Claims
- 1. A compound of the formula ##STR70## or the stereoisomers, pharmaceutically acceptable salts and hydrates thereof, wherein G is selected from:
- (a) a phenyl or heterocyclic ring wherein said heterocyclic ring contains a total of from 3 to 14 ring atoms, wherein said heterocyclic ring incorporates a total of from 1 to 4 ring heteroatoms selected independently from oxygen, nitrogen, and sulfur, wherein the individual rings of said heterocyclic ring may be independently saturated, partially saturated or aromatic, and wherein each of said phenyl or heterocyclic rings may have optionally from 1 to 4 substituents selected independently from halogen, hydroxy, cyano, nitro, oxo, thioxo, aminosulfonyl, phenyl, phenoxy, phenylthio, benzyl, benzoyl, benzyloxy, (C.sub.1 -C.sub.10)alkyl, (C.sub.1 -C.sub.4)perfluoroalkyl, (C.sub.1 -C.sub.10)alkoxy, (C.sub.1 -C.sub.4)perfluoroalkoxy, (C.sub.1 -C.sub.10)alkoxycarbonyl, (C.sub.1 -C.sub.10)alkylthio, (C.sub.1 -C.sub.10)alkylamino, di(C.sub.1 -C.sub.10)alkylamino, (C.sub.1 -C.sub.10)alkylaminocarbonyl, di(C.sub.1 -C.sub.10)alkylaminocarbonyl, (C.sub.1 -C.sub.10)acyl, (C.sub.1 -C.sub.10)perfluoroacyl, (C.sub.1 -C.sub.10)acyloxy, (C.sub.1 -C.sub.6)acylamino and (C.sub.1 -C.sub.6)perfluoroacylamino;
- (b) --CH.sub.2 CN, ##STR71## (d) (C.sub.2 -C.sub.12)alkyl or (C.sub.2 -C.sub.12)perfluoroalkyl wherein each of said (C.sub.2 -C.sub.12)alkyl and (C.sub.2 -C.sub.12)perfluoroalkyl is substituted optionally with from 1-3 substituents selected independently from:
- (1) phenyl, halogen, nitro, cyano, hydroxy, --NR.sup.1 R.sup.2, --OCOR.sup.3, (C.sub.1 -C.sub.4)alkoxy, (C.sub.1 -C.sub.4)perfluoroalkoxy, (C.sub.1 -C.sub.4)thioalkoxy or (C.sub.1 -C.sub.4)perfluorothioalkoxy,
- where R.sup.1 and R.sup.2 in the definition of --NR.sup.1 R.sup.2 are each selected independently from hydrogen, formyl, phenyl, benzyl, benzoyl, (C.sub.3 -C.sub.8)cycloalkyl, (C.sub.3 -C.sub.8)cycloalkenyl, (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)perfluoroalkyl, (C.sub.1 -C.sub.10)alkoxycarbonyl, (C.sub.1 -C.sub.6)acyl, (C.sub.1 -C.sub.6)perfluoroacyl, aminocarbonyl, (C.sub.1 -C.sub.10)alkylaminocarbonyl, di(C.sub.1 -C.sub.10)alkylaminocarbonyl, aminosulfonyl, (C.sub.1 -C.sub.4)alkylaminosulfonyl, di(C.sub.1 -C.sub.4)alkylaminosulfonyl, (C.sub.1 -C.sub.4)perfluoroalkylaminosulfonyl, (C.sub.1 -C.sub.4)perfluoroalkylaminosulfonyl, (C.sub.1 -C.sub.4)alkylsulfonyl, and(C.sub.1 -C.sub.4)perfluoroalkylsulfonyl,
- or where R.sup.1 and R.sup.2, taken together with the nitrogen atom to which they are attached, form a saturated, partially-saturated or aromatic heterocyclic ring, wherein said heterocyclic ring contains a total of from 3 to 14 ring atoms and incorporates optionally an additional 1 to 4 ring heteroatoms selected independently from oxygen, nitrogen and sulfur, wherein said heterocyclic ring may have optionally from 1 to 4 substituents selected independently from halogen, hydroxy, cyano, nitro, oxo, thioxo, aminosulfonyl, phenyl, phenoxy, phenylthio, benzyl, benzoyl, benzyloxy, (C.sub.1 -C.sub.10)alkyl, (C.sub.1 -C.sub.4)perfluoroalkyl, (C.sub.1 -C.sub.10)alkoxy, (C.sub.1 -C.sub.4)perfluoroalkoxy, (C.sub.1 -C.sub.10)alkoxycarbonyl, (C.sub.1 -C.sub.10)alkylthio, (C.sub.1 -C.sub.10)alkylamino, di(C.sub.1 -C.sub.10)alkylamino, (C.sub.1 -C.sub.10)alkylaminocarbonyl, di(C.sub.1 -C.sub.10)alkylaminocarbonyl, (C.sub.1 -C.sub.10)acyl, (C.sub.1 -C.sub.10)perfluoroacyl, (C.sub.1 -C.sub.10)acylamino, and (C.sub.1 -C.sub.10)acyloxy,
- where R.sup.3 in the definition of --OCOR.sup.3 is selected from --NR.sup.1 R.sup.2, phenyl, (C.sub.1 -C.sub.10)alkyl, (C.sub.1 -C.sub.4)perfluoroalkyl, (C.sub.1 -C.sub.6)alkoxy and (C.sub.1 -C.sub.6)perfluoroalkoxy,
- (2) (C.sub.3 -C.sub.8)cycloalkyl or (C.sub.3 -C.sub.8)cycloalkenyl wherein each of said (C.sub.3 -C.sub.8)cycloalkyl and (C.sub.3 -C.sub.8)cycloalkenyl may have optionally from 1 to 4 substituents selected independently from halogen, hydroxy, cyano, nitro, oxo, thioxo, aminosulfonyl, phenyl, phenoxy, phenylthio, benzyl, benzoyl, benzyloxy, (C.sub.1 -C.sub.10)alkyl, (C.sub.1 -C.sub.4)perfluoroalkyl, (C.sub.1 -C.sub.10)alkoxy, (C.sub.1 -C.sub.4)perfluoroalkoxy, (C.sub.1 -C.sub.10)alkoxycarbonyl, (C.sub.1 -C.sub.10)alkylthio, (C.sub.1 -C.sub.10)alkylamino, di(C.sub.1 -C.sub.10)alkylamino, (C.sub.1 -C.sub.10)alkylaminocarbonyl, di(C.sub.1 -C.sub.10)alkylaminocarbonyl, (C.sub.1 -C.sub.10)acyl, (C.sub.1 -C.sub.10)perfluoroacyl, (C.sub.1 -C.sub.10)acylamino, (C.sub.1 -C.sub.10)perfluoroacylamino, (C.sub.1 -C.sub.10)acyloxy, and
- (3) a saturated, partially-saturated or aromatic heterocyclic ring containing a total of from 3 to 14 ring atoms, wherein said heterocyclic ring incorporates a total of from 1 to 4 ring heteroatoms selected independently from oxygen, nitrogen and sulfur, wherein said heterocyclic ring may have optionally from 1 to 4 substituents selected independently from halogen, hydroxy, cyano, nitro, oxo, thioxo, aminosulfonyl, phenyl, phenoxy, phenylthio, benzyl, benzoyl, benzyloxy, (C.sub.1 -C.sub.10)alkyl, (C.sub.1 -C.sub.4)perfluoroalkyl, (C.sub.1 -C.sub.10)alkoxy, (C.sub.1 -C.sub.4)perfluoroalkoxy, (C.sub.1 -C.sub.10)alkoxycarbonyl, (C.sub.1 -C.sub.10)alkylthio, (C.sub.1 -C.sub.10)alkylamino, di(C.sub.1 -C.sub.10)alkylamino, (C.sub.1 -C.sub.10)alkylaminocarbonyl, di(C.sub.1 -C.sub.10)alkylaminocarbonyl, (C.sub.1 -C.sub.10)acyl, (C.sub.1 -C.sub.10)perfluoroacyl, (C.sub.1 -C.sub.10)acylamino, (C.sub.1 -C.sub.10)perfluoroacylamino, (C.sub.1 -C.sub.10)acyloxy,
- provided that (C.sub.2 -C.sub.12)alkyl does not include unsubstituted allyl;
- (e) (C.sub.3 -C.sub.8)cycloalkyl or (C.sub.3 -C.sub.8)cycloalkenyl wherein each of said (C.sub.3 -C.sub.8)cycloalkyl and (C.sub.3 -C.sub.8)cycloalkenyl may have optionally from 1 to 4 substituents selected independently from halogen, hydroxy, cyano, nitro, oxo, thioxo, aminosulfonyl, phenyl, phenoxy, phenylthio, benzyl, benzoyl, benzyloxy, (C.sub.1 -C.sub.10)alkyl, (C.sub.1 -C.sub.4)perfluoroalkyl, (C.sub.1 -C.sub.10)alkoxy, (C.sub.1 -C.sub.4)perfluoroalkoxy, (C.sub.1 -C.sub.10)alkoxycarbonyl, (C.sub.1 -C.sub.10)alkylthio, (C.sub.1 -C.sub.10)alkylamino, di(C.sub.1 -C.sub.10)alkylamino, (C.sub.1 -C.sub.10)alkylaminocarbonyl, di(C.sub.1 -C.sub.10)alkylaminocarbonyl, (C.sub.1 -C.sub.10)acyl, (C.sub.1 -C.sub.10)perfluoroacyl, (C.sub.1 -C.sub.10)acylamino, (C.sub.1 -C.sub.10)perfluoroacylamino, (C.sub.1 -C.sub.10)acyloxy; and
- (f) --(CH.sub.2).sub.n COR.sup.4 where R.sup.4 in the definition of --(CH.sub.2).sub.n COR.sup.4 is selected from hydroxy, phenyl, --NR.sup.1 R.sup.2, (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)perfluoroalkyl, (C.sub.1 -C.sub.4)alkoxy, (C.sub.1 -C.sub.4)perfluoroalkoxy, (C.sub.3 -C.sub.8)cycloalkyl, and (C.sub.3 -C.sub.8)cycloalkenyl,
- where n is an integer from 1 to 4.
- 2. A compound as claimed in claim 1 and the stereoisomers, pharmaceutically acceptable salts and hydrates thereof, wherein G is selected from:
- (a) a phenyl or heterocyclic ring wherein said heterocyclic ring contains a total of from 3 to 7 ring atoms, wherein said heterocyclic ring incorporates a total of from 1 to 4 ring heteroatoms selected independently from oxygen, nitrogen, and sulfur, wherein said heterocyclic ring may be saturated, partially saturated or aromatic, and wherein each of said phenyl or heterocyclic rings may each have optionally from 1 to 4 substituents selected independently from halogen, hydroxy, phenyl, benzyl, benzoyl, benzyloxy, (C.sub.1 -C.sub.10)alkyl, (C.sub.1 -C.sub.4)perfluoroalkyl, (C.sub.1 -C.sub.10)alkoxy, (C.sub.1 -C.sub.4)perfluoroalkoxy, (C.sub.1 -C.sub.10)alkoxycarbonyl, (C.sub.1 -C.sub.10)alkylthio, (C.sub.1 -C.sub.10)alkylamino, di(C.sub.1 -C.sub.10)alkylamino, (C.sub.1 -C.sub.10)alkylaminocarbonyl, di(C.sub.1 -C.sub.10)alkylaminocarbonyl, (C.sub.1 -C.sub.10)acyl, (C.sub.1 -C.sub.10)perfluoroacyl, (C.sub.1 -C.sub.6)acylamino, (C.sub.1 -C.sub.6)perfluoroacylamino, (C.sub.1 -C.sub.10)acyloxy;
- (b) (C.sub.2 -C.sub.12)alkyl wherein said (C.sub.2 -C.sub.12)alkyl is substituted optionally with from 1-3 substituents selected independently from:
- (1) phenyl, halogen, cyano, hydroxy, --NR.sup.1 R.sup.2, --OCOR.sup.3, (C.sub.1 -C.sub.4)alkoxy, or (C.sub.1 -C.sub.4)perfluoroalkoxy,
- where R.sup.3 in the definition of --OCOR.sup.3 is selected from --NR.sup.1 R.sup.2, (C.sub.1 -C.sub.4)alkyl and (C.sub.1 -C.sub.4)perfluoroalkyl,
- (2) (C.sub.3 -C.sub.6)cycloalkyl or (C.sub.3 -C.sub.6)cycloalkenyl wherein each of said (C.sub.3 -C.sub.6)cycloalkyl and (C.sub.3 -C.sub.6)cycloalkenyl may optionally have from 1 to 4 substituents selected independently from hydroxy, (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy, and (C.sub.1 -C.sub.4)alkoxycarbonyl, and
- (3) a saturated, partially-saturated or aromatic heterocyclic ring containing a total of from 3 to 6 ring atoms, wherein said heterocyclic ring incorporates a total of from 1 to 4 ring heteroatoms selected independently from oxygen, nitrogen and sulfur, wherein said heterocyclic ring may have optionally from 1 to 4 substituents selected independently from halogen, hydroxy, phenyl, benzyl, benzoyl, benzyloxy, (C.sub.1 -C.sub.10)alkyl, (C.sub.1 -C.sub.4)perfluoroalkyl, (C.sub.1 -C.sub.10)alkoxy, (C.sub.1 -C.sub.10)alkoxycarbonyl, (C.sub.1 -C.sub.10)alkylthio, (C.sub.1 -C.sub.10)alkylamino, di(C.sub.1 -C.sub.10)alkylamino, (C.sub.1 -C.sub.10)alkylaminocarbonyl, di(C.sub.1 -C.sub.10)alkylaminocarbonyl, (C.sub.1 -C.sub.4)perfluoroalkoxy, (C.sub.1 -C.sub.10)acyl, (C.sub.1 -C.sub.10)acylamino, (C.sub.1 -C.sub.10)perfluoroacylamino, (C.sub.1 -C.sub.10)acyloxy,
- provided that (C.sub.2 -C.sub.12)alkyl does not include unsubstituted allyl;
- (c) (C.sub.3 -C.sub.6)cycloalkyl or (C.sub.3 -C.sub.6)cycloalkenyl wherein each of said (C.sub.3 -C.sub.6)cycloalkyl and (C.sub.3 -C.sub.6)cycloalkenyl may have optionally from 1 to 4 substituents selected independently from hydroxy, (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy, (C.sub.1 -C.sub.10)acylamino, (C.sub.1 -C.sub.10)perfluoroacylamino and (C.sub.1 -C.sub.4)alkoxycarbonyl; and
- (d) --(CH.sub.2).sub.n COR.sup.4, where R.sup.4 in the definition of --(CH.sub.2).sub.n COR.sup.4 is selected from hydroxy, phenyl, --NR.sup.1 R.sup.2, (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)perfluoroalkyl, (C.sub.1 -C.sub.4)alkoxy, (C.sub.1 -C.sub.4)perfluoroalkoxy, (C.sub.3 -C.sub.6)cycloalkyl, and (C.sub.3 -C.sub.6)cycloalkenyl,
- where n is an integer from 1 to 4.
- 3. A compound as claimed in claim 2, and the stereoisomers, pharmaceutically acceptable salts and hydrates thereof, wherein G is (C.sub.2 -C.sub.12)alkyl, wherein said (C.sub.2 -C.sub.12)alkyl is substituted optionally with a group selected from phenyl, halogen, cyano, hydroxy, (C.sub.1 -C.sub.4)alkoxy, or a saturated, partially-saturated or aromatic heterocyclic ring selected from thienyl, pyrazolyl, pyrrolidinyl, pyrrolyl, furanyl, thiazolyl, isoxazolyl, imidazolyl, triazolyl, tetrahydropyranyl, pyridyl, and pyrimidyl, wherein each of said heterocyclic rings may have optionally from 1 to 3 substitutents selected independently from halogen, (C.sub.1 -C.sub.4)acyl, (C.sub.1 -C.sub.4)perfluoroacyl, (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)perfluoroalkyl, (C.sub.1 -C.sub.4)alkoxy, (C.sub.1 -C.sub.4)alkylaminocarbonyl, and (C.sub.1 -C.sub.4)acylamino,
- provided that (C.sub.2 -C.sub.12)alkyl does not include unsubstituted allyl.
- 4. A compound as claimed in claim 2, and the stereoisomers, pharmaceutically acceptable salts and hydrates thereof, wherein G is --(CH.sub.2).sub.n NR.sup.1 R.sup.2 and n is an integer from 2 to 4.
- 5. A compound as claimed in claim 2, and the stereoisomers, pharmaceutically acceptable salts and hydrates thereof, wherein G is --(CH.sub.2).sub.n COR.sup.4 and n is 1 or 2.
- 6. The compound of claim 2, wherein G is --(CH.sub.2).sub.2 OCOCH.sub.3.
- 7. The compound of claim 2, wherein G is --(CH.sub.2).sub.2 OCON(CH.sub.3).sub.2.
- 8. The compound of claim 2, wherein G is ##STR72##
- 9. The compound of claim 2, wherein G is
- 10. The compound of claim 3, wherein G is --(CH.sub.2).sub.4 CH.sub.3.
- 11. The compound of claim 3, wherein G is --(CH.sub.2).sub.2 OCH.sub.3.
- 12. The compound of claim 3, wherein G is --(CH.sub.2).sub.2 OCH.sub.2 CH.sub.3.
- 13. The compound of claim 3, wherein G is --(CH.sub.2).sub.3 OCH.sub.3.
- 14. The compound of claim 3, wherein G is --(CH.sub.2).sub.2 CN.
- 15. The compound of claim 3, wherein G is
- 16. The compound of claim 3, wherein G is
- 17. The compound of claim 3, wherein G is
- 18. The compound of claim 3, wherein G is
- 19. The compound of claim 3, wherein G is
- 20. The compound of claim 4, wherein G is --(CH.sub.2).sub.2 NHS(O).sub.2 CH.sub.3.
- 21. The compound of claim 4, wherein G is --(CH.sub.2).sub.2 NHCHO.
- 22. The compound of claim 4, wherein G is --(CH.sub.2).sub.2 NHCOCH.sub.2 CH.sub.3.
- 23. The compound of claim 4, wherein G is --(CH.sub.2).sub.2 NHCOCF.sub.3.
- 24. The compound of claim 4, wherein G is --(CH.sub.2).sub.2 NHCONHCH.sub.3.
- 25. The compound of claim 4, wherein G is --(CH.sub.2).sub.2 NHCOOCH.sub.3.
- 26. The compound of claim 4, wherein G is --(CH.sub.2).sub.2 NHCOCH.sub.3.
- 27. The compound of claim 4, wherein G is --(CH.sub.2).sub.2 NH.sub.2.
- 28. The compound of claim 5, wherein G is --CH.sub.2 CON(CH.sub.3).sub.2.
- 29. The compound of claim 5, wherein G is --CH.sub.2 CON(CH.sub.2 CH.sub.3).sub.2.
- 30. The compound of claim 5, wherein G is --(CH.sub.2).sub.2 CON(CH.sub.3).sub.2.
- 31. The compound of claim 5, wherein G is --CH.sub.2 COOH.
- 32. A method for inhibiting or decreasing Apo B secretion in a mammal in need thereof which method comprises the administration of an Apo B secretion inhibiting or decreasing amount of a compound of claim 1 or a stereoisomer, pharmaceutically acceptable salt or hydrate thereof.
- 33. A method for the treatment of a condition selected from atherosclerosis, pancreatitis, obesity, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia or diabetes which method comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 1 or a stereoisomer, pharmaceutically acceptable salt or hydrate thereof.
- 34. A method as claimed in claim 33 wherein said condition is selected from hypercholesterolemia, hypertriglyceridemia, or hyperlipidemia.
- 35. A method as claimed in claim 34 wherein said condition is hypercholesterolemia.
- 36. A method as claimed in claim 34 wherein said condition is hypertriglyceridemia.
- 37. A method as claimed in claim 34 wherein said condition is hyperlipidemia.
- 38. A method as claimed in claim 33 wherein said condition is selected from atherosclerosis, obesity, or diabetes.
- 39. A method as claimed in claim 38 wherein said condition is atherosclerosis.
- 40. A method as claimed in claim 38 wherein said condition is obesity.
- 41. A method as claimed in claim 38 wherein said condition is diabetes.
- 42. A pharmaceutical composition which comprises a therapeutically effective amount of a compound of claim 1 or a stereoisomer, pharmaceutically acceptable salt or hydrate thereof in combination with a pharmaceutically-acceptable carrier or diluent.
- 43. A pharmaceutical composition for the treatment of a condition selected from atherosclerosis, pancreatitis, obesity, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia or diabetes in a mammal which comprises a therapeutically effective amount of a compound of claim 1 or the stereoisomer, pharmaceutically acceptable salt or hydrate thereof in combination with a pharmaceutically acceptable carrier or diluent.
- 44. A pharmaceutical composition comprising: a. a therapeutically effective amount of a first compound, wherein said first compound is a compound of claim 1 or a stereoisomer, pharmaceutically acceptable salt or hydrate thereof;
- b. a therapeutically effective amount of a second compound, wherein said second compound is selected from a cholesterol absorption inhibitor, a CETP inhibitor, an HMG-CoA reductase inhibitor, an HMG-CoA synthase inhibitor, an inhibitor of HMG-CoA reductase gene expression, niacin, an antioxidant, an ACAT inhibitor or a squalene synthetase inhibitor; and
- c. a pharmaceutically acceptable carrier or diluent.
- 45. A pharmaceutical composition as claimed in claim 44 wherein said second compound is selected from lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin or rivastatin.
- 46. A pharmaceutical composition as claimed in claim 45 wherein said second compound is atorvastatin.
- 47. A method for the treatment of a condition selected from atherosclerosis, pancreatitis, obesity, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia or diabetes which method comprises administering to a mammal in need of such treatment:
- a. a therapeutically effective amount of a first compound, wherein said first compound is a compound of claim 1 or a stereoisomer, pharmaceutically acceptable salt or hydrate thereof; and
- b. a therapeutically effective amount of a second compound, wherein said second compound is selected from a cholesterol absorption inhibitor, a CETP inhibitor, an HMG-CoA reductase inhibitor, an HMG-CoA synthase inhibitor, an inhibitor of HMG-CoA reductase gene expression, niacin, an antioxidant, an ACAT inhibitor or a squalene synthetase inhibitor.
- 48. A method as claimed in claim 47 wherein said second compound is selected from lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin or rivastatin.
- 49. A method as claimed in claim 48 wherein said second compound is atorvastatin.
- 50. A compound as claimed in claim 1, wherein said compound is selected from:
- {6[(4'-trifluoromethylbiphenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinolin-2-yl}-acetic acid,
- 4'-trifluoromethylbiphenyl-2-carboxylic acid-(n-pentyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide,
- 4'-trifluoromethylbiphenyl-2-carboxylic acid-[2-(3-methoxypropyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide,
- 4'-trifluoromethylbiphenyl-2-carboxylic acid-[2-(2-methoxyethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide,
- 4'-trifluoromethylbiphenyl-2-carboxylic acid-[2-(2-ethoxyethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide,
- 4'-trifluoromethyl-biphenyl-2-carboxylic acid-[2-(2-cyanoethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide, acetic acid 2-{6-[(4'-trifluoromethylbiphenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl ester, and
- dimethylcarbamic acid 2-{6-[(4'-trifluoromethylbiphenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl ester.
- 51. A compound as claimed in claim 1, wherein said compound is selected from:
- 4'-trifluoromethylbiphenyl-2-carboxylic acid-[2-(2-aminoethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide
- 4'-trifluoromethylbiphenyl-2-carboxylic acid-[2-(2-acetylaminoethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide,
- 4'-trifluoromethyl-biphenyl-2-carboxylic acid-[2-(2-dimethylcarbamoylethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide,
- 4'-trifluoromethylbiphenyl-2-carboxylic acid-(2-dimethylcarbamoylmethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide,
- 4'-trifluoromethylbiphenyl-2-carboxylic acid-(2-diethylcarbamoylmethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide,
- 4'-trifluoromethylbiphenyl-2-carboxylic acid-[2-(2-methanesulfonylaminoethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide,
- 4'-trifluoromethylbiphenyl-2-carboxylic acid-{2-[2-(2,2,2-trifluoroacetylamino)-ethyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-amide,
- 4'-trifluoromethylbiphenyl-2-carboxylic acid-[2-(2-propionylaminoethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide,
- (2-{6-[4'-trifluoromethylbiphenyl-2-carbonyl)amino]-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-carbamic acid methyl ester,
- ' -trifluoromethylbiphenyl-2-carboxylic acid-[2-(2-formylaminoethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide, and
- 4'-trifluoromethylbiphenyl-2-carboxylic acid-{2-[2-(3-methylureido)-ethyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}amide.
- 52. A compound as claimed in claim 1, wherein said compound is selected from:
- 4'-trifluoromethylbiphenyl-2-carboxylic acid{2-[2-(1-methyl-1H-pyrrol-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}amide,
- 4'-trifluoromethylbiphenyl-2-carboxylic acid-{2-[2-(2H-[1,2,4]triazol-3-yl-ethyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-amide,
- 4'-trifluoromethylbiphenyl-2-carboxylic acid-[2-(2,2-diphenylethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide,
- 4'-trifluoromethylbiphenyl-2-carboxylic acid-[2-(2-pyridin-2-yl-ethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide,
- 4'-trifluoromethylbiphenyl-2-carboxylic acid-(2-phenylethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide,
- 4'-trifluoromethylbiphenyl-2-carboxylic acid-(2-piperidin-4-yl-1,2,3,4-tetrahydroisoquinolin-6-yl)amide, and
- 4'-trifluoromethylbiphenyl-2-carboxylic acid-[2-(1-trifluoromethylacetyl-piperidin-4-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide.
- 53. A process for the preparation of a compound having the structural formula ##STR73## which process comprises the steps of: (a) cyclizing a diacid of the structural formula ##STR74## or an activated form thereof, with benzylamine to provide a dione derivative of structural formula ##STR75## (b) reducing the product of Step (a) to provide an isoquinoline derivative of structural formula ##STR76## (c) reducing the product of Step (b) to provide an amino derivative of structural formula ##STR77## (d) coupling the product of Step (c) with the compound 4'-trifluoromethylbiphenyl-2-carboxylic acid, or an activated form thereof to provide an amide derivative of structural formula ##STR78## (e) deprotecting the amide derivative of Step (d) to provide said amino derivative of structural formula ##STR79## (f) isolating the amino derivative of Step (e) in the free base form or an acid addition salt thereof.
- 54. A process for the preparation of a compound having the structural formula ##STR80## which process comprises the steps of: (a) deprotecting an amide derivative of the structural formula ##STR81## to provide said amino derivative of structural formula ##STR82## (b) isolating the amino derivative of Step (a) in the free base form or an add addition salt thereof.
- 55. The tosylate acid addition salt of the compound ##STR83##
- 56. A compound having the structural formula or an acid addition salt thereof, wherein R is selected from --NO.sub.2, and --NH.sub.2.
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is the National Stage filing under 35 U.S.C. .sctn.371 based on PCT/IB97/01368, filed internationally on Nov. 3, 1997, which claims priority from U.S. Provisional Application No. 60/032,307, filed Nov. 27, 1996.
PCT Information
Filing Document |
Filing Date |
Country |
Kind |
102e Date |
371c Date |
PCT/IB97/01368 |
11/3/1997 |
|
|
4/20/1999 |
4/20/1999 |
Publishing Document |
Publishing Date |
Country |
Kind |
WO98/23593 |
6/4/1998 |
|
|
US Referenced Citations (1)
Number |
Name |
Date |
Kind |
4022900 |
Mathison |
May 1977 |
|
Foreign Referenced Citations (3)
Number |
Date |
Country |
0643057 |
Feb 1994 |
EPX |
9626205 |
Aug 1996 |
WOX |
9640640 |
Dec 1996 |
WOX |