US 2002/0120146 A1Published application

N-cyclopentyl modulators of chemokine receptor activity

AssigneeMerck & Co., Inc.

InventorsPaul E. Finke, Kerry A. Hilfiker, Malcolm MacCoss, Kevin T. Chapman, Jennifer L. Loebach, Sander G. Mills, Ravi N. Guthikonda, Shrenik K. Shah, Dooseop Kim, Dong-Ming Shen, Bryan Oates

Life of this patent

Estimating the term…

Abstract

The present invention is directed to compounds of the formula I: 1 (wherein R1, R3, R4, R5, R6, R7, R8, X, n, x and y are defined herein) which are useful as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of the chemokine receptors CCR-5 and/or CC R-3.

Claims39

Dependent claims

A compound of the formula I:

65
wherein:
X is selected from:
—(C0-6 alkyl)—Y—(C0-6 alkyl)—,
—(C0-6 alkyl)—C3-8 cycloalkyl-(C0-6 alkyl)—,
C2-10 alkenyl, and C2-10 alkynyl,
where the alkyl is unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from:
(a) halo,
(b) hydroxy,
(c) —O—C1-3 alkyl, and
(d) trifluoromethyl,
and where Y is selected from:
a single bond, —O—, —SO2—, —NR10—, —NR10—SO2—, —SO2—NR10—, —S—, and —SO—,
and where R10 is independently selected from:
hydrogen, C1-6 alkyl, benzyl, phenyl, and C1-6 alkyl-C3-6 cycloalkyl,
which is unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from:
halo, C1-3 alkyl, C1-3 alkoxy and trifluoromethyl;
R1 is selected from:
(1) —CO2H,
(2) —NO2,
(3) -tetrazolyl,
(4) -hydroxyisoxazole,
(5) —SO2NHCO—(C0-3 alkyl)-R9, wherein R9 is independently selected from:
hydrogen, C1-6 alkyl, C5-6 cycloalkyl, benzyl or phenyl, which is unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from:
halo, C1-3 alkyl, C1-3 alkoxy and trifluoromethyl, and
(6)—-P(O)(OH)2;
R3 is selected from the group consisting of:
phenyl and heterocycle,
which is unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from:
(a) halo,
(b) trifluoromethyl,
(c) hydroxy,
(d) C1-3 alkyl,
(e) —O—C1-3 alkyl,
(f) —CO2R9,
(g) —NR9R10, and
(h) —CONR9R10;
R4, R5 and R6 are independently selected from:
hydrogen, C1-10 alkyl, C3-8 cycloalkyl, C3-10 alkenyl,
C2-10 alkynyl, phenyl, —(C1-6 alkyl)-phenyl,
—(C1-6 alkyl)-C3-8 cycloalkyl, naphthyl, biphenyl, and heterocycle,
which is unsubstituted or substituted with 1-7 of R11 where R11 is independently selected from:
(a) halo,
(b) trifluoromethyl,
(c) hydroxy,
(d) C1-3 alkyl,
(e) —O—C1-3 alkyl,
(f) —CO2R9,
(g) —NR9R10, and
(h) —CONR9R10,
or where R4 and R5 may be joined together to form a 3-8 membered saturated ring which may be unsubstituted or substituted with 1-7 of R11,
or where R5 and R6 may be joined together to form a 3-8 membered saturated ring which may be unsubstituted or substituted with 1-7 of R11;
R7 is selected from:
(1) hydrogen,
(2) C1-6 alkyl, which is unsubstituted or substituted with 1-4 substituents where the substituents are independently selected from:
hydroxy, cyano, and halo,
(3) hydroxy, and
(4) halo;
R8 is selected from:
hydrogen, C3-8 cycloalkyl, phenyl, naphthyl, biphenyl, and heterocycle,
which is unsubstituted or substituted with 1-7 of R12 where R12 is independently selected from:
(a) halo,
(b) cyano,
(c) hydroxy,
(d) C1-6 alkyl, which is unsubstituted or substituted with 1-5 of R13 where R13 is independently selected from:
halo, cyano, hydroxy, C1-6 alkoxy, —CO2H, —CO2(C1-6 alkyl), trifluoromethyl, and —NR9R10,
(e) —O—C1-6 alkyl, which is unsubstituted or substituted with 1-5 of R13,
(f) —CF3,
(g) —CHF2,
(h) —CH2F,
(i) —NO2,
(j) C0-6 alkyl-phenyl or C0-6 alkyl-heterocycle, which is unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from:
(i) halo,
(ii) hydroxy,
(iii) C1-6 alkyl, unsubstituted or substituted with 1-5 substituents, each of which is independently selected from halo, cyano, hydroxy, C1-6 alkoxy, —CO2H, —CO2(C1-6 alkyl), trifluoromethyl, and —NR9R10,
(iv) —O—C1-6 alkyl,
(v) —CF3,
(vi) —OCF3,
(vii) —NO2,
(viii) —CN,
(ix) —SO2—C1-6 alkyl,
(x) —CO2R9,
(xi) —NR9R10,
(xii) —CONR9R10,
(xiii) —SO2—NR9R10,
(xiv) —NR9—SO2—R10,
(xv) —C3-8 cycloalkyl,
(xvi) —OC3-8 cycloalkyl, and
(xvii) phenyl;
(k) —CO2R9,
(l) tetrazolyl,
(m) —NR9R10,
(n) —NR9—COR10,
(o) —NR9—CO2R10,
(p) —CO—NR9R10,
(q) —OCO—NR9R10,
(r) —NR9CO—NR9R10,
(s) —S(O)m—R9,wherein m is an integer selected from 0, 1 and 2,
(t) —S(O)2—NR9R10,
(u) —NR9S(O)2—R10,
(v) —NR9S(O)2—NR9R10,
(w) C1-6 alkyl substituted with —C3-8 cycloalkyl, and
(x) —C3-8 cycloalkyl;
n is an integer selected from 1, 2, 3 and 4;
x is an integer selected from 0, 1 and 2, and y is an integer selected from 0, 1 and 2, with the proviso that the sum of x and y is 2;
and pharmaceutically acceptable salts thereof and individual diastereomers thereof.

103 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/075,163Filed 14 Feb 2002
Priority: 11 Jun 1999
Published: 29 Aug 2002
Term ends: Not estimatedThe source records don’t support an estimate.

Classification17 codes

C07D 401/04
Containing two hetero rings: directly linked by a ring-member-to-ring-member bond
C07D 211/14
With radicals containing only carbon and hydrogen atoms attached to ring carbon atoms: with hydrocarbon or substituted hydrocarbon radicals…
C07D 211/18
With hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms: with substituted hydrocarbon radicals attached to…
C07D 211/20
With substituted hydrocarbon radicals attached to ring carbon atoms: with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms

Family

Application60/138,886Us provisional application · filed 11 Jun 1999
Application09/590,750Division · filed 8 Jun 2000
Application10/075,163Division · filed 14 Feb 2002
US 6,358,979 B1Related patent
US 6,593,346 B2Related patent
US 2002/0120146 A1This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound of the formula I:

65
wherein:
X is selected from:
—(C0-6 alkyl)—Y—(C0-6 alkyl)—,
—(C0-6 alkyl)—C3-8 cycloalkyl-(C0-6 alkyl)—,
C2-10 alkenyl, and C2-10 alkynyl,
where the alkyl is unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from:
(a) halo,
(b) hydroxy,
(c) —O—C1-3 alkyl, and
(d) trifluoromethyl,
and where Y is selected from:
a single bond, —O—, —SO2—, —NR10—, —NR10—SO2—, —SO2—NR10—, —S—, and —SO—,
and where R10 is independently selected from:
hydrogen, C1-6 alkyl, benzyl, phenyl, and C1-6 alkyl-C3-6 cycloalkyl,
which is unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from:
halo, C1-3 alkyl, C1-3 alkoxy and trifluoromethyl;
R1 is selected from:
(1) —CO2H,
(2) —NO2,
(3) -tetrazolyl,
(4) -hydroxyisoxazole,
(5) —SO2NHCO—(C0-3 alkyl)-R9, wherein R9 is independently selected from:
hydrogen, C1-6 alkyl, C5-6 cycloalkyl, benzyl or phenyl, which is unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from:
halo, C1-3 alkyl, C1-3 alkoxy and trifluoromethyl, and
(6)—-P(O)(OH)2;
R3 is selected from the group consisting of:
phenyl and heterocycle,
which is unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from:
(a) halo,
(b) trifluoromethyl,
(c) hydroxy,
(d) C1-3 alkyl,
(e) —O—C1-3 alkyl,
(f) —CO2R9,
(g) —NR9R10, and
(h) —CONR9R10;
R4, R5 and R6 are independently selected from:
hydrogen, C1-10 alkyl, C3-8 cycloalkyl, C3-10 alkenyl,
C2-10 alkynyl, phenyl, —(C1-6 alkyl)-phenyl,
—(C1-6 alkyl)-C3-8 cycloalkyl, naphthyl, biphenyl, and heterocycle,
which is unsubstituted or substituted with 1-7 of R11 where R11 is independently selected from:
(a) halo,
(b) trifluoromethyl,
(c) hydroxy,
(d) C1-3 alkyl,
(e) —O—C1-3 alkyl,
(f) —CO2R9,
(g) —NR9R10, and
(h) —CONR9R10,
or where R4 and R5 may be joined together to form a 3-8 membered saturated ring which may be unsubstituted or substituted with 1-7 of R11,
or where R5 and R6 may be joined together to form a 3-8 membered saturated ring which may be unsubstituted or substituted with 1-7 of R11;
R7 is selected from:
(1) hydrogen,
(2) C1-6 alkyl, which is unsubstituted or substituted with 1-4 substituents where the substituents are independently selected from:
hydroxy, cyano, and halo,
(3) hydroxy, and
(4) halo;
R8 is selected from:
hydrogen, C3-8 cycloalkyl, phenyl, naphthyl, biphenyl, and heterocycle,
which is unsubstituted or substituted with 1-7 of R12 where R12 is independently selected from:
(a) halo,
(b) cyano,
(c) hydroxy,
(d) C1-6 alkyl, which is unsubstituted or substituted with 1-5 of R13 where R13 is independently selected from:
halo, cyano, hydroxy, C1-6 alkoxy, —CO2H, —CO2(C1-6 alkyl), trifluoromethyl, and —NR9R10,
(e) —O—C1-6 alkyl, which is unsubstituted or substituted with 1-5 of R13,
(f) —CF3,
(g) —CHF2,
(h) —CH2F,
(i) —NO2,
(j) C0-6 alkyl-phenyl or C0-6 alkyl-heterocycle, which is unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from:
(i) halo,
(ii) hydroxy,
(iii) C1-6 alkyl, unsubstituted or substituted with 1-5 substituents, each of which is independently selected from halo, cyano, hydroxy, C1-6 alkoxy, —CO2H, —CO2(C1-6 alkyl), trifluoromethyl, and —NR9R10,
(iv) —O—C1-6 alkyl,
(v) —CF3,
(vi) —OCF3,
(vii) —NO2,
(viii) —CN,
(ix) —SO2—C1-6 alkyl,
(x) —CO2R9,
(xi) —NR9R10,
(xii) —CONR9R10,
(xiii) —SO2—NR9R10,
(xiv) —NR9—SO2—R10,
(xv) —C3-8 cycloalkyl,
(xvi) —OC3-8 cycloalkyl, and
(xvii) phenyl;
(k) —CO2R9,
(l) tetrazolyl,
(m) —NR9R10,
(n) —NR9—COR10,
(o) —NR9—CO2R10,
(p) —CO—NR9R10,
(q) —OCO—NR9R10,
(r) —NR9CO—NR9R10,
(s) —S(O)m—R9,wherein m is an integer selected from 0, 1 and 2,
(t) —S(O)2—NR9R10,
(u) —NR9S(O)2—R10,
(v) —NR9S(O)2—NR9R10,
(w) C1-6 alkyl substituted with —C3-8 cycloalkyl, and
(x) —C3-8 cycloalkyl;
n is an integer selected from 1, 2, 3 and 4;
x is an integer selected from 0, 1 and 2, and y is an integer selected from 0, 1 and 2, with the proviso that the sum of x and y is 2;
and pharmaceutically acceptable salts thereof and individual diastereomers thereof.

103 more elements

Facts

Application

10/075,163Filed 14 Feb 2002

Priority

11 Jun 1999

Published

29 Aug 2002

Term ends

Not estimatedThe source records don’t support an estimate.

Classification17 codes

C07D 401/04
Containing two hetero rings: directly linked by a ring-member-to-ring-member bond
C07D 211/14
With radicals containing only carbon and hydrogen atoms attached to ring carbon atoms: with hydrocarbon or substituted hydrocarbon radicals…
C07D 211/18
With hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms: with substituted hydrocarbon radicals attached to…
C07D 211/20
With substituted hydrocarbon radicals attached to ring carbon atoms: with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms

Family

Application60/138,886Us provisional application · filed 11 Jun 1999

Application09/590,750Division · filed 8 Jun 2000

Application10/075,163Division · filed 14 Feb 2002

US 6,358,979 B1Related patent

US 6,593,346 B2Related patent

US 2002/0120146 A1This patent

From the US filing history. Foreign family members aren’t listed.