9
S
Trityl detritylation.
(Method L) R 26 NH0 9999
C
Br1^ EB r 0 iPr2NE ord M) 11 R 2a nucleophilic displacement (Method N) R N 1*1- NH R 0R R" X (Method P) P. N el* R NH R 2 a O R" O 23 wherein R 2 a coupled with the carbonyl group to which it is attached is equal to R 2 In order to preferentially prepare one optical isomer over its enantiomer, the skilled practitioner can proceed by one of two routes. The practitioner may first prepare the mixture of enantiomers and then separate the two enantiomers. A commonly employed method for the resolution of the racemic mixture (or mixture of enantiomers) into the individual enantiomers is to first .:10 convert the enantiomers to diastereomers by way of forming a salt with an optically active salt or base. These diastereomers can then be separated using differential solubility, fractional crystallization, chromatography, or like methods. Further details regarding resolution of f5 enantiomeric mixtures can be found in J. Jacques, et al., "Enantiomers, Racemates, and Resolutions", (1991).
In addition to the schemes described above, the practitioner of this invention may also choose an enantiospecific protocol for the preparation of the :20 compounds of Formula I. Scheme IV, infra, depicts a typical such synthetic reaction design which maintains the chiral center present in the starting material in a desired orientation, in this case in the configuration. These S reaction schemes usually produce compounds in which greater than 95 percent of the title product is the desired enantiomer.
Many of the synthetic steps employed in Scheme IV are the same as used in other schemes, especially Scheme
III.
24 Scheme TV 0 0
NN
H
CR) -tryptophan Tritylation 00 0 0 000 0 .0 006 0 00 00 00 0s 0 000 00 00 *0 H trityl rri ty It rvptophan Coupling -0 OCR 3
NH
H trityl
N
H
NH
H trityl Reduction 00 0 0 0* *000 00 00 00 0 S 0 00 0 000~9
S
*00000 -trityldiamine Acylation of secondary amine
OCR
3 -trityltrvptophanamide Deprotection H trityl -tritylacetamide
O)CH
3 N Z N NH CR) -aminoacetamide /Acylation of primary ami n e (Method P) (CH2) R t(CH 2 )m RR)-Cornpound of Formula I 25 The following depicts representative examples of reaction conditions employed in the preparation of the compounds of Formula I.
Method A Coupling of carboxylic acid and primary amine to form amide Wei 6 010 9 40 01~ *c C 009 0 02 I* a* 0r 9*
COO
9* *1 00s 09 90 CLil @900 Preparation of 2-t-butoxycarbonylamino-3-(1H-indol-3-yl)-N- (2-methoxybenzyl)propanamide To a solution of N-(t-butoxycarbonyl)tryptophan (46.4 g, 152.6 mmoles) in 500 ml of dioxane was added carbonyl diimidazole (25.4 g, 156 mmoles) in a portionwise manner. The resulting mixture was stirred for about hours at room temperature and then stirred at 45'C for minutes. Next, 2-methoxybenzylamine (20.7 ml, 158.7 mmoles) was added and the reaction mixture was then stirred for 16 hours at room temperature.
The dioxane was removed under reduced pressure.
The product was partitioned between ethyl acetate and water and was washed successively with 1 N hydrochloric acid, saturated sodium bicarbonate solution, water, and brine, followed by drying over sodium sulfate and removal of the solvent. Final crystallization from methanol yielded 52.2 g of homogeneous product as yellow crystals. Yield 80.8%.
m.p. 157-160'C.
Deprotection of primary amine Synthesis of 2-amino-3-(lH-indol-3-yl)-N-(2methoxybenzyl)propanamide To a mixture of the 2 -t-butoxycarbonylamino-3- (lH-indol-3-yl)-N-(2-methoxybenzyl)propanamide prepared 26 A.i 6.i 0* S~
A
S
supra (25.1 g, 59.2 mmoles) and anisole (12 ml, 110.4 mmoles) at O'C was added dropwise an aqueous solution of trifluoroacetic acid (118 ml, 1.53 moles) in 50 ml of water. This mixture was stirred for one hour at O'C, followed by stirring for about 2.5 hours at ambient temperature. The mixture was then refrigerated for about 16 hours.
The volatiles were removed under reduced pressure. The product was partitioned between ethyl .0 acetate and saturated sodium bicarbonate solution and was then washed with water followed by brine and then dried over sodium sulfate. The solvents were removed in vacuo.
Recrystallization from a 1:1 diethyl ether/cyclohexane solution yielded 18.0 g of homogeneous product as an off-white powder. m.p. 104-108'C.
Method B Reduction of amide carbonyl 0 Synthesis of 2-amino-3-(lH-indol-3-yl)-1-[N-(2methoxybenzyl)amino]propane As AS A 5*
'S
I. To a refluxing solution of 2-amino-3-(iH-indolk-Ss 3 -yl)-N-(2-methoxybenzyl)propanamide (9.81 g, 30.3 mmoles), prepared as described supra, in 100 ml of anhydrous tetrahydrofuran was added dropwise a 10M borane-methyl sulfide complex (9.1 ml, 91.0 mmoles). The resulting mixture was refluxed for about 2 hours. The mixture was cooled to room temperature and the excess borane was quenched by the dropwise addition of 160 ml of methanol.
The resulting mixture was refluxed for 15 minutes and the methanol was removed under reduced pressure.
The residue was dissolved in a saturated methanol solution of hydrochloric acid (250 ml) and the solution refluxed for about 1 hour. The methanol was 27 removed in vacuo and the product was isolated the addition of 5 N sodium hydroxide followed by extraction with diethyl ether. The product was then dried over sodium sulfate.
The solvents were removed in vacuo. Flash chromatography (silica gel, eluting with methanol:methylene chloride:ammonium hydroxide, 10:100:0.5) provided 7.1 g of a mixture of the title compound and the indoline derivative of the title product as an amber oil.
I Method C a dO Acylation of primary amine 4 09) Preparation of 3-(1H-indol-3-yl)-l-[N-(2- "l 15 methoxybenzyl)amino]-2-[N-(2-((4-phenyl)piperazin-lyl)acetyl)amino]propane [Compound of Example 17] 0 A mixture of 2-((4-phenyl)piperazin-l-yl)acetic o0 acid, sodium salt (1.64 g, 6.8 mmoles) and triethylamine hydrobromide (1.24 g, 6.8 mmoles) in 35 ml of anhydrous dimethylformamide was heated to 50'C and remained at that S• temperature for about 35 minutes. The mixture was allowed to cool to room temperature. 1,1-Carbonyl diimidazole (1.05 g, 6.5 mmoles) and 10 ml of anhydrous dimethylformamide were added to the mixture. The resulting mixture was stirred for about 3 hours at room temperature.
A solution of the 2-amino-3-(1H-indol-3-yl)-1- (2-methoxybenzyl)amino]propane and the indoline derivative prepared supra, dissolved in 10 ml of anhydrous dimethylformamide was added to the previousreaction mixture. The resulting mixture was stirred for about 16 hours at room temperature. The dimethylformamide was removed under reduced pressure.
The title product and its indoline derivative were partitioned between ethyl acetate and water and then 28 washed with brine, and dried over sodium sulfate. The solvents were removed in vacuo. This process yielded 3.2 g of a mixture of the title compound and its indoline derivative as a yellow oil. These two compounds were then separated using high performance liquid chromatography using a reverse phase column followed by a silica gel column to give the title product (5.2 yield) as a yellow foam.
l Method D *t,
-I
.90 Techniques of Acylation of Secondary Amine gi S.o Preparation of 1-[N-ethoxycarbonyl-N-(2c*'lI methoxybenzyl)amino]-3- (H-indol-3-yl) (4phenyl)piperazin-1-yl)acetyl)amino]propane [Compound of Example 28]
S*
oo.. To a solution of the 3-(1H-indol-3-yl)-1-[N-(2methoxybenzyl)amino]-2-[N- (2-((4-phenyl)piperazin-lyl)acetyl)amino]propane (0.43 g, 0.85 mmole) and S triethylamine (130 p1, 0.93 mmole) in 5 ml of anhydrous tetrahydrofuran, was added dropwise ethylchloroformate (89 p.1, 0,93 mmole). The resulting mixture was stirred for about 16 hours at room temperature. The tetrahydrofuran f was removed under reduced pressure.
The acylated product was partitioned between ethyl acetate and 0.2 N sodium hydroxide, and was then washed with water and brine successively, then dried over sodium sulfate. Flash chromatography (silica gel, methanol:methylene chloride, 2.5:97.5) provided 390 mg of homogeneous title product as a white foam.
29 S..10 0 0 0 0 S Preparation of 3-(1H-indol-3-yl)-l-[N-(2-methoxybenzyl)-N- (methylaminocarbonyl)amino]-2-[N-(2-((4-phenyl)piperazin-lyl)acetyl)amino]propane [Compound of Example 29] To a room temperature solution of 3-(1H-indol-3yl)-l-[N-(2-methoxybenzyl)amino]-2-[N-(2-((4phenyl)piperazin-l-yl)acetyl)amino]propane (0.40 g, 0.78 mmole) in 10 ml of anhydrous tetrahydrofuran was added dropwise methyl isocyanate (140 2.3 mmoles).-The resulting mixture was then stirred for 16 hours at room temperature. The tetrahydrofuran was removed in vacuo.
The title product was isolated by consecutive washes with ethyl acetate, water, and brine, and then dried over sodium sulfate. Flash chromatography using silica gel and a methanol/methylene chloride (5/95) eluant provided 396 mg of the homogeneous product as a yellow oil.
Alkylation of Secondary Amine Preparation of l-[N-ethyl-N-(2-methoxybenzyl)amino]-3-(1Hindol-3-yl)-2-[N-(2-((4-phenyl)piperazin-lyl)acetyl)amino]propane [Compound of Example 9] o o 00 4 ma 0 To a room temperature solution of 3-(1H-indol-3yl)-l-[N-(2-methoxybenzyl)amino]-2-[N-(2-((4phenyl)piperazin-l-yl)acetyl)amino]propane (0.41 g, 0.80 mmole) in 5 ml of anhydrous N,N-dimethylformamide were added ethyl iodide (120 1.5 mmoles) and potassium carbonate (120 mg, 0.87 mmole). This mixture was then heated to 50'C and maintained at that temperature for about 4 hours after which it was stirred at room temperature for about 16 hours. The N,N-dimethylformamide was then removed under reduced pressure. The product was partitioned 30 0
S
S
S
between ethyl acetate and water, and then washed with brine, before drying over sodium sulfate. The solvents were removed in vacuo. Preparative thin layer chromatography provided 360 mg of the title product as a yellow foam.
Method E Reduction of the carbonyl of an amide S Preparation of 1,2-diamino-3-(lH-indol-3-yl)propane Boron trifluoride etherate (12.3 ml, 0.1 mmole) S was added to a tetrahydrofuran (24.4 ml) solution of tryptophan amide (20.3 g, 0.1 mole) at room temperature with stirring. At reflux with constant stirring, borane methylsulfide (32.25 ml, 0.34 mole) was added dropwise.
The reaction was heated at reflux with stirring for five hours. A tetrahydrofuran:water mixture (26 ml, 1:1) was 0 carefully added dropwise. A sodium hydroxide solution (160 ml, SN) was added and the mixture heated at reflux with stirring for sixteen hours.
The layers of the cooled mixture were separated and the aqueous was extracted twice with 40 ml each of Stetrahydrofuran. These combined tetrahydrofuran extracts S" were evaporated. Ethyl acetate (800 ml) was added and this solution was washed three times with 80 ml saturated sodium chloride solution. The ethyl acetate extract was dried over sodium sulfate, filtered and evaporated to yield 18.4 g of the title compound.
S
S
S
0.504 31 Protection of primary amine Preparation of the 2-amino-l-t-butoxycarbonylamino-3-(1Hindol-3-yl)propane.
Di-t-butyldicarbonate (0.90 ml, 3.9 mmoles) in ml of tetrahydrofuran was added dropwise at room temperature to the 1,2-diamino-3-(1H-indol-3-yl)propane (1.06 g, 5.6 mmoles) produced supra, which was dissolved in 28 ml of tetrahydrofuran. This dropwise addition-occurred over a 5 hour period. The solvent was evaporated. Flash chromatography using ethanol/ammonium hydroxide/ethylacetate yielded 0.51 g (1.76.mmoles, 31%) of the desired carbamate.
16 Acylation of the secondary amine Preparation of l-t-butoxycarbonylamino-3-(1H-indol-3-yl)-2- [N-(2-((4-phenyl)piperazin-l-yl)acetyl)amino]propane ":20 [Compound of Example 151] *O A slurry of 2-((4-phenyl)piperazin-l-yl)acetic acid (2.47 g, 11.2 mmoles) and triethylamine (3.13 ml, 22.5 mmoles) in acetonitrile (1200 ml) was heated to reflux .O briefly with stirring. While the resulting solution was still warm carbonyldiimidazole (1.82 g, 11.2 mmoles) was added and the mixture was heated at reflux for 10 minutes.
The 2-amino-l-t-butoxycarbonylamino-3- (lH-indol-3yl)propane (3.25 g, 11.2 mmoles) in 50 ml of acetonitrile was then added to the reaction. The resulting mixture was refluxed with stirring for 30 minutes and was then stirred at room temperature overnight.
The reaction mixture was then refluxed with stirring for 5 hours and the solvent was then removed in vacuo. The resulting oil was washed with a sodium carbonate solution, followed by six washes with water, 32 which was followed by a wash with a saturated sodium chloride solution. The resulting liquid was dried over sodium sulfate and filtered. The retained residue was then dried in vacuo. The filtrate was reduced in volume and then partially purified by chromatography. The sample from the chromatograaphy was pooled with the residue retained by the filter, combining for 3.94 grams (72% yield) of the title product.
.10 Method F Deprotection of Primary Amine Synthesis of l-amino-3-(lH-indol-3-yl)-2-[N-(2-((4- :15 phenyl)piperazin-l-yl)acetyl)amino propane [Compound of Example 150] To an ice cold soution of 70% aqueous trifluoroacetic acid (2.8 ml of trifluoroacetic acid in :2P ml total volume) were added l-t-butoxycarbonylamino-3-(lHindol-3-yl)-2-[N-(2-((4-phenyl)piperazin-lyl)acetyl)amino]propane (0.80 g, 1.63 mmoles) and anisole (0.4 ml). This mixture was stirred for 35 minutes, resulting in a clear solution. The solution was then stirred for an additional hour and then evaporated.
Ethyl acetate was then added to the resulting liquid, followed by a wash with a sodium carbonate solution. This wash was then followed by three washes with a saturated sodium chloride solution. The resulting solution was then dried over soldium sulfate, filtered and evaporated, resulting in 0.576 g (90% yield) of the title product.
33 Method G Reductive Alkylation of Primary Amine Preparation of 1-[N-(2-chlorobenzyl)amino]-3-(1H-indol-3yl)-2-[N-(2-((4-phenyl)piperazin-l-yl)acetyl)amino]propane.
[Compound of Example 2] 2-Chlorobenzaldehyde (0.112 g, 0.8 mmole) was .*10 combined with the l-amino-3-(lH-indol-3-yl)-2-[N-(2-((4- 0 phenyl)piperazin-l-yl)acetyl)amino]propane (0.156 g, 0.398 S mmole) in toluene. The resulting mixture was then stirred and warmed, and then evaporated. Toluene was then added to the residue and this mixture was again evaporated.
1:5 Tetrahydrofuran was added to the residue and the mixture was then cooled in an ice bath.
Sodium cyanoborohydride (0.025 g, 0.4 mmole) was then added to the reaction mixture. Gaseous hydrogen chloride was periodically added above the liquid mixture.
The mixture was stirred at room temperature for 16 hours and then reduced in volume in vacuo.
A dilute hydrochloric acid solution was then added to the residue and the solution was then extracted twice with ether. The acidic aqueous extract was basified .e 4A by the dropwise addition of 5N sodium hydroxide. This basified solution was then extracted three times with ethyl acetate. The combined ethyl acetate washes were washed with a saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated. This process was followed by chromatography yielding 0.163 g (79% yield) of the title product.
34 Method H Tritylation Preparation of 3-(lH-indol-3-yl)-2-(Ntriphenylmethylamino)propanamide.
Tryptophan amide (26.43 g, 0.130 mole) was suspended in 260 ml of methylene chloride and this mixture was flushed with nitrogen and then put under argon. Trityl chloride (38.06 g, 0.136 mole) was dissolved in 75 ml of methylene chloride. The trityl chloride solution was slowly added to the tryptophan amide solution which sat in an ice bath, the addition taking about 25 minutes. The reaction mixture was then allowed to stir ovenight.
The reaction mixture was then poured into a separation funnel and was washed with 250 ml of water, followed by 250 ml of brine. As the organic layer was filtering through sodium sulfate to dry, a solid precipitated. The filtrate was collected and the solvent was evaporated.
Ethyl acetate was then added to the pooled solid and this mixture was stirred and then refrigerated overnight. The next day the resulting solid was washed several times with cold ethyl acetate and then dried in vacuo. Yield 49.76 g Reduction of Carbonyl Preparation of l-amino-3-(1H-indol-3-yl)-2-(Ntriphenylmethylamino)propane Under argon the 3-(lH-indol-3-yl)-2-(Ntriphenylmethylamino)propanamide (48.46 g, 0.108 mole) was suspended in 270 ml of tetrahydrofuran. This mixture was 35 then heated to reflux. Borane-methyl sulfide complex (41.3 g, 0.543 mole) was then slowly added to the reaction mixture. All of the starting amide dissolved during the addition of the borane-methyl sulfide complex. This solution was then stirred overnight in an 83'C oil bath.
After cooling a 1:1 mixture of tetrahydrofuran:water (75 ml total) was then added to the solution. Sodium hydroxide (5N, 230 ml) was then added to the mixture, which was then heated to reflux for about .0 minutes. 1 CO C eq. eq 0*e 0 ezo *0 S SC C
C
After partitioning the aqueous and organic layers, the organic layer was collected. The aqueous layer was then extracted with tetrahydrofuran. The organic layers were combined and the solvents were then removed by evaporation. The resulting liquid was then partitioned between ethyl acetate and brine and was washed a second time with brine. The solution was then dried over sodium sulfate and the solvents were removed in vacuo to yield 48.68 grams of the desired intermediate.
Substitution of primary amine Preparation of l-[N-(2-methoxybenzyl)amino]-3-(1H-indol-3yl)-2-(N-triphenylmethylamino)propane
C.S~
C
eTo a mixture of l-amino-3-(1H-indol-3-yl)-2-(Ntriphenylmethylamino)propane (48.68 g, 0.109 mole) dissolved in toluene (1.13 1) was added 2methoxybenzaldehyde (23.12 g, 0.169 mole), the 2methoxybenzaldehyde having been previously purified by base wash. The reaction mixture was stirred overnight. The solvents were then removed in vacuo.
The recovered solid was dissolved in 376 ml of a 1:1 tetrahydrofuran:methanol mixture. To this solution was added sodium borohydride (6.83 g, 0.180 mole). This mixture was stirred on ice for about 4 hours. The solvents 36 were removed by evaporation. The remaining liquid was partitioned between 1200 ml of ethyl acetate and 1000 ml of a 1:1 brine:20N sodium hydroxide solution. This was extracted twice with 500 ml of ethyl acetate each and then dried over sodium sulfate. The solvents were then removed by evaporation overnight, yielding 67.60 grams yield) of the desired product.
10 Method J Tritylation e* Preparation of 3-(lH-indol-3-yl)-2-(N- 0o0 triphenylmethylamino)propanoic acid [N-trityltryptophan] Chlorotrimethylsilane (70.0 ml, 0.527 moles) was added at a moderate rate to a stirring slurry of tryptophan (100.0 g, 0.490 mole) in anhydrous methylene chloride (800 20 ml) under a nitrogen atmosphere. This mixture was continuously stirred for 4.25 hours. Triethylamine (147.0 ml, 1.055 moles) was added followed by the addition of a S solution of triphenylmethyl chloride (147.0 g, 0.552 mole) S* in methylene chloride (400 ml) using an addition funnel.
25 The mixture was stirred at room temperature, under a *s h nitrogen atmosphere for at least 20 hours. The reaction *was quenched by the addition of methanol (500 ml).
The solution was concentrated on a rotary evaporator to near dryness and the mixture was redissolved in methylene chloride and ethyl acetate. An aqueous workup involving a 5% citric acid solution (2X) and brine (2X) was then performed. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness on a rotary evaporator. The solid was dissolved in hot diethyl ether followed by the addition of hexanes to promote crystallization. By this process 173.6 g (0.389 37 mole) of analytically pure 3-(lH-indol-3-yl)-2-(Ntriphenylmethylamino)propanoic acid was isolated as a light tan solid in two crops giving a total of 79% yield.
Coupling Preparation of 3-(lH-indol-3-yl)-N-(2-methoxybenzyl)-2-(Ntriphenylmethylamino)propanamide 1 0 To a stirring solution of 3-(1H-indol-3-yl)-2- (N-triphenylmethylamino)propanoic acid (179.8 g, 0.403 mole), 2-methoxybenzylamine (56.0 ml, 0.429 mole), and hydroxybenzotriazole hydrate (57.97 g, 0.429 mole) in anhydrous tetrahydrofuran (1.7 L) and anhydrous N,Ndimethylformamide (500 ml) under a nitrogen atmosphere at S 0C, were added triethylamine (60.0 ml, 0.430 mole) and 1- 3 -dimethylaminopropyl)-3-ethoxycarbodiimide hydrochloride (82.25 g, 0.429 mole). The mixture was allowed to warm to room temperature under a nitrogen atmosphere for at least *20 20 hours. The mixture was concentrated on a rotary Se evaporator and then redissolved in methylene chloride and an aqueous work-up of 5% citric acid solution (2X), saturated sodium bicarbonate solution and brine (2X) was performed. The organic layer was dried over anhydrous 2I^ 5 sodium sulfate, filtered, and concentrated to dryness on a S rotary evaporator. The title product was then filtered as 0 a pink solid in two lots. Isolated 215.8 g (0.381 mole) of analytically pure material (95% yield).
Reduction Preparation of 3-(lH-indol-3-yl)-l-[N-(2methoxybenzyl)amino]-2-(N-triphenylmethylamino)propane Red-Al [a 3.4 M, solution of sodium bis(2methoxyethoxy)aluminum hydride in toluene] (535 ml, 1.819 38 moles), dissolved in anhydrous tetrahydrofuran (400 ml) was slowly added using an addition funnel to a refluxing solution of the acylation product, 3-(1H-indol-3-yl)-N-(2methoxybenzyl)-2-(N-triphenylmethylamino)propanamide (228.6 g, 0.404 mols) produced supra, in anhydrous tetrahydrofuran liter) under a nitrogen atmosphere. The reaction mixture became a purple solution. The reaction was quenched after at least 20 hours by the slow addition of excess saturated Rochelle salt solution (potassium sodium tartrate tetrahydrate). The organic layer was isolated, S washed with brine dried over anhydrous sodium sulfate, filtered, and concentrated to an oil on a rotary evaporator. No further purification was done and the product was used directly in the next step.
.15
S
99 4 .3
S
94 4C
I
Acylation Preparation of 3-(lH-indol-3-yl)-l-[N-(2-methoxybenzyl)acetylamino]-2-(N-triphenylmethylamino)propane To a stirring solution of 3-(1H-indol-3-yl)-1- [25 [N-(2-methoxybenzyl)amino]-2- (N- S triphenylmethylamino)propane (0.404 mole) in anhydrous tetrahydrofuran (1.2 liters) under a nitrogen atmosphere at S 0° 0 C was added triethylamine (66.5 ml, 0.477 mole) and acetic anhydride (45.0 ml, 0.477 mole). After 4 hours, the mixture was concentrated on a rotary evaporator, redissolved in methylene chloride and ethyl acetate, washed with water (2X) and brine dried over anhydrous sodium sulfate, filtered, and concentrated to a solid on a rotary evaporator. The resulting solid was dissolved in chloroform and loaded onto silica gel 60 (230-400 mesh) and eluted with a 1:1 mixture of ethyl acetate and hexanes.
39
U
.4.
Y S a The product was then crystallized from an ethyl acetate/hexanes mixture. The resulting product of 3-(lHindol-3-yl)-l-[N-(2-methoxybenzyl)acetylamino]-2-(Ntriphenylmethylamino)propane was crystallized and isolated over three crops giving 208.97 grams (87% yield) of analytically pure material.
Method L Detritylation SPreparation of 2-amino-3-(1H-indol-3-yl)-1-[N-(2methoxybenzyl)acetylamino]propane Formic acid (9.0 ml, 238.540 mmoles) was added to a stirring solution of 3-(lH-indol-3-yl)-1-[N-(2methoxybenzyl)acetylamino]-2-(Ntriphenylmethylamino)propane (14.11 g, 23.763 mmoles) in 0 anhydrous methylene chloride under a nitrogen atmosphere at 0C. After 4 hours, the reaction mixture was concentrated S to an oil on a rotary evaporator and redissolved in diethyl ether and 1.0 N hydrochloric acid. The aqueous layer was washed twice with diethyl ether and basified with sodium hydroxide to a pH greater than 12. The product was ~U extracted out with methylene chloride The organic extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated on a rotary evaporator to a white foam. The compound 2-amino-3-(1H-indol-3-yl)-1- 2 -methoxybenzyl)acetylamino]propane (7.52 g, 21.397 mmols) was isolated giving a 90% yield. No further purification was necessary.
S
0r a.
S.
4e54
I
V
40 Method M Bromoacetylat ion Preparation of (2-brorno)acetyllainino-3-(1H-indol-3-yl) 1- (2-methoxybenzyl) acetylaminolpropane To a stirring solution of 2-amino-3-(lH-indol-3yl) -1-tN- (2-methoxybenzyl)acetylaminolpropane (7.51 g, 21.369 mmoles) in anhydrous tetrahydrofuran (100'ml) 'under a nitrogen atmosphere at 0 0 C was added diisopropylethylamine (4.1 ml, 23.537 mnioles) and bromoacetyl bromide (2.05 ml, 23.530 mmioles). After 2 age** hours, ethyl acetate was added and the reaction mixture zl 5 washed with water twice, 1.0 N hydrochloric acid (2X), saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to a tan foam on a rotary evaporator. In this manner the 2-t(2-bromo)acetyllamino-3- (lH-indol-3-yl) (2-methoxybenzyl) acetylaminol propane was obtained in quantitative yield. No further purification was necessary.
Method N *6 Nucleophilic Displacement Preparation of 1-IN- (2-methoxybenzyl)acetylamino]-3-(lHindol-3-yl) (4-cyclohexyl)piperazin-lyl) acetyl)aminolpropane [Compound of Example 74] 1-Cyclohexylpiperazine 65 g, 22.492 mmoles) was added to a stirring solution of bromo)acetyll amino-3- (1H-indol-3-yl) (2- 41 methoxybenzyl)acetylamino]propane (21.369 mmoles) and powdered potassium carbonate (3.56 g, 25.758 mmols) in methylene chloride under a nitrogen atmosphere. The reaction mixture was stirred overnight at room temperature.
The salts were filtered and the solution concentrated to a brown foam on a rotary evaporator. The desired product was purified on a Prep 500 column using a 10 L gradient starting with 100% methylene chloride and ending with methanol/94.5% methylene chloride/0.5% ammonium hydroxide.
Impure fractions were combined and purified further by i* reverse phase preparative high performance liquid chromatography (methanol/acetonitrile/water/ammonium acetate). After combining the material from both 4 chromatographic purifications the title compound (10.43 g, 18.663 mmoles) was isolated (87% yield).
a An alternative means of acylation of the primary amine as shown in the final step of the synthesis protocol of Scheme IV is by means of reacting a compound of the e S"*0O formula oe< J N
OCH
3 SNH2
H
with a potassium carboxylate of the formula K o (CH 2
-R
in the presence of isobutylchloroformate and Nmethylmorpholine. This reaction is usually performed in the presence of a non-reactive solvent such as methylene chloride at cool temperatures, usually between -30'C and 42 more preferably at temperatures between -20'C and O'C. In this reaction equimolar amounts of the two reactants are generally employed although other ratios are operable. An example of this preferred means of acylating the primary amine is shown in the following example.
Method P @0 0 0 *e.
0*
S
S
Preparation of 2 -methoxybenzyl)acetylamino]-3- (1H-indol-3-yl)-2-[N-(2-((4-cyclohexyl)piperazin-1yl)acetyl)amino]propane [Compound of Example 4
SI
@4
I
@0654
S
The title compound was prepared by first cooling 15 2 4 -cyclohexyl)piperazin-l-yl)acetic acid potassium salt to a temperature between -8'C and -15'C in 5 volumes of anhydrous methylene chloride. To this mixture was then added isobutylchloroformate at a rate such that the S temperature did not exceed This reaction mixture was f0 then stirred for about 1 hour, the temperature being maintained between -8'C and To this mixture was then added (R)-2-amino-3- (lH-indol-3-yl)-l-[N-( 2 -methoxybenzyl)acetylamino]propane dihydrochloride at such a rate that the temperature did not Sexceed O'C. Next added to this mixture was N-methyl morpholine at a rate such that the temperature did not exceed O'C. This mixture was then stirred for about 1 hour at a temperature between -15'C and -8'C.
The reaction was quenched by the addition of volumes of water. The organic layer was washed once with a saturated sodium bicarbonate solution. The organic phase was then dried over anhydrous potassium carbonate and filtered to remove the drying agent. To the filtrate was then added 2 equivalents of concentrated hydrochloric acid, followed by 1 volume of isopropyl alcohol. The methylene X-8849 (OUS) 43 chloride was then exchanged with isopropyl alcohol under vacuum by distillation.
The final volume of isopropyl alcohol was then concentrated to three volumes by vacuum. The reaction mixture was cooled to 20'C to 25'C and the product was allowed to crystallize for at least one hour. The desired product was then recovered by filtration and washed with sufficient isopropyl alcohol to give a colorless filtrate.
The crystal cake was then dried under vacuum at O The following table illustrates many of the compounds produced using essentially the steps described in Schemes I through IV. A person of ordinary skill in the art would readily understand that a certain order of steps must be employed in many instances to avoid reactions other 0"0 15 than the one sought. For example, as in the above methods, it is frequently necessary to employ a protecting group in order to block a reaction at a particular moiety.
The abbreviations used in the following table are commonly used in the field and would be readily *0 understood by a practitioner in the field. For exmple, the abbreviation "Ph" refers to a phenyl group, "i-Pr" refers to an isopropyl group, "Me" describes a methyl group, "Et" ooo refers to an ethyl group, "t-Bu" describes a tert-butyl group, and the like.
In the following table, the first column gives the example number of the compound. The next columns (may G^ be one, two, or three columns) describe the substitution patterns of the particular example. The column entitled "Mp gives the melting point of the compound if it is a solid or notes the form of the substance at ambient temperature. The next column, entitled defines the mass of the compound as determined by mass spectroscopy.
The following column gives the nuclear magnetic resonance profile of the example compound as synthesized. The final columns give the molecular formula of the example compound as well as its elemental analysis.
0 OJO 0
C
C
C
C
CCC C*S
C
C
S C C. C S C S C SC C
SSC
C C S 55 S C C CC S S*S C C S C SO CC 0 C S C S S e.g S S Example Mp Analysis No. R R' C MS IH NMR Formula Theory/Found C H N H H foam 481 CDC1 3 2.28 (in, IH), 2.32- C 3 0
H
3 5
N
5 0 74.81 7.32 14.54 2.45 (in, 2H), 2.45-2.61 (mn, 74.83 7.38 14.67 211), 2.73 (in, 2.79-3.15 (in, 8H), 3.21 (in, 114), 3.96 (ABq, J=8 Hz, Av=20 Hz, 2H), 4.50 (in, lH), 6.78-6.99 (in, 3H), 7.04 (in, IH), 7.10- 7.59 (in, 1 1H), 7.66 J=8 Hz, 1H), 8.10 (hr s, 1H) H 2-Cl foam 515, 517 for cl isotopes) DMSO-dr, 2.33-2.50 (in, 4H), 2.56-2.75 (in, 2H4), 2.75-3.09 (mn, 8H), 3.20 (mn, 114), 4.78 2H), 5.21 (in, 111), 6.78 J=8 Hz, IH), 6.88 J=8 Hz, 2H1), 6.98 J=8 Hz, 111), 7.06 J=8 Hz, 1H1), 7.13 (mn, 1H), 7.13-7.31 (in, 4H), 7.34 J=7 Hz, 1H), 7.39 (dd, J=2, 6 Hz, IH), 7.50 (dd, J=2, 7 Hz, 1H), 7.55 J=8 Hz, IH), 7.61 J=7 Hz, 1H), 10.81 (hr s, 1H1) 0 C C S. 0 S S S S S S go C C Se 6 0 6 e.g *55 e* '0 so: a gem 9 *0 00 06 00 00 900 ge* e 0. 0.
Example Mp Analysis No. R R 0 MS IH NMR Formula Theory/Found C H N 3 H 2-CF 3 foam 549 CDC1 3 2.12 Cm, 1H), 2.36- C.1 1
H
34
F
3 Ns0 Exact Mass FAB theory: 550.2794 found: 550.2801 H 2-OMe foam 512 (RS) H 2-OMe foam 512 2.44 2H), 2.44.2.60 (m, 2H), 2.77-3.09 Cm, 4.02 211), 4.50 (in, 1H), 6.73-7.00 (in, 3H), 7.00-7.56 (in, 911, 7.56-7.85 Cm, 311), 8.16 (br a, 1H) ODC1 3 2.30-2.43 (in, 2H), 2.43-2.54 Cm, 2H), 2.70-3.10 Cm, 11H1), 3.82 3H), 3.84 2H), 4.44 1H), 6.74.
6.94 (in, 6H), 7.04 (mn, IH), 7.07-7.36 (in, 7H), 7.64 (d, J=8 Hz, IH), 8.09 (hr a, 1H)
CDCI
3 2.30-2.43 (mn, 2H), 2.43-2.56 Cm, 2H), 2.64-3. 12 Cm, I IH), 3.59-3.93 2H), 3.82 3H), 4.43 (in, 1H), 6.68-6.96 Cm, 6H), 7.03 Cm, 111), 7.07-7.45 Cm, 7H), 7.66 J=8 Hz, IH), 8.04 Cbr a, 1H) CDC1 3 2.22-2.38 2H), 2.38-2.50 2H), 2.50-3.27 Cm, I11H), 3.84 Ca, 3H), 3.96 CABq, J=13 Hz, Av=21 Hz, 2H), 4.27 Cm, IH), 6.75-6.97 6H), 6.99-7.39 8H), 7.63 J=8 Hz, 111), 8.12 Cbr s, 1 H)
C
3
,H.
37 Nr)0 2
C
3 1
H
3 7
N
5 0 2 72.77 7.29 13.69 72.49 7.33 13.90 72.77 7.29 13.69 72.58 7.39 13.65 H 2-OMe foam 512 CS) M+ I I
C
3 1
H
3 7 Nr 5 0 2 72.77 7.29 13.69 73.01 -7.50 13.69
S
0. go SS 0: :0 090 0 0
S..
S
S
55 5 0 S *5 SOS *SS SS S I @4 5*
S
5055 5*5 5 0 Example Mp Analysis No. R R' C MS IH NMR Formula Theory/Found C H N 7 H 3-OMe foam 511 CDC1 3 7:3 mixture of amide C 3 lH 37 Nr 5 0 2 72.77 7.29 13.69 rotamers 2.20-3.74 (in, 73.00 7.19 13.91 14H), 3.74 (mn, 1H1), 3.76 (s, 3/10*3H), 3.80 7110*314), 4.13 (ABq, 3=14 Hz, Hz, 7/10*211) 4.67 (in, 1H), 4.70 (ABq, J=14 Hz, Av= 160 Hz, 3/10*21), 6.82-7.00 (in, 6H1), 7.00-7.45 (in, 8H), 7.59 J=8 Hz, 111), 8.10 (br s, 3/10o 111), 8.41 (hr 9, 7/10* 1H1) H 4-OMe foam 511 Et 2-OMe foam 540 (M+11)
CDCJ
3 2.2 1-2.63 (in, 4H), 2.63-2.90 (in, 411), 2.90.3.40 (mn, 6H), 3.75 (mn, 111), 3.77 311), 4.04 (ABq, J=12 Hz, Av=54 Hz, 211), 4.64 (in, 111), 6.83.6.95 (in, 5H), 6.95- 7.48 (in, 8H), 7.50-7.75 (in, 2H), 8,23 (br a, 1H) CDC1 3 1.04 J=8 Hz, 3H), 2.32-2.43 (in, 2H1), 2.43-2.66 (mn, 6H), 2.83-2.9 1 (in, 4H), 2.94 J=5 Hz, 2H), 3.08 (t, J=6 Hz, 2H), 3.65 (ABq, J=14 Hz, Av=22 Hz, 211), 3.77 311), 4.41 J=6 Hz, 1H1), 6.78-6.96 (mn, 611), 7.06- 7.29 (in, 611), 7.33 J=8 Hz, 111), 7.40 J=7 Hz, 111), 7.64 J=8 Hz, 1H), 7.99 (hr s, 111)
C
3 1
H
3 7
N
5 0 2
C.
3 H11 4 .9N0 2 72.77 7.29 13.69 72.58 7.35 13.70 73.44 7.66 12.98 73.21 7.63 13.14 6 0@ S 0 0 0 0 egg
C
*0S S C *6 5 0 4..
00 0 000 0 0 S S 0* 0 00 S. S g@e S..
go 0 @5 #6 4 0 goee 0 0 Example Mp Analysis No. R R' C MS 'H NMR Formula Theory/Found C H N MeO(OC)CH 2 2-OMe foam 584 O:Dd 3 2.37-2.47 (in, 2H), C 34
H
41
N
5 ,0 4 69.96 7.08 11.99 2.50.2.58 (in, 2.78-2.*98 69.69 6.98 11.87 6H), 3.00 211), 3.12 (t, J=6 Hz, 2H), 3.37 (ABq, J=18 Hz, Av=26 Hz, 2H-), 3.65 3H), 3.77 3H), 3.83 2H), 4,.45 1H), 6.80-6.92 (in, 5H), 7.00 (a, 1H), 7.10-7.40 (in, 8H), 7.70 J=9 Hz, 1H), 8.08 1H) 11 HO(OC)CH 2 2-OMe 95- 100 570 1+) Meco H foam 523 DMS0- d 6 2.3 1-2.49 (m, 4H), 2.75 J=8 Hz, 2H), 2.8 1-3.05 (in, 7H), 3.13-3.49 (in, 3H), 3.65-3.80 (mn, 2H), 3.71 3H), 4.20 (mn, 1H), 6.78 J=8 Hz, 1H), 6.83- 6.98 (in, 5H), 7.00-7.10 (m, 2H), 7.21 J=8 Hz, 3H), 7.30 J=9 Hz, 2H), 7.56 (br d, J=8 Hz, 2H), 10.81 (br s, 1H) DMSO-dG 1:1 mixture of amide rotamers 1.99 (s, 1/2*3H), 2.07 1/2o3H), 2.20-2.50 (in, 4H), 2.69-2.95 4H), 2.95-3.12 4H), 3.12-3.52 (in, 1/2 a1H+ IH), 3.63 (in, 1/2 o 4.40 (m, 4.51 (ABq, J=16 Hz, Av= 140 Hz, 1/2*2H), 4.54 (ABq, J=16 Hz, Av=30 Hz, 12-2H), 6.78 J=8 Hz, 1H), 6.86-6.94 (mn, 2H), 6.98 (in, 1H), 7.03-7.15 (mn, 4H), 7.15-7.38 (in, 6H), 7.50-7.60 1.5H), 7.74 J=8 Hz, 1/2o 1H), 10.93 (br s, 1H)
C
33
H
39
N
5 0 4 69.57 6.90 12.29 69.80 6.79 11.99
C
32
H
37
N
5 0 2 73.39 7.12 13.37 73.67 7.23 13.60 24 0 0 0 0 0 *0 S S SO 0 S 00 S@0 SOS OS 09 005 0 004 we* 1 0.0 S.0 Example Mp Analysis No. R IT c MS '11 NMR Formula Theory/Found C H N 13 MeCO 2-Cl foam 557 DMSO-d6 3:2 mixture of C 3 2
H
36
CIN
5 0 2 68.86 6.50 12.55 amide rotamers 1.93 69.06 6.48 12.56 2.09 315 *3H1), 2.25-2.50 (in, 4H), 2.70-2.96 (in, 4H1), 2.96-3.19 (in, 411), 3.20-3.64 (mn, 4.50 (in, 111), 4.59 (ABq, J=16 Hz, Hz, 3/5*2H), 4.64 (s, 21502H), 6.78 J=7 Hz, 111), 6.91 J=8 Hz, 2H1), 6.98 J=7 Hz, 1H1), 7.02.
7. 10 (mn, 2H), 7.12 (mn, IH), 7.16-7.37 (in, 5H), 7.44 (in, 111), 7.50-7.62 (in, 2/501H 7.75 J=8 Hz, *1H1), 10.83 (br s, 1H) MeCO 2-Me 538 CDCI 3 2.06 311), 2.21 (s, 311), 2.1-2.6 (in, 2H), 2.9-3.3 (in, 1211), 3.58 (in, 111), 4.4- 4.6 (in, 2H), 6.8-7.0 7.0-7.4 (in, 911), 7.62 J=7 Hz, 1H1), 8.15 (br s, 111)
C
3 3
H
39
N
5 0 2 73.71 7.31 13.02 74.00 7.37 13.21 MeCO 2-CF 3 foam 592 1+) 2-NO 2 foam 569 MeCO CDC1 3 2.03 311), 2.15- 2.80 (in, 511), 2.80-3.73 (in.
811), 3.88 (in, 111), 4.47-4.93 (in, 311), 6.72.7.03 (in, 411), 7.03-7.45 (in, 7.45-7.76 (in, 411), 8.22 (hr s, 111) CDC1 3 2.05 311), 2.28 (mn, 111), 2.3-2.7 (in, 4H), 2.8-3.2 (in, 811), 3.2-3.9 (in, 211), 4.58 (in, 111), 4.97 (in, 111), 6.8-7.0 (mn, 2H1), 7.0.7.5 (mn, 10H1), 7.5-7.7 (in, 211), 8.12 J=7 Hz, 111), 8.15 (br a, 1H)
C
3 3 11 3 6
F
3
N
5 0 2
C
3 2 H4 3 6
N
6 0 4 66.99 6.13 11.84 66.83 6.20 12.10 67.59 6.38 14.78 67.32 6.35 14.56
C
24 C C C *0 C *m 0 Ce.
SC
S
so ge. :S Co Example Mp Analysis No. R R* C MS '1H NMR Formula Theory/Found C H N 17 MeCO 2-OMe foam 553 DMSO-d 6 3:2 mixture of C 3 3
H
3 9 NB0 3 71.58 7.10 12.65 (RS) amide rotamers 1.97 71.50 7.18 12.73 1.8H1), 2.07 1.214), 2.26- 2.50 (in, 4H1), 2.70-2.96 (in, 4H), 2.96-3.16 (mn, 4141), 3.16.
3.65 (mn, 2H4), 3.72 (s, 2/5o3H), 3.74 3/5*3H), 4.40 (in, 11H), 4.42 (ABq, J1=18 Hz, Av=30 Hz, 3/5o21) 4.46 (ABq, J1=16 Hz, Av=62 Hz, 215*2H), 6.70-7.03 (in, 711), 7.03.7.13 (in, 211), 7. 13-7.29 (in, 3H), 7.34 J1=8 Hz, 111), 7.49- 7.62 (in, 3/511+111), 7.72 (d, J1=6 Hz, 2/15H), 10.93 (hr a, 1H1) Meco 2-OMe foam
(R)
553 Exact Mass FAB caic.: 554.313 1 found:.
554.3144 CDC1 3 2.11 311), 2.4 1- 2.43 (in, 211), 2.50-2.55 (in, 211), 2.87-3.18 (in, 911), 3.78 311), 4.02 (dd, J1= 10, 14 Hz, 111), 4.51 (ABq, J=17 Hz, Av=42 Hz, 211), 4.59 (in, 114), 6.80-6.98 (in, 611), 7.07- 7.45 (in, 811), 7.68 J=8 Hz, 111), 8.14 111)
C
33 11 3 9
N
5 0 3 71.58 7.10 12.65 72.19 7.25 12.93 S S 5 5
S
B
S
090 0.5
S.
S S S 0 0 OS S S 0* *4 0 *0* 5 0
S
00 0 00
S
SOS SW, 5@ S 5 05 *5 S OSS 0 Example Mp Analysis No. R R, *C MS 'H NMR Formula Theory/Found C H N 19 MeCO 2-OMe foam 553 DMSO-d 6 3:2 mixture of C 3 3
H
3 9 Nr 5 0 3 71.58 7.10 12.65 (S) amide rotamers: 1.97 (a, 2.0 7 2/5 *3H), 2.23-2.60 (in, 4H), 2.7 1-2.95 (in, 411), 2.95-3.17 (mn, 4H), 3.17-3.80 (mn, 2H), 3.71 (a, 3/5*2H), 3.74 3/5*3H), 4.26 (in, 1H), 4.44 (ABq, J=16 Hz, Av=26 Hz, 315*2H), 4.45 (ABq, J=16 Hz, Av=60 Hz, 2.15s2H), 6.70-7.02 7H), 7.02-7.12 (mn, 2H1), 7.12.7.30 (mn, 3H), 7.34 J=8 Hz, IH), 7.56 J=10 Hz, 3/5H+1H), 7.70 J= 10 Hz, 2/5e 10. 82 (br s, 1H) 71.62 7.28 12.38 MeCO 3-F 86- 88 541 CDC 3 2.09 3n), 2.23 Cm, IH), 2.3-2.7 Cm, 2H), 2.7-3.2 (in, 8H), 3.30 Cm, 1H), 3.60 Cm, 111), 4.02 111), 4.2- 4.7 (mn, 3H), 6.7-7.0 6H), 7.0-7.5 8H), 7.66 J=7 Hz, 111), 8.16 (hr 9,1H) MeCO 3-OMe foam 553 CDC1 3 2.08 3H), 2.15- 2.63 (in, 4H), 2.72-3.27 (m, 8H), 3.75 (in, IH), 3.78 (s, 3H1), 4.04 Cm, 1H), 4.51 (ABq, J=16 Hz, Av=46 Hz, 2H), 4.56 Cm, 1H), 6.60-6.70 Cm, 2H), 6.72-6.94 51H), 7.04-7.46 (mn, 7H), 7.65 (d, J=8 Hz, IH), 8.04 (hr s, 1H)
C
33 H.1 9
NS
5 0 3 71.58 7.10 12.65 71.32 7.01 12.65 41 9 9 9 9 9* 9 9 9 9 9 0 0 9 9. 9 6 .0e 999 9.9 .9 a* .0 :6 :0 00 04 Poo Example Mp Analysis No. R R' C MS IH NMR Formula Theory/Found c H N 22 MeCO 4-OMe foam 553 (MI DMSO-d6 1:1 mixture of C 3 3
H
3 9
N
5 0 3 71.58 7.10 12.65 amide rotamers 2.01 71.85 7.24 12.65 112*3H), 2.05 1/2*3H), 2.23-2.60 (in, 411), 2.74-3.30 (in, 8H), 3.69 (in, 1H), 3.72 1/203H), 3.74 (s, 1/203H), 4.23 (ABq, J=16 Hz, Av=42 Hz, 112*2H), 4.52 1H1), 4.36 (ABq, J=14 Hz, Av= 164 Hz, 1/2*2H), 6.70-7.16 (in, 1011), 7.24 (in, 2H), 7.35 (in, 1H), 7.55 (in, /2*1H+1H), 7.73 (in, 1/201H), 10.84 (br s, 1H) MeCO 4-SMe dec 569 CDC1 3 2.09 3H), 2.1-2.6 138 (in, 3H), 2.46 3H), 2.8-3.1 (in, 8H), 3.30 (in, 111), 3.55 (in, 111), 3.98 (in, 1H), 4.47 (ABq, J=12 Hz, Av=52 Hz, 2H), 4.58 (in, 1H), 6.8-6.9 (in, 3H), 6.95 J=8 Hz, 211), 7.0-7.4 (in, 911), 7.66 (d, J=8 Hz, 1H), 8.08 (br s, 1H)
C
3 3 3 9 Nr 5
O
2
S
69.57 6.90 12.29 69.86 6.93 12-33 HCO 2-OMe foam 540 (M+1) CDCI 3 2.33-2.47 (mn, 211), 2.50-2.65 (in, 211), 2.87-3.10 (mn, 9H), 3.75 311), 3.77 (in, 111), 4.40 (ABq, Hz, Av=35 Hz, 211), 4.65 (in, 1H), 6.75-6.95 (in, 611), 7.03- 7.42 (in, 8H4), 7.67 J=9 Hz, 111), 8.20 (hr s, 111), 8.33 111)
C
3 2
H
3 7
N
5 0 3 71.21 6.91 12.98 70.99 6.96 13.25 6 LO 0 0 0 4 d..
0 t 00 1 4. 6 0 *6 6 0* 0 0 0 0 Example MIP Analysis No. R R' MS 'H NMR Formula Theory/Found C H N BrCH 2 CO 2-OMe foam 631, 633 CDCI 3 1 2.37-2.47 (in, 2H), __C 3 3
H
3 8 BrN 5
O
3 (M's for Br isotopes) Exact Mass FAB 1): caic.: 632.2236 found:.
632.2213 2.53-2.63 (in, 2H), 2.90O-3.17 (mn, 8H), 3.80 3H), 3.95- 4.13 (in, 2H), 3.98 (ABq, .1=1 1 Hz, Av=61 Hz, 2H), 4.57 (ABq, 3=18 Hz, Hz, 211), 4.67 (mn, 1H), 6.78 J=5 Hz, 1H1), 6.80-6.90 (mn, 411), 7.07 J=3 Hz, 111), 7.10-7.30 (in, 6H), 7.37 J=8 Hz, 111), 7.50 (d, Hz, 1H), 7.70 J=9 Hz, 1H1), 8.07 1H1) ELCO 2-OMe oil 568 CDC1 3 1.12 J=9 Hz, 3H), 2.38 J=9 Hz, 211), 2.33.
2.60 (mn, 4H1), 2.83-3.13 (mn, 811), 3.22 (br d, J=13 Hz, 1H), 3.80 3H), 4.03 (br t, J=13 Hz, 1H1), 4.55 (ABq, Hz, Av=4O Hz, 2H), 4.60 (in, 1H1), 6.83-6.97 (in, 611), 7.10-7.57 (mn, 81H), 7.68 J=8 Hz, 111), 8.24 (br s, 1H)
C
34 11 4 Nr 5 0 3 71.93 7.28 12.34 72.17 7.42 12.10 t'j PhCO 2-OMe foam 615(M*) CDC1 3 2.28-2.57 (in, 4H), 2.77-3.17 (mn, 911), 3.65 (s, 311), 4.22 3=13 Hz, 111), 4.60 (ABq, J=15 Hiz, Hz, 211), 4.82 (in, 111), 6.70- 6.92 (in, 511), 7.02.7.55 (mn, 1411), 7.68 J=7 Hz, 1H1), 8.22 (br s,111)
C
3 sH 4 jN 5 0a 74.12 6.71 11.37 74.38 6.87 11.32 bO
S
0.O 0 ~00e 0 0 *0 S 0 040 *0 6 0 *00 6e 0 S 6 0 (0 *0 J~ 0 .me 0(0 88 0 0 00 0 0000 .505 0 0 Example Mp Analysis No. R R' 0 MS 'H NMR Formula Theory/Found C H N 28 EtOCO 2-OMe foam 584 DMSO- d 6 1.05 J=8 Hz, C 3 4
H
4 1 N60 4 69.96 7.08 12.00 3H), 2.31- 2.45 411), 69.85 7.19 11.98 2.73-2.90 (m 411), 2.93-3. (m 411), 3.22-3.48 (in, 211), 3.66 3H), 3.87-4.03 (in, 2H), 4.26-4.55 (in, 311), 6.77 J=7 Hz, 111), 6.80-7.00 611), 7.05 J=8 Hz, 111), 7.11 (br 9, 111), 7.20 Ct, J=9 Hz, 3H1), 7.32 Hz, 111), 7.52 (br d, J=6 Hz, 2H1) MeNHCO 2-OMe oil 568 DMSO-d6 2.32-2.46 411), 2.55 J=5 Hz, 311), 2.78- 2.90 (in, 411), 2.96-3.10 (mn, 411), 3.18 (dd, J=5, 14 Hz, 111), 3.44 (dd, J=8, 13 Hz, 111), 3.70 311), 4.30 (m, 111), 4.37 (ABq, J=18 Hz, Av=42 Hz, 211), 6.32 (br d, Hz, 1H), 6.77 J=7 Hz, 1H), 6.82-7.00 (in, 611), 7.05 J=8 Hz, 111), 7. 11 Cd, 1=3 Hz, 111), 7.16-7.25 Cm, 3H), 7.32 J=9 Hz, 111), 7.53 J=8 Hz, 111), 7.61 J=9 Hz, 111), 10.82 (br s, 1H1) 03311401603 69.69 7.09 14.78 69.94 7.13 14.83
C.
le 000 0 00 0* 0 le 04 *0: *0.
SO. Ce.
C C S C CC CC S S C C @0 C C Example MP Analysis No. R IV C MS IH NMR Formula Theory/Found C H N MeO(OC)CH 2 CO 2-OMe foam 611 CDC1 3 2.37-2.47 Cm, 2H1), C 35
H
4 1
N
5 0 5 r 68.72 6.76 11.45 2.50-2.60 (in, 2H), 2.82-3.18 68.44 6.76 11.44 (in, 9H), 3.57 2H1), 3.72 3H), 3.78 3H), 4.02 Cdd, 3=10, 14 Hz, 111), 4.47 CABq, J=20 Hz, Av=40 Hz, 214), 4.60 Cm, 111), 6.77-6.92 Cm, 6H), 7.03-7.30 (in, 6H), 7.37 J=7 Hz, 1H), 7.45 Cd, J=10 Hz, 1H), 7.68 (d, J=9 Hz, 111), 8.12 111) 31 HO(OC)CH 2 CO 2-OMe 103- 107 598
(M+I
Exact Mass FAB 1): caic.: 59,8.3029 found:.
598.3046
CDCI
3 2.68-2.90 Cm, 411), 2.90-3.37 (in, 9H), 3.57 Cbr s, 2H), 3.78 311), 3.93 Ct, J=12 Hz, 11), 4.53 (ABq, J=17 Hz, Av=47 Hz, 211), 4.70 1H), 6.77-6.97 Cm, 611), 7.07-7.33 (in, 711), 7.37 J=8 Hz, 1H), 7.63 Cd, J=8 Hz, 111), 7.85 (br s, 1H1), 8.33 (hr a, 114)
C
3 4 11 3 9
N
5 0 32 Me(CO)OCH 2 CO 2-OMe foam 612 CDC1 3 2.10 3H), 2.35- 2.43 (mn, 211), 2.47-2.57 (m, 211), 2.90-3. 13 (in, 9H1), 3.80 CS, 3H), 4.03 (dd, J=10, Hz, 111), 4.40 (ABq, J=19 Hz, Av=30 Hz, 211), 4.57 (mn, 111), 4.85 CABq, J=15 Hz, Av=19 Hz, 211), 6.75-6.90 Cm, 611), 7.03 Cd, J=2 Hz, 1H), 7.10-7.30 511), 7.35- 7.43 Cm, 2H1), 7.66 J=9 Hz, 111), 8.32 (br s, 111)
C
35 11 4 1
N
5 0 5 68.72 6.76 11.45 68.50 6.86 11.20 0 0@ S 0 0 S. S 0 0 S 0 0 S S 0 0 00 S S S .00 0.0 050 05 S 50.
0 S S 0 @0 0 0 S *5 0 0 a S0.0 0.0 Example Mp Analysis No. R R' C MS 1H NMR For mula Theory/Found C H N 33 HOCH 2 CO 2-OMe foam 569 ODCd 3 2.35-2.57 (in, 4H), C 3 3
H
39 NS0 4 68.49 6.97 12.10 2.80.3.17 (mn, 9H1), 3.52 0.5 H120 68.51 6.86 11.91 Hz, 1H), 3.75 (9,3H4), 4.08 (in, 1H1), 4.27 (dd, Hz, 2H), 4.33 J=5 Hz, 2H1), 4.63 (in, 1H), 6.73-6.92 (mn, 6H), 7.03 J=3 Hz, IH), 7.12-7.32 (in, 511), 7.33- 7.40 (mn, 2H), 7.67 Hz, 111), 8.07 (br a, 1H) 34 H 2
NCH
2 C0 Me 2
NCH
2
CO
2-OMe foam 568 2-OMe foam 596 (MI) CDC1 3 2.20 (in, 211), 2.35- 2.45 (in, 211), 2.45-2.53 (in, 211), 2.80-3.07 (in, 8H), 3.30 (dd, J=5, 15 Hz, 1H), 3.47- 3.57 (mn, 211), 3.77 311), 3.93 (dd, J= 10, 15 Hz, 111), 4.42 (ABq, J=20 Hz, Hz, 2H), 4.62 (in, 1H), 6.77- 6.90, (in, 511), 7.03-7.40 (in, 9H), 7.65 J=8 Hz, IH), 8.12 (br s, 1H) CDCl 3 2.30 611), 2.32- 2.50 (in, 411), 2.87-3.05 (in, 8H1), 3.20 2H), 3.33 (dd, J=6, 9 Hz, 1H), 3.78 3H), 3.85 (in, 1H), 4.58 (in, 111) 4.65 (ABq, 3=18 Hz, Av=42 Hz, 211), 6.8 1-6.93 (in, 611), 7.10-7.40 (mn, 811), 7.65 (d, J= 11 Hz, 111), 8.17 (hr s, 1H1)
C
33
H
4
GN
6 (0 3
C
3 5H 4 4
N
6 0 3 69.69 7.09 14.78 69.82 7.14 14.49 70.44 7.43 14.08 70.15 7.39 14.02 9 I 0 S 0 S S S S S S S S See S. S 9 *05 0 S S S. S
S
S. SOS SOS 005 0
S.
C 0 S 0 5 005 Formula No. R RTV
MS
6 t-Bu-O(CO)NH- 2-OMe foam 668
CH
2
CO
37 MeSO 2 2-OMe foam 589 IH NMR Formula
CDCI
3 1.43 911), 2.33-
C
3 8
H
4 8
N
6 0 5 2.57 (in, 4H1), 2.82-3.12 (mn, 3.17 (dd, J=5, 15 Hz, 111), 3.77 311), 3.93-4.10 (in, 3H), 4.42 (ABq, J=18 Hz, Av=41 Hz, 211), 4.60 (mn, IH), 5.50 (br a, 111), 6.73- 6.92 (in, 611), 7.05 IH), 7.08-7.32 (in, 511), 7.35 (d, Hz, 211), 7.65 Hz, 111), 8.10 (br s, 1H) DMSO-d 6 2.28-2.46 (in, 4H), 2.83 J=7 Hz, 4H), 2.90 (9, 311), 2.98-3.04 (in, 411), 3.26- 3.34 (mn, 211), 3.67 3H), 4.30 (mn, 111), 4.36 Hz 211), 6.77 J=8 Hz, 111), 6.84-6.92 (in, 311), 6.92- 7.00 (in, 21H), 7.03-7.09 (in, 211), 7.18-7.30 (mn, 4H), 7.33 J=8 Hz, 1H1), 7.46 J=8 Hz, 111), 7.54 J=9 Hz, 111), 10.82 (br a, 111)
C
32 11 39
N
5 0 4
S
Analysis Theory/Found c H N 68.24 7.23 12.67 68.44 7.50 12.61 65.17 6.67 11.88 64.8'8 6.72 11.60 4
S.
4 0
S
6 0 0 .4 4 4 4 S S S 0 S 4 0 0 54 S 6 4 0@ 4 sOs @4 *5@ 4 4 4 6 44 0 4 4 44 4.
040 S 4 0 4 64 66 S S 0O 4 0 444 4 Exam~ple R Mp Analysis No. Oc MS 111 NMR Formula Theory/Found c H N 38 Me 128- 447 CDCI 3 2.07 311), 2.38-2. 78 (in, 3H), 2.8- C 26
H
3 3 Nr,0 2 69.77 7.43 15.65 129 3.3 (in, 11H1), 3.42 (mn, 1H), 3.67 (in, 1H1), 69.59 7.52 15.65 3.95 (mn, 1H1), 4.58 (mn, 1H1), 6.8-7.0 (in, 3H), 7.1-7.4 (mn, 7H), 7.68 J=7 Hz, 111), 8.21 (br s, 1H) 39 n-Bu foam 489 111 CDC13 0.88 J=6 Hz, 311), 1. 1-1.40 (in, 211), 1.4-1.6 (in, 211), 2.08 3H), 2.2- 2.4 (in, 411), 2.8-3.1 (mn, 811), 3.1-3.4 (in, 311), 3.9 (mn, 1H), 4.5 (br 9, 1H), 6.8-7.0 (in, 3H), 7.0.7.5 (in, 7H1), 7.68 Rd J=6 Hz, 1H1), 8.31 (br s, 111).
n-Hex foam 517 1H1 CDC1 3 0.82-0.92 (in, 3H), 1.12-1.36 (mn, 6H), 1.40-1.70 (in, 311), 2.05 311), 2.3 1- 2.61 (in, 3H), 2.80-3.11 (in, 8H), 3.11-3.42 (mn, 311), 3.9 (mn, IH), 4.5 (mn, 111), 6.75- 6.98 (in, 3H), 7.08-7.48 (in, 711), 7.7 (mn, 1H1), 8.1 (brs, 111).
C
2 qH 3 qN 5 0 2
C
3 1
H
4 3
N
5 0 2 71.13 8.03 14.30 71.40 8.05 14.41 71.92 8.37 13.53 71.85 8.35 13.59 41 (c-hexyl)CH 2 foam 630 CDC1 3 0.65-1.02 (mn, 211), 1.02-1.36 (mn, 311), 1.36-1.87 (mn, 911), 2.07 311), 2.15- 3.70 m, 12H1), 3.95 (in, 1H), 4.57 (mn, 1H), 6.70-7.03 (in, 4H), 7.03-7.23 (in, 4H), -7.3 1 7.44 (in, 211), 7.69 J=10 Hz, 111), 8.16 (br s, 1H)
C
32
H
4 3
N
5 0 2 72.56 8.18 13.22 72.46 8.12 13.07
S
S
'4
SS
S S 5 5 5 S S 5 5. S S. S 5 OSS 555 *SS *S 0 0.0 5 0 S S S. 0 S S *0 S
OS.
S S 0 0 55 55 0 S S Example R Mp Analysis No. 0 c MS IIH NMR Formula Theory/Found C H N 42 Ph 183- 5609- 'HDMSO 1.71 3H), 2.23-2.43(in, 4H), C 3 lH 3 5 Nr 5 0 2 73.04 6.92 13.74 184 2.71-2.94 (mn, 411), 2.94-3.10 (in, 4H), 3.61 73.30 7.11 13.73 (in, IH), 4.03 (mn, 1H), 4.24 (in, 111), 6.77 J=8 Hz, 1H1), 6.92-6.99 (mn, 311), 6.99- 7.12 (mn, 211), 7.21 J=8 Hz, 211), 7.24- 7.35 (mn, 311), 7.4 (mn, 111), 7.40-7.54 (mn, 4H), 10.92 (brs, 1H).
43 PhCH 2
CH
2 537 111 DMS0 (3:2 mixture of amide rotamers) 1.69 3/5*311), 2.00 (a, 2/5o311), 2.50-2.60 (in, 511), 2.70-3.05 (mn, 511), 3.05-3.19 (mn, 411), 3.19-3.36 (in, 211), 3.36-3.64 (in, 211), 4.32 (in, 111), 6.76 (t, J=8 Hz, 111), 6.90 J1=8 Hz, 211), 6.95- 7.39 (in, 11IH), 7.56 (in, 111), 7.76 (in, 2/51IH), 7.92 (mn, 3/5* 111), 10.81 (hr a, 111), 10.85 (hr a, 3/50 111).
C
3 3 113911502 73.71 73.95 7.45 13.07
C
0O
C
a 0* 0* go 0 0 09 0 0 go* 00 *0 09 S*C* :0 S S 0 0 00 0 .0 S S. .a Example Mp Analysis No. R R' c MS 111 NMR Formula Theory/Found C H N 44 H 2-OMe foam 517 CDC1 3 1.10-2.18 C 3 1
H
4 3
N,
5 02 71.92 8.37 13.5 Cm, 12H), 2. 18- 71.69 8.25 13.26 3.18 Cm, 1411), 3.6 1-3.95 2H), 3.93 3H), 4.36 Cm, 1H1), 6.76-6.96 (in, 3H), 7.04-7.44 (in, 5H), 7.42 (d, .1=8 Hz, 1H1), 7.65 3=8 Hz, 1H), 9.13 (br s, 111) H 2-OMe foam 517 CDC1 3 1.13-2.18 3.33 14H), 3.6 1-3.96 Cm, 211), 3.85 Cs, 311), 4.36 Cm, 1H1), 6.80-6.97 Cm, 311), 6.97-7.36 Cm, 611), 7.44 Cd, J1=8 Hz, 111), 9.60 (br s, 1H1)
C
3 1
H
43
N
5 0 2 71.92 8.37 13.53 71.91 8.25 13.42 0. 00 0 go 60 0 *0 0** 0 0* 000 000 00 0 0 ,0 1 0 0 0 0 :a0 0. 00,0.0 Example Mp Analysis No. R R'0C MS IH NMR Formula Theory/Found C H N 46 MeCO H foam 530 CDC1 3 3:1 mixture of amide C 32 H4 4 3
N
5 0 2 72.56 8.18 13.22 I rotainers 1.21-1.69 10H), 1.90- 72.36 8.17 13.12 2.19 (in, 3H), 2.07 3/4*3H), 2.10 1/4*311), 2.37.2.55 (in, 511), 2.65- 3.18 (mn, 6H), 4.02 (dd, J=13 Hz, Hz, IH), 4.50 (ABq,, J=17 Hz, Av=52 Hz, 3/4*2H), 4.67 (ABq, J=17 Hz, Av=228 Hz, 1/4*211), 4.55 (in, 1H1), 6.94-7.44 (mn, 10H1), 7.65 J=8 Hz, 3/4 o1H1), 7.53 J=8 Hz, 1/4o111), 8.08 (br a, 3/40 1H), 8.22 (br s, V14 &1H).
47 MeCO 2-Cl (RS) foam 563 Exact Mass
FAB
theory: 564.3105 found: 564.3130
(M+
1 CDC1 3 1.17-1.80 (in, 1011), 1.90- 2.27 (in, 311), 2.03 311), 2.35-2.59 (in, 5H1), 2.67-3.23 (in, 611), 3.97 (dd, J=10, 15 Hz, IH), 4.53 (in, 1H1), 4.58 (ABq, J=17 Hz, Av=21 Hz, 211), 6.95-7.29 (in, 611), 7.34 J=8 Hz, 2H), 7.42 J=9 Hz, 1H1), 7.63 Cd, J=8 Hz, 1H), 8.19 (br s, 1H1) 032114201N 5 0 2 48 MeCO 2-Cl foam 563 1H1 CDCI 3 1.1-1.8 (in, 1011), 1.8.2.3 (in, 4H1), 2.04 311), 2.4-2.6 (in, 3H), 2.6-2.8 (in, 2H1), 2.8-2.9 (in, 211), 2.9-3.1 (in, 2H1), 3.2 (in, 111), 3.9 (mn, 1H1), 4.5-4.7 (in, 3H), 7.0-7.6 911), 7.62 3=6 Hz, 111), 8.32 (hr s, 1H).
C
32
H
42 C1N 5 0 2 68.13 7.50 12.41 68.20 7.60 12.17 49 MeCO 2-Cl foam 563 111 CDC13 1.3-1.8 (in, 611), 2.04 (s, 1.8-2.1 (in, 311), 2.1-2.3 (in, 311), 2.4-2.6 (in, 511), 2.7-2.8 (in, 211), 2.86 J=2 Hz, 211), 2.9-3.1 (in, 211), 3.2 (in, 111), 3.9 (in, 111), 4.5-4.7 (mn, 311), 7.0-7.5 (in, 911), 7.63 J=7 Hz, 111), 8.38 (hr s, 111)
C
3 2
H
4 2 C1N 5 0 2 68.13 7.50 12.41 68.40 7.61 12.60 0 ~0 0 0 0 0 0 0 @0 0 0 00 6 0 0 00.
*0e *00 00 0 S 000 @00 0 0. 0 0 0 0 0 00 @0 00 0 9 0 0 0@ 0 0000 *4 0 0 0 Example F' Mp Analysis No. R R MS 111 NMR Formula Theory/Found C H1 N 50 MeCO 2-OMe (RS) foam 0 51 MeCO 2-OMe (R) o 52 MeCO 2-OMe (S) 559 (M 559 CDC1 3 1.30-1.86 (in, 1011), 1.93-2.32 (in, 3H), 2.10 3H), 2.45-2.67 (in, 4H), 2.71- 3.18 (in, 511), 2.87 211), 3.76 3H), 3.99 (dd, J =14 Hz, J =10 Hz, 1 4.49, (ABq, J =17 Hz, Dn=41 Hz, 2H), 4.55 (in, 1H1), 6.79- 6.93 (in, 3H), 7.06-7.27 (mn, 4H), 7.36 J=8 Hz, 111), 7.45 J=9 Hz, 111), 7.66 J=8 Hz, 1H), 8.28 (br s, 111) DMSO-d 6 3:2 mixture of amide rotamers, 1.25-1.70 (in, 1011), 1.77-2.00 (in, 311), 1.95 3/5-311), 2.04 2/5-311), 2.10-2.97 (in, 911), 3.10-3.65 (mn, 311), 3.72 2/5-311), 3.74 3/5-3H1), 4.26-4.58 (in, 311), 6.76- 7.12 (mn, 611), 7.13-7.35 (in, 211), 7.42-7.66 (mn, 211), 10.80 (br s, 111) DMSO-d 6 3:2 mixt. of amide rotamers, 1. 15- 1.68 (in, 1011), 1.68-2.20 (in, 311), 1.95 (s, 3/5-3H), 2.04 2/5-311), 2.20-3.00 (in, 911), 3.00-3.65 (in, 311), 3.74 2/5-3H), 3.76 (s, 3/5*31), 4.20-4.60 (in, 311), 6.75-7.15 (in, 611), 7. 15-7.40 (in, 211), 7.40-7.68 (in, 211), 10.78 (br s, 111).
C
33 11 4 5
N
5 0 3
C
33
H
4 5
N
5 0 3
C
33
H
45
N
5 03 70.81 70.57 70.81 71.01 8.10 12.51 8.05 12.39 8.10 12.51 8.39 12.63 70.81 8.10 12.51 70.95 8.05 12.45 2 559 IN:\LIBAA]O1441 :tab 4 9 4. 4 S S S 4 S S 4 5 .4 S 4 4 *OO .ee .4 4
S..
S 0 5 0 0* 0 6* 4. 0 00* 455 S 0 S 05 45 0 S 0*0 0 *54 4 0 Analysis, Example R Mp MS 'H NMR Formula Ter/on No. CC C H N 53 Ph 54 PhCH 2
CH
2 140- 515 11 1 DMSO 1.21-1.58 101H), 1.70 (a, 141 3H), 1.87 (ABq, J=8 Hz, Av=20 Hz, 211), 2.04 (in, 1H1), 2.29-2.49 (in, 4H), 2.45- 2.64 (mn, 2H), 2.63-2.79 (in, 2H), 2.79- 2.95 (in, 214), 3.58 (mn, 111), 4.02 J=12 Hz, 1H), 4.20 (in, 1H), 6.93 J=8 Hz, 1H1), 6.98-7.11 (mn, 214), 7.17-7.53 (mn, 8H1), 10.91 (br a, 1H).
foam 543 111 DMSO (3:2 mixture of amnide rotamers) 1.23-1.57 (in, 101-1), 1.75-1.97 (in, 211), 1.84 3/5*3H), 1.93 (a, 2/5*311), 2.05 (in, 111), 2.23-2.47 (mn, 411), 2.50-2.77 (in, 611), 2.77-2.95 (in, 211), 3.20-3.35 (in, 111), 3.36.3.52 (in, 2H), 3.62 (in, 111), 4.39 (in, 111), 6.97 (in, 111), 7.02-7.3 1 (in, 711), 7.34 Kd J=8 Hz, 111), 7.45 J=8 Hz, 3/511), 7.53-7.67 (mn, 2/5*111+ 111), 10.84 (br a, 111).
C
3 1
H
4 1
N
5 60 2 72.20 8.01 13.58 71.98 8.07 13.53 C331145Ns02 72.89 8.34 12.88 72.60 8.29 12.64
S
0
S
0..
S 0 0 S. S S S S S. S S eSS S S
S
*5 0 *0
S
550 S 5 5 55 0O 5
SOSS
*55 S 0 Example Analysis, No. R Mp, OC MS IH NMR Formula Theory/Found C H N Br foam 473 CDC'I 3 2. 15 3H), 2.81 2.96 (in, C 23
H
26
N
3
O
3 2 Br 58.48 5.55 8.90 2H), 3.15 (A]3q, J=4.3 Hz, AV= 14.6 58.69 5.66 8.94 Hz, IH), 3.72 3H), 3.79 2H), 4.06 4. 15 (in, 1H), 4.30 (mn, 1H), 4.38 (ABqs J=16.7 Hz, AV=49.0 Hz, 211), 6.72 6.81 (mn, 3H), 7.01 (a, 111), 7.13'- 7.30 (mn, 3H), 7.35 7.41 (mn, 2H), 7.71 J=7.8 Hz, MH), 8.04. 1H).
PhO foam 485 CDC1 3 2.00 3H), 2.86 (dd, J=8, 14 H z, 1 3.01 (dd, J=5, 14 Hz, 1H), 3.20 (dd, 3=5, 15 Hz, 1H), 3.70 3H), 4.04 (dd, J=10, 14 Hz, 111), 4.34 (ABq, J=18 Hz, AV=44 Hz, 2H), 4.44 (ABq, J=15 Hz, Av=25 Hz, 2H), 4.42 (mn, 1H), 6.70-6.85 (in, 3H), 6.85-7.06 (mn, 4H), 7.06-7.45 (in, 6H), 7.54 (mn, 1H), 7.71 J=8 Hz, 7.97 (br s, 1H)
C
29 11 3 1 N,0 4 71.73 6.43 8.65 71.48 6.59 .8.46 0 0
S
0 0@ S 0 0 3 S. 6 0 0 0 0* 0 0 0 0 0- S OS 0 0 S 400 egg 05 S 4.e 0 050 550 S SO *O B S 0 0. CO C. S S C 0 6* S 0e** eg go. g S Example Analysis, No. R Mp, *C MS 'H NMR Formula Theory/Found C H N 57 PhS foam 501 CDCI 3 1.92 3H), 2.76 (dd, C 2 9
H
3 jN 3 0 3 S 69.44 6.23 8.38 J=8, 14 Hz, 1H), 2.92 (dd, J=4, 69.55 6.49 8.10 14 Hz, 111), 3.06 (dd, J=4, 14 Hz, I1H), 3.57 211), 3.69 (s, 311), 3.99 (dd, J=8, 14 Hz, 11H), 4.29 (ABq, J=16 Hz, Av=44 Hz, 2H), 4.36 (in, 111), 6.65 (in, 3H), 6.85 J=3 Hz, XH), 7.05-7.37 (in, 911), 7.42 (in, 1H1), 7.67 Kd J=8 Hz, 111), 7.85 (br s, 111) 58 PhNHCH 2
CH
2
NH
foam 528 CDC1 3 2.11 3H), 2.72-2.95 (mn, 4H), 3.00-3.34 (in, 611), 3.72 311), 4.14 (dd, J= 11, 13 Hz, 111), 4.40 (ABq, J=17 Hz, Av=63 Hz, 211), 4.42 (in, 111), 4.78 (br a, 111), 6.65-6.84 (mn, 6H1), 6.95 J=3 Hz, 111), 7.07-7.35 (in, 611), 7.67 J=8 Hz, 1H), 7.80-7.91 (in, 2H1).
C
3 1
H
37 NS0 3 70.56 7.07 13.27 70.35 7.03 13.06
C
I.
C
2>! C0D
C
G
C
C
C
0CC C U
CI.*
0 0 OS 0 C C E. 0 AC C C 0CC C C C C C eq C C eq C CCC a, C 0 AC CC 0 C C CCC CCC C Example Analysis, No. R Mp, *C MS IH NMR Formula Theory/Found C H N 59 1-pyrrolidinyl foam 463 CDCIa 1.66-1.74 4H), 2.11 C 2 7
H
34
N
4 0 3 70.10 7.41 12.11 3H), 2.47 (in,J=19 Hz, 4H), 70.42 7.29 11.75 2.86-3.17 (in, 5H4), 3.74 3H), 4.00 (dd, J= 11, 14 Hz, 111), 4.46 (ABq, JT=17 Hz, Av=46 Hz, 2H), 4.52 (br s, 1H), 6.76- 6.83 (in, 2H), 7.08-7.28 (in, 3H), 7.18 1H), 7.35 J=8 Hz, 1H), 7.52 J=8 Hz, MH), 7.69 J=8 Hz, 1H), 8.38 (br a, 1H) 1-piperidinyl foam 476 CDC1 3 1.37-1.56 (mn, 6H), 2.09 3H), 2.30 (br a, 4H), 280- 3.19 (in, 6H), 3.75 3H), 3.95 (dd, J= 11, 13 Hz, 1H), 4.46 (ABq, J=17 Hz, Av=44 Hz, 2H), 4.53 (mn, 1H), 6.75-6.88 (mn, 3H), 7.04-7.24 (mn, 7.34 J=8 Hz, 1H), 7.68 (d, J=7 Hz, 1H), 8.04 (br a, 1H)
C
28
H
36
N
4 0 3 70.56 7.61 11.58 70.68 7.70 11.58 0 04 0e :4
S
I 5 0. 5 OS S SU S S SO- S CS S 5E*S S S 0 j S~ S .5 S. S 5*5 *i~S S OS Sb
S
U S SO AS. I- S.
Example Analysis, No. R Mp, OC MS IH NMR Formula Theory/Found C H N 61 1.'hexamethyleneiminyt foam 490 CDC1 3 1.52 (br s, 811), 2.09 C 29
H
38
N
4 0 3 70.99 7.81 11.42 3H), 2.54 (br a, 4H4), 2.87-3. 10 71.27 7.98 11.39 (in, 4H), 3.21 (dd, J=5, 13 Hz, 1H1), 3.76 3H), 3.92 (dd, J= 10, 13 Hz, IH), 4.48 (ABq, J=17 Hz, Av=41 Hz, 211), 4.53 (in, 111), 6.73-6.89 (nm, 3H), 7.04-7.25 (in, 4H1), 7.34 J=6 Hz, 111), 7.58 (in, 111), 7.66 (d, J=7 Hz, 111), 8.04 (br 9, 1H1) 4-morph olinyl foam 478 CDC1 3 2.07 311), 2.20-2.29 (in, 211), 2.31-2.4 1 (mn, 2H), 2.85-2.97 (in, 3H1), 3.0 1-3.13 (in, 2H), 3.46-3.67 (in, 4H), 3.77 311), 4.15 (dd, J=10, 13 Hz, 111), 4.47 (A13q, J=17 Hz, Av=48 Hz, 2H), 4.52 (in, 111), 6.77.6.89 (in, 311), 7.02-7.28 (in, 4H), 7.36 J=6 Hz, 1H), 7.46 J=8 Hz, 1H), 7.68 (d, J=7 Hz, 111), 8.02 (br a, 1H)
C
27
H
34
N
4 0 4 67.76 7.16 11.71 67.54 7.18 11.58 1 em
S
,J.
CCS
5 C 0 0
CC.
9 OS 5 em a a
CC.
5J 0 a C 0 5* ~4 a me C mom .me
K-
a go em S S 000.
see a Example Analysis, No. R Mp, OC MS 'H NMR Formula Theory/Found C H N 63 1-indolinyl roam 610 CDC1 3 1.85 3H), 2.85-3.41 C 3 1
H
3 4
N
4 0 3 72.92 6.71 10.97 (in, 7H1), 3.60 (ABq, J=17 Hz, 73.21 6.54 11.03 Av=42 Hz, 2H), 3.73 3H), 4.00 (dd, J=12, 13 Hz, 1H), 4.38 (ABq, J=17 Hz, Av=48 Hz, 2H1), 4.43-4.48 (in, IH), 6.32 J=8 Hz, 111), 6.76 (in, 3H1), 6.97- 7.24 (in, 711), 7.35 J=8 Hz, 1H), T~54 J=8 Hz, 1H1), 7.70 J=8 Hz, 111), 7.99 (br s, 1H) 1,2,3,4tetrabydroisoquinolin 4-yl foam 524 525 (M+1+ CDC1 3 2.06 3H), 2.6 1-3.28 (mn, 9H), 3.48-3.94 (mn, 3H), 3.77 3H), 4.50 (ABq, J=17 Hz, Av=36 Hz, 211), 4.57 (mn, 111), 6.78-6.92 (in, 4H), 6.98-7.26 (in, 811), 7.34 (d J=9 Hz, 1H), 7.62 J=8 Hz, 1H1), 7.98 (br s, 111)
C
3 2
H
36
N
4 0 3 73.26 6.92 10.68 73.31 6.95 10.43 06. Ii..
0 0 S 0 S 00 S 0 *5 0 5 S SS 0 0 @6 0 S* 0 S Example Analysis, No. R Mp, -C MS IH NMR Formula Theory/Found C H N 1-(4-Ph-piperidinyl) foam 552 CDCI 3 1.50-1.91 (in, 4H), 2.08 3H), 2.06-2.22 (mn, C 34 1-1 4 0
N
4 0 3 73.89 7.30 10.14 2H), 2.40 (mn, IH), 2.64 (hr d, J=1 I Hz, IH), 2.80 (hr d, 73.69 7.25 10.31 J= 12 Hiz, I 2.86.2.98 (in, 3H), 3.04-3.18 (mn, 2H), 3.73 3H), 4.01 (dd, J=10, 14 Hz, 1H), 4.46 (ABq, J= 17 Hz, Av=45 Hz, 2H), 4.54 (in, 1H), 6.7,6-6.85 (in, 3H1), 7.02.7.36 (in, 1011), 7.54 J=8 Hz, 111), 7.70 (d, J=8 Hz, 1H1), 8.01 (br a, 1H) 66 1-(4-Me 2 N-piperidinyl) foam 519 CDC1 3 1.26 (in, 1H), 1.48-1.76 (in, 3H), 1.90-2.11 (mn, 3H1), 2.09 3H), 2.25 6H), 2.51 (br d, J=13 Hz, III), 2.73 (br d, .1=12 Hz, 1H), 2.85 2H1), 2.85-3.23 (mn, 311), 3.75 3H1), 3.94 (dd, J=10, 14 Hz, 1H1), 4.47 (ABq, J=17 Hz, Av=43 Hz, 2H), 4.51 (mn, IH), 6.77-6.88 (in, 3H), 7.0 1-7.28 (mn, 4H), 7.35 J=8 Hz, 1H1), 7.41 (d, J=9 Hz, 1H), 7.66 J=7 Hz, 111), 8.09 (hr s, 111) 550 CDC1 3 2.12 3H), 2.21-2.70 (in, 4H), 2.90-3.25 (in, 7H), 3.77 311), 3.95 (dcl, J=10, 14 Hz, 1H), 4.52 (ABq, J=17 Hz, Av=38 Hz, 2H), 4.61 (in, 1H), 5.95 (hr s, 1H), 6.85 (in, 311), 7.00-7.54 (in, 11H1), 7.67 J=8 Hz, 1H), 8.08 (br 9, 1H1) C3QH4 1 Nf0 3
C
3 4
H
3 8
N
4 0 3 69.34 7.95 13.48 69.58 8.01 13.52 73.06 6.87 9.99 73.03 6.95 10.03 67 1-(4-Ph7 A 3 _pipetidinyl) foam 1-(4-AcNH-4-Phpiperidinyl) foam 609 1 H CDC1 3 1.87-2.50 (in, 7H), 2.00 3H1), 2.07 3H), 2.60 (mn, 1H), 2.87-3.19 (in, 511), 3.73 311), 4.06 (dd, J= 10, 14 Hz, 111), 4.46 (ABq, J= 17 Hz, Au =47 Hz, 2H), 4.52 (in, 111), 5.43 (hr s, 1H), 6.75-6.90 (mn, 3H), 7.04-7.48 (in, 110 7.56 J=8 Hz, 111), 7.69 J=8 Hz, 111), 8.10 (hr s, 1H).
C
3 sH 4 3,0 4 70.91 7.11 11.48 70.68 7.13 11.49
S
SO 0 0
S
.00 OSS 0 0 *5 0 0 00S 0 000 500 6 @5 S 0 S 6 5 S 55 56 00 6 0 0 0 0 S 0 S 0 00 0 000 0 0 Example Analysis, No. R Mp, OC MS 'H NMR Formula Theory/Found c H N 69 14(4-(4-CI-Ph)- foam 587 CDC13 2.11 C 3 3
H
3 8
N
5 0 3 C1 67.39 6.51 11.91 piperazinyl) 2.20-2.42 (in, 2H), 67.10 6.77 12.11 2.42-2.58 (in, 2H), 2.82-3.20 (in, 9H), 3.76 3H), 4.01 (in, 1H), 4.50 (ABq, J=16 Hz, Av=42 Hz, 2H), 4.54 (in, 111), 6.68- 6.90 (in, 5H), 7.04- 7.32 (mn, 6H1), 7.35 J=8 Hz, 111), 7.40 (in, 1H), 7.66 J=9 Hz, 111), 8.03 (bra9, 11H) 1-(4-(3-CF 3 -Ph)piperazinyl) foam 621 CDCI 3 2.10 3H), (MI) 2.28-2.42 (in, 2H), 2.42-2.56 (mn, 2H), 2.84-3.20 (mn, 9H), 3.77 311), 4.01 (mn, 1H), 4.49 (ABq, J=18 Hz, Av=42 Hz, 211), 4.56 (in 1H), 6.76- 6.90 (mn, 3H), 6.90- 7.27 (in, 7H1), 7.28- 7.46 (mn, 311), 7.66 J=7 Hz, 1H), 8.06 (br a, 1H1)
C
3 4
H
38
N
5 0 3
F
3 65.69 6.16 11.27 65.47 6.28 11.34 0S 0 ~if 0 0 0 00 0 0 0 0 0 0 0 @0 0 S @0 0 0 S 00 0 000 000 00 0 000 00 0 0 0 00 0 00 00 0 000 000 0 0 S 0 00 *0 0 0 S 0 00 000 0 0 Example Analysis, No. R Mp, *C MS IH NMR Formula Theory/Found C H N 71 1-(4-Me-piperazinyl) foam 492 CDC1 3 2.09 3H), C28H.,7NrQ03 (M+1+ 2.11-2.52 (in, 1 1H), 2.82-2.97 (in, SH), 2.99-3.15 (in, 2H), 3.75 (s, 3H), 4.01 (dd, 4.45 (ABq, J=16 Hz, Av=46 Hz, 2H), 4.51 (mn, 1H), 6.76-6.88 (in, 3H), 7.02-7.24 (mn, 4H), 7.34 J=8 Hz, 1H), 7.41 J=8 Hz, 1H), 7.68 (d, J=8 Hz, 1H), 8.01 (br s, 1H) Exact Mass Data 1) Calc'd: 492.2975 Meas: 492.2977 S S S S. S S 0 5* 0 0 St S 0 0*B @50 @0 5 00t 0 0 5 00 0
SO
50 0 S*0 500 5 0 S 0 05 OS 0 0 0 S S S 050 0 0 Example Analysis, No. R Mp, OC MS IH NMR Formula Theory/Found C H N 73 l-(4-i-Pr-piperazinyl) foam 519 CDC1 3 1.07 (br d, J=6 Hz, 6H), 2.08 3H), C 30
H
4 lNt;0 3 69.34 7.95 13.48 1-(4-cyclohexylpiperazinyl) (RS) 2.20-2.80 (in, 914), 2.83-3.16 (in, 3.77 (s, 3H), 4.00 (dd, J=10, 14 Hz, 4.47 (ABq, J=8 Hz, Av=42 Hz, 2H), 4.53 (in, lH), 6.73- 6.94 (in, 3H), 6.94-7.30 (mn, 4H), 7.30-7.42 (in, 2H), 7.65 J=10 Hz, 1H), 8.06 (hr s, IH) foam 559 CDCI 3 1.05-1.34 (mn, GH), 1.55-1.95 (in, 4H), 2.09 314), 2.20-2.60 (mn, 9H), 2.90 2H), 2.85-3.16 (in, 3H), 3.77 3H), 4.02 (dd, 3=1 1, 13 Hz, 1H1), 4.47 (ABq, J=16 Hz, Av=44 Hz, 2H), 4.54 (mn, 1H), 6.77-6.88 (in, 3H), 7.05-7.25 (in, 4H), 7.31-7.42 (in, 2H), 7.66 J=7 Hz, IH), 8.08 (hr s, 1H) 69.60 8.09 13.49
C
33
H
4 sNs0 3 70.81 8.10 12.51 71.10 8.28 12.53 1-(4-cyclohexylpiperazinyl) (R) foam 560 (M+14
CDCI
3 1.09-1.28 (mn, 5H), 1.64 J= 10 Hz, 1H4), 1.80-1.89 (in,4H), 2.10 3H), 2.24-2.52 (mn, 9H), 2.90 2Hi), 2.95 J=7 Hz, III), 3.02 J=7 Hz, IH), 3.12 (dd, J=5, 14 Hz, 111), 3.77 3H), 4.01 (dd, J=10, 14 Hz, 1H), 4.49 (ABq, J=17 Hz, Av=43 Hz, 214), 4.56 (in.
1H), 6.79-6.87 (in, 3H), 7.05-7.24 (in, 4H), 7.34-7.4 1 (in, 2H), 7.67 Rd J=8 Hz, 1H), 8.22 I1H)
C
33
H
4 6N 5 0 3 70.81 8.10 12.51 70.71 8.21 12.42 1-(4-cyclohexylpiperazinyl) (S) foam 559 IH CDCI3 1.05-1.3 1 (mn, 5H), 1.64 (in, 1H), 1.75-1.90 (mn, 4H), 2.10 3H), 2.24-2.52 (in, 9H), 2.87 2H), 2.95 J=7 Hz, 1H), 3.01 (d, 1=7 Hz, 114), 3.12 (dd, J=5, 14 H~z, IH), 3.77 (s, 3H), 3.99 (dd, 1=10, 14 Hz, 1H), 4.46 (ABq, J=17 Hz, Av=43 Hz, 2H), 4.56 (mn, 1H), 6.75- 6.90 (mn, 3H), 7.05-7.24 (in, 4H), 7.34-7.41 (mn, 2H), 7.67 Kd J=8 Hz, 114), 8.14 1H)
C
33
H
45
N
5 0 3 70.81 8.10 12.51 70.99 8.27 12.76 0 *0 t 0 0 0 4 @00 000 0 0 000 0 0 00 0 4 0 CO *0 0 *0p 0@ 0 S 0 00 S 00 OS 0 0 000 060 U 6 0 0 SO OS a 0 0 *600 040 0 S Example Analysis, No. R Mp, -C MS IH NMR Formula Theory/Found C H N 77 1-(4-PhCH 2 foam 568 CDCI 3 2.08 2.16-2.62 m, 8H), 2.82-2.97 C 3 4
H
4 lN 5 0 3 71.93 7.28 12.34 piperazinyl) (in, 3H), 2.99-3.18 (mn, 2H), 3.41-3.62 (in, 2H), 72.15 7.37 12.56 3.76 3H), 4.02 (dd. J=10. 13 Hz. 1H). 4.49 .piperazinyl) 79 1-(4-MeCO-piperazinyl) (ABq, J=18 Hz, Av=48 Hz, 2H), 4.53 (mn, 1H), 6.76-6.88 (mn, 3H), 7.06 J=3 Hz, IH), 7.06.
7.45 (mn, 1OH), 7.68 J=8 Hz, 1H), 8.06 (hr a, 1H-) foam 555 CDC1 3 2.11 3H), 2.28-2.55 (mn, 4H), 2.88- 3.12 (in, 5H), 3.56-3.86 (in, 3.77 3H), 4.02 (in, 1H), 4.47 (ABq, J=17 Hz, Av=41 Hz, 2H), 4.52 (in, IH), 6.50 (hr a, 111), 6.76-6.86 (mn, 3H), 7.04-7.28 (in, 4H), 7.36 J=7 Hz, 1H), 7.61 (br a, 1H), 7.67 J=7 Hz, 1H), 8. (hr a, IHI, 8.30 J=5 Hz, 214)
C
3 1
H
3 7
N
7 0 3
C
2 9
H
3 7
N
5 0 4 67.01 6.71 17.64 66.90 6.85 17.43 foam 519 520 1+ CDCl 3 1 2.04 3H), 2.09 3H), 2.16-2.48 (in, 4H), 2.86-3.11 (mn, 4H), 3.21-3.65 (in, 5H), 3.78 3H), 4.04 (in, 1H), 4.46 (ABq, J=17 Hz, Av=26 Hz, 2H), 4.50 (mn, 1H), 6.76-6.86 (in, 3H), 7.02-7.28 (mn, 4H), 7.36 J=7 Hz, IH), 7.60 (hr s, IH), 7.66 J=7 Hz, 111), 8.11 (br a,
IH)
67.03 7.18 13.48 66.81 7.20 13.30 4~.j :1 5 SS S S
F
S
eSS *g*
S
6' SOP 5 6 5* 5 4
S
*o 555 5 OSS See S S 5 0 0 5 5 64 55 5* 6 5 6 S. C S S 50 0 @09 5 0 Example Analysis, No. R Mp, OC MS 'H NMR Formula Theory/Found C H -N 1-(4-EtQ(CO)- foam 549 CDCJ 3 1.23 J=7 Hz, 3H), 2.08 311), 2.12- 'C 30
H
39 Nr 5 0 5 65.55 7.15 12.74piperazinyl) 2.40 (in,4H), 2.85-2.97 (in, 3H), 2.98-3.12 (in, 65.29 7.19 12.59 211), 3.22-3.49 (in, 4H), 3.75 3H), 4.03 (mn, 1H), 4.11 J=7 Hz, 2H), 4.44 (ABq, J=17 Hz, Hz, 2H), 4.48 (in, 111), 6.76-6.86 (mn, 311), 7.04-7.25 (mn, 4H), 7.34 J=8 Hz, 111), 7.46 (br 9, IH), 7.66 J=8 Hz, 1H), 8.04 (hr a, 1H1) 81 (2-pyridyl)CH 2
NH
82 (3-pyridyU)CH 2
NH
foam 499 CDCI 3 2.10 311), 2.91 (in, I11), 3.00-3. 16 (in, 214), 3.30 2H), 3.65-3.88 (mn, 2H), 3.77 (s, 311), 4.01 (dd, J=10, 16 Hz, IH), 4.46 (ABq, J=17 Hz, Aiv=53 Hz, 2H), 4.54 (in, IH), 6.74- 6.86 (mn, 211), 7.02.7.28 (in, 711), 7.34 J=8 Hz, 111), 7.56-7.72 (mn, 311), 8.06 (hr a, 111), 8.55 J=6 Hz, 1H)
C
29
H
33
N
5 0 3
C
29 11 33
N
5 0 3 69.72 6.66 14.02 69.75 6.84 13.88 69.72 6.66 14.02 69.51 6.79 13.90 foam 499 CDC1 3 2.08 311), 2.90 (dd, J=8, 15 Hz, 111), 2.97-3. 10 (in, 211), 3.24 211), 3.69 (Aft, J= 14 Hz, Aiv=25 Hz, 211), 3.74 3H), 4.04 (dd, J=13, 16 Hz, 111), 4.45 (ABq, J=18 Hz, Av=53 Hz, 211), 4.50 (in, 111), 6.74-6.87 (in, 311), 7.04 J=4 Hz, 111), 7.08-7.30 (in, 411), 7.35 J=8 Hz, 1H), 7.49 J=8 Hz, 111), 7.60-7.70 (in, 211), 8.12 (hr a, 111), 8.48-8.52 (nm, 211) 00 0 0 0 0 *0e 060 6 09 0 *0 0 S 000 00 0 t~3 9@ 0 0 0 00 0 @0 0 000 so.
*0 S 0 00 @0 0 6 9 60. 0 0 Exam pie Analysis, No. R Mp, MS 'H NMR Formula Theory/Found .cC H N 83. (4-pyridyl)CH 2 NH foam 499 CDC1 3 2.09 3H), 2.84-3.10 (in, 3H), 3.20 2H), C 2 9
H
3 3 NS0 3 69.72 6.66 14.02 3.65 (ABq, J=14 Hz, Av-=25 Hz, 2H), 3.72 3H), 4.08 69.99 6.77 13.79 (dd, J= 12, 15 Hz, 1H), 4.40 (ABq, J= 16 Hz, Av=51 Hz, 2H), 4.48 (mn, 1H), 6.73.6.84 (in, 3H), 7.00 J=3 Hz, 1H), 7.08-7.25 (in, 5H), 7.32 J=8 Hz, 1H), 7.45 (d, J=8 Hz, 1H), 7.67 J=8 Hz, IH), 8.01 (bras, 1H), 8.51 J=7 Hz, 2H) 84 PhNHCOCH 2 NH foam 541 1 H DMS0 (3:2 mixture of amide rotamers) 1.95 (a, 3/503H), 2.20 2/5-3H), 2.75-2.93 (mn, 2H), 3.07-3. 17 (in, 2H), 3.17-3.30 (in, 3H), 3.39 (in, 1H), 3.53 (in, IH), 3.67 2/5* 3H), 3.72 315 4.25-4.6 1 (mn, 3H), 6.77-6.87 (in, 2H), 6.87-7.09 (in, 4H), 7.12 (mn, 1H), 7. 14-7.36 (mn, 4H), 7.55 J=8 Hz, 1H), 7.63 J=8 Hz, 2H), 7.91 J=9 Hz, M/5 1H), 8.05 (di, J=9 Hz, 0 1H), 9.92 (br a, 0.4H), 9.94 (bra9, 0.6 10.78 (br a, O.6H), 10.80 (bra9, 0.4H).
C
3 1
H
3 5 N60 4 68.74 6.51 12.93 68.51 6.56 12.78 0 0 0 go 0: 00 600 00 0 0* 0 0 0 0 0 00 0 0. 0.0 0.
Example Analysis, No. R Mp, 0 C MS IH NMR Formula Theory/Found C H N 86 1.(4.i-Pr-piperazinyl) foam 523 IH CDCI3 0.9-1.1 (in, 6H), C 29
H
38 ClN60 2 6.6 73 33 2.05 3H), 2.1-2.5 (in, 66.72 7.33 13.30 11IH), 2.8-3.1 (in, 3H), 3.2 (in, 11H), 4.0 (in, 1H1), 4.5-4.7 (in, 2H), 6.9-7.4 (in, 9H), 7.63 (d, J1=6 Hz, lH), 8.23 (br s, 1H).
1-(4-cyclohexylpiperazinyl) (R) foam 563 1 H CDCI 3 1.0-1.4 (mn, 6H), 1.6 (mn, 1H), 1.7-1.9 (mn, 4H), 2.08 3H), 2.1-2.6 (in, 9H), 2.8-3.1 (mn, 4H), 4.0 (mn, IH), 4.5-4.7 (in, 3H), 7.0-7.4 (in, 9H), 7.63 J1=6 Hz, 1H), 8.18 (hr 9, 1 H).
C-
32
H
42 C1Nr,0 2 68.13 7.50 12.41 67.93 7.53 12.43
S
0 0 4 SO S S S S S S S* S S S S SO S g* 00 005 0S 0 0 0 Example Analysis, No. R Mp, C MS 1H1 NMR Formula Theory/Found C H N 88 Ph foam 455 CDC1 3 2.10 2.8 1-2.94 C 28
H
29
N
3 0 3 73.82 6.42 9.22 (in, 2H), 3.32 (dd, J=5, 15 73.86 6.44 9.36 Hz, IH), 3.66 3H), 4.21 (dd, J= 13, 15 Hz, 1H), 4.36 (ABq, J=15 Hz, Av=43 Hz, 2H), 4.46 (in, IH), 6.61-6.80 (mn, 3H), 7.00 J=5 Hz, 1H), 7. 10-7.50 (in, 7H), 7.70 J=8 Hz, IH), 7.80 J=6 Hz, 1H), 7.87 (d J=6 Hz, 2H), 7.96 (hr s, 1H) Ph(CH 2 2
(RS)
foam 483 CDCI 3 2.05 3H), 2.45 i(t, J=9 Hz, 2H), 2.72-3.12 (in, 5H1), 3.71 3H1), 4.01 (dd, J=12, 14 Hz, 1H), 4.33 (ABq, J=16 Hz, Av=60 Hz, 2H), 4.38 (mn, 1H), 6.58 J=9 Hz, 1H), 6.66-6.8 1 (mn, 3H), 6.88 J=3 Hz, 1H), 7.09.
7.38 (in, 9H), 7.68 J=7 Hz, 1H), 7.98 (hr s, 1H)
C
30
H
33
N
3 0 3 74.51 6.88 8.69 74.81 7.06 8.39
S
S
S
0
S
ebb SOS
C
S
S
0O C S 0 5 CS S S *5 0 S C *5 S 0 a 0 .S S Exam pie Analysis, No. R Mp, CC MS 1H1 NMR Formula Theory/Found C H N Ph(CH 2 2 foam 283 'H CDC1 3 2.05 3H), 2.46 C 30 H3 3
N
3 0 3 74.51 6.88 8.69 J=8 Hz, 2H), 2.70-2.90 (in, 74.30 6.66 8.46 2H1), 2.96 J=8 Hz, 2H), 3.10 (in, 111), 3.71 3H), 4.03 (in, IH), 4.24 J= 17 Hz, 1H), 4.33-4.50 (mn, 2H), 6.60-6.86 (in, 411), 6.89 (a, 1H1), 7.05-7.40 (in, 9H), 7.69 J=8 Hz, 111), 8.03 111) Ph(CH 2 2
(S)
PhCH2O (R) foam 483 IH CDC13 2.04 311), 2.45 J=8 Hz, 211), 2.73-2.89 (in, 2H), 2.96 J=8 Hz, 211), 3.06 (dd, J=4, 10Hz, IH), 3.71 3H), 4.03 (in, 111), 4.20-4.50 (in, 3H), 6.58-6.88 (in, 4H), 6.89 1H), 7.07- 7.40 (mn, 9H), 7.69 J=8 Hz, 1H), 8.03 1H) foam 485 111 CDC13 2.09 311), 2.83 (dd, J=7, 15 Hz, 111), 2.95 (dd, J=3, 14 Hz, IH), 3. 10 (dd, J=3, 14 Hz, 111), 3.70 (s, 3H), 3.96 (in, 111), 4.22 (mn, 111), 4.26 (in, 1H), 4.72 (s, 111), 5.12 2H), 5.68 (mn, 1H), 6.68-6.83 (in, 2H), 6.97 (in, 111), 7.07-7.46 (in, 1011), 7.66 J=8 Hz, 111), 8.02 (s,
III)
C3GH33N303 74.51 6.88 8.69 74,60 6.96 8.70
C
29
H
3 1
N
3 0 4 71.73 6.43 8.65 71.61 6.21 8.67 0 ~4 0 0 0 OS 0 0 S 0 0 0 0 0 0 0 0 0 @0 0 000 000 4. 0 .00 0 0 0 0 00 0 00 0 000 @00 S 0 0 0 00 00 0 0 00 00 000 0 S Example Analysis, No. R Mp, 0 C MS 1 H NMR Formula Theory/Found C H N 93 PhCH 2 O oil 485 'H CDC1 3 1.70-2.10 (in, 311), C 29
H
31
N
3 0 4 71.73 6.43 8.65 2.75-3.00 (in, 211), 3. 10 (in, 71.90 6.60 8.51 3.70 311), 3.95 (in, 111), 4.10 (in, 111), 4.45 (in, IH), 4.61 1H), 5.13 (s, 211), 5.73 (in, 1H), 6.66-6.85 (in, 211), 6.95 (mn, 111), 7.03.
7.50 (mn, 1011), 7.66 J=8 Hz, 111), 8.02 (br s,111).
Ph(CH 2 )a foam 497 CDC1 3 1.88-2.00 (in, 2H1), 2.09 311), 2. 13-2.23 (in, 2H), 2.61 J=8 Hz, 2H), 2.78-2.92 (in, 2H1), 3.12 (dd, J=4, 9 Hz, 111), 3.69 311), 4. 10 (dd, J=7, 9 Hz, 111), 4.40 (ABq, J=17 Hz, Av=56 Hz, 4.40 (in, 111), 6.61 (br s, 111), 6.67-6.81 (mn, 311), 6.99 1H), 7.04-7.36 (in, 9H), 7.70 J=8 Hz, 111), 7.98 (br 9,111) foam 511 CDC1 3 2.17 3H), 2.57 (t, J=7 Hz, 211), 2.79-2.89 (in, 211), 3. 11 (dd, J=6, 14 Hz, 111), 3.21-3.45 (mn, 211), 3.68 311), 4.09 (dd, J.=12, 14 Hz, 111), 4.38 (ABq, J=16 Hz, Hz, 211), 4.40 (in, 111), 6.71-6.79 (in, 411), 7.01 (d, J=3 Hz, 111), 7.09-7.22 (in, 311), 7.34 J=7 Hz, 111), 7.46 J=8 Hz, 211), 7.56 (in, 111), 7.70 J=8 Hz, 111), 8.00 J=8 Hz, 3H) C31iH35N30 74.82 7.09 8.44 74.58 7.13 8.32 PhCO(CH 2 2
(RS)
C
31
H
33
N
3 0 4 72.78 6.50 8.21 72.71 6.38 7.95
~Z
S. 5 9 0 5 S S S S 5 @5 S e 5 5 5 0.S OSS S. S
S.*
S S 9 9 0* S 5 6 0.5 S
SOS
S 0 S S 09 @9 S S S S S 0 *59 0 0 Example Analysis, No. R Mp, T0 MS IH NMR Formula Th 'eory/Found C H N 96 PhCO(CH 2 2 Oil 511 'H CDC1 3 2.19 3H), 2.58 J=4 Hz, IH), C 3 1
H
33
N
3 0 4 72.78 6.50 8.21 2.180.2.93 (in, 2H), 3.05 (in, 1H), 3.20-3.46 (in, 72.84 6.61 8.22 3H), 3.70 3H), 4.05 (in, 4.26 (in, 1H), 4.33-4.60 (in, 2H), 6.66-6.86 (in, 4H), 7.00 (s, IH), 7.06-7.23 (mn, 3H), 7.30 J=8 Hz, 1H1), 7.43-7.53 (in, 2H), 7.58 J=8 Hz, 1H1), 7.70 (d, J=8 Hz, 1H), 7.97 J=8 Hz, 2H1), 8.12 1H).
(S)
98 PhCO(CH 2 3 oil 511 IH DMSO (4:3 mixture of amide rotainers) 1.70 2.00 3/7 3H), 2.40 (in, IH), 2.60.2.80 (mn, 2H), 3.10-3.25 (in, 3H), 3.50 (in, 111), 3.65 3/7 3.72 4/7 4.25-4.60 (in, 3H), 6.75- 7.35 (in, 8H), 7.45-7.70 (mn, 4H), 7.74 J=8 Hz, IH), 7.80-8.00 (in, 211), 10.77 (in, IH).
foam 525 CDC1 3 2.00-2.11 (mn, 2H1), 2.11 311), 2.25 (t, J=7 Hz, 2H), 2.76-2.91 (mi, 2H), 2.98-3. 16 (in, 3H1), 3.71 3H), 4.04 (dd, 31=11, 13 Hz, 1H), 4.38 (ABq, J=17 Hz, Av=54 Hz, 2H), 4.39 (in, 1H), 6.60-6.8 1 (in, 4H1), 6.98 111), 7.08-7.24 (mn, 311), 7.34 1=9 Hz, 111), 7.45 J=9 Hz, 2H), 7.55 (in, 111), 7.70 J=9 Hz, IH), 7.96 (d, J=8 Hz, 2H), 8.01 (bras, 1H1)
C
3
,H
33
N
3 0 4
C
32
H
3 sN 3 0 4 72.78 6.50 8.21 72.86 6.50 8.17 73.12 6.71 7.99 72.86 6.66 7.73 2 W- S.
0 5 0@ S 0 0 0 5 0 S S 5 5* S S S 00 *SS 0.5 S. *5* 0 *S 0 *0 0* SW
S
5 0*5 555 S 0 S 50 @5 S 0 S Oe** 530 0 Example Mp Analysis, No. R IV CC MS 'H NMR Formula Theory/Found C H N 99 H MeCO foam 377 CDCI 3 1.42 J=8 Hz, 3H), C 23
H
27
N
3 0 2 73.18 7.21 11.13 (RS) 1.92 3H), 2.23 3H), 73.35 7.46 10.90 2.53 (dd, J=8, 14 Hz, IH), 2.85-3.05 (in, 2H), 3.28 (in, 1H), 3.81 (dd, J=10, 14 Hz, 1H), 4.94 J=8 Hz, 114), 6.82 (mn, 1H), 6.82-7.27 (mn, 7H), 7.27-7.45 (in, 2H), 7.54 J=8 Hz, 1H), 8.01 (br s,
IH)
H
(RR)
MeCO foam 377 CDCI 3 1.38 J=8 Hz, 3H), 1.93 3H), 2.17 3H), 2.68 (dd, J=8, 14 Hz, I1H), 2.74 (dd, 3=4, 14 Hz, 1H), 3.20 (dd, J=4, 14 Hz, I1H), 3.91 (dd, J= 10, 14 Hz, I H), 4.37 (mn, 1H), 4.92 (mn, 1H), 6.78-7.27 (mn Hz, 9H), 7.37 Kd J=8 Hz, 1H), 7.75 J=8 Hz, 1H), 7.98 (br s, IH)
C
2 3
H
27
N
3 0 2 73.18 7.21 11,13 73.39 7.33 10.96
OS
C
C
C
S.
C C C C* C C C S C 0 C C C C CO C S C CI.
CCC CS C
*CE
4 C S *5 0 C S C. C e.g C.C C I C C CC C* C C 0 C 0* C 0 Example Mp Analysis, No. R R' C MS 'H NMR Formula Theory/Found C H N 101 H foam 501 CDC1 3 1.32 J=7 Hz, C 3 lH43NrO 74.21 8.64 13.96 piperidinyl)- (M 1 1.15-1.91 (in, 11H), 1.91- 74.50 8.49 11~94 pi peridi nyl)
(RS)
2.23 (in, 3H), 2.30-2.60 (in, 6H), 2.65 (dd, J=6, 14 Hz, 1H1), 2. 72-2.94 (in, 4H), 3.01 (dd, J=6, 14 Hz, 1H), 3.72 J=7 Hz, 1H), 4.35 (in, 1H), 6.95 J=2 Hz, 1H), 7.03-7.42 (in, 9H), 7.64 (d, J=8 Hz, 1H), 8.08 (hr s, 1H) 102 piperidinyl)piperidinyl)
(RR)
H foam 501 DMSOd 6 1.23 J=6 Hz, 3H), 1. 12-1.70 (mn, 11IH), 1.89-2.01 (mn, 2H), 2.01-2.17 (in, 2H), 2.23-2.4,3 (mn, 2.52 (mn, IH), 2.72 (in, 1H), 2.75 (ABq, J=15 Hz, Hz, 2H), 2.83 (dd, J=8, 14 Hz, 1H), 2.95 (dd, J=6, 14 Hz, IH), 3.66 J=6 Hz, 1H), 4.06 (in, IH), 6.95 (t, J=8 Hz, 1H), 6.99-7.10 (mn, 2H), 7.10-7.41 (mn, 6H), 7.49 J=9 Hz, 1H), 7.56 J=8 Hz, IH), 10.78 (hr s, 1H)
C
3 1
H
4 3 NS 74.21 8.64 13.96 73.93 8.65 13.89 103 piperidinyl)piperidlinyl)
(RS)
MeCO foam 543 CDC1 3 1.29-1.88 (mn, 12H), 1.88-2.08 (mn, 2H), 2.15 (s, 3H), 2.21 (in, 1H), 2.36-2.62 (in, 6H), 2.62-2.88 (mn, 4H), 2.96 (dd, J=6, 14 Hz, 1H), 3.28 (dd, J=6, 14 Hz, I H), 3.65 (dd, J=10, 14 Hz, 1H), 3.82 1H), 4.98 (mn, 1H), 6.85-7.45 (in, 9H), 7.48-7.59 (mn, 2H), 8.10 (br s, 1H)
C
33
H
45 NS0 2 72.89 8.34 12.88 73.13 8.27 12.91 0* 9 .24 0 9 S* 0 9
S
0 0 090 0 0 0 0 00 0 0 000 So
S
S 0 0 S 00 9 0* *5 9 000 0 S 0 0 00 *0 0 0 0000 0*S 0 0 Example Mp Analysis, No. R R C MS 'H NMR Formula Theory/Found C H N 104 1-(4-01. MeCO foam 643 DMSO-d 6 2:1 mixture of C3 3 H45NGO 2 72.89 8.34 12.88 piperidinyl)- amide rotamers 1.19-1.84 72.65 8.14 12.71 piperidinyl) 1211), 1.84-2.16 3H-), (RR) 2.06 3H), 2.32-2.52 (in, SH), 2.57-3.00 6H), 3.20 11H), 3.79 (dd, J= 11, 14 Hz, IH), 4.28 (mi, IH), 5.04 (mn, 2/3 *111), 5.49 (in, 1/3 *111), 6.89-7. 15 511), 7.15-7.28 (in, 311), 7.32 (d, J=8 Hz, 111), 7.47 (in, III), 8.41 111), 10.77 (br a, 111) O N
NH
C H N 105 H 2-OMe foam 351 CDCI. 1.97 (a 3H) 2 38(m 11-f '.JM l.
2.73 (d d, J=6, 12 Hz, I 2.82 (dd, J=6, 12 Hz, 111), 2.97 (dd, J=8, 14 Hz, 111), 3.10 (dd, J=6, 14 Hz, 111), 3.75-3.94 Cm, 2H1), 3.82 311), 4.42 (mn, 111), 6.34 (br d, J=8 Hz, 111), 6.77-6.95 (in, 2H), 7.01 J=2 Hz, 111), 7.07- 7.33 (in, 411), 7.37 J=8 Hz, 111), 7.68 Cd, J=8 Hz, 111), 8.13 (bra, 111) 1.
.71.
I I.If. I 1j.Va t8 6.90 12.09 S S S 0 0 .04 @00 4 S B 0 S 0 04 S 4 000 @0 0 *00 000 000 0 0500 9 S S S OS 05 0* 0 5 0 0 0 .0 0 0 0 0* 0 000 0 0 Example .Mp Analysis, No. R R' OC MS IH NMR Formula Theory/Found C H N 106 MeCO 2-OMe 147- 393 CDC1 3 /DMSOd 6 1.95 3H), C 2 3H 2 7 N303 70.21 6.92 10.68 148 2.13 3H), 2.81 (dd, J=8, 16 69.93 7.06 10.58 Hz, 111), 2.89 (dd, J=4, 14 Hz, IH), 3.72 3H), 3.99 Hz, IH), 4.35 IH), 4.37 (ABq, J=16 Hz, Av=58 Hz, 2H), 7.65-7.82 6.99 1H), 1-7.22 3H), 7.37 J=7 Hz, 1H), 7.66 J=8 Hz, IIH), 9.19 (hr 9, 1lH) 1-(4-Phpiperazinyl)
CH
2
CO
2-OMe foam 553 CDC1 3 1.93 3H), 2.72-2.98 (m, 6H), 3.08 (dd, J=6, 15 Hz, 1H), 3.18-3.52 (in, 6H), 3.73 3H), 4.02 J=13 Hz, 1H), 4.33 (d, J=16 Hz, 1H), 4.42 Cm, 1H), 4.64 Kd J= 16 Hz, I1H), 6.45 J=8 Hz, 1H), 6.66-6.95 6H), 7.00 J=3 Hz, 1H), 7.04-7.30 (m, 7.36 J=9 Hz, 1H), 7.67 J=8 Hz, IH), 8.07 (br s, IH) Ca 3
H
3 gNr)0 3 71.58 7.10 12.65 71.33 7.09 12.51 C 9 9 0* C 0 9 0 0 0* C 6 CO C S dbC ebb SOC 00 0 Oeb S 005 g.e 0 00 C S C C S S CO *5 0~ S 0 0 0 00 S 0000 es e.g 0 0 Example Mp Analysis, No. R R' *C MS 1H NMR Formula Theory/Found C H N 108 H foam piperidinyl)piperidinyl)
CH
2
CO
530 CDC]., 2:1 mixture of amide (M4- rotamers 1.24-1.89 (in, 10H), 1) 1.90 2/3 1.96 (a, 1/3e*3H), 1.92-2. 10 (in, 2H), 2.23 (in, 1H), 2.34 (in, 1H), 2.42-2.53 (mn, 2H), 2.62-2.94 (mn, 5H), 3.01- 3.23 (in, 3H), 3.57 (dci, J=12, 14 Hz, 113 *111), 4.06 (dd, J=12, Hz, 2/3' *1I1), 4.43 (br a, 2./30 1 H), 4.57 (Aflq, J=16 Hz, Av=169 Hz, 2/3'211), 4.58 (ABq, J=16 Hz, Av=273 Hz, 1/3*2H), 4.63 (hr a, 1/3*111), 6.38 J=8 Hz, 2/3' 111), 6.73 (di, J=8 Hz, 1/3* 111), 6.84-6.98 (mn, 2H), 7.05.
7.30 (mn, 6H), 7.34 (di, J=7 Hz, 1H), 7.53 J=8 Hz, 1/3*1H), 7.66 (di, J=8 Hz, 2/3 *111), 7.99 (bra9, 2/3 8.13 (br a, 1/3' 1H)
C
32
H-
43 N60 2 72.56 8.18 13.22 72.29 8.04 13.21 109 piperidinyl)piperidinyl)
CH
2
CO
2-Cl foam 563 CDC13 3:1 mixture of amnide rotamera 1.38-1.86 (in, 1111), 1.93 3/4*31), 1.98 (a, 1/4*3H), 1.86-2.12 (in, 2H), 2.18-2.73 (in, 5H1), 2.77-2.98 (in, 311), 2.99-3.19 (in, 3H), 3.57 (dci, J=12, 14 Hz, 1/4* 1H), 4.10 (dci, J= 12, 14 Hz, 3/4' *1JI, 4.41 (in, 3 /4 *1IH), 4.65 (in, 1/4 IH), 4.66 (ABq, J=18 Hz, tiv=107 Hz, 3/4'21), 4.72 (ABq, J=15 Hz, Av=157 Hz, 1/4-2H), 6.40 (hr ci, J=7 Hz, 111), 6.90 (ci, J=7 Hz, 111), 7.02 (hr a, 111), 7.06-7.40 (in, 6H1), 7.55 J=8 Hz, 1/4-1 7.64 (di, J=8 Hz, 3/4. 111), 8.04 (hr s, 1H)
C
32 11 4 2 C1N 5 0 2 68.13 7.50 12.41 66.92 7.48 12.32
S
S
a a.
a *0 S 0
S
0 @50 090 9*
SW
000 0 000 500 0 00 00 S 5 0 0 50 0S 0 0 0 0 *0 0 000t 00 0 0*0 0 0 Example Mp Analysis, No. cc MS 'H NMR Formula Theory/Found C H N 110 foam 537 IH DMSO (3:2 mixture of amide C 3 3
H
3 9
N
5 0 2 73.71 7.31 13.02 rotomers) 1.79 3/5*3H), 1.81 73.64 7.33 13.08 2/5-3H), 2.25-2.46 (in, 4H), 2.59-3.21 (in, IOH), 3.23-3.67 (mn, 4H), 4.46 (in, 1H), 6.76 J=8 Hz, 1H), 6.91 (d, J=8 Hz, 2H), 6.94-7.40 (in, IIH), 7.60 (in, IH), 7.81-8.05 (in, IH), 10.81 (hr s, 2/5, IH), 10.84 (hr s, 315 IH).
*m a 0 go. 090
I
9 S I I 0 ae 0 0 A I I SS 0 a* *V0 00 :09 :0 0 0 0 06009 900 :00 0 S Example Mp Analysis, No. R R' 0 c MS 1 H! NMR Formula Theory/Found C H N 111 5-Br H oil, 590, ODCd 3 2.33-2.45 (in, 2H), 2.45-2.53 C 3 jH 36
N
5
O
2 Br 63.05 6.14 11.86 692 2H). 2.80-3.10 (mn 111). 3.75(s. 63.21 6.21 11.59 (M+1) for Br isotopes) 3.88 3H), 3.94 J=4 Hz, 211), 6.80.6.96 (in, 6H), 7.10 1H1), 7.20.7.36 (mn, 5H), 7.40 (in, 1H), 7.75 1H1), 8.20 I1H) 112 5-OCH 2 Ph H oil 617 DMSO-d6 2.30-2.65 (in, 8H), 2.80- 3.15 (mn, 811), 3.31 IH), 3.64 (a, 2H), 3.72 311), 4.15 (in, 1H1), 6.65- 6.95 (in, 611), 7.05 111), 7.10-7.25 (in, 5H), 7.25-7.40 (mn, 4H), 7.43 (d, J=9 Hz, 211), 7.50 J=9 Hz, 111), 10.70 111) 113 I-Me MeCO oil 567 CDC1 3 2.11 3H), 2.36-2.60 (m, 311), 2.85-3. 20 (in, 1011), 3.71 311), 3.77 311), 3.97 (br s, 1H), 4.36- 4.60 (in, 311), 6.78-7.00 (mn, 7H), 7.10 1H), 7.20-7.35 (in, 611), 7.66 (d, J=8 Hz, 1H)
C
38 H3N 5
O
3 C34H1N.
5 0 3 73.88 7.02 11.34 74.09 7.03 11.31 .71.93 71.69 7.28 12.34 7.36 12.28
I
00 0 21 400
B
*0 C C
C
0
C
.00 @00 9 C a SAC C C 0* S A 040 SI S 0.0 C 000 SO S C 04 a S A CA @0 0s 0 5 I 4 06 6 gee.
00 9 500 S Example MP Analysis, No. R R' 0 C MS 'H NMR Formula Theory/Found C H N 114 6Me MeCO oil FD-MS 'H CDCI 3 2.10(s, 3H), 2.10(in, IH), 2.40.2.70 (in,7H), 2.90-3. 10 C 3 4 11 4 1
N
5 0 3 71.93 7.28 12.34 567 (in, 7H),.3.16 (dd, J=4, 13 Hz, 111), 3.78 3H), 3.97 (mn, 111), 71.72 6.99 12.10 4.40-4.70 (mn, 311), 6.80-7.10 (mn, 8H), 7.16 1H), 7.20-7.40 (mn, 3H), 7.45 7.54 J=8 Hz, 1H), 7.94 (mn, 111).
7-Me MeCO roam 567 MeCO 124- 631, 633 126 for Br isotopes) IH CDCI3 2.08 3H), 2.35-2.53 (in, 711), 2.88-3. 15 (mn, 10H), 3.76 3H), 4.48 (ABq, J=17.1 Hz, Av=41.2 Hz, 2H), 4.55 (mn, lIf), 6.78-6.90 (mn, 6K), 6.96-7.08 (in, SH), 7.22 (in, 3H), 7.40 (in, I1H), 7.50 J=8.0 Hz, 1KH), 7.95 1H).
CDC13 2.12 311), 2.40-2.66 (in, 4H), 2.83-3.20 (mn, 911), 3.80 (s, 3H1), 3.96 (in, 111), 4.43-4.60 (mn, 3H), 6.83-6.96 (in, 611), 7.10 (s, 1H), 7.20-7.33 (in, 5H1), 7.46 (hr s, 1H1), 7.75 111), 8.44 111) DMSO-dG 1:1 mixture of amide rotamers 1.86 1/203H), 1.94 1/2 2.23-2.43 (in, 4H), 2.73-2.93 (in, 411), 2.93-3. 10 (in, 4H1), 3.16 (mn, 111), 3.56 (in, 111), 3.66 112 3.69 (s, 1/2*31), 3.71 1/2*3H), 3.72 1/2*3H), 4.23-4.60 (mn, 311), 6.66-7.00 (in, 7H1), 7.08 211), 7.15-7.26 (in, 411), 7.59 J=8 Hz, 1/2* 1H), 7.77 J 8 Hz, 1/2* 1H), 10.65 1H1)
C
34 4 1 Nr0 3
C
3 3
H
38 Nt;O 3 Br 71.93 7.28 12.34 71.82 7.31 12.32 62.66 6.05 11.07 62.92 6.04 11.25 117 5-OMe MeCO oil 583 Exact Mass
FAB
(M+1) theory: 584.3237 found: 584.3214
C
3 4
H
41
N
5 0 4 118 5-OCH 2 Ph MeCO oil 660 DMSO-d6 3:2 mixture of amide rotamers 1.94 3/5 2.04 2/531), 2.23-2.56 (mn, 5H), 2.66-2.93 (in, 411), 2.93-3. 13 (in, 3H1), 3.30-3.50 (mn, 311), 3.58 (in, 1H1), 3.68 2/5*3H), 3.70 (s, 315*3H), 4.24-4.60 (in, 311), 6.70-7.00 (in, 711), 7.06 111), 7.13- 7.50 (mn, 10H1), 7.55 J=8 Hz, 3/5* 111), 7.66 J=8 Hz, 111), 10.70 111)
C
40 11 45
N
5 0 4 72.81 6.87 10.61 72.58 6.85 10.37
C
C.
C
C
C
C C C is C 6 C ~6 4 C CC U C gee e.g *e e etc C tee C S CC 0 C C S C *C te 0 0 4 0104 C 0~1 0 Example Mp Analysis, No. Oc MIS 'H NMR Formula Theory/Found C H N 119 foam 548 'H CDC13 1.30-1.72 10H), C 32
H
4 2 FNr 5 0 2 70.17 7.73 12.79 1.96-2.24 (in, 611), 2.41-2.56 (in, 69.94 7.80 12.74 2.70-2.77 (mn, 111), 2.85 (s, 2H), 2.87-3.00 (in, 2H1), 3.16 (dd, J=4.7, 13.8 Hz, IH), 4.00 (d d, J= 10. 1, 13.8 Hz, IH), 4.48-4.57 (in, 1H1), 4.55 (ABq, J=17.0 Hz, Av=47.7 Hz, 2H1), 6.93 (mn, 111), 7.08.7.16 (in, 311), 7.21-7.41 (mn, 6H), 8.27 IH).
b
'C
0
C
C
C C C C C
C
I CO S U
CO
gee so. Ce U 4** e C S 06 C £0 q~ 5 CCI
C
S
a CS..
OMe Example MIP Analysis, No. R R' 0 C MS IH NMR Formula,- Theory/Found C H N 120 5-Br H oil 596, DMSO-d6 1.20-1.56 (in, 12H), C 31
H
42 BrN 5
O
2 62.41 7.10 11.74 598 1.75-2.00 (in. 2H), 2.20.2.40 62.63 6.96 12.01 1) for Br isotopes) 7H), 2.60-2.80 (mn, 3H), 2.85 (d, J=6 Hz, 2H), 3.63 (br 9, 2H), 3.74 3H), 4. 10 (mn, I1H), 6.83-6.93 (in, 2H), 7.10-7.23 (mn, 3H), 7.23-7.30 (in, 2H), 7.45 J=8 Hz, 1H), 7.55 IH), 11.10 IH) Ai&b I
WE..
0 So *00 0 0 0 0 @05 SO S S S 0 OS O~ 08 S 0 0 0 0O*@ 0 jOB S Example MP Analysis, No. R R, 0 C MS 'H NMR Formula Theory/Found C H N 121 5-OMe H oil 547 DMSO-d6 1.20-1.70 I1H1), C 32 1 45 Nr 5 0 3 70.17 8.28 12.79 1.66-2.20 (in, 4H1), 2.20-2.43 (mn, 70.29 8.09 12.56 4H), 2.43-2.65 (in, 3H1), 2.65-2.90 (in, 4H), 3.61 2H), 3.77 3H), 3.80 311), 4.13 (in, 1H), 6.70 (mn, 1H), 6.80-7.00 (in, 2H), 7.02 (s, 1H), 7.08 IH), 7.10-7.40 (in, 3H), 7.45 J=8 Hz, 1H), 10.65 (s, 1H) 122 5-QCH 2 Pb H oil 624 DMSO-d6 1.20-1.33 (mn, I11H), 1.80-2.10 (in, 411), 2.25-2.40 (mn, 511), 2.50-2.60 (in, 311), 2.65-2.90 (in, 511), 3.63 211), 3.74 3H), 4.08 (in, IH), 6.77 J=2 Hz, 111), 6.80.7.00 (in, 2H), 7.03 111), 7. 13-7.25 (in, 3H), 7.25-7.50 (mn, 711), 10.70 1H) 12 3 6-F H roam 536 1H1 CDC13 1.22-1.78 (mn, 12H1), 1.95-2.15 (in, 311), 2.43-2.57 (mn, 411), 2.69-3.08 (in, 711), 3.74-3.88 (in, 511), 4.39 (mn, 1H1), 6.85-7.13 (in, 511), 7.21-7.27 (mn, 211), 7.33 (d, J=4.9 Hz, 111), 7.58 (in, 111), 8.25 111).
124 1-Me MeCO oil 573 DMSO-d 6 3:2 mixture of amide rotainers 1.30-1.60 (mn, 1111), 1.80- 1.95 (in, 211), 1.93 3/5*311), 2.03 2/5 *311), 2.05 (mn, 111), 2.40 (br s, 311), 2.50-2.86 (in, 611), 3.14 (in, 111), 3.67 (mn, 111), 3.68 3.71 21596H1), 4.23-4.56 (mn, 311), 6.79 (mn, 111), 6.86-7.28 (in, 511), 7.34 J=8Hz, 111), 7.53 (in, 3/5*2H), 7.63 (in, 21502H1), 8.30 (s, 111)
C
38 3H 49 N60 3
C
3 1 1 42
FN
5 0 2 73.16 7.92 11.23 73.45 7.92 11.14 71.17 8.26 12.21 70.89 8.26 11.91
C
34
H
47 NS0 3 71.17 8.25 12.21 71.30 7.97 12.09 C C
S
C
S
@00 e.g 0 C C C C S 50 0 C 0 C S 0. 6 *5.
C.
S
CS 0 0 0 0@ S 6 0 0S C S 0. S C Example Mp Analysis, No. R R' C MS 'H1 NMR Formula Theory/Found C H N 125 4-Me MeCO foam 573 IH CDC1 3 1.46 (in, 3H), 1.51-1.81 C 34
H
47
N
5 0 3 71.17 8.26 12.21 (in, 7H), 2.01-2.26 (in, 6H), 2.43- 70.84 8.26 11.91 2.68 (mn, 5H), 2.70.2.84 (in, 4H), 2.87 2H), 3.07-3.24 (mn, 311), 3.78 3H1), 3.98 (dd, J=9.8, 13.6 Hz, 1H), 4.45-4.61 (in, 3H1), 6.84 (mn, 3H), 6.88-6.94 (in, 1H),7.03- 7.10 (mn, 2H1), 7.15-7.39 (mn, 3 H), 8.07 111).
MeCO foam 573 111 CDC13 1.25-1.72 (in, 1111), 1.99-2.17 (in, 611), +2.46 (mn, 7H), 2.75 (dd, J= 1.4, 9.7 Hz, 1H1), 2.86 2H), 2.91 J=7.0 Hz, 1H1), 2.99 J=6.3 Hz, 111), 3.14 (dd, 3=4.7, 13.8 Hz, 1H), 3.77 3H1), 3.96 (dd, J= 10.1, 13.8 Hz, 111), 4.49 (ABq, J=17.0 Hz, Lw =40.3 Hz, 211), 4.54 (in, 1H1), 6.82-6.89 (in, 3 7.02 (mn, 2H1), 7.23 H=8.1 Hz, 2H1), 7.42 (in, 211), 7.95 111)
C
34
H
47 N6O3 71.17 8.26 12.21 71.45 8.33 11.96 *go 0 se S S e 0 0 *5 0 C 0 0 00 0 0 0 0@ 0 C 004 Se 0 Example Mp Analysis, No. R R' CC MS 'H NMR Formula Theory/Found C H N 127 6-Me Meco oil 573 III CDC]I 3 1.25-1.40 (in, 2H), 1.40-1.52 (mn, 3H1), 1.52- C 3 4
H
47 NfiO 3 71.17 8.26 12.21 1.80 (in, 6H1), 2.02 J=12 Hz, 2H), 2.09 3H), 2.46 70.99 8.05 12.41 3H), 2.46-2.60 (in, 5H1), 2.75 (in, 1H), 2.86 2H), 2.90 J=15 Hz, 111), 2.95 J=15 Hz, 1H), 3.15 (dd, J=9, 18 Hz, 1H), 3.70 3H), 3.95 (mn, 111), 4.44 111), 4.50-4.60 (mn, 2H), 6.80-6.93 (mn, 311), 6.93- 7.00 (mn, 2H1), 7.14-(9, 1H1), 7.25 111), 7.42 J=9 Hz, 111), 7.53 J=8 Hz, 111), 8.03 (brs, 111) 128 7-Me MeCO roam 573 IH CDC1 3 1.32-1.41 (mn, 4 1.45-1.66 (mn, 6 H), 1.96-2.07 (in, 2 2.09 3 2.19 (in, 1 2.48- 2.58 (mn, 8 2.74 (mn, 1 2.81-3.07 (mn, 4 3.14 (dd, J=4.6,13.8 Hz, 1 3.76 3 3.97 (dd, J= 10.2,13.8 Hz, 1 4.47 (ABq, J= 17.1 Hz, Av=42.3 Hz, 2 4.55 (mn, 1 6.78-6.87 (in, 3 6.96-7.07 (in, 3 7.23 (mn, 1 7.45 J=8.6 Hz, I 7.51 J=7.6 Hz, 1 8.18 1 H).
DMSO-d6 2:1 mixture of amide rotamers; 1.20-1.60 (in, 311), 1.60-1.90 (in, 611), 1.95 2/3*311), 2.07 (s, 1/3e3H), 1.90-2.07 (in, 311), 2.55-2.90 (in, 511), 2.90- 3.20 (mn, 4H), 3.20-3.50 (in, 3H), 3.62 (in, 1H1), 3.73 (s, 3H), 4.20-4.42 (in, 3H), 6.85 (mn, 111), 6.90-7.00 (in, 211), 7.10-7.30 (in, 411), 7.50 (in, 1H), 7.70 (s, 213- 114), 7.75 1/30 111), 11.10 IH)
C
34
H
47 Nr 5 0 3 71.17 8.26 12.21 71.33 8.20 12.29 129 5-Br MeCO oil 638, 640 (M4-1*'a for Br isotopes) Exact Mass FAR
U:
theory.
638.2706 found: 638.2729
C
33 H44BrNrO 3 00 S 0 '.0 0 0 000 **S 0 0 0 0 S 0 0 00 0 S 0 0 S 00 0
**S
0 S S 00 0 0 0 0.0 S 000 005 0 0 0 0 05 00 0 0 0 0 0 0 000 0 0 Example Mp Analysis, No. R R' Oc MS IH NMR Formula Theory/Found c H N 130 .5-OMe MeCO oil 590 DMSO-d6 3:2 mixture of amide rotamers 1.20-1.60 C 3 4
H
4 7
N
5 0 4 69.24 8.03 11.87 (in, 12H), 1.73-1.96 (in, 2H), 1.93 3/5 2.02 69,52 8.14 11.92 21503H), 2.33-2.43 (in, 4H), 2.60-2.90 (in, 6H), 3.57 (in, 1H), 3.70 3H), 3.71 3H), 4.26-4.56 (in, 3H), 6.66 J=6 Hz, 1H), 6.82 (in, 1H), 6.93 (in, 2H), 7.03 2H), 7.20 (in, 2H), 7.44 J=6 Hz, 3/5e 1H), 7.68 J=6 Hz, 2/5 -1 10.65 1H) 131 5-OCH 2 Ph MeCO oil 666 DMSO-d 6 1.16-1.80 (mn, 12H), 1.90 (mn, 6H), 2.20-2.43 (in, 3H), 2.53-2.90 (in, 6H), 3.16 (mn, 111), 3.43 (in, 1H), 3.60 11H), 3.70 J=6 Hz, 3H), 4.20-4.60 (mn, 3H), 6.73-6.88 (in, 3H), 6.88-7.00 (mn, 2H), 7.04 (s, IH), 7.15-7.26 (mn, 3H), 7.26-7.40 (in, 3H), 7.40-7.53 (mn, 2H), 10.70 1H)
C
4 0 HM N 5 0 4 72.15 7.72 10.52 71.95 7.66 10.31 131a 6-F MeCO roam 577 CDCI 3 8 1.32-1.46 (in, 4H), 1.58-1L66 (mn, 6H), 1.97- 2.08 (in, 2H), 2.11 3H), 2.19 (mn, 1H), 2.49 (in, 5H), 2.72-3.04 (in, 5H), 3.13 (dd, J=4.6 Hz, Av= 13.9 Hz, IH), 3.76 3H), 3.97 (dd, J=10.3 Hz, Av=13.7 Hz, 1H), 4.47 (ABq, J=17.0 Hz, Au=42.7 Hz, 2H), 4.49 (in, IH), 6.78-6.90 (mn, 1H), 7.00 1H), 7.04 2.2 Hz, IH), 7.23 (mn, 1H), 7.47 J=8.5Hz, IH), 7.57 (dd, J=5.3Hz, Au=8.7Hz, 1H), 8.62 1H)
C
3 3
H
4 4
FN
5 0 3 68.61 7.68 12.12 68.76 7.86 12.28w
I
r *9 :99 99 9 999 9 999 999 9 99 9 9 9 9 9 9 99 99 SS 9 9 0 0 99 0 9999 9. 9 999 9 9 WMe Example Mp Analysis, No. R OC MS IH NMR Formula %TheorylFound C H N 132 1-(4.(l-piperidinyl)- foam 574 IH CDCI, 3 1.44 3H1), 1.40- C 3 4
H
4 7
N
5 0 3 71.17 8.26 12.21 piperidinyl) 2.00 (in, 13H), 2.08 3H), 70.94 8.38 12.28 2.20-2.40 (in, 2H1), 2.45-2.80 (in, 6H1), 3.16-3.35 (in, 2H), 3.66 (d, J=14 Hz, 111), 3.81 3H), 4.23 J= 14 Hz, IH), 4.60 (ABq, J=14 Hz, Au =28 Hz, 2H), 6.86 J=8 Hz, 1H), 6.96 J=8 Hz, 1H), 7.03-7.20 (in, 4H), 7.27 211), 7.40 J=8 Hz, 1H), 7.60 J=6 Hz, 2H) 133 1.(4-phenyl)piperazinyl foam 568 111 CDC1 3 1.56 311), 2.09 (a, 311), 2.43-2.85 (in, 3H), 2.85- 3.20 (in, 7H1), 3.20-3.50 (in, 3H1), 3.81 311), 4.20 J= 14 Hz, 111), 4.60 (ABq, J=18 Hz, Au=56 Hz, 2H), 6.80-7.00 (in, 6H), 7.00-7.20 (in, 3H1), 7.20.
7.36 (in, 511), 7.59 J=7 Hz, 1H1), 8.24 111).
C.14 4 1 N 5 0 3 71.93 7.28 12.34 71.68 7.49 12.29 24.
0 0@ 0 0 0 0 0 500 000 0 0 0 0 0 0 es.
0 0 0 0 00 0 0 0 00 0 00 00 0 0 0 00* Example Mp Analysis, No. R Oc MS 'H NMR Formula %Theory/Found C H N 134 Br foam 543, 545 IH CDCI3 1.31 (s,12H), 3.07 C 27
H
3 4 BrN 3
O
4 59.56 6.29 7.72 for IA T.1IA U. 1 iUI O IA I I A 58.80 6.21 7.47 Br isotopes) Hz, IH), 3.40 J=14 Hz, 111), 3.66 3H), 3.68 J=14 Hz, 1H), 3.80-3.95 (in, 2H), 4.23 (d, J=16 Hz, 1H), 4.64 J=16 Hz, 1H), 6.82 (d J=8 Hz, 1H), 6.90 (in, 1H), 7.00-7.15 (in, 2H), 7. 15.7.30 (mn, 3H), 7.30-7.40 (in, 2H), 7.55 Kd J=8 Hz, 1H), 8.07 (brs, 1H).
S.-
4 4 4 S. 5 0 0 S S S 4 0* S 0 OS 0 0 0 454 WOO @44 @4 4 *40 4 0O S S. S 0 S 0@ 0 000 044 4. 0 4 @0 45 4 4 @046 4e@ 4 6 Example Mp Analysis, No. R R' 0 C MS 1H NMR Formula %/Theory/Found C H N 135 1-naphthyl-CH 2 H foam 523 CDCI 3 2.32-2.45 (in, 2H1), 2.40 Ca 3 HasN 4
O
2 75.83 7.33 10.72 I1 11-h 245-257(m, 2H) 75.55 7.26 10.60 2.75-3.10 (in, 8H1), 3.36 211), 3.84 3H), 3.92 (ABq, J=12 Hz, Av= 22 Hz, 2H1), 4.48 (in, 6.75-7.00 (mn, 5H), 7.15- 7.42 (mn, 6H1), 7.42-7.64 (in, 3H), 7.74 J=8 Hz, 1H1), 7.83 (d, J=8 Hz, 111), 8.28 J=8 Hz, 1H1) 136 2-naphthyl.CH 2 foam 522 CDC1 3 2.03 (in, 1H), 2.26-2.35 (mn, 211), 2.35-2.55 (mn, 2H), 2.65-2.95 (in, 7H), 2.95-3.10 (in, 2H), 3.18 (dd, J=8, 14 Hz, 111), 3.74-4.03 (in, 2H), 3.85 3H), 4.45 (in, IH), 6.75 J=9 Hz, 211), 6.78-6.97 (in, 311), 7.03- 7.40 (in, 6H), 7.40-7.52 (mn, 2H1), 7.63 1H1), 7.66-7.83 (mn, 311) C.1 3
H
38
N
4 0 2 75.83 7.33 10.72 76.07 7.25 10.66 0 0e 040 0* I0 00.
V* 0 se000 ,t 0.0 se 000 000 to 0 000 *0 0 0 0.0 0o0 Example Mp Analysis, No. R R' OC MS 'H NMR Formula %7Theory/Found C H N 17 3-indolinyl-C11 2 H roam 514 DMSO-d 6 1:1 mixture of C 9 1
IH
39 N60 2 72.48 7.65 13.63 (M+1 4 diastereomera 1.54-1.70(in. 72.57 7.50 13.70 111), 1.86-1.98 (mn, 1H1), 2.52- 2.64 (mn, 6H), 2.84-3. 18 (in, 811) 3.32 (hr s, 1H), 3.54 (in, 1H), 3.64-3.70 (mn, 2H), 3.76 (s, 1/2*3H), 3.78 1/2*3H), 4.03 (in, 111), 5.40 (hr a, 111), 6.44- 6.56 (in, 2H), 6.77 J=7 Hz, 1H), 6.82-6.98 (in, 6H), 7.10- 7.24 (in, 3H), 7.30 (hr d, J=8 Hz, 1H), 7.65 J=9 Hz, 1H) 138 Ph MeCO oil 500 CDCI 3 2.14 3H), 2.60-2.80 (in, 4H1), 3.00-3.20 (in, 2H), 3.20-3.43 (mn, 5H), 3.82 3H), 4.30 (in, 111), 4.40-4.63 (in, 211), 5.18 (in, 111), 6.80-7.06 (in, 6H),.
7.03-7.40 (mn, 8H), 8.24 (br s, 1H1)
C
30 11 36
N
4 0 3 71.97 7.25 11.19 71.67 7.29 11.18 139 3,4-diCi Ph 140 PhCH 2 MeCO oil 568 1 H CDC1 3 2.19 3H), 2.63- 2.83 (in, 2H1), 2.93-3.20 (in, 4H), 3.20-3.50 (mn, 3H), 3.50-3.70 (in, 211), 3.85 3M), 4.23 (in, IH), 4.30-4.60 (in, 211), 5.00 (in, 1H), 6.85-7.06 (mn, 5H), 7.13 (in, IH), 7.20-7.45 (in, 6H), 8.41 (hr a, 1H).
MeCO oil 514 DMSO-d6~ 3:2 mixture of amide (MI) rotamera 1.93 3/5*3H), 2.09 2/5-3H), 2.23-2.46 (mn, 411), 2.60-2.90 (in, 411), 3.00-3.20 (in, 211), 3.30-3.53 (in, 411), 3.75 (s, 3H), 4.20-4.60 (mn, 3H), 6.70.
7.04 (mn, 711), 7.04-7.30 (in, 711), 7.57 J1=9 Hz, 3/5 o 111), 7.71 J=9 1Hz, 2/5 *1 H)
C
30 11 34 C1 2
N
4 0 3 63.27 63.12 6.02 9.84 5.82 9.55
C
3 1
H.
8
N
4 0 3 1 72.35 7.44 10.89 72.57 7.47 10.69 0 9 OS 0 0 0 0 0 0 9 00 0 9 00 0 0 0 000 .00 090 0. 0 0.* S S 0 0 *S 0
OS
00 0 050 550 495 S S SO SO 0
OS..
OOS 9 Example Mp Analysis, No. R R' C MS 'H NMR Formula %Theory/Found C H N 141 1-naphthyl-CH 2 MeCO foam 564 CDCI 3 j 2.13 3H), 2.38-2.70 (in, 4H), 2.82-3.07 C 35
)H
4 0
N
4 0 3 74.44 7.14 9.92 (in, 411), 3.07-3.30 (in, 4H), 3.56 (dd, J=7, 14 H z, 74.50 7.25 9.94 IH), 3.66 3H), 4.14 (in, 1H), 4.34 (Aft, J=16 Hz, Av=58 Hz, 2H), 4.47 (in, 111), 6.52-6.67 (in, 2H), 6.73 J=8 Hz, 111), 6.77-7.00 (in, 3H), 7.09-7.20 (mn, 1H1), 7.20-7.40 (in, 4H), 7.43-7.70 (in, 311), 7.73 J=8 Hz, 1H1), 7.86 J=8 Hz, IH), 8.34 J=8 Hz, 111) 142 2-naphthyl-CH 2 MeCO foam 564 CDC]:, 2.12 311), 2.26-2.50 (in, 4H), 2.59-3.30 C 3 rH 40
N
4 0 3 (MI) (in, 911), 3.78 3H), 3.98 (in, 1H), 4.51 (ABq, J=17 Hz, Av=30 Hz, 2H), 4.63 (mn, 1H), 6.55- 7.03 (in, 6H), 7.05-7.39 (in, 511), 7.39-7.53 (mn, 211), 7.60 (in, IH), 7.7 1-7.85 (in, 3H) 74.44 7.14 9.92 74.46 7.31 9.94 143 3benzotb~thienyl- C11 2 MeCO foam 571 (M+1+ IH CDCI 3 2. 15 311), 2.44-2.60 (in, 411), 2.89- 3.26 (in, 9H), 3.73 311), 4.07 (dd, J=10.4,13.9 Hz, 1H1), 4.43 (ABq, J=16.5 Hz, AV=45.4 Hz, 211), 4.50 (in, 111), 6.74-6.92 (mn, 6H), 7.15 (s, IHI, 7.18-7.30 (in, 311), 7.39 (in, 2 7.57 (d, J=8.1 Hz, 111), 7.87 J=7.4 Hz, 111), 7.98 (d, J=7.6 Hz, 111).
C
3 1H 3 8
N
4 0 3
S
69.45 6.71 9.82 69.23 6.71 9.77 a eg S
U
.1.
6gg S S C. 0 0 S C 0 0 0O 9 *0 C C C egg C@O *0 9 he.
9 0 g S. S go S@ 9 0 0~ 0 0* Example MP Analysis, No. R R' 0C MS IH NMR Formula %TheoryfFound C H N 144 3-indolinyl-CH 2 MeCO 102- 556 CDCI 3 1:1 mixture of diastereomers 1.57-2.08 C 33
H
4 ,Nr)0 3 105 (M+I+)Ex act Mass
FAB
caic.: 556.3287 found: 556.3280 (in, 2H), 2.15 1/2*3H), 2.17 112*3H), 2.75- 3.60 (in, 13H), 3.65-4.00 (in, 2H), 3.82 (s, 1/2*3H), 3.85 1/203H), 4.18-4.48 (mn, 2H), 4.58 2H), 6.70-7.40 (mn, 13H), 7.67 (mn, 1H) 145 N-Ac-3indolinyl-CH 2 MeCO 80.
84 597 Exact Mass
FAR
caic.: 698.3393 found: 598.3397
CDCI
3 j 1:1 mixture of diastereomers 1.70-2.00 (in, 2H), 2.13 1/2*3H), 2.17 1/2*3H), 2.23 1/203H), 2.27 1/2*3H), 2.57-3.53 (in, 12H), 3.63-4.03 (in, 2H), 3.82 1/2o3H), 3.85 112o3H), 4.03-4.33 (in, 2H), 4.52 1/20 111), 4.54 1/2 6.80-7.40 (in, 12H), 7.57 (in, 1 8.19 (mn, 1 H)
C
35 H43N 5 0 4 ft.
ft. .N.
U
ft ft ft ft. ft ft ft ft ft ft ft.. Sftft ft ft ft ft ft ft ft ft ft. ft ft ft ft ft eft t ft 0 ft f t f so t t. t f W~e Example MP Analysis,% No. R 0 C MS 'H NMR Formula Theory/Found C H N 146 Ph oil .506 DMSO-d6 2:1 mixture of amide rotamers 1.30-1.76 C 30
H
42
N
4 0 3 .71.11 8.35 11.06 (in, I1IH), 1.90-2.20 (mn, 4H), 1.96 2/3*3H), 2.00 71.38 8.25 11.07 113*3H), 2.35-2.55 (in, 4H), 2.60-2.95 (in, 4H1), 3.78 (s, 3H), 4.43 2/3*2H), 4.43 (ABq, J=15 Hz, Liv=49 Hz, 113*2H), 4.96 (in, 2/3* 111), 5.24 (in, 1/3*1IH), 6.80-7.05 (in, 311), 7.15.7.40 (mn, 6H), 8.26 J=9 Hz, 1H) 147 3,4-diCl-Ph oil FD 574 FAR Exact Mass Theory: 575.2555 Found: 575.2595 I 111 CDC13 1.40-1.60 (in, 2H), 1.60-1.80 (in, 411), 1.80- 2.05 (nm, 5H), 2.17 3H), 2.18 (in, 111), 2.40-2.80 (mn, 511), 2.80-3.05 (in, 511), 3.85 311), 4.23 (ABq, J= 11 Hz, Av= 14 Hz, 111), 4.48 (ABq, J= 17 Hz, Av=33 Hz, 211), 4.93 (mn, IH), 6.85-7.10 (in, 4H), 7.20-7.40 (mn, 3H)p 8.35 (in, 111)
C
30 H4OCl 2
N
4
O
3
C
3 1 H4N 4
O
3 62.60 7.01- 9.73 63.05 6.91 9.78 71.51 8.52 10.76 71.50 8.25 10.51 PhCH 2 oil 520 DMS0 3:2 mixture of amide rotamers 1.30-1.63 (mIOfi), 1.73-2.00 (mn, 3H1), 1.88 3/5*3H), 2.07 (s, 2.15e31), 2.40 (in, 311), 2.55.2.80 (in, 4H), 3.15-3.50 (in, 511), 3.76 3H), 4.20-4.60 (in, 311), 6.80-7.00 (in, 311), 7.05-7.30 (mn, 6H), 7.49 J=9 Hz, 3/5*111), 7.62 (d, J=9 Hz, 2/5o1H) S 9 9 9w 9 0 S S 0 0* 9 S St 0 0 0*~ 0.0 500 19 S 0 &go te aS 0 0 0 006 6 Example Mp Analysis,% No. R Oc MS 'H NMR Formula Theory/Found C H N 149 3- foam 576 IH CDC1 3 1.41-1.73 (in, 9H), 2.00-2.21 (in, 7H), 2.41- C 33 H44N 4
O
3 S 68.72 7.69 9.71 benzolblthienyl- 2.48 (in, 4H), 2.59 J= 11.4 Hz, 1H), 2.74 J= 12.6 68.47 7.79 9.77
CH
2 Hz, 1H), 2.88 3H), 3.04 (dd, J=4.3,13.9 Hz, 1H), 3.20 (dd, J=6.1,14.5 Hz, 1H), 3.70 3H), 4.04 (dd, 3=10.5,13.9 Hz, 1K), 4.40 (ABq, J=16.5 Hz, Av=46.1 Hz, 2H), 4.50 (in, 1K), 6.73 (mn, 2H), 6.78 J=8.2 Hz, 1H), 7.13 1H), 7.19 (mn, 1H), 7.27 (mn, 2H), 7.57 (d, J=8.*1 Hz, 1K), 7.84 J=7.5 Hz, 1H), 7.96 J=7.6 Hz, 1H) 24 1 0*
B
C
4 49.
B
BC 9 B. B B I Ct *9* B, 0 B S. I 0* 0 I I 04 *4 S*C I N^ NH
R
HO
N N0 Example Mp Analysis No. R R' °C MS IH NMR Formula Theory/Found C H N 150 H H 144- 391 CDCI 3 2.18-2.42 2H), 2.42-2.77 C 2 3 11 29
N
5 0 70.56 7.47 17.89 145 (M 4H), 2.77-3.50 10H),.4.43 70.51 7.60 17.91 1H), 6.73-7.00 3H), 7.07- 7.59 7H), 7.64 J=8 Hz, 1H), 8.24 (br s, 1H) 151 t-Bu-
O(CO)
H 121- 491 CDCI 3 1.63 9H), 2.22-2.67 (m, 122 (M 4H), 2.75-3.23 8H), 3.30 (m, 1H), 3.40 1H), 4.41 1H), 5.03 1H), 6.75-7.00 4H), 7.07-7.70 6H), 7.65 J=8 Hz, 1H), 8.18 (br s, IH) H 188- 495 CDCl 3 /DMSOd 6 1.90-2.74 (m, 189 (M 6H), 2.74-3.40 4H), 3.11 (d, J=7 Hz, 2H), 3.58-3.82 2H), 4.55 1H), 6.63-6.96 3H), 7.00-7.53 10H), 7.68 J=8 Hz, 1H), 7.60-8.00 3H), 9.28 (br s, 1H)
C
2 8
H
3 7
N
5 0 3
C
3 oH 33
N
5 0 2 68.40 7.59 14.25 68.16 7.56 14.05 PhCO 72..70 6.71 14.13 72.46 6.71 13.84 H (c-hexyl)CH 2 foam 487 CDCl 3 0.73-1.41 6H), 1.41-2.08 C 3 oH 41 N50 8H), 2.10-3.38 14H), 4.56 1H), 6.81 J=8 Hz, IH), 6.81- 6.97 4H), 7.02-7.40 4H), 7.57-7.73 2H), 8.10 (br s, IH) 73.88 8.47 14.36 73.60 8.36 14.24 ago 0@0 ag 0 00 a a Wag Example Yield Mp Analysis, No. R RP Puntfi- 0 C MIS 'H NMR Formula %Theory/Found cation c H N 154 t-Bu- (c-hexyl)CH 2 chrom 84 mg foam 644 CDC1 3 0.75-1.00 (in, 2H), 1.00-1.94 C 37
H
52
N
6 0 4 68.92 8.13 13.03 O(CO)NH- (EtOI 43% (in, IOH), 1.44 9H), 2.40-2.65 68.93 8.28 13.11
CH
2 CO EtOAc) (in, 3H), 2.65-3.66 (in, 1 1H), 3.76- 4.20 (mn, 3H), 4.60 (mn, 5.54 (mn, 1H), 6.75-7.05 (in, 3H), 7.05- 7.46 (in, 7H), 7.67 J=8 Hz, 1H), 8.13 (br a, I H) Example Mp Analysis, No. R Oc MS 'H NMR Formula %TheoryfFound C H N 155 144.(1-piperidinyl)- foam 515 CDCI 3 1.3-2.1 (mn, I11H), 2.30 (in, C 3 1 4 1
N
5 0 2 72.20 8.01 13.58 piperidinyl 1H), 2.4-3.3 (in, 12H), 3.00 3H), 72.12 8.22 13.82 4.28 (in, IH), 4.74 (in, IH), 7.1- (in, 1014), 7.68 J=8 Hz, IH), 8.83 (hr s, 1H) 156 1-(4-AcNH-4-Phpiperidinyl) 168- 565 CDC1 3 1.97 3H), 2.0-2.6 (mn, 9 8H), 2.8-3.3 (in, 4H), 2.99 3H), 3.52 (in, 1H), 4.30 (in, IH), 4.72 (in, 111), 5.48 (mn, 111), 7.0-7.7 (mn, 7.68 (in, 1H), 8.41 (hr s, 1H)
C
34
H
39
N
5 0 3 72.19 6.95 12.38 72.47 7.08 12.63 too 0@ 0 0 000 0 0 0 .0 S @0 0 0 000 OS
S
550 0 0 0 S 50 0
OS
*5
S
55 0 0 5 55 *5 0 0 S 0 S S 505 0 Example Mp Analysis, No. R 00 MS 'H NMR Formula %TheoryfFound C H N 157 1-(4-Ph-piperazinyl) foam 509 CDC1 3 2.3-2.7 (in, 3H), 2.7-3.7 (in, C 31
H
35
N
5 0 2 73.06 6.92 13.74 10H), 3.02 3H), 4.30 (in, 1H), 72.91 6.96 13.70 4.78 (in, 1H), 6.7-6.9 (in, 3H), 7.1- (in, 12H1), 7.70 J=7 Hz, 1H), 8.22 (hr s, IH) 158 1-(4-cyclohexylpiperazinyl) foam 515 CDC)., 1.0-1.3 (in, 6H), 1.6-2.0 (mn, 4H1), 2.2.2.6 (in, 9H), 2.9-3.2 (in, 2.99 3H), 4.38 (mn, 1H), 4.75 (mn, 1H), 7.1-7.5 (in, IOH), 7.69 J=6 Hz, 1H), 8.23 (hr s,
C~
1
H
4 1
N
5
O
2 72.40 8.00 13.66 72.20 8.01 13.58 OMe
R
NH
R HA'N~ Example Mp Analysis, No. R pI, Theory/Found MS IH NMR Formula H N 159 PhCH 2 H oil 312 CDC1 3 3:1 mixture of amide Cj 9
H
24
N
2 02 73.05 7.74 8.97 rotamers 1.90-2. 15 (in, 2H), 2.17 72.82 7.68 8.80 3/'4 2.23 1/4 2.62 (dd, J=8, 13 Hz, 1H), 2.83 (dd, 13 Hz, IHi, 3.26-3.55 (in, 3H), 3.84 311), 4.55 J=14 Hz, 3/4*2H), 4.63 J=1I1 Hz, 1/4 *211), 6.80- 7.03 (in, 3H1), 7.13.7.36 (mn, 6H) .0 0.
0* :0 009 0* 0 0: *0 :0 00 0 0 0% 00 0 S.0 00 0.
Analysis, Example MIP, Theory/Found No. R IVO MS 'H NMR Formula C H N 160 I-Me-3-indolyl- H oil 365 CDCl 3 2.00-2.30 (in, 4H), 2.78 (dd, C 22
H
27
N
3 0 2 72.30 7.45 11.50
CH
2 J=7, 15 Hz, I 2.93 (mn, I1H), 72.02 7.43 11.24 3.30-3.60 (in, 4H), 3.75 3H), 3.82 3H), 4.60 (AftJ 16 Hz, Av=30, 2H), 6.83-7.00 (mn, 4H), 7.10 (in, 1H), 7.16-7.33 (mn, 3H), 7.55 (mn, 1H) 161 1618 162 Ph PhCH 2 1.Me-3indolylCH 2 BrCH 2 CO oil 418, 420 (Ms for Br isotopes) BrCH 2 CO oil 432, 434 for Br isotopes) BrCH 2 CO foam 485, 487 (M+~sfor Br isotopes), CDC1 3 2.22 3H), 3.06 (dd, J=3, 14 Hz, 1H), 3.83 2H), 3.87 (s, 314), 4.26 (dd, J=11, 15 Hz, 1H), 4.45 (ABq, J=17 Hz, Av=62 Hz, 2H), 4.93 (in, 1H), 6.88-7.06 (in, 7.23-7.36 (mn, 6H), 8.23 (d, J=6 Hz, 1H) CDC1 3 2.17 3H), 2.66 (dd, J=8, 14 Hz, 1H), 2.84 (dd, J=9, 14 Hz, IH), 2.97 (dd, J=5, 14 Hz, MH), 3.73-3.85 (in, 5H), 4.05 (in, IH), 4.18 (in, 11H), 4.40 (ABq, J=16 Hz, Av=39 Hz, 2H), 6.79-6.90 (mn, 3H), 7.16-7.40 (in, 7H) IH CDCl 3 2.15 3H), 2.90 (dd, J=8, 14 Hz, 1H1), 2.92 (dd J=6, 14 Hz, 1H), 3.10 (dd, J=4, 14 Hz, MH), 3.72 3H), 3.74 3H), 3.80 (s, 2H), 4.07 (mn, 1H), 4.23-4.40 (mn, 2H), 4.46 (mn, 1H), 6.70-6.90 (in, 4H), 7.13 J=8 Hz, 111), 7.20.
7.33 (mn, 311), 7.33 3=12 Hz, 1H), 7.68 3=8 Hz, 111).
C
2
GH
23 BrN 2 0 3
C
21 1H 25 B1rN 2
O
3
C
24
H
2 8 BrN 3 0 3 57.29 5.53 -6.68 57.24 5.48 6.49 58.21 5.81 6.46 58.28 5.80 6.32 59.26 5.80 8.64 59.50 5.76 8.52 %J;f 000 Se 0 0 0' 0:00 0* 0* 00e 05 '0
S..
0 S 0 SS 0 5 S5 0 @50 Se.
S 5 0 0 eS 0* 5 0 5* 0* 5*5 0 0 Exampe MpAnalysis, Exmpe p Theory/Found No. 00 MS IH NMR Formula C H N 163 203- 358 CDC1 3 2.89 (dd, J1=9, 14 Hz, IH), 3.19 (dd, J1=6,14 Hz, C 2 1H 2 2
N
2 0 2 77.07 6.19 7.81 205 1H), 3.54 (dt, J1=4, 14 Hz, IH), 3.75 (in, 1H), 4.54 (mn, 76.83 6.21 7.88 IH), 7.01 (mn, 1H), 7.15 (in, 1H), 7.18-7.35 (mn, 4H), 7.35- 7.55 (mn, 7H), 8.65-8.79 (mn, 4H)
S
4 24 SS.
S S. S S S 5 55 S 5 55 0 5 0 005 00* 55 5 *0 GO: .0 0 :09 0. .0 0. 0 0 0 00 Example Mp, Analysis, No0.
164 165 166 167 R Mc S IH NMR Me 183-184 488 CDC1 3 1.56 3H), 1.90 (in, 11H), 2.10 (mn, XH), 2.35 (in, IH), 2.5-2.6 (br s, 311), 2.75 (mn, 1H1), 2.95 (mn, 1H), 3.20 (mn, IH), 6.9- 7.1 (mn, 211), 7.1-7.6 (mn, 17H), 7.85 (mn, 111), 7.96 (br s, 1H1) n-Bu foam 530 'HCDC1 3 0.51-0.81 (in, 3H1), 0.85-1.31 I (mn, 311), 1.58 1H1), 1.88 211), 1.98 (s, I 2.00-2.10 (mn, 1H), 2.40-2.78 (in, 3H), 2.86-3.00 (in, 2H), 3.20-3.40 (mn, 2H), 6.88 1H1), 6.89-7.08 (in, 2H), 7.09-7.38 (in, 1114), 7.40-7.60 (in, 5H), 7.80-8.00 (mn, 2H).
n-Hex foam 558 IH CDC1 3 0.80-0.88 (in, 611), 0.88-1.30 (in, 711), 1.92 211), 1.98 1H1). 2.20-2.72 (mn, 311), 2.85-3.02 (mn, 111), 3.06-3.38 (in, 211), 6.92 111), 6.97-7.06 (in, 211), 7.11- 7.38 1211), 7.38-7.58 (mn, 511), 7.85- Ph 182-183 550 'HDMSO 1.64 311), 2.55 (in, 111), 2.59- (M+1I 2 .82 3 .30 111), 3.63 (dd, J=7, 14 Hz, 111), 6.72 (d J=2 Hz, 111), 6. 74-6.82 (in, 211), 6.84 J=8 Hz, 111), 6.99 J=8 Hz, 11-1), 7.05-7.21 (in, 1011), 7.21-7.64 (mn, 1011), 10.67 (br s, III).
Theorv/Fond Formula c H N
C
33
H
33
N
3 0 81.28 6.82 8.62 81.26 6.91 8.71
C
3 6
H
3 9
N
3 0 81.63 7.42 7.93 81.90 7.44 8.03
C
3
H
3 N0 81.83 7.77 7.53 C38 43 30 82.10 7.74 7.24
C
3 8
H
3 5
N
3 0 83.03 6.42 7.64 82.80 6.65 7.39.
S
cc
C
S
0
S
S. 0 0 cc. ec.
0 0 0 00@0 I.: 0 0 0* Analysis, Exampe MpTheory/Found No. R c MS IIH NMR Formula C H N 168 PhCH 2
C-
2 174-175 577 'H DMSO (3:2 mixture of amide C 4 0 M.3N 3 O 310.0 72 rotamers) 1.77 3/5*3H), 1.97 82.92 6.83 7.57 2.06.2.44 (in, 4H), 2.64-3.04 (in, 414I), 3.18 IH), 3.38-3.61 (mn, 1H), 6.61.
6.71 2H), 6.88 1H), 6.96-7.08 (in, 2H), 7.08-7.34 14H), 7.41-7.56 (m, 6H), 10.78 (hr 9, 114).
Analysis, Example Mp, Theory/Found No. R R' R' C MS 1H NMR Formula C H N 169 6-Me H 2-OMe oil 566 CDC1 3 1.90 1H), 2.18-2.33 2H), 2.44 3H), C 39
H
39
N
3 0 82.80 6.95 7.43 2.60 (in, IH), 2.68-2.96 2H), 3.48-3.68 3H), 82.81 7.02 7.32 3.80 3H4), 6.86 J=8 Hz, 3H), 6.99-7.46 7.46-7.73 5H), 7.76 1H) 170 H MeCO 2-Cl foam 598 CDC1 3 3:2 mixture of amide rotamera 1.80 3/5*3H), 2.05 2/15*3H), 2.30-2.53 2H), 2.65 (mn, 114), 3.00- 3.33 3H), 3.91 (ABq, J=20 Hz, Av=30 Hz, 3/5*2H), 4.61 (ABq, J=18 Hz, Av=77 Hz, 2/5*2H), 6.58-6.67 (in, 1H), 6.80-6.89 (mn, 2/5e 6.94-7.33 18H), 7.42-7.56 (in, 5H), 7.86 (br s, 1H) 171 6-Me MeCO 2-OMe oil 608 CDC1 3 3:1 mixture of amide rotainers 1.92 3/4*3H-), (M+14) 1.97 1/4 *314), 2.44 3H), 2.56-2.76 2H), 3.04- 3.36 (in, 4H), 3.62 IH), 3.72 3H), 4.03 J=18 Hz, IH), 6.43 J=9 Hz, 1H), 6.58-7.00 Cm, 4H), 7.00- 7.28 Cm, 1 I1-H), 7.40-7.60 Cm, 7H), 7.74 (hr s, I1H)
C
39
H-
36 C1N 3 0
C
4
,H
41
N
3 0 2 78.37 6.07 7.02 78.10 6.25 6.78 81.02 6.80 6.91 80.90 6.66 7.16
NNHI
Ph+kPh Example Analysis, Theory/Found No. R Mp, -C MS 'H NMR Formula C H N 172 3,4-diCl-Ph oil 447 1 H CDC1 3 1.50-1.95 (in, 2H), 2.04 C 27
H
24 Cl 2
N
2 72.48 5.41 6.26 (dd, J=6, 13 Hz, 1H), 2.52 (dd, J=4 72.45 5.38 6.02 12 Hz, 1H), 2.90 (in, 1H), 3.67 (in, 111), 7.03 (in, IH), 7.06-7.36 (in, 12H), 7.40-7.55 (mn, OMe
RN
NH
Ph" Ph Ph Exampe MpAnalysis, Exampe MpTheory/Found No. R R' c MS 1 H NMR Formula C H N 173 Ph H oil 499 CDC1 3 2.25-2.36 (in, 2H), 3.06 (in, 1H), C 35
H
3 4
N
2 0 84.30 6.87 5.62 3.40-3.50 (mn, 2H), 3.54 3H), 3.75-3.90 84.47 6.87 5.74 (mn, 2H), 6.74 J=8 Hz, IH), 6.85 (in, IH), 6.98 (in, 1H), 7.03-7.40 (mn, 7.45-7.60 (mn, 6H) 9 9 9 *0 6 E* 0 9 0 0 05 9 1 99 9 9 090 P.S 090 90 9 5* 9 *9 09 .1 00 9 t 995 9e9 0 S 60 91 0 9 6 0 U 090 6 Analysis, Example Mp, Theory/Found No. R R C MS IH NMR Formula C H N 174 PhCH 2 H oil 513 CDCI 3 1.93-2.10 (in, 2H), 2.-20 111), C 36
H
36
N
2 0 84.34 7.08 5.46 2.23-2.40 211), 2.60 (mn, IH), 2.75 84.41 6.95 6.76 3.55.3.65 2H), 3.82 3H), 6.83- 6.98 4H), 7.03-7.40 14H), 7.53- 7.66 (in, 6H) Ph MeCO foam 540 CDC1 3 2:1 misture of amide rotamers 1.9 Cs, 2/3*3H), 1.96 Cs, 1/3*3H), 2.93 Cm, if!), 3.05 Cm, IH), 3.67 2/3*3H), 3.75 (s, 1/393H), 3.75 Cm, 111), 3.93 J=18 Hz, 2H), 4.21 (ABq J=14 Hz, Av=21 Hz, if!), 6.66-6.90 Cm, 311), 6.90-7.35 7.35-7.55 6H1)
C
3 7
H
36
N
2 0 2 82.19 6.71 5.18 82.37 6.69 5.03 176 3,4-diCl-Ph MeCO 181- 608 (M+ 182.5 for Cl isotope), Exact
M.S.
Theory: 609.2075, Found: 609.2053 1f! CDCI 3 1.99 2.96 (dd, J=6, 14 Hz, 3.12 Cm, 1H), 3.60 Cdd, J=8, 14 Hz, 111), 3.81 3H), 3.90-4.16 311), 6.73-6.96 (in, 411), 6.96-7.30 Cm, 12H1), 7.30-7.49 6f!)
C
3 7
HU
3 C1 2 N0 2 72.90 5.62 4.59 73. 56 5.70 4.66 PhCH 2 MeCO foam 554 CDC1 3 2:1 mixture of amide rotamers 1.90 2/3*311), 1.95 1/3*311), 2.36-2.53 (in, 2.63 Cdd, 3=4, 13 Hz, 1H1), 3.00 (m, i1H), 3.06-3.23 Cm, 2H1), 3.66 1/3*3H), 3.76 Cs, 2f3-3H), 3.85 CABq. J=17 Hz, Av=I 10 Hz, 213*21), 4.59 CABq, J=17 Hz, Av= 100 Hz, 1/302H), 6.42 J=7 Hz, 1H!), 6.68-6.85 6.92-7.05 (in, 211), 7.05- 7.43 (in, 1211), 7.50-7.63 611)
C
3 sH 3 8
N
2 0 2 82.28 6.90 5.05 82.01 6.96 5.25 111 The biological activity of the compounds of the present invention was evaluated employing an initial screening assay which rapidly and accurately measured the binding of the tested compound to known NK-1 and NK-2 receptor sites. Assays useful for evaluating tachykinin receptor antagonists are well known in the art. See. e.g., J. Jukic, et al., Life Sciences, 49:1463-1469 (1991); N.
Kucharczyk, et al., Journal of Medicinal Chemistry, 36:1654-1661 (1993); N. Rouissi, et al., Biochemical and Biophysical Research Communications, 176:894-901 (1991).
NK-1 Recentor Binding Assay Radioreceptor binding assays were performed using a derivative of a previously published protocol. D.G.
S. '15 Payan, et al., Journal of Immunoloav, 133:3260-3265 (1984).
*4 0 In this assay an aliquot of IM9 cells (1 x 106 cells/tube in RPMI 1604 medium supplemented with 10% fetal calf serum) *was incubated with 20 pM 12 5 I-labeled substance P in the presence of increasing competitor concentrations for minutes at 4'C.
The IM9 cell line is a well-characterized and readily available human cell line. See, Annals of the New York Academy of Science, 190: 221-234 (1972); 1" Nature (London), 251:443-444 (1974); Proceedings of the 25 National Academy of Sciences (USA), 71:84-88 (1974). These cells were routinely cultured in RPMI 1640 supplemented with 50 g/ml gentamicin sulfate and 10% fetal calf serum.
4% The reaction was terminated by filtration 3 through aglass fiber filter harvesting system using filters previously soaked for 20 minutes in 0.1% polyethylenimine. Specific binding of labeled substance P was determined in the presence of 20 nM unlabeled ligand.
112 NK-2 Receptor Bindina Assay The CHO-hNK-2R cells, a CHO-derived cell line transformed with the human NK-2 receptor, expressing about 400,000 such receptors per cell, were grown in 75 cm 2 flasks or roller bottles in minimal essential medium (alpha modification) with 10% fetal bovine serum. The gene sequence of the human NK-2 receptor is given in N.P.
Gerard, at al., Journal of Biological Chemistry, 265:20455- 20462 (1990).
For preparation of membranes, 30 coifluent roller bottle cultures were dissociated by washing each roller bottle with 10 ml of Dulbecco's phosphate buffered saline (PBS) without calcium and magnesium, followed by 15 addition of 10 ml of enzyme-free cell dissociation solution (PBS-based, from Specialty Media, Inc.). After an additional 15 minutes, the dissociated cells were pooled and centrifuged at 1,000 RPM for 10 minutes in a clinical centrifuge. Membranes were prepared by homogenization of the cell pellets in 300 ml 50 mM Tris buffer, pH 7.4 with a Tekmar® homogenizer for 10-15 seconds, followed by S* centrifugation at 12,000 RPM (20,000 x g) for 30 minutes using a Beckman JA-14® rotor. The pellets were washed once using the above procedure. and the final pellets were Z5 resuspended in 100-120 ml 50 mM Tris buffer, pH 7.4, and 4 P ml aliquots stored frozen at -70 The protein S concentration of this preparation was 2 mg/ml.
For the receptor binding assay, one 4-ml aliquot of the CHO-hNK-2R membrane preparation was suspended in ml of assay buffer containing 50 mM Tris, pH 7.4, 3 mM manganese chloride, 0.02% bovine serum albumin (BSA) and 4 pg/ml chymostatin. A 200 p. volume of the homogenate pg protein) was used per sample. The radioactive ligand was 1 2 5 I]iodohistidyl-neurokinin A (New England Nuclear, .NEX-252), 2200 Ci/mmol. The ligand was prepared in assay buffer at 20 nCi per 100 pl; the final concentration in 113 the assay was 20 pM. Non-specific binding was determined using 1 M eledoisin. Ten concentrations of eledoisin from 0.1 to 1000 nM were used for a standard concentrationresponse curve.
All samples and standards were added to the incubation in 10 .1 dimethylsulfoxide (DMSO) for screening (single dose) or in 5 1l DMSO for IC 50 determinations. The order of additions for incubation was 190 or 195 1l assay buffer, 200 .1 homogenate, 10 or 5 p. sample in DMSO, 100 1l radioactive ligand. The samples were incubated 1 hr at room temperature and then filtered on a 48 well Brandel cell harvester through GF/B filters which had been presoaked for two hours in 50 mM Tris buffer, pH 7.7, containing 0.5% BSA. The filter was washed 3 times with *15 approximately 3 ml of cold 50 mM Tris buffer, pH 7.7. The filter circles were then punched into 12 x 75 mm polystyrene tubes and counted in a gamma counter.
Table II, infra, depicts the results of several such neurokinin binding assays. Column 1 provides the :example number of the test antagonist compound as detailed in Table 1, supra. The next colums define the the concentration of the test compound (in nanomolar quantities) which inhibits fifty percent of the binding of the appropriate neurokinin, as defined in the column 7 heading, or the percent inhibition of such binding at the concentration noted. Certain values represent the average Sof more than one experiment.
d 114 Table II Example IC50 No. n I4n 153 1700 0* 0 000 S 0@ S S
S
SS S
OS
*0 .5
S
OOS
*600
SO
*5 S 2 3 4 5 6 7 8 9 10 11 12 13 1500 62 62% 1 P.M 230 130
S*
S S
S.
5.5.
S S 0@ S 5* 0 S S 55
S
00 See
S
0006V4 84 19 65 1.6 1.3 3.1 2.1 640 820 2400 1600 1000 115 Example No.
16 17 18 00 0 0 000 0 00 00 0 000 0 *0 0 0@ @0 *0
S
000 @000 00 0* 0 *0 0 0
S.
00 0@ 0 OS 0 S 90 0@.e0 0 @09 NK -1 IC 50 rim 4.2 0.85 1.1 434 6.0 4.6 2.1.
13 1.2 4.4 0.75 1.6 1.7 9.2 NK -2 IC5 0 rumi 1200 1600 870 1200 3300 810 640 480 650 710 1000 1500 680 6200 116
S.
0 0 SO0 C
C.
0 S 0SS *0 S 0e @0 0@ 00 C00 0*eq 0@ 0* S Examnple No.
32 33 34 36 37 38 39 40 41 42 43 44 46 47 NK- 1 1C5 0 0.98 1.9 6.2 0.89 10 4.2 30% 139 21.3 7.7 16% 1 PM4 179 25 65 2.2 0.25 NK -2 IC fliv 1100 670 590 600 120 600 8000 910 930 1200 39 54% at
;IM
5300 2400 1800 00 5 0 00 0000 0@ 00 S S. 0@ 9* 0 *ee. es C S 117 cc C C cce cc C C cc. S Cc 0 C C o S.
S.
C
**O
cc eq CO Example No.
48 49 51 52 53 54 56 57 58 59 NK -1 IC50 nM 0.24 135 0.25 0.37 250 58% 5 P 30.1 71 150 14 7.3 24 NK -2 IC5 0 3400 5200 2100 340 3700 3900
S.
cc c U CO cc 00 C S. B C C C cc
C
ce ccc
C
1, 60 118 Example No.
61 62 63 64 65 66 6 0 6 *6 0 6 .66 6 a. 0 6e
S.
6s 6
S..
.009 09 06 0 66 0 6 66 0e i.
0* 66 6 60 6 6
S
6~S** 9 67 68 69 70 71 73 74 76 77 NK- 1 IC5 0 7.2 43 74 30 7.2 4.6 3.8 0.41 5.4 13 7.5 0.99 0.36 0.18 69 0.88 NK -2 IC5 0 nM 940 5900 490 240 600 7200 750 2400 830 1000 8900 1000 850 1400 630 119 NK-1 NK-2 Example IC50 No. rmnM 78 10 2100 79 38 6100 19 3400 81 13 1100 *82 13 1200 83 8.4 5200 84 41.1 510 86 0.36 87 0.77 120 5600 *a89 170 1200 91 3000 92 97.2 120 Examnpl e No.
93 94 96 0*0* 97 0e100 102 00105 100 NK -1 IC 50 rim 16% 1JIW 85 9.6 34.4 1300 21 1 JIM 77% 1 PIM 97 210 82 0.62 630 68 NK -2 IC nM 760 1000 600 54% 10 gIm 40% 10 pLm 6000 59%
W
3700 1600 15200 33%
JIM
121 NK-1 NK-2 Example IC50 No. riM rim 107 74% @3 420 1JimU 108 76% @3 3500 1 A±m 109 190 2000 110 148 120 111200 490 112 270 S.*113 7.8 1200 114 29.2 940 115 15.4 :116 58 930 117 33 118 310 119 9.5 2700 122 Examnpl e No.
120 121 122 123 *eu *124 126 127 0 0 126 127 *0 000 0@130 132 130 NY,- 1 IC5 0 rim 2500 850 550 27 0.93 0.66 2.8 7.3 1. 1 19 67 0.7 4.2 11.6 NK -2 IC Dlv 2500 1400 2100 3400 3000 123 NK-l1 NK-2 Example IC50 -1C50 No. nM nM 134 14% 1 RM 135 75% 430 1 PM 136 47% 710 137 220 2700 13 77 144 5210 138 770 2500 124
S.
S S 0
S*
5 0
S
5* 0 5 0 0@
S.
0 000 0550
OS
S. S Examnple No.
146 147' 148 149 150 151 152 153 154 155 156 157 158 NK -1 420 196 24 1.2 45% 1 PM 1400 1200 650 76% 1 PiN 63% 5 p.M 78%
JIM
88% 450 NK -2 nM 3900 430 8500 1700 2000 540 210 12200 9500 2900 3800
OS
0 0* Oe* 0 5 55 5 S. S 0 5
OS
OSSS*0
S
S
550000 125 Example No.
159 160 161 0O 0 6 0 0e 0 0 00. 0 0 0 0 @0 0* *00 *000 00 0e S 0@ 0 0 @0 @060 *0 0@ S SO S 0* 00 0
S
161a 162 .163 164 165 166 167 168 169 170 171 172 NK -1 IC5 0 n±4 54% p.M 0 5 p-M 24% gm 77% 5 pM 375 0% 5 p-y 3% 5 p.M 0% 5 p.M 0% 5 p.m 13% 5 PM 8 5 p-m 67 0 5 gIm 46% pm NK -2 IC n.M 11 10 Jm 19 000 0% 10 W14 17 600 0% 10 g14 44% 10 Jim 6200 10450 10000 21000 >100 000 13900 0 05000.
2%9 10 Jim 6% PM4 126 NK-1 NK-2 Example IC50 No. nM nM 173 74 2000 174 175 176 177 0% 5 PM 28%
JIM
9% 5 P.M 0%
M
6400 9% 10 4M 0% 10 JM 12% 10 M @9 9e S ab 0 .9
S
*0 0@4s 6g a.
0* 9 9 0* 009 0 *0 a *9 S @0 Since the compounds of Formula I are effective tachykinin receptor antagonists, these compounds are of value in the treatment of a wide variety of clinical conditions which are characterized by the presence of an excess of tachykinin. Thus, the invention provides methods for the treatment or prevention of a physiological disorder 0 associated with an excess of tachykinins, which method comprises administering to a mammal in need of said treatment an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof. The term "physiological disorder associated with an excess of tachykinins" encompasses those disorders associated with an inappropriate stimulation of tachykinin receptors, regardless of the actual amount of tachykinin present in the locale.
These physiological disorders may include disorders of the central nervous system such as anxiety, depression, psychosis, and schizophrenia; neurodegenerative" disorders such as dementia, including senile dementia of the Alzheimer's type, Alzheimer's disease, AIDS-associated 127 dementia, and Down's syndrome; demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis and other neuropathological disorders such as peripheral neuropathy, such as diabetic and chemotherapy-induced neuropathy, and post-herpetic and other neuralgias; acute and chronic obstructive airway diseases such as adult respiratory distress syndrome, bronchopneumonia, bronchospasm, chronic bronchitis, drivercough, and asthma; inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis, and rheumatoid arthritis; disorders of the musculo-skeletal-system, such as osteoporosis; allergies such as eczema and rhinitis; hypersensitivity disorders such as poison ivy; ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and 5 the like; cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria, and other eczematoid dermatites; addiction disorders such as alcoholism; stressrelated somatic disorders; reflex sympathetic dystrophy .such as shoulder/hand syndrome; dysthymic disorders; a..2 0 adverse immunological reactions such as rejection of S• transplanted tissues and disorders related to immune enhancement or suppression such as systemic lupus erythematosis; gastrointestinal disorders or diseases associated with the neuronal control of viscera such as ulcerative colitis, Crohn's disease and irritable bowel syndrome; disorders of bladder function such as bladder detrusor hyper-reflexia and incontinence; artherosclerosis; fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis; irritative symptoms of benign prostatic hypertrophy; disorders of blood flow caused by vasodilation and vasospastic diseases such as angina, migraine, and Reynaud's disease; and pain or nociception, for example, that attributable to or associated with any of the foregoing conditions, especially the transmission of pain in migraine. For example the compounds of Formula I may suitably be used in the treatment of disorders of the 128 central nervous system such as anxiety, psychosis, and schizophrenia; neurodegenerative disorders such as Alzheimer's disease and Down's syndrome; respiratory diseases such as bronchospasm and asthma; inflammatory diseases such as inflammatory bowel disease, osteoarthritis and rheumatoid arthritis; adverse immunological disorders such as rejection of transplanted tissues; gastrointestinal disorders and diseases such as disorders associated with the neuronal control of viscera such as ulcerative colitis, Crohn's disease and irritable bowel syndrome; incontinence; disorders of blood flow caused by vasodilation- and pain or nociception, for example, that attributable to or associated with any of the foregoing conditions or the transmission of pain in migraine.
The results of several experiments demonstrate that many of the compounds of Formula I are selective tachykinin receptor antagonists. These compounds preferentially bind one tachykinin receptor subtype compared to other such receptors. Such compounds are especially preferred.
'*MQ For example, NK-1 antagonists are most especially preferred in the treatment of pain, especially chronic pain, such as neuropathic pain, post-operative pain, and migraines, pain associated with arthritis, cancer-associated pain, chronic lower back pain, cluster headaches, herpes neuralgia, phantom limb pain, central pain, dental pain, neuropathic pain, opiod-resistant pain, visceral pain, surgical pain, bone injury pain, pain during labor and delivery, pain resulting from burns, post partum pain, angina pain, and genitourinary tract-related pain including cystitis.
In addition to pain, NK-1 antagonists are especially preferred in the treatment and prevention of urinary incontinence; irritative symptoms of benign prostatic hypertrophy; motility disorders of the gastrointestinal tract, such as irritable bowel syndrome; 129 acute and chronic obstructive airway diseases, such as bronchospasm, bronchopneumonia, asthma, and adult respiratory distress syndrome; artherosclerosis; inflammatory conditions, such as inflammatory bowel disease, ulcerative colitis, Crohn's disease, rheumatoid arthritis, osteoarthritis, neurogenic inflammation, allergies, rhinitis, cough, dermatitis, urticaria, psoriasis, conjunctivitis, irritation-induced miosis; tissue transplant rejection; plasma extravasation resulting 0 from cytokine chemotherapy and the like; spinal cord trauma; stroke; cerebral stroke (ischemia); Alzheimer's disease; Parkinson's disease; multiple sclerosis; amyotrophic lateral sclerosis; schizophrenia; anxiety; and depression.
e 1 a.
*a *aw a. a ac *6 a.rg a. 6* Oa +a 6* 7* ai a. a as a as a a a 15 NK-2 antagonists are especially preferred in the treatment of urinary incontinence, bronchospasm, asthma, adult respiratory distress syndrome, motility disorders of the gastrointestinal tract, such as irritable bowel syndrome, and pain.
20 In addition to the n vitro binding assays described supra, many of the compounds of this invention have also been tested in in vivo model systems for conditions associated with an excess of tachykinins. Of these compounds tested in vivo many have shown efficacy against said conditions.
The compounds of Formula I are usually administered in the form of pharmaceutical compositions.
These compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. These compounds are effective as both injectable and oral compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.
The present invention also includes pharmaceutical compositions which contain, as the active 130 ingredient, the compounds of Formula I associated with pharmaceutically acceptable carriers. In making the compositions of the present invention the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be a solid, semisolid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing for example up to 0* by weight of the active compound, soft and hard gelatin 15 capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
In preparing a formulation, it may be necessary to mill the active compound to provide the appropriate particle size prior to combining with the other 20 ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
SSome examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally, include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxybenzoates; sweetening agents; and flavoring agents. The compositions of the invention can be 131 formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
The compositions are preferably formulated in a unit dosage form, each dosage containing from about 5 to about 100 mg, more usually about 10 to about 30 mg, of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages dosages for human subjects and other mammals, each unit 10 containing a predetermined quantity of active material 0 calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
S. The active compound is effective over a wide 5905 S 0dosage range. For examples, dosages per day normally fall within the range of about 0.5 to about 30 mg/kg of body weight. In the treatment of adult humans, the range of about 1 to about 15 mg/kg/day, in single or divided dose, *9 ."is especially preferred. However, it will be understood that the amount of the compound actually administered will be determined by a physician, in the light of the relevant *o o *circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, and the severity of the patient's 25 symptoms, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way.
In some instances dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several smaller doses for administration throughout the day.
For preparing solid cmoposiions such as tablets the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound 132 of the present invention. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dipsersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention.
The tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage .and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
The liquid forms in which the novel compositions 25 of the present invention may be incorporated for solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as 'elixirs and similar pharmaceutical vehicles.
Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. Preferably the compositions are 133 administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face mask, tent, or intermittent positive pressure breathing machine.
Solution, suspension, or powder compsoitions may be administered, preferably orally or nasally, from devices 1i0 which deliver the formulation in an appropriate manner.
The following examples illustrate the pharmaceutical compositions of the present invention.
S S
S.*
0o 5* S
S
0o oei o
N
134 Formulation Example 1
C
.me 0@
SOS
*c C
CS..
S S 6* 5 p Hard gelatin capsules containing the following ingredients are prepared: Quantity Inredient (ma/cansule) Compound of Example 51 30.0 10 Starch 305.0 Magnesium stearate The above ingredients are mixed and filled into 15 hard gelatin capsules in 340 mg quantities.
Formulation Example 2 A tablet formula is prepared using the 20 ingredients below: Ingredient Compound of Example 66 Cellulose, microcrystalline Colloidal silicon dioxide Stearic acid Quantity (ma/tablet) 25.0 200.0 10.0 The components are blended and compressed to form tablets, each weighing 240 mg.
135 Formulation Example 3
S
see 0 *0 Does
S
00 *5.9 0* A dry powder inhaler formulation is prepared containing the following components: Inaredient Weiaht Compound of Example 17 Lactose The active mixture is mixed with the lactose and the mixture is added to a dry powder inhaling appliance.
Formulation Example 4 Tablets, each containing 30 mg of active ingredient, are prepared as follows:
S
Inaredient Compound of Example 14 Starch Microcrystalline cellulose SPolyvinylpyrrolidone (as 10% solution in water) Sodium carboxymethyl starch Magnesium stearate Talc Total Quantity (ma/tablet) 30.0 mg 45.0 mg 35.0 mg 4.0 mg 4.5 mg 0.5 mg 1.0 ma 120 mg 136 The active ingredient, starch and cellulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve. The granules so produced are dried at 50-60 0 C and passed through a 16 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 30 mesh U.S. sieve, are 10 then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 120 mg.
9..
Formulation ExamDle Capsules, each containing 40 mg of medicament are made as follows: Quantity Inaredient (ma/capsule) Compound of Example 13 40.0 mg Starch 109.0 mg Magnesium stearate 1.0 ma STotal 150.0 mg The active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. mesh U.S. sieve, and filled into hard gelatin, capsules in 150 mg quantities.
137 Formulation Example 6 Suppositories, each containing 25 mg of active ingredient are made as follows: Inaredient Amount Compound of Example 18 25 mg Saturated fatty acid glycerides to 2,000 mg S" The active ingredient is passed through a No. mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2.0 g capacity and allowed to cool.
Formulation Example 7 0* Suspensions, each containing 50 mg of medicament per 5.0 ml dose are made as follows: inaredin Amount Compound of Example 43 50.0 mg Xanthan gum 4.0 mg Sodium carboxymethyl cellulose (11%) Microcrystalline cellulose 50.0 mg Sucrose 1.75 g Sodium benzoate 10.0 mg Flavor and Color q.v.
Purified water to 5.0 ml 138 The medicament, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water. The sodium benzoate, flavor, and color are diluted with some of the water and added with stirring.
Sufficient water is then added to produce the required volume.
.0 Formulation Examnle 8 1 0S *r S
S.
*5* 0505 *r S Capsules, each containing 15 mg of medicament, are made as follows: Inoredient Compound of Example 58 Quantity (ma/casule) 15.0 mg 0* 49 0* S S S. S 5 Starch Magnesium stearate 407.0 mg 3.0 ma 425.0 mg Total The active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. mesh U.S. sieve, and filled into hard gelatin capsules in 425 mg quantities.
139 Formulation Example 9 An intravenous formulation may be prepared as follows: Inaredient Compound of Example 91 Ouantit 250.0 mg 1000 ml @0 0 900 0 ,,l 0 0* S 0 0e 00 Isotonic saline Formulation Example A topical formulation may be prepared as follows: Inredient Compound of Example 67 Quantity 1-10 g Emulsifying Wax Liquid Paraffin 30 g 20 g White Soft Paraffin to 100 g The white soft paraffin is heated until molten. The liquid Spraffin and emulsifying wax are incorporated and stirred until dissolved. The compound of Example 67 is added and stirring is continued until dispersed. The mixture is then cooled until solid.
140 Formulation Examnle 11 Sublingual or buccal tablets, each containing mg of active ingredient, may be prepared as follows: Quantity Inaredient per Tablet Active Ingredient 10.0 mg .010 Glycerol 210.5 mg *Water 143.0 mg 000 Sodium Citrate 4.5 mg S Polyvinyl Alcohol 26.5 mg Polyvinylpyrrolidone 155 ma Total 410.0 mg The glycerol, water, sodium citrate, polyvinyl alcohol, and polyvinylpyrrolidone are admixed together by continuous stirring and maintaining the temperature at about 90 0
C.
0 When the polymers have gone into solution, the solution is cooled to about 50-55°C and the medicament is slowly admixed. The homogenous mixture is poured into forms made of an inert material to produce a drug-containing diffusion matrix having a thickness of about 2-4 mm. This diffusion matrix is then cut to form individual tablets having the appropriate size.
Another preferred formulation employed in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled 141 amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, U.S. Patent 5,023,252, issued June 11, 1991, herein incorporated by reference. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
Frequently, it will be desirable or necessary to introduce the pharmaceutical composition to the brain, either directly or indirectly. Direct techniques usually 10 involve placement of a drug delivery catheter into the 0* host's ventricular system to bypass the bloqd-brain barrier. One such implantable delivery system, used for S. the transport of biological factors to specific anatomical regions of the body, is described in U.S. Patent 5,011,472, issued April 30, 1991, which is herein incorporated by refernce.
6* 6*
C
S rr 4060*5
S
Indirect techniques, which are generally preferred, usually involve formulating the compositions to provide for drug latentiation by the conversion of hydrophilic drugs into lipid-soluble drugs or prodrugs.
Latentiation is generally achieved through blocking of the hydroxy, carbonyl, sulfate, and primary amine groups present on the drug to render the drug more lipid soluble and amenable to transportation across the blood-brain barrier. Alternatively, the delivery of hydrophilic drugs may be enhanced by intra-arterial infusion of hypertonic solutions which can transiently open the blood-brain barrier.

Claims (15)

  1. 3-indolyl which groups may be optionally substituted. [IkA\-IBVV]02 174 &lc:n Ic 1 43a 3. A comnpound as claimed in claim 1 or claim 2 wherein n is 1.
  2. 4. A compound as claimed in any one of claims I to 3wherein R 2 i -CO-R or C 1 -C 4 alkylsulfonyl. A compound as claimed in any one of claimrs I to 3 wherein R 2 is acetyl or meIthySLsulfonyl. I RA I BVV10217AI~ j
  3. 6. A compound as claimed in claim 5 of the formula a N/ R 1~ N N H R 2 N H 0 wherein Ra is halo, CI-C 3 alkoxy, C 1 -C 3 alkylthio, nitro, trifluoromethyl, or Cl-C 3 alkyl.
  4. 7. A compound as claimed in claim 6 wherein Ra is C 1 C 3 alkoxy, chioro, fluoro, trifluoromethyl or Cl-C 3 alkylthio.
  5. 8. A compound as claimed in claim 6 or claim 7 wherein RI is piperazinyl, piperidinyl, substituted piperazinyl, or substituted piperidinyl.
  6. 9. A compound as claimed in claim 8 wherein R 1 is 1 -(4-phenyl)piperazinyl, 1 -(4-cyclohexyl)piperazinyl, 1 -(4-phenyl)piperidinyl, a: lo 1 -(4-cyclohexyl)piperidinyl, 1 -(4-isopropyl)piperazinyl, 1 -piperidinyl)]piperidinyl. A compound as claimed in claim 9 wherein the compound is s* methoxybenzyl)acetylamino]-3-(l1H-indol-3-yl)-2-[N-(2-((4-phenyl)piperazin- l-yl)- acetyl)amino]propane, 1 -[N-(2-chlorobenzyl)acetylamino] -3-(1H-indol-3-yl)-2- [N-(2-((4-phenyl)piperazin- 1-yl)acetyl)aminolpropane, 1 (2-(methoxybenzyl)acetylamino] lH-indol-3-yl)-2-[N-(2-((4-cyclohexyl)piperazin- l-yl)- acetyl)amino]propane, 1-[N-(2-chlorobenzyl)acetylaminol-3-(11I-indol-3-yl)-2-[N-(2- ((4-cyclohexyl)piperazin- 1 -yl)acetyl)amino] propane, 1 methoxybenzyl)acetylamino]-3-(1 H-indol-3-yl)-2-[N-(2-((4-phenyl)piperidin- 1-yl)- acetyl)amnino]propane, 1 -[N-(2-chlorobenzyl)acetylamino]-3-( 1H-indol-3-yl)-2-[N-(2- ((4-phenyl)piperidin- 1-yl)acetyl)amino]propane, 1 -[N-(2-methoxybenzyl)acetylamino] 1H-indol-3-yl)-2-[N-(2-((4-cyclohexyl)piperidin-1-y)acetyl)amino]propafle, 1 (2-chlorobenzyl)acetylamino]-3-(1H-indol-3-yI)-2-N-(2-((4-cyclohexyl)piperidin-1lyl)- acetyl)aminolpropane, 1 -[N-(2-methoxybenzyl)acetylamino-3-( 1H-indol-3-yl)-2-[N-(2- ((4-isopropyl)piperazin- 1-yl)acetyl)amino]propane, 1 -[N-(2-chlorobenzyl) it( 25 acetylamino] -3-(l1H-indol-3-yl)-2-[N-(2-((4-isopropyl)piperazin- l-yl)- acetyl)amino]propane, 1 -[N-(2-methoxybenzyl)acetylamino]-3-( lH-indol-3-yl)-2-[N- (2-(4-piperidin- 1-yl)piperidin- 1-yl)acetyl)aminolpropane, or 1 chlorobenzyl)acetylamino]-3-( 1H-indol-3-yl)-2-[N-(2-(4-(piperidin- 1-yl)piperidin- l-yl)- acetyl)aminolpropane.
  7. 11. A non peptide tachykinin receptor antagonist, substantially as hereinbefore described with reference to any one of the Examples.
  8. 12. A pharmaceutical formulation comprising as an active ingredient a compound as claimed in any one of claims 1 to 11, associated with one or more pharmaceutically acceptable carriers, diluents, or excipients therefor. IN:\LIBAA11441:tab 145
  9. 13. A pharmaceutical formulation substantially as herein described with reference to any one of Formulation Examples 1 to 11.
  10. 14. A method for the treatment or prophylaxis of a physiological disorder associated with an excess of tachykinins in a mammal, which method comprises administering to said mammal an effective amount of at least one compound according to any one of claims 1 to 1 1 or of a composition according to claim 12 or 13. The use of a compound according to any one of claims 1 to 11 for the preparation of a medicament for the treatment or prophylaxis of a physiological disorder in a mammal associated with an excess of tachykinins. in 16. A compound according to any one of claims 1 to 11 or a pharmaceutical formulation according to claim 12 or 13 when used for the treatment or prophylaxis of a physiological disorder in a mammal associated with an excess of tachykinins.
  11. 17. A compound according to any one of claims 1 to 11 or a pharmaceutical lormulation according to claim 12 or 13 for use in the treatment or prophylaxis of a physiological disorder in a mammal associated with an excess oftachykinins.
  12. 18. The method according to claim 14, the use according to claim 15 or the compound or formulation according to claim 16 or 17 wherein the physiological disorder associated with an excess of tachykinins is selected from the group consisting of anxiety, depression, psychosis, schizophrenia, dementia, Alzheimer's disease, Down's Syndrome, l0 multiple sclerosis, cerebral stroke, amyotrophic lateral sclerosis, adult respiratory distress syndrome, bronchopneumonia, bronchospasm, asthma, urinary incontinence, irritable bowel syndrome, inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis, rheumatoid arthritis, pain and nociception.
  13. 19. A process for preparing a compound as claimed in any one of claims 6 to 2 which process comprises reacting a compound of the formula 0 0 II II RI CO C (Ci-C 6 alkyl) CH 2 0 0 \with a compound of the formula R 4 N NH 2 R 2 N H -:zandl then optionally salifying. IR.\LIBVV]02174.doc.njc 146 A process for preparing a compound of any one of claims 6 to 10 which process is substantially as herein described with reference to any one of the Method Examples A to P.
  14. 21. A compound whenever produced by the process of claim 18 or
  15. 22. A medicament whenever manufactured by the use of claim 15 or 18. Dated 12 May, 2000 Eli Lilly and Company Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON Li [R IBVV02 74.doc:njic
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993010073A1 (en) * 1991-11-12 1993-05-27 Pfizer Inc. Acyclic ethylenediamine derivatives as substance p receptor antagonists
WO1993022279A1 (en) * 1992-04-28 1993-11-11 Battelle Memorial Institute Diamine derivatives having selective affinity for sigma receptors

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993010073A1 (en) * 1991-11-12 1993-05-27 Pfizer Inc. Acyclic ethylenediamine derivatives as substance p receptor antagonists
WO1993022279A1 (en) * 1992-04-28 1993-11-11 Battelle Memorial Institute Diamine derivatives having selective affinity for sigma receptors

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