US 5,294,716 AGranted

Chemical process for making angiotesin II antagonist compounds

AssigneeImperial Chemical Industries PLC

InventorsAndrew P. Thomas, David M. G. Martin, Stanley A. Lee, Lyn Powell

Life of this patent

Estimating the term…

Abstract

The invention provides a novel chemical process for the manufacture of quinoline, pyridine and imidazole derivatives of the formula IV wherein Q, Y.sup.1 and Y.sup.2 have the various meanings defined herein, and their non-toxic salts, which are angiotensin II inhibitors. The process involves the removal of an electron-deficient phenyl group or a pyridyl or pyrimidyl group from a compound of the formula VI as defined herein.

Claims9

Dependent claims

A process for the manufacture of a compound of the formula IV

or a non-toxic salt thereof, wherein Q is selected from
(1) a 4-quinolyloxy moiety of the formula Va ##STR2## in which R.sup.1 is hydrogen, (1-8C)alkyl, (3-8C)cycloalkyl, phenyl or substituted (1-4C)alkyl, the latter containing one or more fluoro substituents or bearing a (3-8C)cycloalkyl, hydroxy, (1-4C)alkoxy or phenyl substituent;
R.sup.2 is hydrogen, (1-8C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl-(1-4C)alkyl, carboxy, (1-4C)alkoxycarbonyl, cyano, nitro, phenyl or phenyl(1-4C)alkyl;
R.sup.3 and R.sup.4 are independently selected from hydrogen, (1-4C)alkyl, (1-4C)alkoxy, fluoro(1-4C)alkoxy, halogeno, hydroxy, trifluoromethyl, cyano, nitro, amino, (1-4C)alkanoylamino, alkylamino and dialkylamino of up to 6 carbon atoms, dialkylamino-alkyl of 3 to 8 carbon atoms, (1-4C)alkanoyl, carbamoyl, N-alkylcarbamoyl and di-(N-alkyl)carbamoyl of up to 7 carbon atoms, carboxy, (1-4C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, and substituted (1-4C)alkyl, the latter bearing an amino, hydroxy or (1-4C)alkoxy substituent;
or R.sup.3 and R.sup.4 together form (1-4C)alkylenedioxy attached to adjacent carbon atoms of the benzene moiety of formula I;
and Ra is selected from hydrogen, (1-4C)alkyl, (1-4C)alkoxy, halogeno, trifluoromethyl, cyano or nitro;
(2) a 4-pyridyloxy moiety of the formula Vb ##STR3## in which T.sup.1 is hydrogen, (1-8C)alkyl, (3-8C)cycloalkyl, phenyl or substituted (1-4C)alkyl, the latter containing one or more fluoro substituents or bearing a (3-8C)cycloalkyl, (1-4C)alkoxy or phenyl substituent;
T.sup.2 is hydrogen, (1-8C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl-(1-4C)alkyl, carboxy, (1-4C)alkoxycarbonyl, (3-6C)alkenyloxycarbonyl, cyano, nitro, phenyl or phenyl(1-4C)alkyl;
T.sup.3 is selected from halogeno, (1-4C)alkoxy, amino, alkylamino and dialkylamino of up to 6 carbon atoms, and any of the values defined above for T.sup.1 ;
T.sup.4 is selected from hydrogen, (1-4C)alkyl optionally bearing an amino, (1-4C)alkanoylamino, phenylcarbonylamino, hydroxy or (1-4C)alkoxy substituent, carboxy, (1-4C)alkoxycarbonyl, (3-6C)alkenyloxycarbonyl, cyano, nitro, carbamoyl, (1-4C)alkanoyl, N-alkylcarbamoyl and di-(N-alkyl)carbamoyl of up to 7 carbon atoms, formyl, halogeno, amino, alkylamino and dialkylamino of up to 6 carbon atoms, 3-(1-4C)alkylureido and (1-4C)alkanoylamino;
or T.sup.4 is a group of the formula --A.sup.1.A.sup.2.E wherein A.sup.1 is carbonyloxy, A.sup.2 is (1-6C)alkylene and E is selected from hydroxy, (1-4C)alkoxy, phenyloxy, phenyl(1-4C)alkoxy, pyridyl(1-4C)alkoxy, 4-morpholino(1-4C)alkoxy, phenylamino, amino, alkylamino and dialkylamino of up to 6 carbon atoms, (1-4C)alkanoylamino, (1-4C)alkylsulphonylamino, phenylsulphonylamino, sulphamoylamino (--NH.SO.sub.2.NH.sub.2), carboxamidomethylamino (--NH.CH.sub.2.CO.NH.sub.2), (1-4C)alkanoyloxy, phenylcarbonyloxy, aminocarbonyloxy (--O.CO.NH.sub.2), (1-4C)alkylaminocarbonyloxy, carboxy, (1-4C)alkoxycarbonyl, carbamoyl, N-alkylcarbamoyl and di-(N-alkyl)carbamoyl of up to 7 carbon atoms, (1-4C)alkanoyl, 4-morpholino, 1-imidazolyl and succinimido group;
or E is a group of the formula --A.sup.3.E.sup.1 wherein A.sup.3 is oxy, oxycarbonyl or imino and E.sup.1 is a 5 or 6-membered saturated or unsaturated heterocyclic ring containing 1 or 2 nitrogen atoms and linked to A.sup.3 by a ring carbon atom;
or A.sup.3 is oxycarbonyl and E.sup.1 is a 4-morpholino group or a 5 or 6-membered saturated heterocyclic ring containing 1 or 2 nitrogen atoms, optionally bearing a (1-4C)alkyl group and linked to A.sup.3 by a ring nitrogen atom;
and wherein E.sup.1 the remainder of the ring atoms are carbon;
or T.sup.3 and T.sup.4 together form (3-6C)alkylene, one of the methylene groups of which may optionally be replaced by a carbonyl group, or (3-6C)alkenylene;
and
(3) an 1-imidazolyl moiety of the formula Vc ##STR4## in which Alk. is a (3-10C)alkyl group and X.sup.1 is selected from hydrogen, fluoro, chloro, bromo, iodo, nitro, trifluoromethyl and cyano;
Y.sup.1 is selected from hydrogen, 91-4C)alkyl, (1-4C)alkoxy, halogeno, (1-4C)alkanoyl, trifluoromethyl, cyano and nitro;
and
Y.sup.2 is selected from hydrogen, (1-4C)alkyl, (1-4C)alkoxy, halogeno, trifluoromethyl, cyano and nitro;
which is characterised in that a compound of the formula VI ##STR5## wherein P.sup.1 is an electron-deficient phenyl group or is a pyridyl or pyrimidyl group, and Q, Y.sup.1 and Y.sup.2 have any of the meanings defined hereinbefore, is reacted with a base selected from an alkali metal hydroxide, (1-12C)alkanolate, (1-12C)alkanethiolate, phenolate, thiophenolate and diphenylphosphide, wherein any phenyl ring of the latter three groups may optionally bear a (1-4C)alkyl, (1-4C)alkoxy or halogeno substituent;
whereafter:
when a non-toxic salt of a compound of formula IV is desired, it is obtained by reaction with the appropriate acid or base affording a physiologically acceptable ion, or by any other conventional salt formation procedure;
and
when an optically active form of a compound of formula IV is desired the process is carried out with an optically active starting material, or a racemic form of a compound of formula IV is resolved by reaction with an optically active form of a suitable organic base followed by conventional separation of the diastereomeric mixture of salts thus obtained, and liberation of the desired optically active form of said compound of formula IV by conventional treatment with acid;
and wherein Q, Y.sup.1 and Y.sup.2 have any of the meanings defined above.

23 more elements

Dependencies are inferred from the claim text.

patentgrep

Loading patent…

Abstract

A process for the manufacture of a compound of the formula IV

or a non-toxic salt thereof, wherein Q is selected from
(1) a 4-quinolyloxy moiety of the formula Va ##STR2## in which R.sup.1 is hydrogen, (1-8C)alkyl, (3-8C)cycloalkyl, phenyl or substituted (1-4C)alkyl, the latter containing one or more fluoro substituents or bearing a (3-8C)cycloalkyl, hydroxy, (1-4C)alkoxy or phenyl substituent;
R.sup.2 is hydrogen, (1-8C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl-(1-4C)alkyl, carboxy, (1-4C)alkoxycarbonyl, cyano, nitro, phenyl or phenyl(1-4C)alkyl;
R.sup.3 and R.sup.4 are independently selected from hydrogen, (1-4C)alkyl, (1-4C)alkoxy, fluoro(1-4C)alkoxy, halogeno, hydroxy, trifluoromethyl, cyano, nitro, amino, (1-4C)alkanoylamino, alkylamino and dialkylamino of up to 6 carbon atoms, dialkylamino-alkyl of 3 to 8 carbon atoms, (1-4C)alkanoyl, carbamoyl, N-alkylcarbamoyl and di-(N-alkyl)carbamoyl of up to 7 carbon atoms, carboxy, (1-4C)alkoxycarbonyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, and substituted (1-4C)alkyl, the latter bearing an amino, hydroxy or (1-4C)alkoxy substituent;
or R.sup.3 and R.sup.4 together form (1-4C)alkylenedioxy attached to adjacent carbon atoms of the benzene moiety of formula I;
and Ra is selected from hydrogen, (1-4C)alkyl, (1-4C)alkoxy, halogeno, trifluoromethyl, cyano or nitro;
(2) a 4-pyridyloxy moiety of the formula Vb ##STR3## in which T.sup.1 is hydrogen, (1-8C)alkyl, (3-8C)cycloalkyl, phenyl or substituted (1-4C)alkyl, the latter containing one or more fluoro substituents or bearing a (3-8C)cycloalkyl, (1-4C)alkoxy or phenyl substituent;
T.sup.2 is hydrogen, (1-8C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl-(1-4C)alkyl, carboxy, (1-4C)alkoxycarbonyl, (3-6C)alkenyloxycarbonyl, cyano, nitro, phenyl or phenyl(1-4C)alkyl;
T.sup.3 is selected from halogeno, (1-4C)alkoxy, amino, alkylamino and dialkylamino of up to 6 carbon atoms, and any of the values defined above for T.sup.1 ;
T.sup.4 is selected from hydrogen, (1-4C)alkyl optionally bearing an amino, (1-4C)alkanoylamino, phenylcarbonylamino, hydroxy or (1-4C)alkoxy substituent, carboxy, (1-4C)alkoxycarbonyl, (3-6C)alkenyloxycarbonyl, cyano, nitro, carbamoyl, (1-4C)alkanoyl, N-alkylcarbamoyl and di-(N-alkyl)carbamoyl of up to 7 carbon atoms, formyl, halogeno, amino, alkylamino and dialkylamino of up to 6 carbon atoms, 3-(1-4C)alkylureido and (1-4C)alkanoylamino;
or T.sup.4 is a group of the formula --A.sup.1.A.sup.2.E wherein A.sup.1 is carbonyloxy, A.sup.2 is (1-6C)alkylene and E is selected from hydroxy, (1-4C)alkoxy, phenyloxy, phenyl(1-4C)alkoxy, pyridyl(1-4C)alkoxy, 4-morpholino(1-4C)alkoxy, phenylamino, amino, alkylamino and dialkylamino of up to 6 carbon atoms, (1-4C)alkanoylamino, (1-4C)alkylsulphonylamino, phenylsulphonylamino, sulphamoylamino (--NH.SO.sub.2.NH.sub.2), carboxamidomethylamino (--NH.CH.sub.2.CO.NH.sub.2), (1-4C)alkanoyloxy, phenylcarbonyloxy, aminocarbonyloxy (--O.CO.NH.sub.2), (1-4C)alkylaminocarbonyloxy, carboxy, (1-4C)alkoxycarbonyl, carbamoyl, N-alkylcarbamoyl and di-(N-alkyl)carbamoyl of up to 7 carbon atoms, (1-4C)alkanoyl, 4-morpholino, 1-imidazolyl and succinimido group;
or E is a group of the formula --A.sup.3.E.sup.1 wherein A.sup.3 is oxy, oxycarbonyl or imino and E.sup.1 is a 5 or 6-membered saturated or unsaturated heterocyclic ring containing 1 or 2 nitrogen atoms and linked to A.sup.3 by a ring carbon atom;
or A.sup.3 is oxycarbonyl and E.sup.1 is a 4-morpholino group or a 5 or 6-membered saturated heterocyclic ring containing 1 or 2 nitrogen atoms, optionally bearing a (1-4C)alkyl group and linked to A.sup.3 by a ring nitrogen atom;
and wherein E.sup.1 the remainder of the ring atoms are carbon;
or T.sup.3 and T.sup.4 together form (3-6C)alkylene, one of the methylene groups of which may optionally be replaced by a carbonyl group, or (3-6C)alkenylene;
and
(3) an 1-imidazolyl moiety of the formula Vc ##STR4## in which Alk. is a (3-10C)alkyl group and X.sup.1 is selected from hydrogen, fluoro, chloro, bromo, iodo, nitro, trifluoromethyl and cyano;
Y.sup.1 is selected from hydrogen, 91-4C)alkyl, (1-4C)alkoxy, halogeno, (1-4C)alkanoyl, trifluoromethyl, cyano and nitro;
and
Y.sup.2 is selected from hydrogen, (1-4C)alkyl, (1-4C)alkoxy, halogeno, trifluoromethyl, cyano and nitro;
which is characterised in that a compound of the formula VI ##STR5## wherein P.sup.1 is an electron-deficient phenyl group or is a pyridyl or pyrimidyl group, and Q, Y.sup.1 and Y.sup.2 have any of the meanings defined hereinbefore, is reacted with a base selected from an alkali metal hydroxide, (1-12C)alkanolate, (1-12C)alkanethiolate, phenolate, thiophenolate and diphenylphosphide, wherein any phenyl ring of the latter three groups may optionally bear a (1-4C)alkyl, (1-4C)alkoxy or halogeno substituent;
whereafter:
when a non-toxic salt of a compound of formula IV is desired, it is obtained by reaction with the appropriate acid or base affording a physiologically acceptable ion, or by any other conventional salt formation procedure;
and
when an optically active form of a compound of formula IV is desired the process is carried out with an optically active starting material, or a racemic form of a compound of formula IV is resolved by reaction with an optically active form of a suitable organic base followed by conventional separation of the diastereomeric mixture of salts thus obtained, and liberation of the desired optically active form of said compound of formula IV by conventional treatment with acid;
and wherein Q, Y.sup.1 and Y.sup.2 have any of the meanings defined above.

23 more elements