Sulfonylamino carboxylic acid N-arylamides as guanylate cyclase activators
View Patent ↗The present invention relates to compounds of the formula I in which A 1 , A 2 , R 2 and R 3 have the meanings indicated in the claims, which are valuable pharmaceutical active compounds for the therapy and prophylaxis of diseases, for example of cardiovascular disorders such as high blood pressure, angina pectoris, cardiac insufficiency, thromboses or atherosclerosis. The compounds of the formula I have the ability to modulate the endogenous production of cyclic guanosine monophosphate (cGMP) and are generally suitable for the therapy and prophylaxis of disease states which are associated with a disturbed cGMP balance. The invention relates to the use of compounds of the formula I for the therapy and prophylaxis of the designated disease states and for the production of pharmaceuticals therefor, novel compounds of the formula I, pharmaceutical preparations comprising them and processes for their preparation.
1. A compound of the formula Ik
in any stereoisomeric form,
or a physiologically tolerable salt thereof,
or a mixture thereof,
in which
the ring A 2 , which includes the carbon atoms which carry the groups CO—NH-phenyl-R 1 and NH—SO 2 R 2 , is a thiophene ring;
R 1 is a substituent from the group consisting of CO—(C 1 -C 10 )-alkyl, CO-aryl, CO—NR 5 R 6 , —NH—CO—(C 1 -C 10 )-alkyl, —O-aryl, —NH—CO-aryl, —N(CO—(C 1 -C 10 )-alkyl) 2 , —N(CO-aryl) 2 , —NH—SO 2 —(C 1 -C 10 )-alkyl, —NH—SO 2 -aryl, —N(SO 2 —(C 1 -C 10 )-alkyl) 2 and —N(SO 2 -aryl) 2 , in which all alkyl radicals can be substituted by one or more identical or different radicals R 4 ;
R 2 is aryl, heterocyclyl or NR 5 R 6 ;
R 3 is one or more identical or different substituents from the group consisting of hydrogen, halogen, CF 3 , OH, —O—(C 1 -C 10 )-alkyl, —O—(C 1 -C 7 )-alkyl-R 7 , —O-aryl, SH, —S—(C 1 -C 10 )-alkyl, —S—(C 1 -C 7 )-alkyl-R 7 , —S-aryl, (C 1 -C 2 )-alkylenedioxy, CN, NO 2 , NR 8 R 9 , CO—NR 5 R 6 , COOH, CO—O—(C 1 -C 5 )-alkyl, heterocyclyl, S(O) n —(C 1 -C 7 )-alkyl, S(O) n -aryl, S(O) n —NR 5 R 6 and (C 1 -C 7 )-alkyl which can be substituted by one or more identical or different radicals R 4 ;
R 4 is fluorine, OH, —O—(C 1 -C 10 )-alkyl, —O—(C 1 -C 7 )-alkyl-R 7 , —O-aryl, SH, —S—(C 1 -C 10 )-alkyl, —S—(C 1 -C 7 )-alkyl-R 7 , —S-aryl, —P(O)(O—(C 1 -C 5 )-alkyl) 2 , —P(O)(OH) 2 , CN, NR 8 R 9 , CO—NH 2 , CO—NH—(C 1 -C 3 )-alkyl, CO—N((C 1 -C 3 )-alkyl) 2 , COOH, CO—O—(C 1 -C 5 )-alkyl, heterocyclyl or oxo;
R 5 is hydrogen, (C 1 -C 10 )-alkyl which can be substituted by one or more identical or different substituents R 4 and/or by aryl, or is aryl, heterocyclyl, CO—(C 1 -C 10 )-alkyl, CO-aryl, CO-heterocyclyl, SO 2 —(C 1 -C 10 )-alkyl, S 2 -aryl or S 2 -heterocyclyl;
R 6 , independently of R 5 , has one of the meanings indicated for R 5 , or R 5 and R 6 , together with the nitrogen atom to which they are bonded, form a 5-membered to 8-membered saturated or partially unsaturated ring, which in addition to the nitrogen atom carrying the groups R 5 and R 6 can also contain one or more further ring heteroatoms from the group consisting of N, O and S and which can be substituted by one or more identical or different substituents from the group consisting of fluorine, (C 1 -C 5 )-alkyl, (C 1 -C 3 )-hydroxyalkyl, —(C 1 -C 3 )-alkyl-O—(C 1 -C 4 )-alkyl, aryl, CF 3 , OH, —O—(C 1 -C 7 )-alkyl, —O-aryl, —O—(C 2 -C 4 )-alkyl-O—(C 1 -C 4 )-alkyl, (C 2 -C 3 )-alkylenedioxy, NR 8 R 9 , CN, CO—NH 2 , CO—NH—(C 1 -C 3 )-alkyl, CO—N((C 1 -C 3 )-alkyl) 2 , COOH, CO—O—(C 1 -C 5 )-alkyl, CHO, CO—(C 1 -C 5 )-alkyl, S(O) n —(C 1 -C 4 )-alkyl, S(O) n —NH 2 , S(O) n —NH—(C 1 -C 3 )-alkyl, S(O) n —N((C 1 -C 3 )-alkyl) 2 , oxo, —(CH 2 ) m —NH 2 , —(CH 2 ) m —NH—(C 1 -C 4 )-alkyl and —(CH 2 ) m —N((C 1 -C 4 )-alkyl) 2 , where in the substituent —(CH 2 ) m —N((C 1 -C 4 )-alkyl) 2 the two alkyl groups can be linked by a single bond and then together with the nitrogen atom carrying them form a 5-membered to 7-membered ring which in addition to the nitrogen atom and the carbon atoms can additionally also contain an oxygen atom, a sulfur atom or a group NR 5 as a ring member;
R 7 is OH, —O—(C 1 -C 7 )-alkyl, NH 2 , —NH—(C 1 -C 4 )-alkyl or —N((C 1 -C 4 )-alkyl) 2 , where in the substituent N((C 1 -C 4 )-alkyl) 2 the two alkyl groups can be linked by a single bond and then together with the nitrogen atom carrying them form a 5-membered to 7-membered ring which in addition to the nitrogen atom and the carbon atoms can additionally also contain an oxygen atom a sulfur atom or a group NR 5 as a ring member;
R 8 is hydrogen or (C 1 -C 7 )-alkyl which can be substituted by one or more identical or different substituents from the group consisting of OH, —O—(C 1 -C 5 )-alkyl, NH 2 , —NH—(C 1 -C 4 )-alkyl and —N((C 1 -C 4 )-alkyl) 2 , where in the substituent N((C 1 -C 4 )-alkyl) 2 the two alkyl groups can be linked by a single bond and then together with the nitrogen atom carrying them form a 5-membered to 7-membered ring which in addition to the nitrogen atom and the carbon atoms can additionally also contain an oxygen atom, a sulfur atom or a group NR 5 as a ring member;
R 9 , independently or R 8 , has one of the meanings of R 8 or is CO—(C 1 -C 4 )-alkyl;
aryl is phenyl, naphthyl or heteroaryl, which can all be substituted by one or more identical or different substituents from the group consisting of halogen, (C 1 -C 5 )-alkyl, phenyl, tolyl, CF 3 , NO 2 , OH, —O—(C 1 -C 5 )-alkyl, —O—(C 2 -C 4 )-alkyl-O—(C 1 -C 3 )-alkyl, (C 1 -C 2 )-alkylenedioxy, NH 2 , —NH—(C 1 -C 3 )-alkyl, —N((C 1 -C 3 )-alkyl) 2 , NH—CHO, —NH—CO—(C 1 -C 5 )-alkyl, CN, CO—NH 2 , CO—NH—(C 1 -C 3 )-alkyl, CO—N((C 1 -C 3 )-alkyl) 2 , COOH, CO—O—(C 1 -C 5 )-alkyl, heterocyclyl, CHO, CO—(C 1 -C 5 )-alkyl, S(O) n —(C 1 -C 4 )-alkyl, S(O) n -phenyl, S(O) n -tolyl, S(O) 2 —NH 2 , S(O) 2 —NH—(C 1 -C 3 )-alkyl and S(O) 2 —N((C 1 -C 3 )-alkyl) 2 ;
heteroaryl is the radical of a monocyclic 5-membered or 6-membered aromatic heterocycle or of a bicyclic 8-membered to 10-membered aromatic heterocycle which in each case contain one or more ring heteroatoms from the group consisting of N, O and S;
heterocyclyl is the radical of a monocyclic or polycyclic, 5-membered to 11-membered saturated or partially unsaturated heterocycle which contains one or more ring heteroatoms from the group consisting of N, O and S and which can be substituted by one or more identical or different substituents from the group consisting of fluorine, (C 1 -C 5 )-alkyl, OH, —O—(C 1 -C 5 )-alkyl, —O—(C 2 -C 4 )-alkyl-O—(C 1 -C 3 )-alkyl, NH 2 , —NH—(C 1 -C 3 )-alkyl, —N((C 1 -C 3 )-alkyl) 2 , CN, CO—NH 2 , CO—NH(C 1 -C 3 )-alkyl, CO—N(C 1 -C 3 )-alkyl) 2 , COOH and CO—O—(C 1 -C 5 )-alkyl;
n is 0, 1 or 2; and
m is 2, 3 or 4.
2. A pharmaceutical preparation, which comprises one or more compounds as claimed in claim 1 and a pharmaceutically acceptable vehicle and/or additive.
3. A compound of the formula Ik
in any stereoisomeric form,
or a physiologically tolerable salt thereof,
or a mixture thereof,
in which
the ring A 2 , which includes the carbon atoms which carry the groups CO—NH-phenyl-R 1 and NH—SO 2 R 2 , is a thiophene ring;
R 1 is a substituent from the group consisting of CO—(C 1 -C 10 )-alkyl, CO-aryl, CO—NR 5 R 6 , —NH—CO—(C 1 -C 10 )-alkyl, —NH—CO-aryl, —N(CO—(C 1 -C 10 )-alkyl) 2 , —N(CO-aryl) 2 , —NH—SO 2 —(C 1 -C 10 )-alkyl, —NH—SO 2 -aryl, —N(SO 2 -(C 1 -C 10 )-alkyl) 2 and —N(SO 2 -aryl) 2 , in which all alkyl radicals can be substituted by one or more identical or different radicals R 4 ;
R 2 is aryl, heterocyclyl or NR 5 R 6 ;
R 3 is one or more identical or different substituents from the group consisting of hydrogen, halogen, CF 3 , OH, —O—(C 1 -C 10 )-alkyl, —O—(C 1 -C 7 )-alkyl-R 7 , —O-aryl, SH, —S—(C 1 -C 10 )-alkyl, —S—(C 1 -C 7 )-alkyl-R 7 , —S-aryl, (C 1 -C 2 )-alkylenedioxy, CN, NO 2 , NR 8 R 9 , CO—NR 5 R 6 , COOH, CO—O—(C 1 -C 5 )-alkyl, heterocyclyl, S(O) n —(C 1 -C 7 )-alkyl, S(O) n -aryl, S(O) n —NR 5 R 6 and (C 1 -C 7 )-alkyl which can be substituted by one or more identical or different radicals R 4 ;
R 4 is fluorine, OH, —O—(C 1 -C 10 )-alkyl, —O—(C 1 -C 7 )-alkyl-R 7 , —O-aryl, SH, —S—(C 1 -C 10 )-alkyl, —S—(C 1 -C 7 )-alkyl-R 7 , —S-aryl, —P(O)(O—(C 1 -C 5 )-alkyl) 2 , —P(O)(OH) 2 , CN, NR 8 R 9 , CO—NH 2 , CO—NH—(C 1 -C 3 )-alkyl, CO—N((C 1 -C 3 )-alkyl) 2 , COOH, CO—O—(C 1 -C 5 )-alkyl, heterocyclyl or oxo;
R 5 is hydrogen, (C 1 -C 10 )-alkyl which can be substituted by one or more identical or different substituents R 4 and/or by aryl, or is aryl, heterocyclyl, CO—(C 1 -C 10 )-alkyl, CO-aryl, CO-heterocyclyl, SO 2 -(C 1 -C 10 )-alkyl, SO 2 -aryl or SO 2 -heterocyclyl;
R 6 , independently of R 5 , has one of the meanings indicated for R 5 , or R 5 and R 6 , together with the nitrogen atom to which they are bonded, form a 5-membered to 8-membered saturated or partially unsaturated ring, which in addition to the nitrogen atom carrying the groups R 5 and R 6 can also contain one or more further ring heteroatoms from the group consisting of N, O and S and which can be substituted by one or more identical or different substituents from the group consisting of fluorine, (C 1 -C 5 )-alkyl, (C 1 -C 3 )-hydroxyalkyl, —(C 1 -C 3 )-alkyl-O—(C 1 -C 4 )-alkyl, aryl, CF 3 , OH, —O—(C 1 -C 7 )-alkyl, —O-aryl, —O—(C 2 -C 4 )-alkyl-O—(C 1 -C 7 )-alkyl, (C 2 -C 3 )-alkylenedioxy, NR 8 R 9 , CN, CO—NH 2 , CO—NH—(C 1 -C 3 )-alkyl, CO—N((C 1 -C 3 )-alkyl) 2 , COOH, CO—O—(C 1 -C 5 )-alkyl, CHO, CO—(C 1 -C 5 )-alkyl, S(O) n —(C 1 -C 4 )-alkyl, S(O) n —NH 2 , S(O) n —NH—(C 1 -C 3 )-alkyl, S(O) n —N((C 1 -C 3 )-alkyl) 2 , oxo, —(CH 2 ) m —NH 2 , (CH 2 ) m —NH—(C 1 -C 4 )—alkyl and —(CH 2 ) m —N((C 1 -C 4 )-alkyl) 2 , where in the substituent —(CH 2 ) m —N((C 1 -C 4 )-alkyl) 2 the two alkyl groups can be linked by a single bond and then together with the nitrogen atom carrying them form a 5-membered to 7-membered ring which in addition to the nitrogen atom and the carbon atoms can additionally also contain an oxygen atom, a sulfur atom or a group NR 5 as a ring member;
R 7 is OH, —O—(C 1 -C 4 )-alkyl, NH 2 , —NH—(C 1 -C 4 )-alkyl or —N((C 1 -C 4 )-alkyl) 2 , where in the substituent N((C 1 -C 4 )-alkyl) 2 the two alkyl groups can be linked by a single bond and then together with the nitrogen atom carrying them form a 5-membered to 7-membered ring which in addition to the nitrogen atom and the carbon atoms can additionally also contain an oxygen atom a sulfur atom or a group NR 5 as a ring member;
R 8 is hydrogen or (C 1 -C 7 )-alkyl which can be substituted by one or more identical or different substituents from the group consisting of OH, —O—(C 1 -C 5 )-alkyl, NH 2 , —NH—(C 1 -C 4 )-alkyl and —N((C 1 -C 4 )-alkyl) 2 , where in the substituent N((C 1 -C 4 )-alkyl) 2 the two alkyl groups can be linked by a single bond and then together with the nitrogen atom carrying them form a 5-membered to 7-membered ring which in addition to the nitrogen atom and the carbon atoms can additionally also contain an oxygen atom, a sulfur atom or a group NR 5 as a ring member;
R 9 , independently or R 8 , has one of the meanings of R 8 or is CO—(C 1 -C 4 )-alkyl;
aryl is phenyl, naphthyl or heteroaryl, which can all be substituted by one or more identical or different substituents from the group consisting of halogen, (C 1 -C 5 )-alkyl, phenyl, tolyl, CF 3 , NO 2 , OH, —O—(C 1 -C 5 )-alkyl, —O—(C 2 -C 4 )-alkyl-O—(C 1 -C 3 )-alkyl, (C 1 -C 2 )-alkylenedioxy, NH 2 , —NH—(C 1 -C 3 )-alkyl, —N((C 1 -C 3 )-alkyl) 2 , NH—CHO, —NH—CO—(C 1 -C 5 )-alkyl, CN, CO—NH 2 , CO—NH—(C 1 -C 3 )-alkyl, CO—N((C 1 -C 3 )-alkyl) 2 , COOH, CO—O—(C 1 -C 5 )-alkyl, heterocyclyl, CHO, CO—(C 1 -C 5 )-alkyl, S(O) n —(C 1 -C 4 )-alkyl, S(O) n -phenyl, S(O) n -tolyl, S(O) 2 —NH 2 , S(O) 2 —NH—(C 1 -C 3 )-alkyl and S(O) 2 —N((C 1 -C 3 )-alkyl) 2 ;
heteroaryl is the radical of a monocyclic 5-membered or 6-membered aromatic heterocycle or of a bicyclic 8-membered to 10-membered aromatic heterocycle which in each case contain one or more ring heteroatoms from the group consisting of N, O and S;
heterocyclyl is the radical of a monocyclic or polycyclic, 5-membered to 11-membered saturated or partially unsaturated heterocycle which contains one or more ring heteroatoms from the group consisting of N, O and S and which can be substituted by one or more identical or different substituents from the group consisting of fluorine, (C 1 -C 5 )-alkyl, OH, —O—(C 1 -C 5 )-alkyl, —O—(C 2 -C 4 )-alkyl-O—(C 1 -C 3 )-alkyl, NH 2 , —NH—(C 1 -C 3 ) —N((C 1 -C 3 )-alkyl) 2 , CN, CO—NH 2 , CO—NH(C 1 -C 3 )-alkyl, CO—N(C 1 -C 3 )-alkyl) 2 , COOH and CO—O—(C 1 -C 5 )-alkyl;
n is 0, 1 or 2; and
m is 2, 3 or 4.