US 7,405,221 B2 · Substituted pyrimidines

Abstract

Novel compounds of the structural formula (I) are antagonists and/or inverse agonists of the Cannabinoid-1 (CB1) receptor and are useful in the treatment, prevention and suppression of diseases mediated by the CB1 receptor. The compounds of the present invention are useful as centrally acting 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, movement disorders, and schizophrenia. The compounds are also useful for the treatment of substance abuse disorders, the treatment of obesity or eating disorders, as well as the treatment of asthma, constipation, chronic intestinal pseudo-obstruction, and cirrhosis of the liver

A compound of structural formula I:

or a pharmaceutically acceptable salt thereof, wherein:
R1 is selected from:
(1) —OC1-6alkyl, unsubstituted or substituted with one to three Rc substituents,
(2) cycloalkyloxy-, unsubstituted or substituted with one to three Rc substituents,
(3) cycloalkyl-C1-4alkyloxy-, unsubstituted or substituted with one to three Rc substituents,
(4) cycloheteroalkyloxy-, unsubstituted or substituted with one to three Rc substituents,
(5) cycloheteroalkyl-C1-4alkyloxy, unsubstituted or substituted with one to three Rc substituents,
(6) phenyloxy, unsubstituted or substituted with one to three Rc substituents,
(7) heteroaryloxy, unsubstituted or substituted with one to three Rc substituents,
(8) phenyl-C1-4alkyloxy, unsubstituted or substituted with one to three Rc substituents,
(9) heteroaryl-C1-4alkyloxy, unsubstituted or substituted with one to three Rc substituents,
(10) —NRaRb,
(11) —NRbC(O)Ra,
(12) —CO2H,
(13) C1-6alkyloxycarbonyl-, unsubstituted or substituted with one to three Rc substituents,
(14) cycloalkyloxycarbonyl-, unsubstituted or substituted with one to three Rc substituents,
(15) cycloalkyl-C1-4alkyloxycarbonyl-, unsubstituted or substituted with one to three Rc substituents,
(16) phenyloxycarbonyl, unsubstituted or substituted with one to three Rc substituents,
(17) heteroaryloxycarbonyl, unsubstituted or substituted with one to three Rc substituents,
(18) phenyl-C1-4alkyloxycarbonyl, unsubstituted or substituted with one to three Rc substituents,
(19) heteroaryl-C1-4alkyloxycarbonyl, unsubstituted or substituted with one to three Rc substituents,
(20) —C(O)NRaRb,
(21) cyano,
(22) —SO2C1-6alkyl, unsubstituted or substituted with one to three Rc substituents;
provided that R1 is not NH2;
R2 is selected from:
(1) hydrogen,
(2) C1-10alkyl,
(3) —ORa,
(4) —NRaRb,
(5) —NRaC(O)Rb,
(6) —CO2Ra,
(7) —C(O)NRaRb,
(8) cyano,
(9) —SRa, and
(10) —SO2Ra;
wherein R3 and R4 are each independently selected from:
each Ra is independently selected from:
(1) hydrogen,
(2) C1-10alkyl,
(3) C2-10alkenyl,
(4) cycloalkyl,
(5) cycloalkyl-C1-10alkyl;
(6) cycloheteroalkyl,
(7) cycloheteroalkyl-C1-10alkyl;
(8) aryl,
(9) heteroaryl,
(10) aryl-C1-10alkyl, and
(11) heteroaryl-C1-10alkyl;
and
each Rb is independently selected from:
(1) hydrogen,
(2) C1-10alkyl,
(3) C2-10alkenyl,
(4) cycloalkyl,
(5) cycloalkyl-C1-10alkyl;
(6) cycloheteroalkyl,
(7) cycloheteroalkyl-C1-10 alkyl;
(8) aryl,
(9) heteroaryl,
(10) aryl-C1-10alkyl, and
(11) heteroaryl-C1-10alkyl, or
Ra and Rb together with the nitrogen atom to which they are attached form a bridged or unbridged heterocyclic ring of 4 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and N—Rd,
each Ra and Rb may be unsubstituted or substituted with one to three substituents selected from Rc;
each Rc is independently selected from:
(1) C1-10alkyl,
(2) —ORd,
(3) —NReS(O)mRd,
(4) halogen,
(5) —SRd,
(6) —S(O)mNRdRe,
(7) —NRdRe,
(8) —C(O)Rd,
(9) —CN,
(10) —C(O)NRdRe,
(11) —NReC(O)Rd,
(12) —NReC(O)ORde,
(13) —NReC(O)NRdRe,
(14) —CF3,
(15) —OCF3,
(16) cycloheteroalkyl,
(17) aryl,
(18) arylC1-4alkyl,
(19) heteroaryl, and
(20) heteroarylC1-4alkyl;
Rd and Re are independently selected from:
(1) hydrogen,
(2) C1-10alkyl,
(3) C2-10 alkenyl,
(4) cycloalkyl,
(5) cycloalkyl-C1-10alkyl;
(6) cycloheteroalkyl,
(7) cycloheteroalkyl-C1-10 alkyl;
(8) aryl,
(9) heteroaryl,
(10) aryl-C1-10alkyl, and
(11) heteroaryl-C1-10alkyl, or
Rd and Re together with the nitrogen atom to which they are attached form a bridged or unbridged heterocyclic ring of 4 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and N—Rf,
each Rd and Re may be unsubstituted or substituted with one to three substituents selected from Rf;
Rf is independently selected from:
(1) halogen,
(2) C1-10alkyl,
(3) —O—C1-4alkyl,
(4) —S—C1-4alkyl,
(5) —CN,
(6) —CF3, and
(7) —OCF3;
each Rg is independently selected from:
(1) halogen,
(2) C1-10alkyl,
(3) —O—C1-4alkyl,
(4) —S—C1-4alkyl,
(5) —CN,
(6) —CF3, and
(7) —OCF3;
and
m is selected from 1 and 2.

114 more elements

Substituted pyrimidines

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Substituted pyrimidines

Life of this patent

Abstract

Claims14