Claims
- 1. A compound of Formula I ##STR39## or pharmaceutically acceptable salts, hydrates and stereoisomers thereof wherein:
- X is a bond or is selected from --(CH.sub.2).sub.n --, --CH(CN)--, ##STR40## n is selected from 1, 2 and 3; m is selected from zero, 1, 2 and 3;
- p is selected from zero, 1 and 2;
- R.sup.1 is selected from
- (1) --H,
- (2) --OH,
- (3) halogen,
- (4) --NR.sup.8 R.sup.8,
- (5) --NR.sup.8 COR.sup.9,
- (6) --NR.sup.8 COH,
- (7) --NR.sup.8 SO.sub.2 R.sup.9, and
- (8) ##STR41## R.sup.2 is independently selected at each occurrence from --H and --C.sub.1-6 alkyl;
- R.sup.3 is selected from --H, --C.sub.1-12 alkyl, heterocycle and ##STR42## R.sup.4 is selected from --H, C.sub.1-12 alkyl, --CN, --CON(R.sup.6)R.sup.6 and --COOC.sub.1-6 alkyl;
- R.sup.5a, R.sup.5b, R.sup.9a, R.sup.9b, and R.sup.9c are each independently selected from:
- (1) --H, --C.sub.1-12 alkoxy, --C.sub.1-6 alkyl, halogen, --OH, --CN, --(CH.sub.2).sub.m N(R.sup.2)COC.sub.1-6 alkyl, --CON(R.sup.2)R.sup.2, --CON(R.sup.2)OR.sup.2, --CO.sub.2 R.sup.2, --S(O).sub.p --C.sub.1-6 alkyl, --N (R.sup.2)SO.sub.2 R.sup.7, --N(R.sup.2)R.sup.2, --OCH.sub.2 CON(R.sup.2)R.sup.2, --OCH.sub.2 CO.sub.2 --C.sub.1-6 alkyl, aryl, --CF.sub.3 and --CH.sub.2 Y wherein Y is selected from --CN, --C.sub.1-12 alkoxy, --CON(R.sup.2)R.sup.2, --CO.sub.2 R.sup.2 and --N(R.sup.2)SO.sub.2 R.sup.7 ; or
- (2) when R.sup.5a and R.sup.5b are bonded to adjacent carbon atoms, then R.sup.5a and R.sup.5a together with the carbon atoms to which they are attached may form a phenyl ring or a heterocycle ring, or
- (3) when R.sup.9a and R.sup.9b are bonded to adjacent carbon atoms, then R.sup.9a and R.sup.9b together with the carbon atoms to which they are attached may form a phenyl ring or a heterocycle ring;
- with the proviso that when R.sup.1 is NH.sub.2 or F, R.sup.2 is hydrogen, R.sup.3 is methyl, R.sup.4 is H or methyl, X is (CH.sub.2).sub.2, R.sup.5a is hydrogen, then R.sup.5b is other than H, OH or methoxy;
- R.sup.6 is independently selected at each occurrence from: --H, --C.sub.1-12 alkyl, --C.sub.3-6 cycloalkyl, aralkyl, aryl and heterocycle, or both R.sup.6 groups together with the nitrogen to which they are attached may form a 5-10 membered heterocycle;
- R.sup.7 is selected from C.sub.1-6 alkyl, aryl and aralkyl;
- R.sup.8 is independently selected at each occurrence from --H and C.sub.1-10 alkyl;
- R.sup.9 is selected from C.sub.1-10 alkyl and --NR.sup.8 R.sup.8 ;
- aryl is selected from phenyl, 1-naphthyl and 2-naphthyl and is unsubstituted or mono- or di-substituted, wherein the substituents are independently selected at each occurrence from R.sup.5a ; and
- heterocycle is an unsubstituted or mono- or di-substituted group selected from:
- (1) a 5 or 6-membered saturated or unsaturated heterocyclic ring comprised of carbon atoms and from 1 to 4 heteroatoms independently selected from --O--, --S--, --N-- and --NH--, and
- (2) a benzene ring fused to a saturated or unsaturated 5 or 6-membered heterocyclic ring comprised of carbon atoms and from 1 to 4 heteroatoms independently selected from --O--, --S--, --N-- and --NH--, and wherein substituents on the heterocycle are independently selected at each occurrence from nitro, keto, azo, thiazo, and R.sup.5a.
- 2. The compound of claim 1 having the Formula Ia ##STR43## or pharmaceutically acceptable salts, hydrates and stereoisomers thereof wherein:
- X is a bond or is selected from --(CH.sub.2)--, --CH(CN)--, ##STR44## R.sup.3 is selected from --H, --C.sub.1-12 alkyl and ##STR45## and R.sup.5a and R.sup.5b are each independently selected from: --H, halogen, --C.sub.1-12 alkoxy, --C.sub.1-6 alkyl, --CON(R.sup.2)R.sup.2 and --CON(R.sup.2)OR.sup.2.
- 3. The compound of claim 1 having the Formula Ia ##STR46## or pharmaceutically acceptable salts, hydrates and stereoisomers thereof wherein:
- X is a bond;
- R.sup.3 is ##STR47## R.sup.4 is selected from --H, and --C.sub.1-12 alkyl; and R.sup.5a and R.sup.9a are each independently selected from:
- (1) --C.sub.1-12 alkoxy, --OH, --CN, --CON(R.sup.2)R.sup.2, --CON(R.sup.2)OR.sup.2, and --CH.sub.2 Y wherein Y is selected from --CN, --C.sub.1-12 alkoxy, --CON(R.sup.2)R.sup.2, --CO.sub.2 R.sup.2 and --N(R.sup.2)SO.sub.2 R.sup.7 ; or
- (2) when R.sup.5a and R.sup.5b are bonded to adjacent carbon atoms, then R.sup.5a and R.sup.5b together with the carbon atoms to which they are attached may form a phenyl ring or a heterocycle ring, or
- (3) when R.sup.9a and R.sup.9b are bonded to adjacent carbon atoms, then R.sup.9a and R.sup.9b together with the carbon atoms to which they are attached may form a phenyl ring or a heterocycle ring.
- 4. The compound of claim 1 having the Formula Ia ##STR48## or pharmaceutically acceptable salts, hydrates and stereoisomers thereof wherein:
- X is a bond;
- R.sup.3 is selected from --H and --C.sub.1-12 alkyl;
- R.sup.4 is --CON(R.sup.6)R.sup.6 ; and
- R.sup.5a is selected from: --C.sub.1-12 alkoxy, --OH, --CN, --CON(R.sup.2)R.sup.2, and --CON(R.sup.2)OR.sup.2.
- 5. The compound of claim 1 having the Formula Ia ##STR49## or pharmaceutically acceptable salts, hydrates and stereoisomers thereof wherein:
- X is --(CH.sub.2)--; ##STR50## R.sup.3 is R.sup.4 is selected from --H, --C.sub.1-12 alkyl, --CN and --CON(R.sup.6)R.sup.6 ; and
- R.sup.5a is selected from --H, halogen and --CF.sub.3 ; and
- R.sup.9a is selected from
- (1) --CN, --CON(R.sup.2)R.sup.2, --CON(R.sup.2)OR.sup.2, --OH, --C.sub.1-6 alkyl and --C.sub.1-12 alkoxy; or
- (2) when R.sup.9a and R.sup.9b are bonded to adjacent carbon atoms, then R.sup.9a and R.sup.9b together with the carbon atoms to which they are attached may form a phenyl ring or a heterocycle ring.
- 6. The compound of claim 1 having the Formula Ia ##STR51## or pharmaceutically acceptable salts, hydrates and stereoisomers thereof wherein: ##STR52## X is selected from --CH(CN)--and R.sup.3 and R.sup.4 are independently selected from --H and --C.sub.1-12 alkyl; and
- R.sup.5a is selected from: --C.sub.1-12 alkoxy, --OH, --CN, --CON(R.sup.2)R.sup.2 and --CON(R.sup.2)OR.sup.2.
- 7. The compound of claim 1 wherein:
- X is a bond or is selected from --(CH.sub.2)n--, --CH(CN)--, ##STR53## n is selected from 1, 2 and 3; m is selected from zero, 1, 2 and 3;
- p is selected from zero, 1 and 2;
- R.sup.1 is selected from
- (1) --H,
- (2) --OH,
- (3) halogen,
- (4) --NR.sup.8 R.sup.8,
- (5) --NR.sup.8 COR.sup.9,
- (6) --NR.sup.8 COH,
- (7) --NR.sup.8 SO.sub.2 R.sup.9, and
- (8) ##STR54## R.sup.2 is independently selected at each occurrence from --H and --C.sub.1-6 alkyl;
- R.sup.3 is selected from --H, substituted --C.sub.1-12 alkyl, heterocycle and ##STR55## R.sup.4 is selected from --H, --C.sub.1-12 alkyl, --CN, --CON(R.sup.2)R.sup.2 and --COOC.sub.1-6 alkyl;
- R.sup.5a, R.sup.5a, R.sup.9a and R.sup.9b are each independently selected from:
- (1) --H, --C.sub.1-12 alkoxy, --C.sub.1-6 alkyl, halogen, --OH, --CN, --(CH.sub.2).sub.m N(R.sup.2)COC.sub.1-6 alkyl, --CON(R.sup.2)R.sup.2, --CO.sub.2 C.sub.1-6 alkyl, --S(O).sub.p --C.sub.1-6 alkyl, --N(R.sup.2)SO.sub.2 R.sup.7, --N(R.sup.2)R.sup.2, --OCH.sub.2 CON(R.sup.2)R.sup.2, and --OCH.sub.2 CO.sub.2 --C.sub.1-6 alkyl; or
- (2) when R.sup.5a and R.sup.5a are bonded to adjacent carbon atoms, then R.sup.5a and R.sup.5b together with the carbon atoms to which they are attached may form a heterocycle ring, or
- (3) when R.sup.9a and R.sup.9b are bonded to adjacent carbon atoms, then R.sup.9a and R.sup.9b together with the carbon atoms to which they are attached may form a heterocycle ring;
- with the proviso that when R.sup.1 is NH.sub.2 or F, R.sup.2 is hydrogen, R.sup.3 is methyl, R.sup.4 is H or methyl, X is (CH.sub.2).sub.2, R.sup.5a is hydrogen, then R.sup.5b is other than H, OH or methoxy;
- R.sup.7 is selected from C.sub.1-6 alkyl, aryl and aralkyl;
- R.sup.8 is independently selected at each occurrence from --H and C.sub.1-10 alkyl;
- R.sup.9 is selected from C.sub.1-10 alkyl and --NR.sup.8 R.sup.8 ;
- aryl is selected from phenyl, 1-naphthyl and 2-naphthyl and is unsubstituted or mono- or di-substituted, wherein the substituents are independently selected at each occurrence from R.sup.5a ; and
- heterocycle is an unsubstituted or mono- or di-substituted group selected from:
- (1) a 5 or 6-membered saturated or unsaturated heterocyclic ring comprised of carbon atoms and from 1 to 4 heteroatoms independently selected from --O--, --S--, --N-- and --NH--, and
- (2) a benzene ring fused to a saturated or unsaturated 5 or 6-membered heterocyclic ring comprised of carbon atoms and from 1 to 4 heteroatoms independently selected from --O--, --S--, --N-- and --NH--,
- and wherein substituents on the heterocycle are independently selected at each occurrence from nitro, keto, azo, thiazo, and R.sup.5a.
- 8. A compound of claim 1 selected from the group:
- N-�1-(3,4)-dimethoxyphenyl)-2-phenylethyl!-2-hydroxy-2-pyridin-3-yi-ethylamine;
- N-�1-(3,4)-dimethoxyphenyl)-2-phenylethyl!-2-hydroxy-2-(chloropyrid-5-yl)-ethylamine;
- .alpha.-���(R)-2-hydroxy-2-(pyridin-3-yl)ethyl!amino!methyl!-N,N-dimethylbenzeneacetamide;
- .alpha.-���(R)-2-hydroxy-2-(2-chloropyrid-5-yl)ethyl!amino!methyl!-N,N-dimethylbenzeneacetamide;
- (R)-N-�1-(3,4)-dimethoxyphenyl)-2-phenylethyl!-2-hydroxy-2-(chloropyrid-5-yl)-ethylamine;
- (R)-N-�1-(3,4)-dimethoxyphenyl)-2-phenylethyl!-2-hydroxy-2-pyridin-3-yl-ethylamine;
- (R),(R)-N-�1-(3,4)-dimethoxyphenyl)-2-phenylethyl!-2-hydroxy-2-(chloropyrid-5-yl)-ethylamine;
- (R),(R)-N-�1-(3,4)-dimethoxyphenyl)-2-phenylethyl!-2-hydroxy-2-pyridin-3-yl-ethylamine;
- (R),(S)-N-�1-(3,4)dimethoxyphenyl)-2-phenylethyl!-2-hydroxy-2-(chloropyrid-5-yl)-ethylamine;
- (R),(S)-N-�1-(3,4)-dimethoxyphenyl)-2-phenylethyl!-2-hydroxy-2-pyridin-3-yl-ethylamine;
- N-�1-(3,4)-dimethoxyphenyl)-2-phenylethyl!-2-hydroxy-2-(6-aminopyridin-3-yl)-ethylamine; and
- (R)-N-�1-(3,4)-dimethoxyphenyl)-2-phenylethyl!-2-hydroxy-2-(6-aminopyridin-3-yl)-ethylamine.
- 9. A method for the treatment of diabetes which comprises administering to a diabetic patient a therapeutically effective amount of a compound of claim 1.
- 10. A method for the treatment of obesity which comprises administering to an obese patient a therapeutically effective amount of a compound of claim 1.
- 11. A method for lowering triglyceride levels and cholesterol levels or raising high density lipoprotein levels which comprises administering to a patient needing lower triglyceride and cholesterol levels or higher high density lipoprotein levels a therapeutically effective amount of a compound of claim 1.
- 12. A method for treating atherosclerotic disease which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of claim 1.
- 13. A method for decreasing intestinal motility which comprises administering to a patient in need of decreased intestinal motility, a therapeutically effective amount of a compound of claim 1.
- 14. A method for reducing neurogenic inflammation of airways which comprises administering to a patient in need of reduced neurogenic inflammation, a therapeutically effective amount of a compound of claim 1.
- 15. A method for treating depression which comprises administering to a depressed patient a therapeutically effective amount of a compound of claim 1.
- 16. A method for treating gastrointestinal disorders which comprises administering to a patient with gastrointestinal disorders a therapeutically effective amount of a compound of claim 1.
- 17. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and an inert carrier.
RELATED APPLICATIONS
This application claims priority to U.S. provisional application Ser. No. 60/006,070, filed Oct. 24, 1995, and to U.S. provisional application Ser. No. 60/004,332, filed Sep. 26, 1995.
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Bobowski et al, J. of Heterocyclic Chemistry, vol. 19, No. 1, Jan.-Feb., 1982, pp. 21-27. |