Claims
- 1. A method for reducing the adverse effects of smooth muscle contractions which comprises administering to a patient in need thereof, a compound of the formula: ##STR4## wherein: R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are, independently, hydrogen, COOR.sub.15, halogen, nitro, cyano, C.sub.1-10 alkoxy, C.sub.1-10 haloalkoxy, sulfonic acid, C.sub.1-10 alkylsulfonyl, C.sub.6-12 arylsulfonyl, C.sub.6-12 aralkylsulfonyl, C.sub.1-10 alkylsulfinyl, C.sub.6-12 alkylsulfinyl, C.sub.6-12 aralkylsulfinyl, sulfamoyl, C.sub.1-10 alkylsulfamido, C.sub.6-12 arylsulfamido, C.sub.1-10 alkanoyl, C.sub.6-12 aryloyl, C.sub.6-12 aralkanoyl, amino, C.sub.1-10 alkylamino, C.sub.2-10 dialkylamino, C.sub.6-12 aralkylamino, C.sub.6-12 arylamino, carboxamido, C.sub.1 -C.sub.10 alkylcarboxamido, C.sub.6-12 arylcarboxamido, C.sub.1-10 haloalkyl, C.sub.1-10 alkyl, C.sub.2-12 alkenyl, C.sub.6-12 aryl, C.sub.6-12 aralkyl; with the proviso that at least one of R.sub.4 and R.sub.5 is COOR.sub.15
- R.sub.9 is hydrogen, C.sub.1-10 alkyl and C.sub.1-10 haloalkyl;
- R.sub.10 is hydrogen, C.sub.1-10 alkyl, C.sub.1-10 haloalkyl, or C.sub.2 -C.sub.12 alkylidene;
- R.sub.15 is hydrogen, metal cation, acetylamido, alkoxyacetoyl or a related moiety which delivers the carboxylate in vivo;
- the dotted line is an optional double bond; with the proviso that when R.sub.10 is an alkylidene moiety, the bond is absent; and
- W is nitrogen or carbon bearing a hydrogen, or R.sub.4, R.sub.5 or R.sub.6 as hereinbefore defined, or pharmaceutical salts thereof.
- 2. The method of claim 1 wherein:
- R.sub.1, R.sub.2 and R.sub.3 are, independently, hydrogen, cyano, C.sub.1-10 perhaloalkoxy, sulfonic acid, C.sub.1-10 alkylsulfonyl, C.sub.6-12 arylsulfonyl, C.sub.6-12 aralkylsulfonyl, C.sub.1-10 alkylsulfinyl, C.sub.6-12 alkylsulfinyl, C.sub.6-12 aralkylsulfinyl, sulfamoyl, C.sub.1-10 alkylsulfamido, C.sub.6-12 arylsulfamido, C.sub.1-10 alkanoyl, C.sub.6-12 aryloyl, C.sub.6-12 aralkanoyl, amino, C.sub.1-10 alkylamino, C.sub.2-10 dialkylamino, C.sub.6-12 aralkylamino, C.sub.6-12 arylamino, carboxamido, C.sub.1-10 alkylcarboxamido, C.sub.6-12 arylcarboxamido, C.sub.1-10 perhaloalkyl; with the provisos: (1) that R.sub.1, R.sub.2 and R.sub.3 may not all simultaneously be hydrogen, and (2) when R.sub.1 and R.sub.2 are hydrogen, R.sub.3 may not be meta-CF.sub.3 ;
- R.sub.4, R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are, independently, hydrogen, COOR.sub.15, halogen, nitro, cyano, C.sub.1-10 alkoxy, C.sub.1-10 haloalkoxy, sulfonic acid, C.sub.1-10 alkylsulfonyl, C.sub.6-12 arylsulfonyl, C.sub.6-12 aralkylsulfonyl, C.sub.1-10 alkylsulfinyl, C.sub.6-12 arylsulfinyl, C.sub.6-12 aralkylsulfinyl, sulfamoyl, C.sub.1-10 alkylsulfamico, C.sub.6-12 arylsulfamico, C.sub.1-10 alkanoyl, C.sub.6-12 aryloyl, C.sub.6-12 aralkanoyl, amino, C.sub.1-10 alkylamino, C.sub.2-10 dialkylamino, C.sub.6-12 aralkylamino, C.sub.6-12 arylamino, carboxamido, C.sub.1-10 alkylcarboxamido, C.sub.6-12 arylcarboxamido, C.sub.1-10 haloalkyl, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.6-12 aryl, and C.sub.6-12 aralkyl, with the proviso that at least one of R.sub.4 and R.sub.5 is COOR.sub.15 ;
- R.sub.9 is hydrogen, C.sub.1-10 alkyl and C.sub.1-10 haloalkyl;
- R.sub.10 is hydrogen, C.sub.1-10 alkyl, C.sub.1-10 haloalkyl, or C.sub.2-12 alkylidene;
- R.sub.15 is hydrogen, metal cation, acetylamido, alkoxyacetoyl or a related moiety which delivers the carboxylate in vivo;
- the dotted line is an optional double bond; with the proviso that when R.sub.10 is an alkylidene moiety, the bond is absent; and
- W is nitrogen or carbon bearing a hydrogen, or R.sub.4, R.sub.5 or R.sub.6 as hereinbefore defined; or pharmaceutically acceptable salts thereof.
- 3. The method of claim 1 wherein R.sub.15 is selected from the group consisting of hydrogen, a metal cation, a moiety selected from: ##STR5## wherein R.sub.11, R.sub.12, R.sub.13, and R.sub.14 are, independently, hydrogen, C.sub.1-10 alkyl, C.sub.6-12 aryl, or C.sub.6-12 aralkyl.
- 4. The method of claim 1 wherein W is carbon bearing a hydrogen.
- 5. The method of claim 1 wherein W is NH.sub.2.
- 6. The method or claim 1 wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are, independently, selected from hydrogen, halogen, COOR.sub.15, nitro, cyano, C.sub.1-6 alkoxy, C.sub.1-6 alkanoyl, C.sub.1-6 haloalkoxy, C.sub.6-10 aryloyl, C.sub.1-6 alkylsulfonyl, C.sub.1-6 haloalkylsulfonyl, C.sub.6-10 arylsulfonyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkyl, amino, and C.sub.1-6 dialkylamino.
- 7. The method of claim 1 wherein at least one of R.sub.1, R.sub.2 and R.sub.3 is C.sub.1-6 perhaloalkyl.
- 8. The method of claim 1 wherein at least one of R.sub.1, R.sub.2 and R.sub.3 is trifluoromethyl.
- 9. The method of claim 1 wherein one of R.sub.1, R.sub.2 and R.sub.3 is 4-trifluoro-methyl.
- 10. The method of claim 1 wherein R.sub.6, R.sub.7 and R.sub.8 are independently selected from.
- 11. The method of claim 1 wherein at least one of R.sub.6, R.sub.7 and R.sub.8 is a halogen.
- 12. The method of claim 1 wherein one of R.sub.6, R.sub.7 and R.sub.8 is 4-chloro.
- 13. The method of claim 1 wherein R.sub.4 is COOR.sub.15.
- 14. The method of claim 1 wherein R.sub.4 is COOH.
- 15. The method of claim 1 wherein R.sub.10 is alkylidene.
- 16. The method of claim 1 wherein R.sub.9 is C.sub.1-6 alkyl.
- 17. The method of claim 1 wherein R.sub.9 is methyl.
- 18. The method of claim 1 wherein the double bond is present.
- 19. The method of claim 1 wherein the compound is (E)-2-[2-Methyl-3-(4-trifluoromethyl-phenyl)-acryloylamino]-benzoic acid lithium salt, or a pharmaceutical salt thereof.
- 20. The method of claim 1 wherein the compound is 2-[3-(4-Trifluoromethyl-phenyl)propionyl-amino]-benzoic acid, or a pharmaceutical salt thereof.
- 21. The method of claim 1 wherein the compound is (E)-2-[3-(4-Bromo-phenyl)-acryloylamino]-benzoic acid, or a pharmaceutical salt thereof.
- 22. The method of claim 1 wherein the compound is (E)-2-[3[(4-Trifluoromethyl-phenyl)acryloyl-amino]-benzoic acid, or a pharmaceutical salt thereof.
- 23. The method of claim 1 wherein the compound is (E)-2-[3[(4-Trifluoromethyl-phenyl)-acryloylamino]-benzoic acid lithium salt hemihydrate, or a pharmaceutical salt thereof.
- 24. The method of claim 1 wherein the compound is 2-[3-(4-Trifluoromethyl-phenyl)-but-3-enoylamino]-benzoic acid, or a pharmaceutical salt thereof.
- 25. The method of claim 1 wherein the compound is (E)-2-[3-(4-Trifluoromethyl-phenyl)-but-2-enoylamino]-benzoic acid sodium salt, or a pharmaceutical salt thereof.
- 26. The method of claim 1 wherein the compound is (E)-5-Chloro-2-[2-methyl-3-(4-trifluoromethyl-phenyl)-acryloylamino-benzoic acid, or a pharmaceutical salt thereof.
- 27. The method of claim 1 wherein the compound is (E)-5-Chloro-2-[2-methyl-3-(4-trifluoromethyl-phenyl)-acryloylamino]-benzoic acid lithium salt hemihydrate, or a pharmaceutical salt thereof.
- 28. The method of claim 1 wherein the compound is (E)-4-Chloro-2-[2-methyl-3-(4-trifluoromethyl-phenyl)-acryloylamino]-benzoic acid, or a pharmaceutical salt thereof.
- 29. The method of claim 1 wherein the compound is (E)-4-Chloro-2-[2-methyl-3-(4-trifluoromethyl-phenyl)-acryloylamino]-benzoic acid lithium salt hemihydrate, or a pharmaceutical salt thereof.
- 30. The method of claim 1 wherein the compound is (E)-2-[2-Methyl-3-(4-trifluoromethyl-phenyl)-acryloylamino]-nicotinic acid, or a pharmaceutical salt thereof.
- 31. The method of claim 1 wherein the compound is (E)-5-Methoxy-2-[2-methyl-3-(4-trifluoromethyl-phenyl)-acryloylamino]-benzoic acid, or a pharmaceutical salt thereof.
- 32. The method of claim 1 wherein the compound is (E)-2-[2-Methyl-3-(4-trifluoromethyl-phenyl)-acryloylamino]-benzoic acid diethylcarbamoylmethyl ester, or a pharmaceutical salt thereof.
- 33. The method of claim 1 in which the smooth muscle adversely contracting causes urinary incontinence.
- 34. The method of claim 1 in which the smooth muscle adversely contracting causes irritable bowel syndrome.
- 35. The method of claim 1 in which the smooth muscle adversely contracting causes asthma.
- 36. The method of claim 1 in which the smooth muscle adversely contracting is associated with congestive heart failure, hypertension, angina, and cardiac arrhythmias.
- 37. The method of claim 1 in which the smooth muscle adversely contracting is associated with cerebral vascular disease.
- 38. A method of activating potassium channels in smooth muscle cells of a patient suffering from a condition associated with insufficient potassium channel activity comprising administering to a patient in need thereof a compound of formula (I): ##STR6## wherein: R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are, independently, hydrogen, COOR.sub.15, halogen, nitro, cyano, C.sub.1-10 alkoxy, C.sub.1-10 haloalkoxy, sulfonic acid, C.sub.1-10 alkylsulfonyl, C.sub.6-12 arylsulfonyl, C.sub.6-12 aralkylsulfonyl, C.sub.1-10 alkylsulfinyl, C.sub.6-12 arylsulfinyl, C.sub.6-12 aralkylsulfinyl, sulfamoyl, C.sub.1-10 alkylsulfamido, C.sub.6-12 arylsulfamido, C.sub.1-10 alkanoyl, C.sub.6-12 aryloyl, C.sub.6-12 aralkanoyl, amino, C.sub.1-10 alkylamino, C.sub.2-10 dialkylamino, C.sub.6-12 aralkylamino, C.sub.6-12 arylamino, carboxamido, C.sub.1-10 alkylcarboxamido, C.sub.6-12 arylcarboxamido, C.sub.1-10 haloalkyl, C.sub.1-10 alkyl, C.sub.2-12 alkenyl, C.sub.6-12 aryl, C.sub.6-12 aralkyl; with the proviso that at least one of R.sub.4 and R.sub.5 is COOR.sub.15 ;
- R.sub.9 is hydrogen, C.sub.1-10 alkyl and C.sub.1-10 haloalkyl;
- R.sub.10 is hydrogen, C.sub.1-10 alkyl, C.sub.1-10 haloalkyl, or C.sub.2-12 alkylidene;
- R.sub.15 is hydrogen, metal cation, acetylamido, alkoxyacetoyl or a related moiety which delivers the carboxylate in vivo;
- the dotted line is an optional double bond; with the proviso that when R.sub.10 is an alkylidene moiety, the double bond is absent; and
- W is nitrogen or carbon bearing a hydrogen, or R.sub.4, R.sub.5 or R.sub.6 as hereinbefore defined; or pharmaceutical salts thereof.
- 39. The method of claim 36 wherein the patient is suffering from anxiety, cerebral anoxia or a neurodegenerative disorder.
- 40. A method of achieving chloride channel blockade in smooth muscle cells of a patient suffering from a condition associated with undesired chloride channel activity comprising treating the patient with a therapeutically effective amount of a compound of formula (I): ##STR7## wherein: R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are, independently, hydrogen, COOR.sub.15, halogen, nitro, cyano, C.sub.1-10 alkoxy, C.sub.1-10 haloalkoxy, sulfonic acid, C.sub.1-10 alkylsulfonyl, C.sub.6-12 arylsulfonyl, C.sub.6-12 aralkylsulfonyl, C.sub.1-10 alkylsulfinyl, C.sub.6-12 arylsulfinyl, C.sub.6-12 aralkylsulfinyl, sulfamoyl, C.sub.1-10 alkylsulfamido, C.sub.6-12 arylsulfamido, C.sub.1-10 alkanoyl, C.sub.6-12 aryloyl, C.sub.6-12 aralkanoyl, amino, C.sub.1-10 alkylamino, C.sub.2-10 dialkylamino, C.sub.6-12 aralkylamino, C.sub.6-12 arylamino, carboxamido, C.sub.1-10 alkylcarboxamido, C.sub.6-12 arylcarboxamido, C.sub.1-10 haloalkyl, C.sub.1-10 alkyl, C.sub.2-12 alkenyl, C.sub.6-12 aryl, C.sub.6-12 aralkyl; with the proviso that at least one of R.sub.4 and R.sub.5 is COOR.sub.15 ;
- R.sub.9 is hydrogen, C.sub.1-10 alkyl and C.sub.1-10 haloalkyl;
- R.sub.10 is hydrogen, C.sub.1-10 alkyl, C.sub.1-10 haloalkyl, or C.sub.2-12 alkylidene;
- R.sub.15 is hydrogen, metal cation, acetylamido, alkoxyacetoyl or a related moiety which delivers the carboxylate in vivo;
- the dotted line is an optional double bond; with the proviso that when R.sub.10 is an alkylidene moiety, the double bond is absent; and
- W is nitrogen or carbon bearing a hydrogen, or R.sub.4, R.sub.5 or R.sub.6 as hereinbefore defined; or pharmaceutical salts thereof.
- 41. The method of claim 38 wherein the condition is urinary incontinence, irritable bladder disease/irritable bowel disease, asthma, hypertension, stroke, congestive heart disease, angina or cardiac arrhythmias.
BACKGROUND OF INVENTION
This application claims the benefit of U.S. Provisional application Ser. No. 60/054,901, filed Aug. 5, 1997.
US Referenced Citations (1)
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5888529 |
Bunnett et al. |
Mar 1999 |
|
Non-Patent Literature Citations (1)
Entry |
Nie et al, Chemical Abstracts, No. 125:292668, 1996. |