US 2010/0144791 A1 · CANNABINOID RECEPTOR ANTAGONISTS/INVERSE AGONISTS USEFUL FOR TREATING OBESITY

Abstract

The present invention provides novel pyrazoles that are useful as cannabinoid receptor antagonists and pharmaceutical compositions thereof and methods of using the same for treating obesity, diabetes, and/or cardiometabolic disorders.

Claims26

Dependent claims

1-11. (canceled)

A method of treating a disease, comprising:

administering to a mammal in need thereof a therapeutically effective amount of a compound of formula I or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the disease is selected from obesity, diabetes, cardiometabolic disorders, and a combination thereof:
wherein:
X and Y are independently selected from H, halogen, C1-6 alkyl, NO2, CF3, NR2, OR, CO2R, (CH2)nCO2R, O(CH2)nCO2R, OCH2CH═CHCO2R, CH2O(CH2)nCO2R, CH2CH2CH═CHCO2R, O(CH2)nPO(OR)2, CH2O(CH2)nPO(OR)2, NRa(CH2)nCO2R, NRa(CH2)nPO(OR)2, NRaCH2CH═CHCO2R, NRaSO2CH3, NRaCO(CH2)nCO2R, O(CH2)nC6H4CO2R, O(CH2)nC6H4(CH2)nCO2R, CH2O(CH2)nC6H4CO2R, O(CH2)nC6H4CONH2, O(CH2)nC6H4(CH2)nCONH2, CH2O(CH2)nC6H4CONH2, O(CH2)nC6H4-tetrazole, CH2O(CH2)nC6H4-tetrazole, O(CH2)nC6H4(CH2)n-tetrazole, NRa(CH2)nC6H4CO2R, CH2NRa(CH2)nC6H4CO2R, NRa(CH2)nC6H4CONH2, CH2NRa(CH2)nC6H4CONH2, NRa(CH2)nC6H4-tetrazole, CH2NRa(CH2)nC6H4-tetrazole, —CN, (CH2)mC(NH)NH2, CONR2, (CH2)nCONR2, O(CH2)nCONR2, CH2O(CH2)nCONH2, NRa(CH2)nCONR2, OCH2CH═CHCONR2, CH2OCH2CH═CHCONR2, NRaCH2CH═CHCONR2, -tetrazole, O(CH2CH2O)pR, NRa(CH2CH2O)pR, and SO2NRaCH3;
X′ and Y′ are independently selected from H, halogen, C1-6 alkyl, NO2, CF3, NR2, OR, CO2R, (CH2)nCO2R, O(CH2)nCO2R, OCH2CH═CHCO2R, CH2O(CH2)nCO2R, CH2OCH2CH═CHCO2R, O(CH2)nPO(OR)2, CH2O(CH2)nPO(OR)2, NRa(CH2)nCO2R, NRa(CH2)nPO(OR)2, NRaCH2CH═CHCO2R, NRaSO2CH3, NRaCO(CH2)nCO2R, O(CH2)nC6H4CO2R, O(CH2)nC6H4(CH2)nCO2R, CH2O(CH2)nC6H4CO2R, O(CH2)nC6H4CONH2, O(CH2)nC6H4(CH2)nCONH2, CH2O(CH2)nC6H4CONH2, O(CH2)nC6H4-tetrazole, CH2O(CH2)nC6H4-tetrazole, O(CH2)nC6H4(CH2)n-tetrazole, NRa(CH2)nC6H4CO2R, CH2NRa(CH2)nC6H4CO2R, NRa(CH2)nC6H4CONH2, CH2NRa(CH2)nC6H4CONH2, NRa(CH2)nC6H4-tetrazole, CH2NRa(CH2)nC6H4-tetrazole, —CN, (CH2)mC(NH)NH2, CONR2, (CH2)nCONR2, O(CH2)nCONR2, CH2O(CH2)nCONH2, NRa(CH2)nCONR2, OCH2CH═CHCONR2, CH2OCH2CH═CHCONR2, NRaCH2CH═CHCONR2, -tetrazole, O(CH2CH2O)pR, NRa(CH2CH2O)pR, and SO2NRaCH3;
A is selected from H, C1-6 alkyl, (CH2)mC3-6-cycloalkyl, (CH2)m-heteroaryl, and (CH2)m-aryl, wherein each aryl and heteroaryl is substituted with 0-1 groups selected from CF3, halogen, C1-4 alkyl, —CN, CONR2, NO2, NR2, and OR;
R′ is
R″ is selected from H, C1-6 alkyl and (CH2)0-6 aryl;
Z is selected from H, C1-6 alkyl, aryl, NR2, OR, —CN, (CH2)mC(NH)NH2, CO2R, (CH2)nCO2R, O(CH2)nCO2R, CH2O(CH2)nCO2R, NRaCH(A)CO2R, CH2NRaCH(A)CO2R, NRa(CH2)nCO2RCH2NRa(CH2)nCO2ROCH2CH═CHCO2R, CH2OCH2CH═CHCO2R, O(CH2)nPO(OR)2, CH2O(CH2)nPO(OR)2, O(CH2)nC6H4CO2R, CH2O(CH2)nC6H4CO2R, CONR2, (CH2)nCONR2, O(CH2)nCONR2, CH2O(CH2)nCONR2, OCH2CH═CHCONR2, CH2OCH2CH═CHCONR2, CH2NRa(CH2)ntetrazole, CH2O(CH2)ntetrazole, and (CH2)mtetrazole;
Q is selected from N, CH, and CQ′;
Q′ is selected from H, CO2R, (CH2)nCO2R, CH2O(CH2)nCO2R, CH2OCH2CH═CHCO2R, CH2O(CH2)nPO(OR)2, CONR2, (CH2)nCONR2, CH2O(CH2)nCONR2, CH2OCH2CH═CHCONR2, and (CH2)mtetrazole;
V is selected from H, C1-6 alkyl, C2-6 alkenyl, CF3, aryl, —CN, (CH2)mC(NH)NH2, (CH2)mCO2R, (CH2)mCONR2, (CH2)m-tetrazole, (CH2)mCONRaCH(A)-(CH2)mCO2R, (CH2)mCONRa(CH2)m-phenyl-(CH2)mCO2R, (CH2)mCONRa(CH2)m-phenyl-(CH2)m-tetrazole, CH2O(CH2)nCO2R, CH2NRa(CH2)nCO2R, CH2O(CH2)nCONH2, CH2NRa(CH2)nCONH2, and CH2O(CH2)ntetrazole;
R is independently selected from H, C1-6 alkyl;
Ra is independently selected from H, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;
m is selected from 0, 1, 2, 3, and 4;
n is selected from 1, 2, 3, and 4;
and,
p is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12;
provided that at least one of the following is satisfied:
(a) at least one of X, Y, X′, and Y′ is other than H, halogen, C1-6 alkyl, NO2, —CN, CF3, OR, and phenyl;
(b) Z is present and is other than H, —C1-6 alkyl, aryl, NR2, and OR;
(c) Q is present and is CQ′ where Q′ is other than H;
and/or
(d) V is other than H, —CN, CF3C2-6 alkenyl, aryl, and C1-6 alkyl.

20 more elements

A method of treating a co-morbidity of obesity, comprising:

administering to a mammal in need thereof a therapeutically effective amount of a compound of formula I or a stereoisomer or pharmaceutically acceptable salt thereof:
wherein:
X and Y are independently selected from H, halogen, C1-6 alkyl, NO2, CF3, NR2, OR, CO2R, (CH2)nCO2R, O(CH2)nCO2R, OCH2CH═CHCO2R, CH2O(CH2)nCO2R, CH2OCH2CH═CHCO2R, O(CH2)nPO(OR)2, CH2O(CH2)nPO(OR)2, NRa(CH2)nCO2R, NRa(CH2)nPO(OR)2, NRaCH2CH═CHCO2R, NRaSO2CH3, NRaCO(CH2)nCO2R, O(CH2)nC6H4CO2R, O(CH2)nC6H4(CH2)nCO2R, CH2O(CH2)nC6H4CO2R, O(CH2)nC6H4CONH2, O(CH2)nC6H4(CH2)nCONH2, CH2O(CH2)nC6H4CONH2, O(CH2)nC6H4-tetrazole, CH2O(CH2)nC6H4-tetrazole, O(CH2)nC6H4(CH2)n-tetrazole, NRa(CH2)nC6H4CO2R, CH2NRa(CH2)nC6H4CO2R, NRa(CH2)nC6H4CONH2, CH2NRa(CH2)nC6H4CONH2, NRa(CH2)nC6H4-tetrazole, CH2NRa(CH2)nC6H4-tetrazole, —CN, (CH2)mC(NH)NH2, CONR2, (CH2)nCONR2, O(CH2)nCONR2, CH2O(CH2)nCONH2, NRa(CH2)nCONR2, OCH2CH═CHCONR2, CH2OCH2CH═CHCONR2, NRaCH2CH═CHCONR2, -tetrazole, O(CH2CH2O)pR, NRa(CH2CH2O)pR, and SO2NRaCH3;
X′ and Y′ are independently selected from H, halogen, C1-6 alkyl, NO2, CF3, NR2, OR, CO2R, (CH2)nCO2R, O(CH2)nCO2R, OCH2CH═CHCO2R, CH2O(CH2)nCO2R, CH2OCH2CH═CHCO2R, O(CH2)nPO(OR)2, CH2O(CH2)nPO(OR)2, NRa(CH2)nCO2R, NRa(CH2)nPO(OR)2, NRaCH2CH═CHCO2R, NRaSO2CH3, NRaCO(CH2)nCO2R, O(CH2)nC6H4CO2R, O(CH2)nC6H4(CH2)nCO2R, CH2O(CH2)nC6H4CO2R, O(CH2)nC6H4CONH2, O(CH2)nC6H4(CH2)nCONH2, CH2O(CH2)nC6H4CONH2, O(CH2)nC6H4-tetrazole, CH2O(CH2)nC6H4-tetrazole, O(CH2)nC6H4(CH2)n-tetrazole, NRa(CH2)nC6H4CO2R, CH2NRa(CH2)nC6H4CO2R, NRa(CH2)nC6H4CONH2, CH2NRa(CH2)nC6H4CONH2, NRa(CH2)nC6H4-tetrazole, CH2NRa(CH2)nC6H4-tetrazole, —CN, (CH2)mC(NH)NH2, CONR2, (CH2)nCONR2, O(CH2)nCONR2, CH2O(CH2)nCONH2, NRa(CH2)nCONR2, OCH2CH═CHCONR2, CH2OCH2CH═CHCONR2, NRaCH2CH═CHCONR2, -tetrazole, O(CH2CH2O)pR, NRa(CH2CH2O)pR, and SO2NRaCH3;
A is selected from H, C1-6 alkyl, (CH2)mC3-6-cycloalkyl, (CH2)m-heteroaryl, and (CH2)m-aryl, wherein each aryl and heteroaryl is substituted with 0-1 groups selected from CF3, halogen, C1-4 alkyl, —CN, CONR2, NO2, NR2, and OR;
R′ is
R″ is selected from H, C1-6alkyl and (CH2)0-6 aryl;
Z is selected from H, C1-6 alkyl, aryl, NR2, OR, —CN, (CH2)mC(NH)NH2, CO2R, (CH2)nCO2R, O(CH2)nCO2R, CH2O(CH2)nCO2R, NRaCH(A)CO2R, CH2NRaCH(A)CO2R, NRa(CH2)nCO2RCH2NRa(CH2)nCO2ROCH2CH═CHCO2R, CH2OCH2CH═CHCO2R, O(CH2)nPO(OR)2, CH2O(CH2)nPO(OR)2, O(CH2)nC6H4CO2R, CH2O(CH2)nC6H4C2R, CONR2, (CH2)nCONR2, O(CH2)nCONR2, CH2O(CH2)nCONR2, OCH2CH═CHCONR2, CH2OCH2CH═CHCONR2, CH2NRa(CH2)ntetrazole, CH2O(CH2)ntetrazole, and (CH2)mtetrazole;
Q is selected from N, CH, and CQ′;
Q′ is selected from H, CO2R, (CH2)nCO2R, CH2O(CH2)nCO2R, CH2OCH2CH═CHCO2R, CH2O(CH2)nPO(OR)2, CONR2, (CH2)nCONR2, CH2O(CH2)nCONR2, CH2OCH2CH═CHCONR2, and (CH2)mtetrazole;
V is selected from H, C1-6 alkyl, C2-6 alkenyl, CF3, aryl, —CN, (CH2)mC(NH)NH2, (CH2)mCO2R, (CH2)mCONR2, (CH2)m-tetrazole, (CH2)mCONRaCH(A)-(CH2)mCO2R, (CH2)m CONRa(CH2)m-phenyl-(CH2)mCO2R, (CH2)mCONRa(CH2)m-phenyl-(CH2)m-tetrazole, CH2O(CH2)nCO2R, CH2NRa(CH2)nCO2R, CH2O(CH2)nCONH2, CH2NRa(CH2)nCONH2, and CH2O(CH2)ntetrazole;
R is independently selected from H, C1-6 alkyl;
Ra is independently selected from H, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;
m is selected from 0, 1, 2, 3, and 4;
n is selected from 1, 2, 3, and 4;
and,
p is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12;
provided that at least one of the following is satisfied:
(a) at least one of X, Y, X′, and Y′ is other than H, halogen, C1-6 alkyl, NO2, —CN, CF3, OR, and phenyl;
(b) Z is present and is other than H, —C1-6 alkyl, aryl, NR2, and OR;
(c) Q is present and is CQ′ where Q′ is other than H;
and/or
(d) V is other than H, —CN, CF3, C2-6 alkenyl, aryl, and C1-6 alkyl.

20 more elements

A method of treating a disease, comprising:

administering to a mammal in need thereof a therapeutically effective amount of
a. a compound of formula I or a stereoisomer or pharmaceutically acceptable salt thereof, and
b. a second therapeutic agent;
wherein the disease is selected from obesity, diabetes, cardiometabolic disorders, and a combination thereof and the second therapeutic agent is useful for treating the disease:
wherein:
X and Y are independently selected from H, halogen, C1-6 alkyl, NO2, CF3, NR2, OR, CO2R, (CH2)nCO2R, O(CH2)nCO2R, OCH2CH═CHCO2R, CH2O(CH2)nCO2R, CH2OCH2CH═CHCO2R, O(CH2)nPO(OR)2, CH2O(CH2)nPO(OR)2, NRa(CH2)nCO2R, NRa(CH2)nPO(OR)2, NRaCH2CH═CHCO2R, NRaSO2CH3, NRaCO(CH2)nCO2R, O(CH2)nC6H4CO2R, O(CH2)nC6H4(CH2)nCO2R, CH2O(CH2)nC6H4CO2R, O(CH2)nC6H4CONH2, O(CH2)nC6H4(CH2)nCONH2, CH2O(CH2)nC6H4CONH2, O(CH2)nC6H4-tetrazole, CH2O(CH2)nC6H4-tetrazole, O(CH2)nC6H4(CH2)n-tetrazole, NRa(CH2)nC6H4CO2R, CH2NRa(CH2)nC6H4CO2R, NRa(CH2)nC6H4CONH2, CH2NRa(CH2)nC6H4CONH2, NRa(CH2)nC6H4-tetrazole, CH2NRa(CH2)nC6H4-tetrazole, —CN, (CH2)mC(NH)NH2, CONR2, (CH2)nCONR2, O(CH2)nCONR2, CH2O(CH2)nCONH2, NRa(CH2)nCONR2, OCH2CH═CHCONR2, CH2OCH2CH═CHCONR2, NRaCH2CH═CHCONR2, -tetrazole, O(CH2CH2O)pR, NRa(CH2CH2O)pR, and SO2NRaCH3;
X′ and Y′ are independently selected from H, halogen, C1-6 alkyl, NO2, CF3, NR2, OR, CO2R, (CH2)nCO2R, O(CH2)nC2R, OCH2CH═CHCO2R, CH2O(CH2)nCO2R, CH2OCH2CH═CHCO2R, O(CH2)nPO(OR)2, CH2O(CH2)nPO(OR)2, NRa(CH2)nCO2R, NRa(CH2)nPO(OR)2, NRaCH2CH═CHCO2R, NRaSO2CH3, NRaCO(CH2)nCO2R, O(CH2)nC6H4CO2R, O(CH2)nC6H4(CH2)nCO2R, CH2O(CH2)nC6H4CO2R, O(CH2)nC6H4CONH2, O(CH2)nCONH2, CH2O(CH2)nC6H4CONH2, O(CH2)nC6H4-tetrazole, CH2O(CH2)nC6H4-tetrazole, O(CH2)nC6H4(CH2)n-tetrazole, NRa(CH2)nC6H4CO2R, CH2NRa(CH2)nC6H4C2R, NRa(CH2)nC6H4CONH2, CH2NRa(CH2)nC6H4CONH2, NRa(CH2)nC6H4-tetrazole, CH2NRa(CH2)nC6H4-tetrazole, —CN, (CH2)mC(NH)NH2, CONR2, (CH2)nCONR2, O(CH2)nCONR2, CH2O(CH2)nCONH2, NRa(CH2)nCONR2, OCH2CH═CHCONR2, CH2OCH2CH═CHCONR2, NRaCH2CH═CHCONR2, -tetrazole, O(CH2CH2O)pR, NRa(CH2CH2O)pR, and SO2NRaCH3;
A is selected from H, C1-6 alkyl, (CH2)m—C3-6-cycloalkyl, (CH2)m-heteroaryl, and (CH2)m-aryl, wherein each aryl and heteroaryl is substituted with 0-1 groups selected from CF3, halogen, C1-4 alkyl, —CN, CONR2, NO2, NR2, and OR;
R′ is
R″ is selected from H, C1-6 alkyl and (CH2)0-6 aryl;
Z is selected from H, C1-6 alkyl, aryl, NR2, OR, —CN, (CH2)mC(NH)NH2, CO2R, (CH2)nC2R, O(CH2)nCO2R, CH2O(CH2)nC2R, NRaCH(A)CO2R, CH2NRaCH(A)CO2R, NRa(CH2)nCO2RCH2NRa(CH2)nCO2ROCH2CH═CHCO2R, CH2OCH2CH═CHCO2R, O(CH2)nPO(OR)2, CH2O(CH2)nPO(OR)2, O(CH2)nC6H4CO2R, CH2O(CH2)nC6H4CO2R, CONR2, (CH2)nCONR2, O(CH2)nCONR2, CH2O(CH2)nCONR2, OCH2CH═CHCONR2, CH2OCH2CH═CHCONR2, CH2NRa(CH2)ntetrazole, CH2O(CH2)ntetrazole, and (CH2)mtetrazole;
Q is selected from N, CH, and CQ′;
Q′ is selected from H, CO2R, (CH2)nCO2R, CH2O(CH2)nCO2R, CH2OCH2CH═CHCO2R, CH2O(CH2)nPO(OR)2, CONR2, (CH2)nCONR2, CH2O(CH2)nCONR2, CH2OCH2CH═CHCONR2 and (CH2)mtetrazole;
V is selected from H, C1-6 alkyl, C2-6 alkenyl, CF3, aryl, —CN, (CH2)mC(NH)NH2, (CH2)mCO2R, (CH2)mCONR2, (CH2)m-tetrazole, (CH2)mCONRaCH(A)-(CH2)mCO2R, (CH2)mCONRa(CH2)m-phenyl-(CH2)mCO2R, (CH2)mCONRa(CH2)m-phenyl-(CH2)m-tetrazole, CH2O(CH2)nCO2R, CH2NRa(CH2)nCO2R, CH2O(CH2)nCONH2, CH2NRa(CH2)nCONH2, and CH2O(CH2)ntetrazole;
R is independently selected from H, C1-6 alkyl;
Ra is independently selected from H, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;
m is selected from 0, 1, 2, 3, and 4;
n is selected from 1, 2, 3, and 4;
and,
p is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12;
provided that at least one of the following is satisfied:
(a) at least one of X, Y, X′, and Y′ is other than H, halogen, C1-6 alkyl, NO2, —CN, CF3, OR, and phenyl;
(b) Z is present and is other than H, —C1-6 alkyl, aryl, NR2, and OR;
(c) Q is present and is CQ′ where Q′ is other than H;
and/or
(d) V is other than H, —CN, CF3, C2-6 alkenyl, aryl, and C1-6 alkyl.

23 more elements

Dependencies are inferred from the claim text.

Facts

Application

12/701,528Filed 6 Feb 2010

Priority

10 Mar 2006

Published

10 Jun 2010

Term ends

Not estimatedThe source records don’t support an estimate.

Classification24 codes

C07F 9/65583
Containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common…: each of…
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 1/16
Drugs for disorders of the alimentary tract or the digestive system: for liver or gallbladder disorders, e.g. hepatoprotective agents,…
A61P 3/04
Drugs for disorders of the metabolism: anorexiants; Antiobesity agents

Family

Application60/781,485Us provisional application · filed 10 Mar 2006

Application11/684,016Division · filed 9 Mar 2007

Application12/701,528Division

US 2007/0213302 A1Published application

US 7,687,481 B2Related patent

US 8,088,798 B2Related patent

US 2010/0144791 A1This patent

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

Cannabinoid receptor antagonists/inverse agonists useful for treating obesity

Life of this patent

Abstract

Claims26

Cannabinoid receptor antagonists/inverse agonists useful for treating obesity

Life of this patent

Abstract

Claims26