US 2003/0114495 A1 · Substituted imidazoles as cannabinoid receptor modulators

Abstract

The use of compounds of the present invention as antagonists and/or inverse agonists of the Cannabinoid-1 (CB1) receptor particularly in the treatment, prevention and suppression of diseases mediated by the Cannabinoid-1 (CB1) receptor. The invention is concerned with the use of these novel compounds to selectively antagonize the Cannabinoid-1 (CB1) receptor. As such, compounds of the present invention are useful as psychotropic drugs in the treatment of psychosis, memory deficits, cognitive disorders, migraine, neuropathy, neuro-inflammatory disorders including multiple sclerosis and Guillain-Barre syndrome and the inflammatory sequelae of viral encephalitis, cerebral vascular accidents, and head trauma, anxiety disorders, stress, epilepsy, Parkinson's disease, and schizophrenia. The compounds are also useful for the treatment of substance abuse disorders, particularly to opiates, alcohol, and nicotine. The compounds are also useful for the treatment of obesity or eating disorders associated with excessive food intake and complications associated therewith. Novel compounds of structural formula (I) are also claimed.

A method of treating a disease mediated by the Cannabinoid-1 receptor comprising administration to a patient in need of such treatment of a therapeutically effective amount of a compound of structural formula I:

89
R1 is selected from:
(1) hydrogen,
(2) C1-10alkyl,
(3) C2-10alkenyl,
(4) C2-10alkynyl,
(5) cycloalkyl,
(6) cycloalkyl-C1-10alkyl,
(7) cycloheteroalkyl,
(8) cycloheteroalkyl-C1-10alkyl,
(9) aryl,
(10) heteroaryl,
(11) aryl-C1-10alkyl, and
(12) heteroaryl-C1-10alkyl;
wherein alkyl, alkenyl, alkynyl, and cycloalkyl are optionally substituted with one to four substituents independently selected from Ra, and aryl and heteroaryl are optionally substituted with one to four substituents independently selected from Rb;
R2 is selected from:
(1) C1-10alkyl,
(2) C2-10alkenyl,
(3) C2-10alkynyl,
(4) cycloalkyl,
(5) cycloalkyl-C1-10alkyl,
(6) cycloheteroalkyl,
(7) cycloheteroalkyl-C1-10 alkyl,
(8) aryl,
(9) heteroaryl,
(10) aryl-C1-10alkyl,
(11) heteroaryl-C1-10alkyl,
(12) —ORd,
(13) —NRdRe, and
(14) —NRdS(O)mRe;
wherein alkyl, alkenyl, alkynyl, and cycloalkyl are optionally substituted with one to four substituents independently selected from Ra, and aryl, cycloheteroalkyl, and heteroaryl are optionally substituted with one to four substituents independently selected from Rb;
Ar1 and Ar2 are independently selected from phenyl, naphthyl, thienyl, furanyl, pyrrolyl, benzothienyl, benzofuranyl, indanyl, indenyl, indolyl, tetrahydronaphthyl, 2,3-dihydrobenzofuranyl, dihydrobenzopyranyl, and 1,4-benzodioxanyl, each optionally substituted with one or two groups independently selected from Rc;
each Ra is independently selected from:
(1) —ORd,
(2) —NRdS(O)mRe,
(3) —NO2,
(4) halogen,
(5) —S(O)mRd,
(6) —SRd,
(7) —S(O)2ORd,
(8) —S(O)mNRdRe,
(9) —NRdRe,
(10) —O(CRfRg)nNRdRe,
(11) —C(O)Rd,
(12) —CO2Rd,
(13) —CO2(CRfRg)nCONRdRe,
(14) —OC(O)Rd,
(15) —CN,
(16) —C(O)NRdRe,
(17) —NRdC(O)Re,
(18) —OC(O)NRdRe,
(19) —NRdC(O)ORe,
(20) —NRdC(O)NRdRe,
(21) —CRd(N—ORe),
(22) CF3,
(23) —OCF3,
(24) C3-8cycloalkyl, and
(25) cycloheteroalkyl;
each Rb is independently selected from:
(1) Ra,
(2) C1-10alkyl,
(3) C2-10alkenyl,
(4) C2-10alkynyl,
(5) aryl, and
(6) aryl-C1-10alkyl;
wherein alkyl, alkenyl, alkynyl, and aryl are optionally substituted with one to four substituents selected from a group independently selected from Rc;
each Rc is independently selected from:
(1) halogen,
(2) —NRdRe
(3) C1-4alkyl,
(4) C1-4alkoxy,
(5) aryl,
(6) aryl C1-4alkyl,
(7) hydroxy,
(8) CF3,
(9) —OCF3,
(10) —C(O)Rd,
(11) —CO2Rd;
(12) —C(O)NRdRe,
(13) —OC(O)C1-4alkyl,
(14) —NRdC(O)Re,
(15) —OC(O)NRdRe,
(16) —NRdC(O)ORe,
(17) —NRdC(O)NRdRe,
(18) —OC(O)NRdRe, and
(19) aryloxy;
Rd and Re are independently selected from hydrogen, C1-10alkyl, unsubstituted or substituted with one to three substituents selected from Rh, C2-10alkenyl;
C2-10alkynyl;
cycloalkyl, unsubstituted or substituted with one to three substituents selected from Rh;
cycloalkyl-C1-10alkyl;
cycloheteroalkyl, unsubstituted or substituted with one to three substituents selected from Rh;
cycloheteroalkyl-C1-10alkyl;
aryl, unsubstituted or substituted with one to three substituents selected from Rh;
heteroaryl, unsubstituted or substituted with one to three substituents selected from Rh;
aryl-C1-10alkyl;
and heteroaryl-C1-10alkyl;
or
Rd and Re together with the atom(s) to which they are attached form a heterocyclic ring of 4 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and N—Rd;
Rf and Rg are independently selected from hydrogen, C1-10alkyl, C2-10alkenyl, C-10alkynyl;
cycloalkyl;
cycloalkyl-C1-10alkyl;
cycloheteroalkyl;
cycloheteroalkyl-C1-10alkyl;
aryl;
heteroaryl;
aryl-C1-10alkyl;
and heteroaryl-C1-10alkyl;
or
Rf and Rg together with the carbon to which they are attached form a ring of 5 to 7 members containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen;
each Rh is independently selected from:
(1) halogen,
(2) amino,
(3) carboxy,
(4) C1-4alkyl,
(5) C1-4alkoxy,
(6) aryl,
(7) aryl C1-4alkyl,
(8) hydroxy,
(9) CF3,
(10) OC(O)C1-4alkyl, and
(11) aryloxy;
m is selected from 1 and 2;
and
n is selected from 1, 2, and 3;
and pharmaceutically acceptable salts thereof.

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Substituted imidazoles as cannabinoid receptor modulators

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Substituted imidazoles as cannabinoid receptor modulators

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Abstract

Claims23