US 8,138,175 B2Granted

Heterocyclyl compounds

AssigneeHoffmann-La Roche Inc.

InventorsJean-Michel Adam, Johannes Aebi, Alfred Binggeli, Luke Green, Guido Hartmann, Hans P. Maerki, Patrizio Mattei, Fabienne Ricklin, Olivier Roche

Life of this patent

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Abstract

The invention is concerned with novel heterocyclyl compounds of formula (I): wherein A, X, R3, R4, R5, R6, R7, R8, R9, R10, m, n and p are as defined in the description and in the claims, as well as physiologically acceptable salts thereof. These compounds are antagonists of CCR2 receptor, CCR5 receptor and/or CCR3 receptor and may be used as medicaments.

Claims23

Dependent claims

A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
A is phenyl or napthyl, which is optionally substituted by one to three substituents independently selected from the group consisting of halogen, aryl, halo C1-6 alkyl, and halo C1-6 alkoxy;
X is —N(R1)(R2);
R1 and R2 are independently selected from the group consisting of:
(1) hydrogen,
(2) C1-6 alkyl,
(3) C3-6 alkenyl,
(4) C3-6 alkynyl,
(5) hydroxy C2-6 alkyl,
(6) C1-6 alkoxy C2-6 alkyl,
(7) C3-7 cycloalkyl, which is optionally substituted one to three times by Rd,
(8) C3-7 cycloalkyl C1-6 alkyl, wherein the C3-7 cycloalkyl portion of said C3-7 cycloalkyl C1-6 alkyl is optionally substituted one to three times by Rd,
(9) C7-10 bicycloalkyl,
(10) phenyl C1-3 alkyl, wherein the phenyl portion of said phenyl C1-3 alkyl is optionally substituted one to three times by Rd,
(11) heteroaryl C1-3 alkyl, wherein the heteroaryl portion of said heteroaryl C1-3 alkyl is optionally substituted one to three times by Rd,
(12) heterocyclyl, which is optionally substituted one to three times by Rd, and
(13) heterocyclyl C1-6 alkyl, wherein the heterocyclyl portion of said heterocyclyl C1-6 alkyl is optionally substituted one to three times by Rd;
provided that at least one of R1 and R2 is not hydrogen;
or alternatively,
R1 and R2, together with the nitrogen atom to which they are attached, form a heterocyclyl optionally substituted one to three times by Rd, and wherein:
(a) one of the ring carbon atoms of said heterocyclyl formed by R1 and R2 is optionally replaced with a carbonyl group;
and/or (b) one of the ring carbon atoms of said heterocyclyl formed by R1 and R2 is also a ring carbon atom of another ring which is a C3-7 cycloalkyl or heterocyclyl, which is optionally substituted by a C1-6 alkyl, and wherein one or two ring carbon atoms of said C3-7 cycloalkyl or heterocyclyl is optionally replaced by a carbonyl group;
R3 and R4 are independently selected from the group consisting of:
(1) hydrogen,
(2) hydroxy,
(3) C1-6 alkyl,
(4) C1-6 alkoxy,
(5) C3-7 cycloalkyl,
(6) C3-7 cycloalkyl C1-6 alkyl,
(7) C1-6 alkoxycarbonyl,
(8) carboxyl,
(9) carbamoyl,
(10) mono or di-C1-6 alkyl substituted carbamoyl,
(11) C1-6 alkoxycarbonyloxy,
(12) mono or di-C1-6 alkyl substituted aminocarbonyloxy,
(13) hydroxy-C1-6 alkyl,
(14) C1-6 alkoxy-C1-6 alkyl,
(15) halogen or halo C1-6 alkyl,
(16) optionally substituted heterocyclyl-carbonyl, and
(17) RaaRbbN—C(O)— wherein Raa and Rbb are independently selected from the group consisting of hydrogen, C1-6 alkyl, hydroxy-C1-6 alkyl and C3-7 cycloalkyl;
or alternatively,
R3 and R4, together with the carbon atom to which they are attached, form C3-7 cycloalkyl or heterocyclyl optionally substituted by one to three substituents independently selected from the group consisting of C1-4 alkyl, halo C1-4 alkyl and halogen;
R5 and R6 are independently hydrogen, C1-6 alkyl or C3-7 cycloalkyl, wherein said C1-6 alkyl and said C3-7 cycloalkyl are optionally substituted by one to three substituents independently selected from the group consisting of:
(1) amino, (2) hydroxy, (3) carboxyl, (4) carbamoyl, (5) mono or di-C1-6 alkyl substituted carbamoyl and (6) C1-6 alkoxycarbonyl;
or alternatively R5 and R6, together with the carbon atom to which they are attached, form C3-7 cycloalkyl or heterocyclyl;
R7, R8, R9 and R10 are independently hydrogen, C1-6 alkyl, C3-7 cycloalkyl, or aryl;
wherein said C1-6 alkyl is optionally substituted by one to three substituents independently selected from the group consisting of:
(1) hydroxy,
(2) C1-6 alkoxy,
(3) carboxyl,
(4) carbamoyl,
(5) mono or di-C1-6 alkyl substituted carbamoyl,
(6) C1-6 alkoxycarbonyl,
(7) aryl, optionally substituted by one to three substituents independently selected from the group consisting of halogen, C1-6 alkyl, halo C1-6 alkyl, C1-6 alkoxy and halo C1-6 alkoxy, and
(8) heteroaryl, optionally substituted by one to three substituents independently selected from the group consisting of halogen, C1-6 alkyl, halo C1-6 alkyl, C1-6 alkoxy and halo C1-6 alkoxy;
Rd is selected from the group consisting of:
(1) hydroxy,
(2) cyano,
(3) NRaRb,
(4) halogen,
(5) C1-6 alkyl,
(6) halo C1-6 alkyl,
(7) hydroxy C1-6 alkyl,
(8) C1-6 alkoxy,
(9) C1-6 alkoxy C1-6 alkyl,
(10) C3-7 cycloalkyl,
(11) C1-6 alkoxycarbonyl,
(12) acyl,
(13) —C(O)NRaRb,
(14) —NRa—C(O)—Rb,
(15) —NRa—C(O)—ORb,
(16) —NRa—C(O)—NRb,
(17) —NRa—SO2—Rb,
(18) —NRa—SO2—NRbRc,
(19) —OC(O)NRaRb,
(20) —OC(O)ORa,
(21) C1-6 alkylsulfonyl,
(22) C1-6 alkylsulfinyl,
(23) C1-6 alkylthio,
(24) phenyl or phenyl C1-3 alkyl, wherein the phenyl or phenyl portion of said phenyl C1-3 alkyl is optionally substituted one to three times by a substituent independently selected from the group consisting of hydroxy, cyano, NRaRb, halogen, C1-6 alkyl, halo C1-6 alkyl, hydroxy C1-6 alkyl, C1-6 alkoxycarbonyl, acyl, —C(O)NRaRb, —NRa—C(O)—Rb, —NRa—C(O)—ORb, —NRa—C(O)—NRb, —NRa—SO2—Rb, —NRa—SO2—NRbRc,
—OC(O)NRaRb, —OC(O)ORa, C1-6 alkylsulfonyl, C1-6 alkylsulfinyl, and C1-6 alkylthio;
(25) heteroaryl or heteroaryl C1-3 alkyl, wherein the heteroaryl or heteroaryl portion of said heteroaryl C1-3 alkyl is optionally substituted one to three times by a substituent independently selected from the group consisting of hydroxy, cyano, NRaRb, halogen, C1-6 alkyl, halo C1-6 alkyl, hydroxy C1-6 alkyl, C1-6 alkoxycarbonyl, acyl, —C(O)NRaRb, —NRa—C(O)—Rb, —NRa—C(O)—ORb, —NRa—C(O)—NRb, —NRa—SO2—Rb, —NRa—SO2—NRbRc,
—OC(O)NRaRb, —OC(O)ORa, C1-6 alkylsulfonyl, C1-6 alkylsulfinyl, and C1-6 alkylthio;
and
(26) heterocyclyl, which is optionally substituted one to three times by a substituent independently selected from the group consisting of hydroxy, cyano, NRaRb, halogen, C1-6 alkyl, halo C1-6 alkyl, hydroxy C1-6 alkyl, C1-6 alkoxycarbonyl, acyl, —C(O)NRaRb, —NRa—C(O)—Rb, —NRa—C(O)—ORb, —NRa—C(O)—NRb, —NRa—SO2—Rb, —NRa—SO2—NRbRc,
—OC(O)NRaRb, —OC(O)ORa, C1-6 alkylsulfonyl, C1-6 alkylsulfinyl, and C1-6 alkylthio, and wherein one or two ring carbon atoms of the heterocyclyl is optionally replaced with a carbonyl group;
Ra, Rb and Rc are independently hydrogen or C1-6 alkyl;
m is an integer of 0 to 3;
n is an integer of 0 to 3;
m+n is an integer of 1 to 5;
and
p is 1.

89 more elements

Dependencies are inferred from the claim text.

Facts

Application: 12/507,858Filed 23 Jul 2009
Priority: EP 0816127828 Jul 2008
Published: US 2010/0022518 A128 Jan 2010
Granted: 20 Mar 2012
Term ends: Not estimatedThe source records don’t support an estimate.

Classification20 codes

C07D 401/06
Containing two hetero rings: linked by a carbon chain containing only aliphatic carbon atoms
A61P 1/04
Drugs for disorders of the alimentary tract or the digestive system: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of…
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics
A61P 9/00
Drugs for disorders of the cardiovascular system

Family

US 2010/0022518 A1Pre-grant publication · published 28 Jan 2010
US 8,138,175 B2This patent

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

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Abstract

A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
A is phenyl or napthyl, which is optionally substituted by one to three substituents independently selected from the group consisting of halogen, aryl, halo C1-6 alkyl, and halo C1-6 alkoxy;
X is —N(R1)(R2);
R1 and R2 are independently selected from the group consisting of:
(1) hydrogen,
(2) C1-6 alkyl,
(3) C3-6 alkenyl,
(4) C3-6 alkynyl,
(5) hydroxy C2-6 alkyl,
(6) C1-6 alkoxy C2-6 alkyl,
(7) C3-7 cycloalkyl, which is optionally substituted one to three times by Rd,
(8) C3-7 cycloalkyl C1-6 alkyl, wherein the C3-7 cycloalkyl portion of said C3-7 cycloalkyl C1-6 alkyl is optionally substituted one to three times by Rd,
(9) C7-10 bicycloalkyl,
(10) phenyl C1-3 alkyl, wherein the phenyl portion of said phenyl C1-3 alkyl is optionally substituted one to three times by Rd,
(11) heteroaryl C1-3 alkyl, wherein the heteroaryl portion of said heteroaryl C1-3 alkyl is optionally substituted one to three times by Rd,
(12) heterocyclyl, which is optionally substituted one to three times by Rd, and
(13) heterocyclyl C1-6 alkyl, wherein the heterocyclyl portion of said heterocyclyl C1-6 alkyl is optionally substituted one to three times by Rd;
provided that at least one of R1 and R2 is not hydrogen;
or alternatively,
R1 and R2, together with the nitrogen atom to which they are attached, form a heterocyclyl optionally substituted one to three times by Rd, and wherein:
(a) one of the ring carbon atoms of said heterocyclyl formed by R1 and R2 is optionally replaced with a carbonyl group;
and/or (b) one of the ring carbon atoms of said heterocyclyl formed by R1 and R2 is also a ring carbon atom of another ring which is a C3-7 cycloalkyl or heterocyclyl, which is optionally substituted by a C1-6 alkyl, and wherein one or two ring carbon atoms of said C3-7 cycloalkyl or heterocyclyl is optionally replaced by a carbonyl group;
R3 and R4 are independently selected from the group consisting of:
(1) hydrogen,
(2) hydroxy,
(3) C1-6 alkyl,
(4) C1-6 alkoxy,
(5) C3-7 cycloalkyl,
(6) C3-7 cycloalkyl C1-6 alkyl,
(7) C1-6 alkoxycarbonyl,
(8) carboxyl,
(9) carbamoyl,
(10) mono or di-C1-6 alkyl substituted carbamoyl,
(11) C1-6 alkoxycarbonyloxy,
(12) mono or di-C1-6 alkyl substituted aminocarbonyloxy,
(13) hydroxy-C1-6 alkyl,
(14) C1-6 alkoxy-C1-6 alkyl,
(15) halogen or halo C1-6 alkyl,
(16) optionally substituted heterocyclyl-carbonyl, and
(17) RaaRbbN—C(O)— wherein Raa and Rbb are independently selected from the group consisting of hydrogen, C1-6 alkyl, hydroxy-C1-6 alkyl and C3-7 cycloalkyl;
or alternatively,
R3 and R4, together with the carbon atom to which they are attached, form C3-7 cycloalkyl or heterocyclyl optionally substituted by one to three substituents independently selected from the group consisting of C1-4 alkyl, halo C1-4 alkyl and halogen;
R5 and R6 are independently hydrogen, C1-6 alkyl or C3-7 cycloalkyl, wherein said C1-6 alkyl and said C3-7 cycloalkyl are optionally substituted by one to three substituents independently selected from the group consisting of:
(1) amino, (2) hydroxy, (3) carboxyl, (4) carbamoyl, (5) mono or di-C1-6 alkyl substituted carbamoyl and (6) C1-6 alkoxycarbonyl;
or alternatively R5 and R6, together with the carbon atom to which they are attached, form C3-7 cycloalkyl or heterocyclyl;
R7, R8, R9 and R10 are independently hydrogen, C1-6 alkyl, C3-7 cycloalkyl, or aryl;
wherein said C1-6 alkyl is optionally substituted by one to three substituents independently selected from the group consisting of:
(1) hydroxy,
(2) C1-6 alkoxy,
(3) carboxyl,
(4) carbamoyl,
(5) mono or di-C1-6 alkyl substituted carbamoyl,
(6) C1-6 alkoxycarbonyl,
(7) aryl, optionally substituted by one to three substituents independently selected from the group consisting of halogen, C1-6 alkyl, halo C1-6 alkyl, C1-6 alkoxy and halo C1-6 alkoxy, and
(8) heteroaryl, optionally substituted by one to three substituents independently selected from the group consisting of halogen, C1-6 alkyl, halo C1-6 alkyl, C1-6 alkoxy and halo C1-6 alkoxy;
Rd is selected from the group consisting of:
(1) hydroxy,
(2) cyano,
(3) NRaRb,
(4) halogen,
(5) C1-6 alkyl,
(6) halo C1-6 alkyl,
(7) hydroxy C1-6 alkyl,
(8) C1-6 alkoxy,
(9) C1-6 alkoxy C1-6 alkyl,
(10) C3-7 cycloalkyl,
(11) C1-6 alkoxycarbonyl,
(12) acyl,
(13) —C(O)NRaRb,
(14) —NRa—C(O)—Rb,
(15) —NRa—C(O)—ORb,
(16) —NRa—C(O)—NRb,
(17) —NRa—SO2—Rb,
(18) —NRa—SO2—NRbRc,
(19) —OC(O)NRaRb,
(20) —OC(O)ORa,
(21) C1-6 alkylsulfonyl,
(22) C1-6 alkylsulfinyl,
(23) C1-6 alkylthio,
(24) phenyl or phenyl C1-3 alkyl, wherein the phenyl or phenyl portion of said phenyl C1-3 alkyl is optionally substituted one to three times by a substituent independently selected from the group consisting of hydroxy, cyano, NRaRb, halogen, C1-6 alkyl, halo C1-6 alkyl, hydroxy C1-6 alkyl, C1-6 alkoxycarbonyl, acyl, —C(O)NRaRb, —NRa—C(O)—Rb, —NRa—C(O)—ORb, —NRa—C(O)—NRb, —NRa—SO2—Rb, —NRa—SO2—NRbRc,
—OC(O)NRaRb, —OC(O)ORa, C1-6 alkylsulfonyl, C1-6 alkylsulfinyl, and C1-6 alkylthio;
(25) heteroaryl or heteroaryl C1-3 alkyl, wherein the heteroaryl or heteroaryl portion of said heteroaryl C1-3 alkyl is optionally substituted one to three times by a substituent independently selected from the group consisting of hydroxy, cyano, NRaRb, halogen, C1-6 alkyl, halo C1-6 alkyl, hydroxy C1-6 alkyl, C1-6 alkoxycarbonyl, acyl, —C(O)NRaRb, —NRa—C(O)—Rb, —NRa—C(O)—ORb, —NRa—C(O)—NRb, —NRa—SO2—Rb, —NRa—SO2—NRbRc,
—OC(O)NRaRb, —OC(O)ORa, C1-6 alkylsulfonyl, C1-6 alkylsulfinyl, and C1-6 alkylthio;
and
(26) heterocyclyl, which is optionally substituted one to three times by a substituent independently selected from the group consisting of hydroxy, cyano, NRaRb, halogen, C1-6 alkyl, halo C1-6 alkyl, hydroxy C1-6 alkyl, C1-6 alkoxycarbonyl, acyl, —C(O)NRaRb, —NRa—C(O)—Rb, —NRa—C(O)—ORb, —NRa—C(O)—NRb, —NRa—SO2—Rb, —NRa—SO2—NRbRc,
—OC(O)NRaRb, —OC(O)ORa, C1-6 alkylsulfonyl, C1-6 alkylsulfinyl, and C1-6 alkylthio, and wherein one or two ring carbon atoms of the heterocyclyl is optionally replaced with a carbonyl group;
Ra, Rb and Rc are independently hydrogen or C1-6 alkyl;
m is an integer of 0 to 3;
n is an integer of 0 to 3;
m+n is an integer of 1 to 5;
and
p is 1.

89 more elements

Facts

Application

12/507,858Filed 23 Jul 2009

Priority

EP 0816127828 Jul 2008

Published

US 2010/0022518 A128 Jan 2010

Granted

20 Mar 2012

Term ends

Not estimatedThe source records don’t support an estimate.

Classification20 codes

C07D 401/06
Containing two hetero rings: linked by a carbon chain containing only aliphatic carbon atoms
A61P 1/04
Drugs for disorders of the alimentary tract or the digestive system: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of…
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics
A61P 9/00
Drugs for disorders of the cardiovascular system