Claims
- 1. A compound of formula (I): ##STR15## wherein: R.sub.1 is OCH.sub.3, Br, isopropyl, or Ar;
- R.sub.2 is H, OH, C.sub.1-5 alkoxy, C.sub.1-5 alkyl, N(R.sub.5).sub.2, NO.sub.2, Br, F, I, Cl, CF.sub.3, or X(C(R.sub.5).sub.2)OR.sub.5 ;
- R.sub.3 is hydrogen, (CH.sub.2).sub.n XR.sub.5, C(O)R.sub.5, CO.sub.2 R.sub.5, CON(R.sub.5).sub.2, oxazolinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, imidazolyl, tetrazolyl, imidazolinyl, thiazolinyl, isoxazolyl, oxadiazolyl, or thiadiazolyl, each of these heterocyclic rings being unsubstituted or substituted by one or two C.sub.1-3 alkyl or fluoroalkyl groups;
- R.sub.4 is morpholinyl, piperazinyl or piperidinyl, each moiety being unsubstituted or substituted by one or two C.sub.1-5 alkyl, OH, NO.sub.2 or N(R.sub.5).sub.2 groups;
- R.sub.5 is hydrogen or C.sub.1-8 alkyl;
- X is O or NR.sub.5 ;
- Ar is phenyl, anthracenyl, naphthyl, indolyl, pyridinyl, thiophenyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, imidazolyl, oxadiazolyl, pyrrolyl or pyrimidinyl; each moiety being unsubstituted or substituted by one or two Z groups;
- Z is H, OH, CO.sub.2 R.sub.5, C.sub.1-10 alkoxy, C.sub.1-5 alkyl, N(R.sub.5).sub.2, NO.sub.2, Br, F, I, Cl, CF.sub.3, or X(CH.sub.2).sub.n OR.sub.5 ; and
- n is 1 to 6; and
- pharmaceutically acceptable salts thereof;
- provided that when n is 1, R.sub.5 is not hydrogen in X(CH.sub.2).sub.n OR.sub.5.
- 2. A compound according to claim 1 wherein:
- R.sub.1 is C.sub.1-5 alkyl or Ar;
- R.sub.2 is hydrogen, C.sub.1-5 alkyl or Ar;
- R.sub.3 is selected from the group consisting of CO.sub.2 R.sub.5, oxazolinyl, tetrazolyl, and oxazolyl, unsubstituted or substituted by one or two C.sub.1-2 alkyl or fluoroalkyl groups;
- R.sub.4 is morpholinyl, piperazinyl or piperidinyl, unsubstituted or substituted by one or two C.sub.1-5 alkyl groups;
- R.sub.5 is C.sub.1-5 alkyl;
- X is O;
- Ar is phenyl, unsubstituted or substituted by one or two Z groups; and
- n is 2.
- 3. A compound according to claim 1 wherein:
- R.sub.1 is isopropyl or phenyl substituted by dichloro, CHO, OCH.sub.2 OCH.sub.3 ; and
- R.sub.5 is methyl or ethyl.
- 4. A compound according to claim 1 selected from the group consisting of:
- ethyl 5-(2-morpholin-4-ylethoxy)-1-(4-(2-formylphenyl)phenyl)pyrazole-4-carboxylate,
- ethyl 5-(2-morpholin-4-ylethoxy)-1-(4-naphthylphenyl)pyrazole-4-carboxylate,
- ethyl 5-(2-morpholin-4-ylethoxy)-1-(4-(2-methoxymethoxyphenyl)phenyl)-pyrazole-4-carboxylate,
- ethyl 5-(2-morpholin-4-ylethoxy)-1-(4-(2-hydroxyphenyl)phenyl)pyrazole-4-carboxylate,
- ethyl 5-(2-morpholin-4-ylethoxy)-1-(4-(2,6-dimethylphenyl)phenyl)pyrazole-4-carboxylate,
- ethyl 5-(2-morpholin-4-ylethoxy)-1-(4-(2,6-dichlorophenyl)phenyl)pyrazole-4-carboxylate,
- ethyl 5-(2-morpholin-4-ylethoxy)-1-(4-(2-(2-methylpropanyl)phenyl)phenyl)-pyrazole-4-carboxylate,
- ethyl 5-(2-morpholin-4-ylethoxy)-1-(4-(2-propoxyphenyl)phenyl)pyrazole-4-carboxylate,
- ethyl 5-(2-morpholin-4-ylethoxy)-1-(4-(2-hydroxmethylphenyl)phenyl)pyrazole-4-carboxylate,
- ethyl 5-(2-morpholin-4-ylethoxy)-1-(4-(2-ethoxyphenyl)phenyl)pyrazole-4-carboxylate,
- ethyl 5-(2-morpholin-4-ylethoxy)-1-(4-(2-hydroxyethoxyphenyl)phenyl)-pyrazole-4-carboxylate,
- ethyl 5-(2-morpholin-4-ylethoxy)-1-(4-(2-nitrophenyl)phenyl)pyrazole-4-carboxylate,
- ethyl 5-(2-morpholin-4-ylethoxy)-1-(4-(2-acetoxynitrilephenyl)phenyl)pyrazole-4-carboxylate,
- ethyl 5-(2-morpholin-4-ylethoxy)-1-(4-(2,3-dichlorophenyl)phenyl)pyrazole-4-carboxylate,
- 5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(1-ethyl)-tetrazole,
- 5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(2-ethyl)-tetrazole,
- 5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-carboxylic acid,
- 5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazol-4-yl methanol,
- 5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-N,N-dimethylcarbamidate,
- 5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-carbamide,
- (+/-)-ethyl 5-((1-methyl-2-piperidinyl)methoxy)-1-(4-isopropylphenyl)pyrazole-4-carboxylate,
- 5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole,
- 5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-methyl,
- ethyl 5-(2-morpholin-4-ylethoxy)-1-(4-(3,5-bis(trifluoromethyl)phenyl)-phenyl)pyrazole-4-carboxylate,
- ethyl 5-(2-morpholin-4-ylethoxy)-1-(4-phenylphenyl)pyrazole-4-carboxylate,
- ethyl 5-(2-morpholin-4-ylethoxy)-1-(4-(3,5-dichlorophenyl)phenyl)pyrazole-4-carboxylate,
- ethyl 5-(2-morpholin-4-ylethoxy)-1-(4-(3-chlorophenyl)phenyl)pyrazole-4-carboxylate,
- ethyl 5-(2-morpholin-4-ylethoxy)-1-(4-(4-chlorophenyl)phenyl)pyrazole-4-carboxylate,
- ethyl 5-(2-morpholin-4-ylethoxy)-1-(4-(4-formylphenyl)phenyl)pyrazole-4-carboxylate,
- ethyl 5-(2-morpholin-4-ylethoxy)-1-(4-(2,4-dichlorophenyl)phenyl)pyrazole-4-carboxylate,
- ethyl 5-(2-morpholin-4-ylethoxy)-1-(4-(4-methoxyphenyl)phenyl)pyrazole-4-carboxylate,
- ethyl 5-(2-morpholin-4-ylethoxy)-1-(4-(4-methylphenyl)phenyl)pyrazole-4-carboxylate,
- ethyl 5-(2-morpholin-4-ylethoxy)-1-(4-(3-aminophenyl)phenyl)pyrazole-4-carboxylate,
- 5-(2-morpholin-4-ylethoxy)-1-(4-(4-carboxyphenyl)phenyl)pyrazole-4-carboxylic acid,
- methyl 5-(2-morpholin-4-ylethoxy)-1-(4-(4-methoxycarbonylphenyl)-phenyl)pyrazole-4-carboxylate,
- ethyl 5-(2-morpholin-4-ylethoxy)-1-(4-(2-N-diethylacetamidephenyl)-phenyl)pyrazole-4-carboxylate,
- ethyl 5-(2-morpholin-4-ylethoxy)-1-(4-(2-octoxyphenyl)phenyl)pyrazole-4-carboxylate,
- ethyl 5-(2-morpholin-4-ylethoxy)-1-(4-(2-tert-butyloxycarbomethoxyphenyl)-phenyl)pyrazole-4-carboxylate,
- ethyl 5-(2-morpholin-4-ylethoxy)-1-(4-(2-benzyloxyphenyl)phenyl)pyrazole-4-carboxylate,
- 5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-methyl ketone,
- 5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazol-4-yl-N-ethylcarboxamide,
- ethyl 5-(2-morpholin-4-ylethoxy)-1-(4-(2-carbomethoxyphenyl)phenyl)pyrazole-4-carboxylate,
- ethyl 5-(2-morpholin-4-ylethoxy)-1-(4-anthracenylphenyl)pyrazole-4-carboxylate,
- ethyl 5-(2-morpholin-4-ylethoxy)-1-(4-(2-n-butoxyphenyl)phenyl)pyrazole-4-carboxylate,
- ethyl 5-(2-morpholin-4-ylethoxy)-1-(4-(2-methoxyethoxyphenyl)phenyl)-pyrazole-4-carboxylate,
- methyl 5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-carboxylate,
- isopropyl 5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-carboxylate,
- propyl 5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-carboxylate,
- 5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-oxazoline,
- 5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(5-methyl)oxazoline,
- (R)-(-)-5-(2-morpholin-4-ylethoxy)-1-[4-(2,6-dichlorophenyl)phenyl]pyrazole-4-(5-methyl)oxazoline, (S)-(+)-5-(2-morpholin-4-ylethoxy)-1-[4-(2,6-dichlorophenyl)phenyl]pyrazole-4-(5-methyl)oxazoline, 5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(2-methyl)oxadiazole,
- 4-methoxymethyl-5-(2-morpholin-4-ylethoxy)-1-(4-(2-methylnaphthyl)phenyl)-pyrazole,
- 5-(2-morpholin-4-ylethoxy)-1-(4-(2,6-dichlorophenyl)phenyl)pyrazole,
- 5-(2-morpholin-4-ylethoxy)-1-(4-(2,3-dichlorophenyl)phenyl)pyrazole,
- 5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-nitrile,
- 5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-tetrazole,
- 5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(1-methyl)-tetrazole,
- 5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(2-methyl)-tetrazole,
- ethyl 5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-carboxylate,
- 5-(2-morpholin-4-ylethoxy)-1-[4-(2,6-dichlorophenyl)phenyl]pyrazole-4-(1-methyl)-tetrazole, 5-(2-morpholin-4-ylethoxy)-1-[4-(2,6-dichlorophenyl)phenyl]pyrazole-4-(2-methyl)-tetrazole, and ethyl 5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-carboxylate.
- 5. A compound according to claim 1 selected from the group consisting of:
- ethyl 5-(2-morpholin-4-ylethoxy)-1-(4-(2-formylphenyl)phenyl)pyrazole-4-carboxylate,
- ethyl 5-(2-morpholin-4-ylethoxy)-1-(4-(2-methoxymethoxyphenyl)phenyl)-pyrazole-4-carboxylate,
- ethyl 5-(2-morpholin-4-ylethoxy)-1-(4-(2-hydroxyphenyl)phenyl)pyrazole-4-carboxylate,
- ethyl 5-(2-morpholin-4-ylethoxy)-1-(4-(2,6-dimethylphenyl)phenyl)pyrazole-4-carboxylate;
- ethyl 5-(2-morpholin-4-ylethoxy)-1-(4-(2,6-dichlorophenyl)phenyl)pyrazole-4-carboxylate,
- ethyl 5-(2-morpholin-4-ylethoxy)-1-(4-(2-(2-methylpropanyl)phenyl)phenyl)-pyrazole-4-carboxylate,
- ethyl 5-(2-morpholin-4-ylethoxy)-1-(4-(2-propoxyphenyl)phenyl)pyrazole-4-carboxylate,
- ethyl 5-(2-morpholin-4-ylethoxy)-1-(4-(2-hydroxmethylphenyl)phenyl)pyrazole-4-carboxylate,
- ethyl 5-(2-morpholin-4-ylethoxy)-1-(4-(2-ethoxyphenyl)phenyl)pyrazole-4-carboxylate;
- ethyl 5-(2-morpholin-4-ylethoxy)-1-(4-(2-hydroxyethoxyphenyl)phenyl)-pyrazole-4-carboxylate,
- ethyl 5-(2-morpholin-4-ylethoxy)-1-(4-(2-nitrophenyl)phenyl)pyrazole-4-carboxylate,
- ethyl 5-(2-morpholin-4-ylethoxy)-1-(4-(2-acetoxynitrilephenyl)phenyl)pyrazole-4-carboxylate,
- ethyl 5-(2-morpholin-4-ylethoxy)-1-(4-(2,3-dichlorophenyl)phenyl)pyrazole-4-carboxylate,
- 5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(1-methyl)-tetrazole,
- 5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(2-methyl)-tetrazole,
- 5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(1-ethyl)-tetrazole, and
- 5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(2-ethyl)-tetrazole.
- 6. A compound according to claim 1 selected from the group consisting of:
- ethyl 5-(2-morpholin-4-ylethoxy)-1-(4-(2-methoxymethoxyphenyl)phenyl)-pyrazole-4-carboxylate,
- ethyl 5-(2-morpholin-4-ylethoxy)-1-(4-(2,6-dichlorophenyl)phenyl)pyrazole-4-carboxylate,
- ethyl 5-(2-morpholin-4-ylethoxy)-1-(4-(2,3-dichlorophenyl)phenyl)pyrazole-4-carboxylate,
- 5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(1-methyl)-tetrazole,
- 5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(2-methyl)-tetrazole,
- ethyl 5-(2-morpholin-4-ylethoxy)-1-(4-(2-nitrophenyl)phenyl)pyrazole-4-carboxylate,
- 5-(2-morpholin-4-ylethoxy)-1-[4-(2,6-dichlorophenyl)phenyl]pyrazole-4-(1-ethyl)-tetrazole, and
- 5-(2-morpholin-4-ylethoxy)-1-[4-(2,6-dichlorophenyl)phenyl]pyrazole-4-(2-ethyl)-tetrazole.
- 7. A compound according to claim 1 selected from the group consisting of:
- ethyl 5-(2-morpholin-4-ylethoxy)-1-(4-(2-methoxymethoxyphenyl)phenyl)-pyrazole-4-carboxylate,
- ethyl 5-(2-morpholin-4-ylethoxy)-1-(4-(2,6-dichlorophenyl)phenyl)pyrazole-4-carboxylate,
- 5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(1-ethyl)-tetrazole, and
- 5-(2-morpholin-4-ylethoxy)-1-(4-isopropylphenyl)pyrazole-4-(2-ethyl)-tetrazole.
- 8. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.
- 9. A method of antagonizing cannabinoid 2 receptors which comprises administering to a subject in need thereof, an effective amount of a compound of claim 1.
- 10. A method of treatment of diseases caused by an excess of cannabinoid comprising administering to a subject in need thereof an effective amount of a cannabinoid receptor 2 antagonist according to claim 1.
- 11. A method of treating an immunologically-mediated inflammatory disease selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, psoriasis, multiple sclerosis, diabetes and thyroiditis which comprises administering to a subject in need thereof an effective amount of a compound according to claim 1.
- 12. A method of treating a disease selected from the group consisting of ankylosing spondylitis, gout, gouty arthritis, osteoarthritis and osteoporosis which comprises administering to a subject in need thereof an effective amount of a compound according to claim 1.
- 13. A method of treating renal ischemia which comprises administering to a subject in need thereof an effective amount of a compound according to claim 1.
Parent Case Info
This application is a 371 of PCT/US98/01175 filed Jan. 20, 1998, which claims the benefit of provisional application 60/035,073 filed Jan. 21, 1997.
PCT Information
Filing Document |
Filing Date |
Country |
Kind |
102e Date |
371c Date |
PCT/US98/01175 |
1/20/1998 |
|
|
10/15/1999 |
10/15/1999 |
Publishing Document |
Publishing Date |
Country |
Kind |
WO98/31227 |
7/23/1998 |
|
|
US Referenced Citations (2)
Number |
Name |
Date |
Kind |
5462960 |
Barth et al. |
Oct 1995 |
|
5948777 |
Bender et al. |
Sep 1999 |
|
Foreign Referenced Citations (1)
Number |
Date |
Country |
WO 9325535 |
Dec 1993 |
WOX |