Back to results
US 2004/0006069 A1Published application
Substituted tetrahydroisoquinolines as C5a receptor modulators
AssigneeNeurogen Corporation
InventorsKyungae Lee, Scott Mitchell, Robert Ohliger, Lu Yan Zhang, He Zhao, Kevin Currie
Life of this patent
Estimating the term…
Abstract
1 Substituted tetrahydroisoquinolines and related compounds are provided. Such compounds are ligands that may be used to modulate C5a receptor activity in vivo or in vitro, and are particularly useful in the treatment of conditions associated with pathological C5a receptor activation in humans, domesticated companion animals and livestock animals. Pharmaceutical compositions and methods for using them to treat such disorders are provided, as are methods for using such ligands for receptor localization studies.
Claims52
A compound of Formula I:
- 168
- or a pharmaceutically acceptable salt thereof, wherein:
- x is 1, 2 or 3;
- R represents from 0 to 4 substituents independently chosen from halogen, hydroxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, cyano, amino, nitro, —COOH, carboxamide, optionally substituted mono- and di-alkyl amino, optionally substituted haloalkyl, and optionally substituted haloalkoxy;
- R1 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, aryl, heteroaryl, (aryl)alkyl, (heteroaryl)alkyl, and indanyl, each of which is optionally substituted;
- R2, R3 and each occurrence of R4 are independently selected from hydrogen, halogen, optionally substituted alkyl, and optionally substituted alkoxy;
- R5 and R6 are independently selected from
- (i) hydrogen, halogen, hydroxy, amino, and cyano;
- and
- (ii) alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, and mono- and di-(alkyl)amino, each of which is optionally substituted;
- R7 is:
- (a) (i) hydrogen;
- or (ii) alkyl, alkenyl, alkynyl, alkoxy or arylalkyl, each of which is optionally substituted;
- and
- Ar1 is:
- (i) phenyl, naphthyl, biphenyl, or heterocycle, each of which is optionally substituted;
- or
- (ii) optionally substituted phenyl fused to a 5- to 7-membered saturated or partially unsaturated ring having from 5 to 7 ring atoms, with 0, 1, or 2 ring atoms independently chosen from N, O and S, and with remaining ring atoms being carbon;
- or
- (b) taken together with Ar1 and the carbon atom to which R7 and Ar1 are attached to form an optionally substituted group of the formula:
- 169
- wherein p is an integer from 1 to about 3;
- and
- Ar2 is (i) optionally substituted aryl or (ii) optionally substituted heteroaryl having 5 to 7 ring atoms and from 1 to 3 ring heteroatoms independently selected from N, O and S.
21 more elements
A compound of the Formula VI
- 175
- or a pharmaceutically acceptable salt thereof, wherein:
- R is hydrogen, fluoro, chloro, hydroxy, methyl, or methoxy;
- R4 is hydrogen, methyl, or ethyl;
- R8 is hydrogen, fluoro, chloro, methyl, or methoxy;
- R9 is fluoro, chloro, methyl, ethyl, methoxy, ethoxy, mono-, di- or tri-fluoromethyl, or mono-, di-, or tri-fluoromethoxy;
- R9A represents 0, 1, or 2 substituents independently selected from hydrogen, fluoro, chloro, methyl, methoxy, mono-, di- and tri-fluoromethyl, and mono-, di-, and tri-fluoromethoxy;
- R10 is hydrogen, fluoro, chloro, hydroxy, methyl, methoxy, mono-, di-, or tri-fluoromethyl, or mono-, di-, or tri-fluoromethoxy;
- and
- R10A represents from 0 to 3 substituents independently selected from hydrogen, fluoro, chloro, hydroxy, methyl, methoxy, mono-, di- and tri-fluoromethyl, and mono-, di-, and tri-fluoromethoxy.
7 more elements
A compound of Formula VIII
- 177
- or a pharmaceutically acceptable salt thereof, wherein:
- A is N or CR10;
- B is N or CR10A, wherein at least one of A and B is not N;
- R is hydrogen, fluoro, chloro, hydroxy, methyl, or methoxy;
- R4 is hydrogen, methyl, or ethyl;
- R8 is hydrogen, fluoro, chloro, methyl or methoxy;
- R10, if present, is hydrogen, fluoro, chloro, hydroxy, nitro, cyano, methyl, methoxy, mono-, di- or tri-fluoromethyl, or mono-, di-, or tri-fluoromethoxy;
- R10A, if present, is hydrogen, fluoro, chloro, hydroxy, nitro, cyano, methyl, methoxy, mono-, di- or tri-fluoromethyl, or mono-, di-, or tri-fluoromethoxy;
- and
- R10B represents from 0 to 3 substituents independently selected from fluoro, chloro, hydroxy, nitro, cyano, methyl, methoxy, mono-, di- and tri-fluoromethyl, and mono-, di-, and tri-fluoromethoxy.
8 more elements
A compound of Formula XII
- 182
- or a pharmaceutically acceptable salt thereof, wherein:
- R represents from 0 to 4 substituents independently chosen from fluoro, chloro, hydroxy, C1-C6alkoxy, C1-C6alkyl, C1-C2haloalkyl, and C1-C2haloalkoxy;
- R1 and Ar2 are independently chosen from:
- (i) phenyl(C0-C1alkyl), substituted with from 0 to 3 substituents independently selected from halogen, hydroxy, C1-C6alkoxy, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, cyano, amino, nitro, —COOH, carboxamide, mono- and di-(C1-C6alkyl)amino, C1-C6haloalkyl and C1-C6haloalkoxy;
- and
- (ii) 2-indanyl, substituted with 0, 1 or 2 substituents independently selected from fluoro, chloro, hydroxy, methyl, ethyl, methoxy, ethoxy, mono-, di- and tri-fluoromethyl, and mono-, di- and tri-fluoromethoxy;
- R4 is C1-C6alkyl, C1-C2haloalkyl, fluoro or chloro;
- R7 is hydrogen or C1-C6alkyl;
- R9 represents from 0 to 5 substituents independently chosen from hydrogen, halogen, hydroxy, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy;
- and represents a single or double bond.
8 more elements
A compound of Formula XIII
- 183
- or a pharmaceutically acceptable salt thereof, wherein:
- R1 and Ar2 are independently chosen from:
- (i) phenyl(C0-C1alkyl), substituted with from 0 to 3 substituents independently selected from halogen, hydroxy, C1-C6alkoxy, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, cyano, amino, nitro, —COOH, carboxamide, mono- and di-(C1-C6alkyl) amino, C1-C6haloalkyl, and C1-C6haloalkoxy;
- and
- (ii) 2-indanyl, substituted with 0, 1 or 2 substituents independently selected from fluoro, chloro, hydroxy, methyl, ethyl, methoxy, ethoxy, mono-, di- and tri-fluoromethyl, and mono-, di- and tri-fluoromethoxy;
- R4 is C1-C6alkyl, haloC1-C6alkyl, fluoro or chloro;
- R3 and R7 are independently hydrogen or C1-C6alkyl;
- and
- R9 and R10 independently represent from 0 to 5 substituents independently chosen from hydrogen, halogen, hydroxy, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy.
7 more elements
A compound of Formula XIV
- 184
- or a pharmaceutically acceptable salt thereof, wherein:
- R represents from 0 to 2 substituents independently chosen from fluoro, chloro, hydroxy, C1-C6alkoxy, C1-C6alkyl, C1-C2alkyl, and C1-C2alkoxy;
- R1 and Ar2 are independently chosen from:
- (i) phenyl(C0-C1alkyl), substituted with from 0 to 3 substituents independently selected from halogen, hydroxy, C1-C6alkoxy, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, cyano, amino, nitro, —COOH, carboxamide, mono- and di-(C1-C6alkyl) amino, haloC1-C6alkyl and haloC1-C6alkoxy;
- and
- (ii) 2-indanyl, substituted with 0, 1 or 2 substituents independently selected from fluoro, chloro, hydroxy, methyl, ethyl, methoxy, ethoxy, mono-, di- and tri-fluoromethyl, and mono-, di- and tri-fluoromethoxy;
- R4 is C1-C6alkyl, haloC1-C6alkyl, fluoro or chloro;
- R7 is hydrogen or C1-C6alkyl;
- and
- R9 represents from 0 to 5 substituents independently chosen from hydrogen, halogen, hydroxy, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy.
8 more elements
37 A compound of or salt claim 1, having a enantiomeric excess of at least 90%.
Dependencies are inferred from the claim text.