US6121283A
Expired / Lapsed
US
⏱️ 0.0 years remaining
Apo B-secretion/MTP inhibitory amides
Assignee: Pfizer Inc
•
Filing: 1997-11-03
•
Granted: 2000-09-19
•
Expires: 2017-11-03
Abstract
Abstract This invention is directed to compounds of formula (I) or the stereoisomers, pharmaceutically acceptable salts and hydrates thereof. The compounds are Apo B/MTP inhibitors and are useful in the treatment of various disorders and conditions such as atherosclerosis, pancreatitis, obesity, hypercholesteremia, hypertriglyceridemia, hyperlipidemia, and diabetes. The compounds of this invention are also useful in combination with other pharmaceutical agents including cholesterol biosynthesis inhibitors and cholesterol absorption inhibitors,especially HMG-CoA reductase inhibitors and HMG-CoA synthase inhibitors; HMG-CoA reductase gene expression inhibitors; CETP inhibitors; bile acid sequestrants; fibrates; cholesterol absorption inhibitors; ACAT inhibitors, squalene synthetase inhibitors, ion-exchange resins, anti-oxidants and niacin. This invention is also directed to intermediates and processes useful in the preparation of compounds of formula (I) ##STR1##
Inventors
- 👤 George Chang
- 👤 George Joseph Quallich
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-31 15:42
CPC Classifications
C; C07; C07D; C07D401/00; C07D401/02; C07D401/04; A; A61; A61P; A61P3/00; A61P3/04; A61P3/06; A61P3/08; A61P3/10; A61P43/00; A61P9/00; A61P9/10; C07D217/00; C07D217/02; C07D217/04; C07D401/06; C07D405/00; C07D405/02; C07D405/04; C07D405/06; C07D409/00; C07D409/02; C07D409/06; C07D417/00; C07D417/02; C07D417/06
Claims Analysis
Total Claims: 61
Claim 1
Independent Claim
1038 words
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 1 -C 10 )alkyl, (C 1 -C 4 )perfluoroalkyl, (C 1 -C 10 )alkoxy, (C 1 -C 4 )perfluoroalkoxy, (C 1 -C 10 )alkoxycarbonyl, (C 1 -C 10 )alkylthio, (C 1 -C 10 )alkylamino, di(C 1 -C 10 )alkylamino, (C 1 -C 10 )alkylaminocarbonyl, di(C 1 -C 10 )alkylaminocarbonyl, (C 1 -C 10 )acyl, (C 1 -C 10 )perfluoroacyl, (C 1 -C 10 )acyloxy, (C 1 -C 6 )acylamino and (C 1 -C 6 )perfluoroacylamino; (b) --CH 2 CN, ##STR71## (d) (C 2 -C 12 )alkyl or (C 2 -C 12 )perfluoroalkyl wherein each of said (C 2 -C 12 )alkyl and (C 2 -C 12 )perfluoroalkyl is substituted optionally with from 1-3 substituents selected independently from: (1) phenyl, halogen, nitro, cyano, hydroxy, --NR 1 R 2 , --OCOR 3 , (C 1 -C 4 )alkoxy, (C 1 -C 4 )perfluoroalkoxy, (C 1 -C 4 )thioalkoxy or (C 1 -C 4 )perfluorothioalkoxy, where R 1 and R 2 in the definition of --NR 1 R 2 are each selected independently from hydrogen, formyl, phenyl, benzyl, benzoyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkenyl, (C 1 -C 4 )alkyl, (C 1 -C 4 )perfluoroalkyl, (C 1 -C 10 )alkoxycarbonyl, (C 1 -C 6 )acyl, (C 1 -C 6 )perfluoroacyl, aminocarbonyl, (C 1 -C 10 )alkylaminocarbonyl, di(C 1 -C 10 )alkylaminocarbonyl, aminosulfonyl, (C 1 -C 4 )alkylaminosulfonyl, di(C 1 -C 4 )alkylaminosulfonyl, (C 1 -C 4 )perfluoroalkylaminosulfonyl, (C 1 -C 4 )perfluoroalkylaminosulfonyl, (C 1 -C 4 )alkylsulfonyl, and(C 1 -C 4 )perfluoroalkylsulfonyl, or where R 1 and R 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 1 -C 10 )alkyl, (C 1 -C 4 )perfluoroalkyl, (C 1 -C 10 )alkoxy, (C 1 -C 4 )perfluoroalkoxy, (C 1 -C 10 )alkoxycarbonyl, (C 1 -C 10 )alkylthio, (C 1 -C 10 )alkylamino, di(C 1 -C 10 )alkylamino, (C 1 -C 10 )alkylaminocarbonyl, di(C 1 -C 10 )alkylaminocarbonyl, (C 1 -C 10 )acyl, (C 1 -C 10 )perfluoroacyl, (C 1 -C 10 )acylamino, and (C 1 -C 10 )acyloxy, where R 3 in the definition of --OCOR 3 is selected from --NR 1 R 2 , phenyl, (C 1 -C 10 )alkyl, (C 1 -C 4 )perfluoroalkyl, (C 1 -C 6 )alkoxy and (C 1 -C 6 )perfluoroalkoxy, (2) (C 3 -C 8 )cycloalkyl or (C 3 -C 8 )cycloalkenyl wherein each of said (C 3 -C 8 )cycloalkyl and (C 3 -C 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 1 -C 10 )alkyl, (C 1 -C 4 )perfluoroalkyl, (C 1 -C 10 )alkoxy, (C 1 -C 4 )perfluoroalkoxy, (C 1 -C 10 )alkoxycarbonyl, (C 1 -C 10 )alkylthio, (C 1 -C 10 )alkylamino, di(C 1 -C 10 )alkylamino, (C 1 -C 10 )alkylaminocarbonyl, di(C 1 -C 10 )alkylaminocarbonyl, (C 1 -C 10 )acyl, (C 1 -C 10 )perfluoroacyl, (C 1 -C 10 )acylamino, (C 1 -C 10 )perfluoroacylamino, (C 1 -C 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 1 -C 10 )alkyl, (C 1 -C 4 )perfluoroalkyl, (C 1 -C 10 )alkoxy, (C 1 -C 4 )perfluoroalkoxy, (C 1 -C 10 )alkoxycarbonyl, (C 1 -C 10 )alkylthio, (C 1 -C 10 )alkylamino, di(C 1 -C 10 )alkylamino, (C 1 -C 10 )alkylaminocarbonyl, di(C 1 -C 10 )alkylaminocarbonyl, (C 1 -C 10 )acyl, (C 1 -C 10 )perfluoroacyl, (C 1 -C 10 )acylamino, (C 1 -C 10 )perfluoroacylamino, (C 1 -C 10 )acyloxy, provided that (C 2 -C 12 )alkyl does not include unsubstituted allyl; (e) (C 3 -C 8 )cycloalkyl or (C 3 -C 8 )cycloalkenyl wherein each of said (C 3 -C 8 )cycloalkyl and (C 3 -C 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 1 -C 10 )alkyl, (C 1 -C 4 )perfluoroalkyl, (C 1 -C 10 )alkoxy, (C 1 -C 4 )perfluoroalkoxy, (C 1 -C 10 )alkoxycarbonyl, (C 1 -C 10 )alkylthio, (C 1 -C 10 )alkylamino, di(C 1 -C 10 )alkylamino, (C 1 -C 10 )alkylaminocarbonyl, di(C 1 -C 10 )alkylaminocarbonyl, (C 1 -C 10 )acyl, (C 1 -C 10 )perfluoroacyl, (C 1 -C 10 )acylamino, (C 1 -C 10 )perfluoroacylamino, (C 1 -C 10 )acyloxy; and (f) --(CH 2 ) n COR 4 where R 4 in the definition of --(CH 2 ) n COR 4 is selected from hydroxy, phenyl, --NR 1 R 2 , (C 1 -C 4 )alkyl, (C 1 -C 4 )perfluoroalkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )perfluoroalkoxy, (C 3 -C 8 )cycloalkyl, and (C 3 -C 8 )cycloalkenyl, where n is an integer from 1 to 4.
Claim 2
Dependent Claim
1038 words
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 1 -C 10 )alkyl, (C 1 -C 4 )perfluoroalkyl, (C 1 -C 10 )alkoxy, (C 1 -C 4 )perfluoroalkoxy, (C 1 -C 10 )alkoxycarbonyl, (C 1 -C 10 )alkylthio, (C 1 -C 10 )alkylamino, di(C 1 -C 10 )alkylamino, (C 1 -C 10 )alkylaminocarbonyl, di(C 1 -C 10 )alkylaminocarbonyl, (C 1 -C 10 )acyl, (C 1 -C 10 )perfluoroacyl, (C 1 -C 10 )acyloxy, (C 1 -C 6 )acylamino and (C 1 -C 6 )perfluoroacylamino; (b) --CH 2 CN, ##STR71## (d) (C 2 -C 12 )alkyl or (C 2 -C 12 )perfluoroalkyl wherein each of said (C 2 -C 12 )alkyl and (C 2 -C 12 )perfluoroalkyl is substituted optionally with from 1-3 substituents selected independently from: (1) phenyl, halogen, nitro, cyano, hydroxy, --NR 1 R 2 , --OCOR 3 , (C 1 -C 4 )alkoxy, (C 1 -C 4 )perfluoroalkoxy, (C 1 -C 4 )thioalkoxy or (C 1 -C 4 )perfluorothioalkoxy, where R 1 and R 2 in the definition of --NR 1 R 2 are each selected independently from hydrogen, formyl, phenyl, benzyl, benzoyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkenyl, (C 1 -C 4 )alkyl, (C 1 -C 4 )perfluoroalkyl, (C 1 -C 10 )alkoxycarbonyl, (C 1 -C 6 )acyl, (C 1 -C 6 )perfluoroacyl, aminocarbonyl, (C 1 -C 10 )alkylaminocarbonyl, di(C 1 -C 10 )alkylaminocarbonyl, aminosulfonyl, (C 1 -C 4 )alkylaminosulfonyl, di(C 1 -C 4 )alkylaminosulfonyl, (C 1 -C 4 )perfluoroalkylaminosulfonyl, (C 1 -C 4 )perfluoroalkylaminosulfonyl, (C 1 -C 4 )alkylsulfonyl, and(C 1 -C 4 )perfluoroalkylsulfonyl, or where R 1 and R 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 1 -C 10 )alkyl, (C 1 -C 4 )perfluoroalkyl, (C 1 -C 10 )alkoxy, (C 1 -C 4 )perfluoroalkoxy, (C 1 -C 10 )alkoxycarbonyl, (C 1 -C 10 )alkylthio, (C 1 -C 10 )alkylamino, di(C 1 -C 10 )alkylamino, (C 1 -C 10 )alkylaminocarbonyl, di(C 1 -C 10 )alkylaminocarbonyl, (C 1 -C 10 )acyl, (C 1 -C 10 )perfluoroacyl, (C 1 -C 10 )acylamino, and (C 1 -C 10 )acyloxy, where R 3 in the definition of --OCOR 3 is selected from --NR 1 R 2 , phenyl, (C 1 -C 10 )alkyl, (C 1 -C 4 )perfluoroalkyl, (C 1 -C 6 )alkoxy and (C 1 -C 6 )perfluoroalkoxy, (2) (C 3 -C 8 )cycloalkyl or (C 3 -C 8 )cycloalkenyl wherein each of said (C 3 -C 8 )cycloalkyl and (C 3 -C 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 1 -C 10 )alkyl, (C 1 -C 4 )perfluoroalkyl, (C 1 -C 10 )alkoxy, (C 1 -C 4 )perfluoroalkoxy, (C 1 -C 10 )alkoxycarbonyl, (C 1 -C 10 )alkylthio, (C 1 -C 10 )alkylamino, di(C 1 -C 10 )alkylamino, (C 1 -C 10 )alkylaminocarbonyl, di(C 1 -C 10 )alkylaminocarbonyl, (C 1 -C 10 )acyl, (C 1 -C 10 )perfluoroacyl, (C 1 -C 10 )acylamino, (C 1 -C 10 )perfluoroacylamino, (C 1 -C 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 1 -C 10 )alkyl, (C 1 -C 4 )perfluoroalkyl, (C 1 -C 10 )alkoxy, (C 1 -C 4 )perfluoroalkoxy, (C 1 -C 10 )alkoxycarbonyl, (C 1 -C 10 )alkylthio, (C 1 -C 10 )alkylamino, di(C 1 -C 10 )alkylamino, (C 1 -C 10 )alkylaminocarbonyl, di(C 1 -C 10 )alkylaminocarbonyl, (C 1 -C 10 )acyl, (C 1 -C 10 )perfluoroacyl, (C 1 -C 10 )acylamino, (C 1 -C 10 )perfluoroacylamino, (C 1 -C 10 )acyloxy, provided that (C 2 -C 12 )alkyl does not include unsubstituted allyl; (e) (C 3 -C 8 )cycloalkyl or (C 3 -C 8 )cycloalkenyl wherein each of said (C 3 -C 8 )cycloalkyl and (C 3 -C 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 1 -C 10 )alkyl, (C 1 -C 4 )perfluoroalkyl, (C 1 -C 10 )alkoxy, (C 1 -C 4 )perfluoroalkoxy, (C 1 -C 10 )alkoxycarbonyl, (C 1 -C 10 )alkylthio, (C 1 -C 10 )alkylamino, di(C 1 -C 10 )alkylamino, (C 1 -C 10 )alkylaminocarbonyl, di(C 1 -C 10 )alkylaminocarbonyl, (C 1 -C 10 )acyl, (C 1 -C 10 )perfluoroacyl, (C 1 -C 10 )acylamino, (C 1 -C 10 )perfluoroacylamino, (C 1 -C 10 )acyloxy; and (f) --(CH 2 ) n COR 4 where R 4 in the definition of --(CH 2 ) n COR 4 is selected from hydroxy, phenyl, --NR 1 R 2 , (C 1 -C 4 )alkyl, (C 1 -C 4 )perfluoroalkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )perfluoroalkoxy, (C 3 -C 8 )cycloalkyl, and (C 3 -C 8 )cycloalkenyl, where n is an integer from 1 to 4.
Claim 3
Dependent Claim
585 words
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 1 -C 10 )alkyl, (C 1 -C 4 )perfluoroalkyl, (C 1 -C 10 )alkoxy, (C 1 -C 4 )perfluoroalkoxy, (C 1 -C 10 )alkoxycarbonyl, (C 1 -C 10 )alkylthio, (C 1 -C 10 )alkylamino, di(C 1 -C 10 )alkylamino, (C 1 -C 10 )alkylaminocarbonyl, di(C 1 -C 10 )alkylaminocarbonyl, (C 1 -C 10 )acyl, (C 1 -C 10 )perfluoroacyl, (C 1 -C 6 )acylamino, (C 1 -C 6 )perfluoroacylamino, (C 1 -C 10 )acyloxy; (b) (C 2 -C 12 )alkyl wherein said (C 2 -C 12 )alkyl is substituted optionally with from 1-3 substituents selected independently from: (1) phenyl, halogen, cyano, hydroxy, --NR 1 R 2 , --OCOR 3 , (C 1 -C 4 )alkoxy, or (C 1 -C 4 )perfluoroalkoxy, where R 3 in the definition of --OCOR 3 is selected from --NR 1 R 2 , (C 1 -C 4 )alkyl and (C 1 -C 4 )perfluoroalkyl, (2) (C 3 -C 6 )cycloalkyl or (C 3 -C 6 )cycloalkenyl wherein each of said (C 3 -C 6 )cycloalkyl and (C 3 -C 6 )cycloalkenyl may optionally have from 1 to 4 substituents selected independently from hydroxy, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, and (C 1 -C 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 1 -C 10 )alkyl, (C 1 -C 4 )perfluoroalkyl, (C 1 -C 10 )alkoxy, (C 1 -C 10 )alkoxycarbonyl, (C 1 -C 10 )alkylthio, (C 1 -C 10 )alkylamino, di(C 1 -C 10 )alkylamino, (C 1 -C 10 )alkylaminocarbonyl, di(C 1 -C 10 )alkylaminocarbonyl, (C 1 -C 4 )perfluoroalkoxy, (C 1 -C 10 )acyl, (C 1 -C 10 )acylamino, (C 1 -C 10 )perfluoroacylamino, (C 1 -C 10 )acyloxy, provided that (C 2 -C 12 )alkyl does not include unsubstituted allyl; (c) (C 3 -C 6 )cycloalkyl or (C 3 -C 6 )cycloalkenyl wherein each of said (C 3 -C 6 )cycloalkyl and (C 3 -C 6 )cycloalkenyl may have optionally from 1 to 4 substituents selected independently from hydroxy, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 10 )acylamino, (C 1 -C 10 )perfluoroacylamino and (C 1 -C 4 )alkoxycarbonyl; and (d) --(CH 2 ) n COR 4 , where R 4 in the definition of --(CH 2 ) n COR 4 is selected from hydroxy, phenyl, --NR 1 R 2 , (C 1 -C 4 )alkyl, (C 1 -C 4 )perfluoroalkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )perfluoroalkoxy, (C 3 -C 6 )cycloalkyl, and (C 3 -C 6 )cycloalkenyl, where n is an integer from 1 to 4.
Claim 4
Dependent Claim
137 words
A compound as claimed in claim 2, and the stereoisomers, pharmaceutically acceptable salts and hydrates thereof, wherein G is (C 2 -C 12 )alkyl, wherein said (C 2 -C 12 )alkyl is substituted optionally with a group selected from phenyl, halogen, cyano, hydroxy, (C 1 -C 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 1 -C 4 )acyl, (C 1 -C 4 )perfluoroacyl, (C 1 -C 4 )alkyl, (C 1 -C 4 )perfluoroalkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkylaminocarbonyl, and (C 1 -C 4 )acylamino, provided that (C 2 -C 12 )alkyl does not include unsubstituted allyl.
Claim 5
Dependent Claim
36 words
A compound as claimed in claim 2, and the stereoisomers, pharmaceutically acceptable salts and hydrates thereof, wherein G is --(CH 2 ) n NR 1 R 2 and n is an integer from 2 to 4.
Claim 6
Dependent Claim
31 words
A compound as claimed in claim 2, and the stereoisomers, pharmaceutically acceptable salts and hydrates thereof, wherein G is --(CH 2 ) n COR 4 and n is 1 or 2.
Claim 7
Dependent Claim
15 words
The compound of claim 2, wherein G is --(CH 2 ) 2 OCOCH 3 .
Claim 8
Dependent Claim
17 words
The compound of claim 2, wherein G is --(CH 2 ) 2 OCON(CH 3 ) 2 .
Claim 9
Dependent Claim
9 words
The compound of claim 2, wherein G is ##STR72##
Claim 10
Dependent Claim
8 words
The compound of claim 2, wherein G is
Claim 11
Dependent Claim
15 words
The compound of claim 3, wherein G is --(CH 2 ) 4 CH 3 .
Claim 12
Dependent Claim
15 words
The compound of claim 3, wherein G is --(CH 2 ) 2 OCH 3 .
Claim 13
Dependent Claim
17 words
The compound of claim 3, wherein G is --(CH 2 ) 2 OCH 2 CH 3 .
Claim 14
Dependent Claim
15 words
The compound of claim 3, wherein G is --(CH 2 ) 3 OCH 3 .
Claim 15
Dependent Claim
13 words
The compound of claim 3, wherein G is --(CH 2 ) 2 CN.
Claim 16
Dependent Claim
8 words
The compound of claim 3, wherein G is
Claim 17
Dependent Claim
8 words
The compound of claim 3, wherein G is
Claim 18
Dependent Claim
8 words
The compound of claim 3, wherein G is
Claim 19
Dependent Claim
8 words
The compound of claim 3, wherein G is
Claim 20
Dependent Claim
8 words
The compound of claim 3, wherein G is
Claim 21
Dependent Claim
17 words
The compound of claim 4, wherein G is --(CH 2 ) 2 NHS(O) 2 CH 3 .
Claim 22
Dependent Claim
13 words
The compound of claim 4, wherein G is --(CH 2 ) 2 NHCHO.
Claim 23
Dependent Claim
17 words
The compound of claim 4, wherein G is --(CH 2 ) 2 NHCOCH 2 CH 3 .
Claim 24
Dependent Claim
15 words
The compound of claim 4, wherein G is --(CH 2 ) 2 NHCOCF 3 .
Claim 25
Dependent Claim
15 words
The compound of claim 4, wherein G is --(CH 2 ) 2 NHCONHCH 3 .
Claim 26
Dependent Claim
15 words
The compound of claim 4, wherein G is --(CH 2 ) 2 NHCOOCH 3 .
Claim 27
Dependent Claim
15 words
The compound of claim 4, wherein G is --(CH 2 ) 2 NHCOCH 3 .
Claim 28
Dependent Claim
15 words
The compound of claim 4, wherein G is --(CH 2 ) 2 NH 2 .
Claim 29
Dependent Claim
15 words
The compound of claim 5, wherein G is --CH 2 CON(CH 3 ) 2 .
Claim 30
Dependent Claim
17 words
The compound of claim 5, wherein G is --CH 2 CON(CH 2 CH 3 ) 2 .
Claim 31
Dependent Claim
17 words
The compound of claim 5, wherein G is --(CH 2 ) 2 CON(CH 3 ) 2 .
Claim 32
Dependent Claim
11 words
The compound of claim 5, wherein G is --CH 2 COOH.
Claim 33
Dependent Claim
44 words
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.
Claim 34
Dependent Claim
49 words
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.
Claim 35
Dependent Claim
17 words
A method as claimed in claim 33 wherein said condition is selected from hypercholesterolemia, hypertriglyceridemia, or hyperlipidemia.
Claim 36
Dependent Claim
12 words
A method as claimed in claim 34 wherein said condition is hypercholesterolemia.
Claim 37
Dependent Claim
12 words
A method as claimed in claim 34 wherein said condition is hypertriglyceridemia.
Claim 38
Dependent Claim
12 words
A method as claimed in claim 34 wherein said condition is hyperlipidemia.
Claim 39
Dependent Claim
17 words
A method as claimed in claim 33 wherein said condition is selected from atherosclerosis, obesity, or diabetes.
Claim 40
Dependent Claim
12 words
A method as claimed in claim 38 wherein said condition is atherosclerosis.
Claim 41
Dependent Claim
12 words
A method as claimed in claim 38 wherein said condition is obesity.
Claim 42
Dependent Claim
12 words
A method as claimed in claim 38 wherein said condition is diabetes.
Claim 43
Dependent Claim
32 words
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.
Claim 44
Dependent Claim
52 words
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.
Claim 45
Dependent Claim
89 words
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.
Claim 46
Dependent Claim
22 words
A pharmaceutical composition as claimed in claim 44 wherein said second compound is selected from lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin or rivastatin.
Claim 47
Dependent Claim
14 words
A pharmaceutical composition as claimed in claim 45 wherein said second compound is atorvastatin.
Claim 48
Dependent Claim
108 words
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.
Claim 49
Dependent Claim
21 words
A method as claimed in claim 47 wherein said second compound is selected from lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin or rivastatin.
Claim 50
Dependent Claim
13 words
A method as claimed in claim 48 wherein said second compound is atorvastatin.
Claim 51
Dependent Claim
34 words
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.
Claim 52
Dependent Claim
39 words
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.
Claim 53
Dependent Claim
28 words
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.
Claim 54
Dependent Claim
138 words
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.
Claim 55
Dependent Claim
138 words
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.
Claim 56
Dependent Claim
57 words
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.
Claim 57
Dependent Claim
57 words
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.
Claim 58
Dependent Claim
9 words
The tosylate acid addition salt of the compound ##STR83##
Claim 59
Dependent Claim
9 words
The tosylate acid addition salt of the compound ##STR83##
Claim 60
Dependent Claim
24 words
A compound having the structural formula or an acid addition salt thereof, wherein R is selected from --NO 2 , and --NH 2 .
Claim 61
Dependent Claim
24 words
A compound having the structural formula or an acid addition salt thereof, wherein R is selected from --NO 2 , and --NH 2 .
References Cited (Backward Citations)
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