Substituted 4-amino-3,5-dicyano-2-thiopyridines and use thereof
View Patent ↗The present application relates to novel substituted 4-amino-3,5-dicyano-2-thiopyridine derivatives, to processes for their preparation, to their use for the treatment and/or prophylaxis of diseases and to their use for preparing medicaments for the treatment and/or prophylaxis of diseases, preferably for the treatment and/or prevention of hypertension and other cardiovascular disorders.
1. A compound of the formula (I)
in which
ring A represents a 4- to 7-membered saturated heterocycle which is attached via nitrogen and which may contain a further ring heteroatom from the group consisting of N, O and S and which may be
(i) substituted up to five times by identical or different substituents from the group consisting of (C 1 -C 4 )-alkyl which for its part may be mono- or disubstituted by identical or different substituents from the group consisting of oxo, hydroxyl, (C 1 -C 4 )-alkoxy, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino and (C 3 -C 6 )-cycloalkyl,
and/or
(ii) mono- or disubstituted by identical or different substituents from the group consisting of oxo, thioxo, hydroxyl, (C 1 -C 4 )-alkoxy, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino and (C 3 -C 6 )-cyclo-alkyl,
R 1 represents 5- to 10-membered heteroaryl having one or two ring heteroatoms selected from the group consisting of N, O, and S, each of which radicals may be
(i) mono- or disubstituted by identical or different radicals selected from the group consisting of halogen, nitro, cyano, (C 1 -C 6 )-alkyl, trifluoromethyl, hydroxyl, (C 1 -C 6 )-alkoxy, amino, mono-(C 1 -C 6 )-alkylamino, di-(C 1 -C 6 )-alkylamino, mono-(C 1 -C 6 )-alkenylamino, carboxyl, (C 1 -C 6 )-alkoxycarbonyl, carbamoyl, mono-(C 1 -C 6 )-alkylaminocarbonyl and di-(C 1 -C 6 )-alkylaminocarbonyl
and/or
(ii) substituted by pyrrolidino, piperidino, morpholino, piperazino, N′-(C 1 -C 4 )-alkylpiperazino or a group of the formula -L-R 3 in which
L represents a bond, NH or O
and
R 3 represents phenyl or 5- or 6-membered heteroaryl having up to three ring heteroatoms from the group consisting of N, O and S, each of which radicals may be mono- to trisubstituted by identical or different radicals selected from the group consisting of halogen, nitro, cyano, (C 1 -C 6 )-alkyl, trifluoromethyl, hydroxyl, (C 1 -C 6 )-alkoxy, difluoromethoxy, trifluoromethoxy, amino, mono-(C 1 -C 6 )-alkylamino, di-(C 1 -C 6 )-alkylamino, (C 1 -C 6 )-alkoxycarbonyl and carboxyl,
and
R 2 represents hydrogen or represents (C 1 -C 6 )-alkyl or (C 1 -C 6 )-alkoxy, each of which radicals may be substituted by hydroxyl, (C 1 -C 4 )-alkoxy, carboxyl, (C 1 -C 4 )-alkoxycarbonyl or up to three times by fluorine
or
R 2 represents a group of the formula —NR 4 R 5 in which
R 4 and R 5 are identical or different and independently of one another represent hydrogen or (C 1 -C 6 )-alkyl which may be mono- or disubstituted by identical or different radicals from the group consisting of hydroxyl, (C 1 -C 4 )-alkoxy, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino, carboxyl, (C 1 -C 4 )-alkoxycarbonyl and a 4- to 7-membered heterocycle,
where the heterocycle mentioned contains one or two ring heteroatoms from the group consisting of N, O and S and for its part may be mono- or disubstituted by identical or different radicals from the group consisting of (C 1 -C 4 )-alkyl, hydroxyl, oxo and (C 1 -C 4 )-alkoxy,
or
R 4 and R 5 together with the nitrogen atom, to which they are attached, form a 4- to 7-membered heterocycle which may contain a further ring heteroatom from the group consisting of N, O or S and may be mono- or disubstituted by identical or different radicals from the group consisting of (C 1 -C 4 )-alkyl, hydroxyl, oxo, (C 1 -C 4 )-alkoxy, azetidino, pyrrolidino, piperidino and morpholino,
and salts, N-oxides, and salts of the N-oxides thereof.
2. The compound of the formula (I) as claimed in claim 1 in which
R 1 represents 5- or 6-membered heteroaryl having one or two ring heteroatoms selected from the group consisting of N, O, and S, each of which radicals is
(i) mono- or disubstituted by identical or different radicals selected from the group consisting of halogen, nitro, cyano, (C 1 -C 6 )-alkyl, trifluoromethyl, hydroxyl, (C 1 -C 6 )-alkoxy, amino, mono-(C 1 -C 6 )-alkylamino, di-(C 1 -C 6 )-alkylamino, mono-(C 2 -C 6 )-alkenylamino, carboxyl, (C 1 -C 6 )-alkoxycarbonyl, carbamoyl, mono-(C 1 -C 6 )-alkylaminocarbonyl and di-(C 1 -C 6 )-alkylaminocarbonyl
and/or
(ii) substituted by pyrrolidino, piperidino, morpholino, piperazino, N′-(C 1 -C 4 )-alkylpiperazino or a group of the formula -L-R 3 in which
L represents a bond, NH or O
and
R 3 represents phenyl or 5- or 6-membered heteroaryl having up to three ring heteroatoms from the group consisting of N, O and S, each of which radicals may be mono- to trisubstituted by identical or different radicals selected from the group consisting of halogen, nitro, cyano, (C 1 -C 6 )-alkyl, trifluoromethyl, hydroxyl, (C 1 -C 6 )-alkoxy, difluoromethoxy, trifluoromethoxy, amino, mono-(C 1 -C 6 )-alkylamino, di-(C 1 -C 6 )-alkylamino, (C 1 -C 6 )-alkoxycarbonyl and carboxyl,
or
R 1 represents N-oxidopyridyl.
3. The compound of the formula (I) of claim 1 in which
ring A represents a 5- to 7-heteroatom saturated heterocycle which is attached via nitrogen and which may contain a further ring heteroatom from the group consisting of N and O and which may be
(i) substituted up to five times by identical or different substituents from the group consisting of (C 1 -C 3 )-alkyl which for its part may be mono- or disubstituted by identical or different substituents from the group consisting of oxo, hydroxyl, (C 1 -C 3 )-alkoxy, amino, mono-(C 1 -C 3 )-alkylamino, di-(C 1 -C 3 )-alkylamino and (C 3 -C 5 )-cycloalkyl,
and/or
(ii) mono- or disubstituted by identical or different radicals selected from the group consisting of oxo, hydroxyl, (C 1 -C 3 )-alkoxy, amino, mono-(C 1 -C 3 )-alkylamino, di-(C 1 -C 3 )-alkylamino and (C 3 -C 5 )-cycloalkyl,
R 1 represents 5- or 6-membered heteroaryl having one or two ring heteroatoms selected from the group consisting of N, O, and S, each of which radicals is
(i) mono- or disubstituted by identical or different radicals selected from the group consisting of fluorine, chlorine, cyano, (C 1 -C 4 )-alkyl, amino, mono-(C 1 -C 4 )-alkylamino and di-(C 1 -C 4 )-alkylamino
and/or
(ii) substituted by morpholino, N′-(C 1 -C 4 )-alkylpiperazino or a group of the formula -L-R 3 in which
L represents a bond or NH
and
R 3 represents phenyl or 5- or 6-membered heteroaryl having up to three ring heteroatoms from the group consisting of N, O and S, each of which radicals may be mono- to trisubstituted by identical or different radicals selected from the group consisting of fluorine, chlorine, cyano, (C 1 -C 4 )-alkyl, trifluoromethyl, (C 1 -C 4 )-alkoxy, trifluoromethoxy and carboxyl,
or
R 1 represents N-oxidopyridyl,
and
R 2 represents hydrogen or represents (C 1 -C 4 )-alkoxy which may be substituted up to three times by fluorine
or
R 2 represents a group of the formula —NR 4 R 5 in which
R 4 represents hydrogen or (C 1 -C 4 )-alkyl which may be substituted by hydroxyl, (C 1 -C 4 )-alkoxy, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino, carboxyl, (C 1 -C 4 )-alkoxycarbonyl or a 5- or 6-membered heterocycle,
where the heterocycle mentioned contains one or two ring heteroatoms from the group consisting of N and O and for its part may be mono- or disubstituted by identical or different radicals from the group consisting of methyl, ethyl, hydroxyl, methoxy and ethoxy,
R 5 represents hydrogen or methyl
or
R 4 and R 5 together with the nitrogen atom, to which they are attached, form a 5- or 6-membered heterocycle which may contain a further ring heteroatom from the group consisting of N or O and may be mono- or disubstituted by identical or different radicals from the group consisting of methyl, ethyl, hydroxyl, methoxy and ethoxy.
4. The compound of the formula (I) of claim 1 in which
ring A represents a group of the formula
in which
* denotes the point of attachment to the pyridine ring,
R A1 , R A2 , R A3 and R A4 independently of one another represent hydrogen or methyl,
R A5 represents hydrogen, methyl, ethyl, 2-hydroxyethyl or cyclopropylmethyl
and
R A6 represents hydrogen, methyl, ethyl, hydroxymethyl, 2-hydroxyethyl, cyclopropylmethyl, hydroxyl, methoxy or ethoxy,
R 1 represents oxazolyl, thiazolyl or pyridyl, each of which radicals is
(i) mono- or disubstituted by identical or different radicals selected from the group consisting of fluorine, chlorine, methyl and amino
or
(ii) substituted by a group of the formula -L-R 3 in which
L represents a bond or NH
and
R 3 represents phenyl or pyridyl, each of which radicals may be mono- or disubstituted by identical or different radicals selected from the group consisting of fluorine, chlorine, cyano, methyl and methoxy,
or
R 1 represents N-oxidopyridyl,
and
R 2 represents hydrogen, methoxy or a group of the formula —NR 4 R 5 in which
R 4 represents hydrogen or (C 1 -C 4 )-alkyl which may be substituted by hydroxyl, amino, methylamino, ethylamino, dimethylamino or diethylamino,
R 5 represents hydrogen
or
R 4 and R 5 together with the nitrogen atom to which they are attached form a group of the formula
in which
# denotes the point of attachment to the pyridine ring,
R B1 represents hydrogen or hydroxyl
and
R B2 represents hydrogen or methyl.
5. A process for preparing the compounds of the formula (I) of claim 1 in which R 2 represents NH 2 , wherein the compound of the formula (II)
is initially, in an inert solvent in the presence of a base, reacted with a compound of the formula (III)
in which R 1 has the meaning given in claim 1 and
X represents a suitable leaving group such as halogen, mesylate, tosylate or triflate,
to give a compound of the formula (IV)
in which R 1 has the meaning given above,
and this compound is then, in an inert solvent or without further solvent, reacted with a compound of the formula (V)
in which ring A has the meaning given in claim 1 ,
to give a compound of the formula (I-A)
in which R 1 and ring A have the meanings given above,
and the compounds of the formula (I-A) are, if appropriate, converted with the appropriate (i) solvents and/or (ii) bases or acids into their salts, N-oxides, or salts of N-oxides.
6. A pharmaceutical composition comprising a compound according to claim 1 and an inert nontoxic pharmaceutically suitable auxiliary.