US 5,698,691 A · Condensed cyclic compounds and their use

Abstract

Disclosed is a squalene synthetase inhibitor which comprises the compound represented by the formula ##STR1## wherein R.sub.1 is hydrogen or an optionally substituted hydrocarbon group; R.sub.2 is hydrogen, an optionally substituted alkyl group, an optionally substituted phenyl group or an optionally substituted aromatic heterocyclic ring group; X' is a substituent comprising an optionally esterified carboxyl group, an optionally substituted carbamoyl group, an optionally substituted hydroxyl group, an optionally substituted amino group or an optionally substituted heterocyclic radical having a protonizable hydrogen; Ring A is an optionally substituted benzene ring or an optionally substituted aromatic heterocyclic ring; Ring J' is a 7- to 8-membered heterocyclic ring containing at most three ring constituting hetero atoms; D is C or N; the Ring J' optionally having, besides R.sub.1, R.sub.2 and X', a further substituent; provided that the condensed ring composed of Ring A and ring J' is not a 2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine ring, or a pharmaceutically acceptable salt thereof, and which is useful for the prophylaxis or therapy of hypercholesteremia or coronary sclerosis of mammals.

A compound of the formula (I):

##STR136## in which R.sub.1 is hydrogen or a hydrocarbon group selected from the group consisting of
(1) C.sub.1-7 alkyl,
(2) C.sub.2-6 alkenyl,
(3) C.sub.2-6 alkynyl,
(4) C.sub.3-9 cycloalkyl,
(5) 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 1-cyclobuten-1-yl or 1-cyclopenten-1-yl,
(6) 2,4-cyclopentadien-1-yl, 2-4-cyclohexadien-1-yl or 2,5-cyclohexadien-1-yl,
(7) phenyl, naphthyl, anthryl, phenanthryl or acenaphthylenyl, and
(8) C.sub.1-5 acyl group which may be substituted by one to five halogens;
R.sub.2 ' is phenyl which may be substituted by one to three substituents selected from the group consisting of
(1) halogen,
(2) C.sub.1-4 alkyl which may be substituted by 1 to 5 halogens,
(3) C.sub.1-4 alkoxy which may be substituted by 1 to 5 halogens,
(4) hydroxyl which may be substituted by (i) C.sub.1-4 alkyl, (ii) C.sub.3-6 cycloalkyl, (iii) phenyl, 1-naphthyl or 2-naphthyl, or (iv) benzyl or phenethyl,
(5) nitro and
(6) cyano;
X' is -X.sub.1 -Y
wherein X.sub.1 is C.sub.1-7 alkylene, Y is
(A) carboxyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, sec-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, phenoxycarbonyl, 1-naphthoxycarbonyl or benzyloxycarbonyl,
(B) carbamoyl which may be substituted by one or two substituents selected from the group consisting of
(1) C.sub.1-6 alkyl which may be substituted by one to three substituents selected from the group consisting of (i) carboxyl which may be esterified by C.sub.1-5 alkyl, (ii) furyl, thienyl, indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidyl or imidazolyl, (iii) amino, (iv) hydroxyl and (v) phenyl,
(2) C.sub.3-6 cycloalkyl which may be substituted by one to three substituents selected from the group consisting of (i) carboxyl group which may be esterified by C.sub.1-5 alkyl, (ii) furyl, thienyl, indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidyl or imidazolyl, (iii) amino, (iv) hydroxyl and (v) phenyl
(3) phenyl, 1-naphthyl or 2-naphthyl, each of said groups being unsubstituted or substituted by (i) halogen atoms and (ii) carboxyl which may be esterified by a C.sub.1-4 alkyl, and
(4) benzyl or phenethyl, each of said groups being unsubstituted or substituted by (i) halogen or (ii) carboxyl which may be esterified by a C.sub.1-4 alkyl,
in which two substituents on the nitrogen atom of the carbamoyl group may form, taken together with the nitrogen, a cyclic amino group selected from the group consisting of 1-azetidinyl, 1-pyrrolidinyl, piperidino, morpholino and 1-piperzinyl;
(C) hydroxyl which may be substituted by
(1) C.sub.1-4 alkyl,
(2) C.sub.3-6 cycloalkyl,
(3) phenyl, 1-naphthyl or 2-naphthyl, each of said groups being unsubstituted or substituted by (i) halogen or (ii) carboxyl which may be esterified by a C.sub.1-4 alkyl, or
(4) benzyl or phenethyl, each of said groups being unsubstituted or substituted by substituents selected from the group consisting of (i) halogen or (ii) carboxyl which may be esterified by a C.sub.1-4 alkyl,
(D) amino which may be substituted by
(1) C.sub.1-4 alkyl,
(2) C.sub.3-6 cycloalkyl,
(3) phenyl, 1-naphthyl or 2-naphthyl, each of said groups being unsubstituted or substituted by (i) halogen or (ii) carboxyl group which may be esterified by a C.sub.1-4 alkyl, or
(4) benzyl or phenethyl, each of said groups being Unsubstituted or substituted by (i) halogen or (ii) carboxyl group which may be esterified by a C.sub.1-4 alkyl,
in which two substituents on the nitrogen atom of the amino group may form, taken together with the nitrogen, a cyclic amino group selected from the group consisting of 1-azetidinyl, 1-pyrrolidinyl, piperidino, morpholino and 1-piperzinyl, or
(E) tetrazol-5-yl or a group represented by the formula ##STR137## wherein i stands for --O-- or --S--, j stands for --CO--, --CS-- or --SO.sub.2 --, which may be substituted by C.sub.1-4 alkyl, C.sub.3-5 alkanoyl or benzoyl;
##STR138## is a group selected from ##STR139## ring A may be substituted by one to three substituents selected from the group consisting of
(1) halogen,
(2) C.sub.1-4 alkyl which may be substituted by one to three halogens,
(3) C.sub.1-4 alkoxy which may be substituted by one to three halogens,
(4) nitro, and
(5) cyano;
and
ring J.sub.1 may have
(1) oxo, or
(2) thioxo,
on the carbon atom of the ring J.sub.1, provided that the condensed ring composed of Ring A and ring J.sub.1 is not a 2-oxo-(2,3-dihydro or 2,3,5,-tetrahydro)-1H-1,4-benzodiazepene ring.

45 more elements

Condensed cyclic compounds and their use

Life of this patent

Condensed cyclic compounds and their use

Life of this patent

Abstract

Claims15