Patent EA-001539-B1 (EA)
Title: Amides ingibiting secretion of b apolyprotein (apo b) and/or microsome protein triglycerides transfer (mtr)
Inventor: CHANG GEORGE
IPC: A61K31/47
Filed: 1997-11-03
Abstract: 1. A compound of the formula   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 rings 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, (C1-C10)alkyl, (C1-C4)perfluoroalkyl, (C1-C10)alkoxy, (C1-C4)perfluoroalkoxy, (C1-C10) alkoxycarbonyl, (C1-C10)alkylthio, (C1-C10)alkylamino, di(C1-Clo)alkylamino, (C1C10)alkylaminocarbonyl, di(C1-C10)alkylaminocarbonyl, (C1-C10)acyl, (C1-C10) perfluoroacyl, (C1-C10)acyloxy, (C1-C6)acylamino and (C1-C6)perfluoroacylamino; (b) -CH2CN,   (d) (C2-C12)alkyl or (C2-C12)perfluoroalkyl wherein each of said (C2-C12)alkyl and (C2-C12)perfluoroalkyl is substituted optionally with from 1-3 substituents selected independently from: (1) phenyl, halogen, nitro, cyano, hydroxy, -NR<1>R<2>, -OCOR<3>, (C1-C4)alkoxy, (C1-C4)perfluoroalkoxy, (C1-C4)thioalkoxy or (C1-C4)perfluorothioalkoxy, where R<1> and R<2> in the group of -N-R<1>R<2> are each selected independently from hydrogen, formyl, phenyl, benzyl, benzoyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkenyl, (C1-C4)alkyl, (C1-C4)perfluoroalkyl, (C1-C10)alkoxycarbonyl, (C1-C6)acyl, (C1-C6)perfluoroacyl, aminocarbonyl, (C1-C10)alkylaminocarbonyl, di(C1-C10)alkylaminocarbonyl, aminosulfonyl, (C1-C4)alkylaminosulfonyl, di(C1-C4)alkylaminosulfonyl, (C1-C4)perfluoroalkylaminosulfonyl, (C1-C4)alkylsulfonyl, and (C1-C4)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 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, (C1-C10)alkyl, (C1-C4)perfluoroalkyl, (C1-C10)alkoxy, (C1-C4)perfluoroalkoxy, (C1-C10)alkoxycarbonyl, (C1-C10)alkylthio, (C1-C10)alkylamino, di(C1-C10)alkylamino, (C1-C10)alkylaminocarbonyl, di(C1-C10)alkylaminocarbonyl, (C1-C10)acyl, (C1-C10)perfluoroacyl, (C1-C10)acylamino, and (C1-C10)acyloxy, where R<3> in the definition of -OCOR<3> is selected from -NR<1>R<2>, phenyl, (C1-C10)alkyl, (C1-C4)perfluoroalkyl, (C1-C6)alkoxy and (C1-C6)perfluoroalkoxy, (2) (C3-C8)cycloalkyl or (C3-C8)cycloalkenyl wherein each of said (C3-C8)cycloalkyl and (C3-C8)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, (C1-C10)alkyl, (C1-C4)perfluoroalkyl, (C1-C10)alkoxy, (C1-C4)perfluoroalkoxy, (C1-C10)alkoxycarbonyl, (C1-C10)alkylthio, (C1-C10)alkylamino, di(C1-C10)alkylamino, (C1-C10)alkylaminocarbonyl, di(C1-C10)alkylaminocarbonyl, (C1-C10)acyl, (C1-C10)perfluoroacyl, (C1-C10)acylamino, (C1-C10)perfluoroacylamino, (C1-C10)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, (C1-C10)alkyl, (C1-C4)perfluoroalkyl, (C1-C10)alkoxy, (C1-C4) perfluoroalkoxy, (C1-C10)alkoxycarbonyl, (C1-C10)alkylthio, (C1-C10)alkylamino, di(C1-C10)alkylamino, (C1-C10)alkylaminocarbonyl, di(C1-C10)alkylaminocarbonyl, (C1-C10)acyl, (C1-C10)perfluoroacyl, (C1-C10)acylamino, (C1-C10)perfluoroacylamino, (C1-C10)acyloxy, provided that (C2-C12)alkyl does not include unsubstituted alkyl; (e) (C3-C8)cycloalkyl or (C3-C8)cycloalkenyl wherein each of said (C3-C8)cycloalkyl and (C3-C8)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, (C1-C10)alkyl, (C1-C4)perfluoroalkyl, (C1-C10)alkoxy, (C1-C4)perfluoroalkoxy, (C1-C10)alkoxycarbonyl, (C1-C10)alkylthio, (C1-C10)alkylamino, di(C1-C10)alkylamino, (C1C10)alkylaminocarbonyl, di(C1-C10)alkylaminocarbonyl, (C1-C10)acyl, (C1-C10)perfluoroacyl, (C1-C10)acylamino, (C1-C10)perfluoroacylamino, (C1-C10)acyloxy; and (f) -(CH2)nCOR<4>, where R<4> in the definition of -(CH2)nCOR<2> is selected from hydroxy, phenyl, -NR<1>R<2>, (C1-C4)alkyl, (C1-C4)perfluoroalkyl, (C1-C4)alkoxy, (C1-C4)perfluoroalkoxy, (C3-C8)cycloalkyl, and (C3-C8)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, (C1-C10)alkyl, (C1-C4)perfluoroalkyl, (C1-C10)alkoxy, (C1-C4)perfluoroalkoxy, (C1-C10)alkoxycarbonyl, (C1-C10)alkylthio, (C1-C10)alkylamino, di(C1-C10) alkylamino, (C1-C10)alkylaminocarbonyl, di(C1-C10)alkylaminocarbonyl, (C1-C10)acyl, (C1-C10)perfluoroacyl, (C1-C10)acylamino, (C1-C6)perfluoroacylamino, (C1-C10)acyloxy; (b) (C2-C12)alkyl wherein said (C2-C12)alkyl is substituted optionally with from 1-3 substituents selected from: (1) phenyl, halogen, cyano, hydroxy, -NR<1>R<2>, -OCOR<3>, (C1-C4)alkoxy, or (C1-C4)perfluoroalkoxy, where R<3> in the definition of -OCOR<3> is selected from -NR<1>R<2>, (C1-C4)alkyl and (C1-C4)perfluoroalkyl, (2) (C3-C6)cycloalkyl or (C3-C6)cycloalkenyl wherein each of said (C3-C6)cycloalkyl and (C3-C6)cycloalkenyl may optionally have from 1 to 4 substituents selected independently from hydroxy, (C1-C4)alkyl, (C1-C4)alkoxy, and (C1-C4)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, (C1-C10)alkyl, (C1-C4)perfluoroalkyl, (C1-C10)alkoxy, (C1-C10)alkoxycarbonyl,(C1-C10)alkylthio, (C1-C10)alkylamino, di(C1-C10)alkylamino, (C1-C10)alkylaminocarbonyl, di(C1-C10)alkylaminocarbonyl, (C1-C4)perfluoroalkoxy, (C1-C10)acyl, (C1-C10)acylamino, (C1-C10)perfluoroacylamino, (C1-C10)acyloxy, provided that (C2-C12)alkyl does not include unsubstituted allyl; (c) (C3-C6)cycloalkyl or (C3-C6)cycloalkenyl wherein each of said (C3-C6)cycloalkyl and (C3-C6)cycloalkenyl may have optionally from 1 to 4 substituents selected independently from hydroxy, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C10)acylamino, (C1-C10)perfluoroacylamino and (C1-C4)alkoxycarbonyl; and (d) -(CH2)nCOR<4>, where R<4> in the definition of -(CH2)nCOR<4> is selected from hydroxy, phenyl, -NR<1>R<2>, (C1-C4)alkyl, (C1-C4)perfluoroalkyl, (C1-C4)alkoxy, (C1-C4)perfluoroalkoxy, (C3-C6)cycloalkyl, and (C3-C6)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 (C2-C12)alkyl, wherein said (C2-C12)alkyl is substituted optionally with a group selected from phenyl, halogen, cyano, hydroxy, (C1-C4)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 substituents selected independently from halogen, (C1-C4)acyl, (C1-C4)perfluoroacyl, (C1-C4)alkyl, (C1-C4)perfluoroalkyl, (C1-C4)alkoxy, (C1-C4)alkylaminocarbonyl, and (C1-C4)acylamino, provided that (C2-C12) 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 -(CH2)nNR<1>R<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 -(CH2)nCOR<4> and n is 1 or 2. 6. The compound of claim 2, wherein G is -(CH2)2OCOCH3, -(CH2)2OCON(CH3)2,   -(CH2)4CH3, -(CH2)2OCH3, -(CH2)OCH2CH3, -(CH2)3OCH3, -(CH2)2CN,   -(CH2)2NHS(O)2CH3, -(CH2)2NHCHO, -(CH2)2NHCOCH2CH3, -(CH2)2NHCOCF3, -(CH2)2NHCONHCH3, -(CH2)2NHCOOCH3, -(CH2)2NHCOCH3, -(CH2)2NH2, -(CH2)2CON(CH3)2, -(CH2)2CON(CH2CH3)2, -(CH2)2CON(CH3)2, -CH2COOH. 7. 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 hy