US 5,631,293 AGranted

Preparation of amino acid-substituted benzoylguanidines as diagnostic agents

AssigneeHoechst Aktiengesellschaft

InventorsHeinz-Werner Kleemann, Hans-Jochen Lang, Jan-Robert Schwark, Andreas Weichert, Wolfgang Scholz, Udo Albus

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Abstract

Amino acid-substituted benzoylguanidines, a process for their preparation, their use as a medicament or diagnostic agent and a medicament containing them Benzoylguanidines of the formula I ##STR1## in which the radicals R(1) to R(5) have the meanings given in the description, are described. They are prepared by reacting a compound of the formula II ##STR2## in which R(1) to R(5) and L have the meanings given in the description, with guanidine. The compound I is suitable for the preparation of cardiovascular medicaments.

Claims9

Dependent claims

A compound of the formula I ##STR14## in which:

one of the three substituents R(1), R(2) and R(3) is --Y--[4-[(CH.sub.2).sub.k --CHR(7)--(C.dbd.O)R(8)]phenyl], --Y--[3-[(CH.sub.2).sub.k --CHR(7)--(C.dbd.O)R(8)]phenyl] or --Y--[2-[(CH.sub.2).sub.k --CHR(7)--(C.dbd.O)R(8)]phenyl], in which the phenyl is in each case unsubstituted or substituted by 1-2 substituents from the group consisting of F, Cl, --CF.sub.3, methyl, hydroxyl, methoxy and --NR(37)R(38);
R(37) and R(38) independently of one another are hydrogen or --CH.sub.3 ;
Y is a bond, oxygen, --S-- or --NR(9);
R(9) is hydrogen or --(C.sub.1 -C.sub.4)-alkyl;
R(7) is --OR(10) or --NR(10)R(11);
R(10) and R(11) independently of one another are hydrogen, --(C.sub.1 -C.sub.8)-alkyl, --(C.sub.1 -C.sub.8)-alkanoyl, --(C.sub.1 -C.sub.8)-alkoxycarbonyl, benzyl, benzyloxycarbonyl;
or
R(10) is trityl;
R(8) is --OR(12) or --NR(12)R(13);
R(12) and R(13) independently of one another are hydrogen, --(C.sub.1 -C.sub.8)-alkyl or benzyl;
k is zero, 1, 2, 3 or 4;
and the other particular radicals R(1), R(2) and R(3) independently of one another are --(C.sub.1 -C.sub.8)-alkyl, --(C.sub.2 -C.sub.8)-alkenyl or --(CH.sub.2).sub.m R(14);
m is zero, 1 or 2;
R(14) is --(C.sub.3 -C.sub.8)-cycloalkyl or phenyl, which is unsubstituted or substituted by 1-3 substituents chosen from the group consisting of F, Cl, --CF.sub.3, methyl, methoxy and --NR(15)R(16);
R(15) and R(16) are hydrogen or --CH.sub.3 ;
or
the other particular radicals R(1), R(2) and R(3) independently of one another are R(18)R(19)N--C.dbd.Y')--NH--SO.sub.2 --;
Y' is oxygen, --S-- or --N--R(20);
R(18) and R(19) independently of one another are hydrogen, --(C.sub.1 -C.sub.8)-alkyl, --(C.sub.3 -C.sub.6)-alkenyl or --(CH.sub.2).sub.t --R(21);
t is zero, 1, 2, 3 or 4;
R(21) is --(C.sub.5 -C.sub.7)-cycloalkyl or phenyl, which is unsubstituted or substituted by 1-3 substituents chosen from the group consisting of F, Cl, --CF.sub.3, methoxy and --(C.sub.1 -C.sub.4)-alkyl;
or
R(18) and R(19) together are 4 or 5 methylene groups, one CH.sub.2 group of which can be replaced by oxygen, --S--, --NH--, --N--CH.sub.3 or --N-benzyl;
R(20) is as defined for R(18) or amidine;
or
the other particular radicals R(1), R(2) and R(3) independently of one another are hydrogen, F, Cl, Br, I, --C.tbd.N, X--(CH.sub.2).sub.p --(C.sub.q F.sub.2q+1), R(22)--SO.sub.u --, R(23)R(24)N--CO--, R(25)--CO-- or R(26)R(27)N--SO.sub.2 --, in which the perfluoroalkyl group is straight-chain or branched;
X is a bond, oxygen, --S-- or --NR(28);
u is zero, 1 or 2;
p is zero, 1 or 2;
q is 1, 2, 3, 4, 5 or 6;
R(22), R(23), R(25) and R(26) independently of one another are --(C.sub.1 -C.sub.8)-alkyl, --(C.sub.3 -C.sub.6)-alkenyl, --(CH.sub.2).sub.n --R(29) or --CF.sub.3 ;
n is zero, 1, 2, 3 or 4;
R(28) is hydrogen or --(C.sub.1 -C.sub.3)-alkyl;
R(29) is --(C.sub.3 -C.sub.7)-cycloalkyl or phenyl, which is unsubstituted or substituted by 1-3 substituents chosen from the group consisting of F, Cl, --CF.sub.3, methyl, methoxy and --NR(30)R(31);
R(30) and R(31) are hydrogen or --(C.sub.1 -C.sub.4)-alkyl;
or
R(23), R(25) and R(26) are hydrogen;
R(24) and R(27) independently of one another are hydrogen or --(C.sub.1 -C.sub.4)-alkyl;
or
R(23) and R(24), and R(26) and R(27), together are 4 or 5 methylene groups, one CH.sub.2 group of which can be replaced by oxygen, --S--, --NH--, --N--CH.sub.3 or --N-benzyl;
or
the other particular radicals R(1), R(2) and R(3) independently of one another are --OR(35) or --NR(35)R(36);
R(35) and R(36) independently of one another are hydrogen or --(C.sub.1 -C.sub.6)-alkyl;
or
R(35) and R(36) together are 4-7 methylene groups, one CH.sub.2 group of which can be replaced by oxygen, --S--, --NH--, --N--CH.sub.3 or --N-benzyl;
R(4) and R(5) independently of one another are hydrogen, --(C.sub.1 -C.sub.4)-alkyl, F, Cl, --OR(32), --NR(33)R(34) or --C.sub.r F.sub.2r+1 ;
R(32), R(33) and R(34) independently of one another are hydrogen or --(C.sub.1 -C.sub.3)-alkyl;
r is 1, 2, 3 or 4;
or a pharmaceutically tolerated salt thereof.

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Dependencies are inferred from the claim text.

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Abstract

A compound of the formula I ##STR14## in which:

one of the three substituents R(1), R(2) and R(3) is --Y--[4-[(CH.sub.2).sub.k --CHR(7)--(C.dbd.O)R(8)]phenyl], --Y--[3-[(CH.sub.2).sub.k --CHR(7)--(C.dbd.O)R(8)]phenyl] or --Y--[2-[(CH.sub.2).sub.k --CHR(7)--(C.dbd.O)R(8)]phenyl], in which the phenyl is in each case unsubstituted or substituted by 1-2 substituents from the group consisting of F, Cl, --CF.sub.3, methyl, hydroxyl, methoxy and --NR(37)R(38);
R(37) and R(38) independently of one another are hydrogen or --CH.sub.3 ;
Y is a bond, oxygen, --S-- or --NR(9);
R(9) is hydrogen or --(C.sub.1 -C.sub.4)-alkyl;
R(7) is --OR(10) or --NR(10)R(11);
R(10) and R(11) independently of one another are hydrogen, --(C.sub.1 -C.sub.8)-alkyl, --(C.sub.1 -C.sub.8)-alkanoyl, --(C.sub.1 -C.sub.8)-alkoxycarbonyl, benzyl, benzyloxycarbonyl;
or
R(10) is trityl;
R(8) is --OR(12) or --NR(12)R(13);
R(12) and R(13) independently of one another are hydrogen, --(C.sub.1 -C.sub.8)-alkyl or benzyl;
k is zero, 1, 2, 3 or 4;
and the other particular radicals R(1), R(2) and R(3) independently of one another are --(C.sub.1 -C.sub.8)-alkyl, --(C.sub.2 -C.sub.8)-alkenyl or --(CH.sub.2).sub.m R(14);
m is zero, 1 or 2;
R(14) is --(C.sub.3 -C.sub.8)-cycloalkyl or phenyl, which is unsubstituted or substituted by 1-3 substituents chosen from the group consisting of F, Cl, --CF.sub.3, methyl, methoxy and --NR(15)R(16);
R(15) and R(16) are hydrogen or --CH.sub.3 ;
or
the other particular radicals R(1), R(2) and R(3) independently of one another are R(18)R(19)N--C.dbd.Y')--NH--SO.sub.2 --;
Y' is oxygen, --S-- or --N--R(20);
R(18) and R(19) independently of one another are hydrogen, --(C.sub.1 -C.sub.8)-alkyl, --(C.sub.3 -C.sub.6)-alkenyl or --(CH.sub.2).sub.t --R(21);
t is zero, 1, 2, 3 or 4;
R(21) is --(C.sub.5 -C.sub.7)-cycloalkyl or phenyl, which is unsubstituted or substituted by 1-3 substituents chosen from the group consisting of F, Cl, --CF.sub.3, methoxy and --(C.sub.1 -C.sub.4)-alkyl;
or
R(18) and R(19) together are 4 or 5 methylene groups, one CH.sub.2 group of which can be replaced by oxygen, --S--, --NH--, --N--CH.sub.3 or --N-benzyl;
R(20) is as defined for R(18) or amidine;
or
the other particular radicals R(1), R(2) and R(3) independently of one another are hydrogen, F, Cl, Br, I, --C.tbd.N, X--(CH.sub.2).sub.p --(C.sub.q F.sub.2q+1), R(22)--SO.sub.u --, R(23)R(24)N--CO--, R(25)--CO-- or R(26)R(27)N--SO.sub.2 --, in which the perfluoroalkyl group is straight-chain or branched;
X is a bond, oxygen, --S-- or --NR(28);
u is zero, 1 or 2;
p is zero, 1 or 2;
q is 1, 2, 3, 4, 5 or 6;
R(22), R(23), R(25) and R(26) independently of one another are --(C.sub.1 -C.sub.8)-alkyl, --(C.sub.3 -C.sub.6)-alkenyl, --(CH.sub.2).sub.n --R(29) or --CF.sub.3 ;
n is zero, 1, 2, 3 or 4;
R(28) is hydrogen or --(C.sub.1 -C.sub.3)-alkyl;
R(29) is --(C.sub.3 -C.sub.7)-cycloalkyl or phenyl, which is unsubstituted or substituted by 1-3 substituents chosen from the group consisting of F, Cl, --CF.sub.3, methyl, methoxy and --NR(30)R(31);
R(30) and R(31) are hydrogen or --(C.sub.1 -C.sub.4)-alkyl;
or
R(23), R(25) and R(26) are hydrogen;
R(24) and R(27) independently of one another are hydrogen or --(C.sub.1 -C.sub.4)-alkyl;
or
R(23) and R(24), and R(26) and R(27), together are 4 or 5 methylene groups, one CH.sub.2 group of which can be replaced by oxygen, --S--, --NH--, --N--CH.sub.3 or --N-benzyl;
or
the other particular radicals R(1), R(2) and R(3) independently of one another are --OR(35) or --NR(35)R(36);
R(35) and R(36) independently of one another are hydrogen or --(C.sub.1 -C.sub.6)-alkyl;
or
R(35) and R(36) together are 4-7 methylene groups, one CH.sub.2 group of which can be replaced by oxygen, --S--, --NH--, --N--CH.sub.3 or --N-benzyl;
R(4) and R(5) independently of one another are hydrogen, --(C.sub.1 -C.sub.4)-alkyl, F, Cl, --OR(32), --NR(33)R(34) or --C.sub.r F.sub.2r+1 ;
R(32), R(33) and R(34) independently of one another are hydrogen or --(C.sub.1 -C.sub.3)-alkyl;
r is 1, 2, 3 or 4;
or a pharmaceutically tolerated salt thereof.

46 more elements