Fused cyanopyridines and the use thereof
View Patent ↗The present application relates to novel substituted fused cyanopyridine derivatives, to processes for their preparation, to their use for the treatment and/or prevention of diseases and to their use for preparing medicaments for the treatment and/or prevention of diseases, preferably for the treatment and/or prevention of cardiovascular disorders.
1. A compound of the formula (I)
in which
ring Q represents a group of the formula
where
* represents in each case the point of attachment to the C2 atom,
# represents in each case the point of attachment to the C3 atom,
R 3 represents hydrogen or (C 1 -C 4 )-alkyl,
R 4 represents hydrogen or (C 1 -C 4 )-alkyl,
R 5 represents hydrogen, (C 1 -C 4 )-alkyl or amino,
R 6 represents in each case hydrogen, (C 1 -C 4 )-alkyl or allyl,
in which (C 1 -C 4 )-alkyl may be substituted by a substituent selected from the group consisting of hydroxycarbonyl, (C 1 -C 4 )-alkoxycarbonyl and amino,
R 7 represents in each case hydrogen, (C 1 -C 4 )-alkyl, trifluoromethyl, amino, mono-(C 1 -C 4 )-alkylamino or di-(C 1 -C 4 )-alkylamino,
in which (C 1 -C 4 )-alkyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of hydroxyl, methoxy and amino, and either
i) R 8A represents in each case hydrogen, hydroxyl, (C 1 -C 4 )-alkoxy or mono-(C 1 -C 4 )-alkylamino,
in which (C 2 -C 4 )-alkoxy and mono-(C 2 -C 4 )-alkylamino may be substituted by a hydroxyl substituent,
and
R 8B represents hydrogen,
or
R 8A together with R 8B forms an oxo, N—(C 1 -C 4 )-alkylimino, N—(C 1 -C 4 )-alkoxyimino or (C 1 -C 4 )-alkoxycarbonylmethylidene group,
and
R 9A and R 9B independently of one another represent in each case hydrogen or (C 1 -C 4 )-alkyl or together with the carbon atom to which they are attached form a spiro-linked 3-to 5-membered cycloalkyl ring,
and
R 10 represents hydrogen, (C 1 -C 4 )-alkyl or phenyl,
in which (C 1 -C 4 )-alkyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of hydroxyl and amino,
X represents S or O,
R 1 represents a 5- to 10-membered heteroaryl,
where (C 6 -C 10 )-aryl and 5- to 10-membered heteroaryl may be substituted by 1 or 2 substituents independently of one another 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, hydroxycarbonyl, (C 1 -C 6 )-alkoxycarbonyl, aminocarbonyl, mono-(C 1 -C 6 )-alkylaminocarbonyl, di-(C 1 -C 6 )-alkylaminocarbonyl, pyrrolidino, piperidino, morpholino, piperazino and N′-(C 1 -C 4 )-alkylpiperazino, phenyl and 5- or 6-membered heteroaryl,
in which phenyl and 5- or 6-membered heteroaryl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of halogen, nitro, cyano, (C 1 -C 6 )-alkyl, difluoromethyl, trifluoromethyl, hydroxyl, (C 1 -C 6 )-alkoxy, difluoromethoxy, trifluoromethoxy, amino, mono-(C 1 -C 6 )-alkylamino, di-(C 1 -C 6 )-alkyl-amino, hydroxycarbonyl and (C 1 -C 6 )-alkoxycarbonyl,
R 2 represents (C 5 -C 6 )-cycloalkyl, 5- or 6-membered heterocyclyl, phenyl or 5- or 6-membered heteroaryl,
where (C 5 -C 6 )-cycloalkyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of (C 1 -C 6 )-alkyl, hydroxyl, oxo, (C 1 -C 6 )-alkoxy, amino, mono-(C 1 -C 6 )-alkylamino and di-(C 1 -C 6 )-alkylamino,
in which (C 1 -C 6 )-alkyl and (C 1 -C 6 )-alkoxy may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of hydroxyl, (C 1 -C 4 )-alkoxy and (C 3 -C 7 )-cycloalkyl,
in which (C 3 -C 7 )-cycloalkyl for its part may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of (C 1 -C 4 )-alkyl, hydroxyl, oxo and (C 1 -C 4 )-alkoxy,
and
where 5- or 6-membered heterocyclyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of oxo, thioxo, hydroxyl, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy, (C 1 -C 6 )-alkylcarbonyl, amino, mono-(C 1 -C 6 )-alkylamino, di-(C 1 -C 6 )-alkylamino and (C 3 -C 7 )-cycloalkyl,
in which (C 1 -C 6 )-alkyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, oxo, hydroxyl, trifluoromethyl, (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-alkylcarbonyloxy, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino and (C 3 -C 7 )-cycloalkyl,
in which (C 3 -C 7 )-cycloalkyl for its part may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of (C 1 -C 4 )-alkyl, hydroxyl, oxo and (C 1 -C 4 )-alkoxy,
and
in which (C 1 -C 6 )-alkylcarbonyl may be substituted by a substituent selected from the group consisting of hydroxyl and (C 1 -C 4 )-alkoxy,
and
in which (C 3 -C 7 )-cycloalkyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of (C 1 -C 4 )-alkyl, hydroxyl, oxo and (C 1 -C 4 )-alkoxy,
and
where phenyl and 5- or 6-membered heteroaryl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of halogen, cyano, hydroxyl, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy, (C 3 -C 7 )-cycloalkoxy and —NR A R B ,
in which (C 1 -C 6 )-alkyl may be substituted by 1 to 3 substituents selected from the group consisting of fluorine,
and
in which (C 1 -C 6 )-alkoxy may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, (C 3 -C 7 )-cycloalkyl, oxo, hydroxyl, (C 1 -C 4 )-alkoxy, hydroxycarbonyl, amino, mono-(C 1 -C 4 )-alkylamino and di-(C 1 -C 4 )-alkylamino,
and
in which (C 3 -C 7 )-cycloalkoxy may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of (C 1 -C 4 )-alkyl, hydroxyl, oxo and (C 1 -C 4 )-alkoxy,
and
in which
R A represents hydrogen or (C 1 -C 6 )-alkyl,
in which (C 1 -C 6 )-alkyl for its part may be substituted by a substituent selected from the group consisting of hydroxyl and (C 1 -C 4 )-alkoxy,
R B represents hydrogen, (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, (C 1 -C 4 )-alkylsulfonyl or (C 3 -C 7 )-cycloalkylsulfonyl,
in which (C 1 -C 6 )-alkyl for its part may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of (C 3 -C 7 )-cycloalkyl, oxo, hydroxyl, (C 1 -C 4 )-alkoxy, hydroxycarbonyl, amino, mono-(C 1 -C 4 )-alkylamino and di-(C 1 -C 4 )-alkylamino,
and
in which (C 3 -C 7 )-cycloalkyl for its part may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of (C 1 -C 4 )-alkyl, hydroxyl, oxo and (C 1 -C 4 )-alkoxy,
or
in which two adjacent substituents at the phenyl together with the carbon atoms to which they are attached may form a 1,3-dioxolane or 2,2-difluoro-1,3-dioxolane, or an N-oxide, salt, or salt of the N-oxide thereof,
except for the compounds 5,6,7,8-tetrahydro-2-[[(2-methylphenyl)methyl]thio]-4-(2-thienyl)-3-quinolinecarbonitrile, 5,6,7,8-tetrahydro-2-[(2-phenylmethyl)thio]-4-(2-thienyl)-3-quinolinecarbonitrile, 5,6,7,8-tetrahydro-2-[[(2-methylphenyl)methyl]thio]-4-(4-pyridyl)-3-quinolinecarbonitrile, 5,6,7,8-tetrahydro-2-[(phenylmethyl)thio]-4-phenyl-3-quinolinecarbonitrile, 5,6,7,8-tetrahydro-2-[(phenylmethyl)thio]-4-(4-chlorophenyl)-3-quinolinecarbonitrile, 6,7-dihydro-4-(4-hydroxyphenyl)-2-[(phenylmethyl)thio]-5H-cyclopentapyridine-3-carbonitrile.
2. The compound of the formula (I) as claimed in claim 1 in which
ring Q represents a group of the formula
where
* represents in each case the point of attachment to the C2 atom,
# represents in each case the point of attachment to the C3 atom,
R 3 represents hydrogen or methyl,
R 4 represents hydrogen or methyl,
R 5 represents hydrogen or methyl,
R 6 represents in each case hydrogen or methyl,
R 7 represents in each case hydrogen or methyl, and either
i) R 8A represents in each case hydrogen or hydroxyl, and
R 8B represents hydrogen, or
ii) R 8A together with R 8B forms an oxo group, and
R 9A and R 9B independently of one another represent in each case hydrogen or methyl,
X represents S or O,
R 1 represents a 5- or 6-membered heteroaryl,
where phenyl and 5- or 6-membered heteroaryl are substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, chlorine, cyano, (C 1 -C 4 )-alkyl, trifluoromethyl, hydroxyl, (C 1 -C 4 )-alkoxy, amino, hydroxycarbonyl, (C 1 -C 4 )-alkoxycarbonyl, aminocarbonyl, phenyl and 5- or 6-membered heteroaryl,
in which phenyl and 5- or 6-membered heteroaryl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, chlorine, nitro, cyano, (C 1 -C 4 )-alkyl, difluoromethyl, trifluoromethyl, hydroxyl, (C 1 -C 4 )-alkoxy, difluoromethoxy, trifluoromethoxy, amino, hydroxycarbonyl and (C 1 -C 4 )-alkoxy-carbonyl,
R 2 represents cyclohexyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl or pyridyl,
where cyclohexyl may be substituted by a substituent selected from the group consisting of hydroxyl and (C 1 -C 4 )-alkoxy,
in which (C2-C4)-alkoxy may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of hydroxyl and methoxy, and
where piperidinyl, piperazinyl and morpholinyl may be substituted by a substituent selected from the group consisting of (C 1 -C 4 )-alkyl, hydroxyl, (C 1 -C 4 )-alkoxy and (C 1 -C 4 )-alkylcarbonyl,
in which (C 1 -C 4 )-alkyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of hydroxyl, methoxy, ethoxy, methylcarbonyloxy and ethylcarbonyloxy, and
in which (C 1 -C 4 )-alkylcarbonyl may be substituted by a substituent selected from the group consisting of hydroxyl, methoxy and ethoxy, and
where phenyl and pyridyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, chlorine, cyano, hydroxyl, (C 1 -C 4 )-alkyl and (C 1 -C 4 )-alkoxy,
in which (C 2 -C 4 )-alkoxy may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of oxo, hydroxyl, (C 1 -C 4 )-alkoxy, hydroxycarbonyl and amino, and
where pyrazolyl, imidazolyl, oxazolyl and thiazolyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, chlorine, cyano, hydroxyl, (C 1 -C 4 )-alkyl and (C 1 -C 4 )-alkoxy,
in which (C2-C4)-alkoxy may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of oxo, hydroxyl, (C 1 -C 4 )-alkoxy, hydroxycarbonyl and amino, except for the compound 5,6,7,8-tetrahydro-2-[[(2-methylphenyl)methyl]thio]-4-(4-pyridyl)-3-quinolinecarbonitrile.
3. The compound of the formula (I) as claimed in claim 1 in which
ring Q represents a group of the formula
where
* represents in each case the point of attachment to the C2 atom,
# represents in each case the point of attachment to the C3 atom,
R 3 represents hydrogen,
R 4 represents hydrogen,
R 5 represents hydrogen or methyl,
R 6 represents in each case hydrogen or methyl, and
R 7 represents hydrogen or methyl,
X represents S or O,
R 1 represents a 5- or 6-membered heteroaryl,
where phenyl and 5- or 6-membered heteroaryl are substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, chlorine, cyano, methyl, ethyl, trifluoromethyl, hydroxyl, methoxy, ethoxy, amino, hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, phenyl and 5- or 6-membered heteroaryl,
in which phenyl and 5- or 6-membered heteroaryl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, chlorine, methyl, ethyl, difluoromethyl, trifluoromethyl, hydroxyl, methoxy, ethoxy, amino, hydroxycarbonyl, methoxycarbonyl and ethoxycarbonyl,
R 2 represents phenyl, pyrazolyl or pyridyl,
where phenyl and pyridyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, chlorine, cyano, hydroxyl, (C 1 -C 4 )-alkyl and (C 1 -C 4 )-alkoxy,
in which (C 2 -C 4 )-alkoxy may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of oxo, hydroxyl, (C 1 -C 4 )-alkoxy, hydroxycarbonyl and amino, and
where pyrazolyl may be substituted by a substituent selected from the group consisting of fluorine, chlorine, cyano, hydroxyl, (C 1 -C 4 )-alkyl and (C 1 -C 4 )-alkoxy,
in which (C 2 -C 4 )-alkoxy may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of oxo, hydroxyl, (C 1 -C 4 )-alkoxy, hydroxycarbonyl and amino.
4. The compound of the formula (I) as claimed in claim 1 , in which
ring Q represents a group of the formula
in which
* represents in each case the point of attachment to the C2 atom,
# represents in each case the point of attachment to the C3 atom,
R 3 represents hydrogen,
R 4 represents hydrogen,
R 5 represents methyl,
R 6 represents hydrogen, and
R 7 represents hydrogen or methyl,
X represents S or O,
R 1 represents thiazolyl or oxazolyl,
where thiazolyl and oxazolyl are substituted by a phenyl substituent,
in which phenyl may be substituted by a substituent selected from the group consisting of fluorine, chlorine, cyano, methyl, methoxy, hydroxycarbonyl and methoxycarbonyl, and
where thiazolyl and oxazolyl may be substituted by a substituent selected from the group consisting of fluorine, chlorine, cyano, methyl, ethyl, methoxy, amino, hydroxycarbonyl and methoxycarbonyl,
R 2 represents a group of the formula
where
## represents the point of attachment to the bicycle,
in which
R 9 represents hydrogen or (C 1 -C 4 )-alkoxy,
in which (C2-C4)-alkoxy may be substituted by 1 or 2 hydroxyl substituents.
5. A process for preparing compounds of the formula (I) as defined in claim 1 , comprising
[A] reacting a compound of the formula (II)
in which X, R 1 and R 2 each have the meanings given in claim 1 , in an inert solvent or in the absence of a solvent with a compound of the formula (III)
in which R 7 has the meaning given in claim 1 and
X 1 represents hydroxyl or —OC(O)R 7 ,
in which R 7 has the meaning given above,
to give a compound of the formula (I-A)
which X, R 1 , R 2 and R 7 each have the meanings given above, or
[B] reacting a compound of the formula (II) in an inert solvent or in the absence of a solvent in the presence of a suitable source of ammonia with a compound of the formula (IV)
in which R 5 has the meaning given in claim 1 and
R 11 represents (C 1 -C 4 )-alkyl,
to give compounds of the formula (I-B)
in which X, R 1 , R 2 and R 5 each have the meanings given in claim 1 , or
[C] reacting a compound of the formula (V)
in which R 2 has the meaning given in claim 1 and
ring Q represents a group of the formula
where
* represents in each case the point of attachment to the C2 atom,
# represents in each case the point of attachment to the C3 atom,
R 6 represents hydrogen, (C 1 -C 4 )-alkyl or allyl,
in which (C 1 -C 4 )-alkyl may be substituted by a substituent selected from the group consisting of hydroxycarbonyl, (C 1 -C 4 )-alkoxycarbonyl and amino,
R 7 represents in each case hydrogen or (C 1 -C 4 )-alkyl, and either
i) R 8A and R 8B represent hydrogen, or
ii) R 8A together with R 8B forms an oxo group, in an inert solvent initially with an alkali metal sulfide to give a compound of the formula (VI)
in which R 2 has the meaning given above,
Ak + represents an alkali metal salt, and
ring Q represents a group of the formula
where
* represents in each case the point of attachment to the C2 atom,
# represents in each case the point of attachment to the C3 atom,
R 6 represents in each case hydrogen, (C 1 -C 4 )-alkyl or allyl,
in which (C 1 -C 4 )-alkyl may be substituted by a substituent selected from the group consisting of hydroxycarbonyl, (C 1 -C 4 )-alkoxycarbonyl and amino,
R 7 represents hydrogen or (C 1 -C 4 )-alkyl, and either
i) R 8A and R 8B represent hydrogen, or
ii) R 8A together with R 8B forms an oxo group,
in the presence of a suitable base with a compound of the formula (VII)
in which R 1 has the meaning given in claim 1 and
X 2 represents a suitable leaving group,
to give a compound of the formula (I-C)
in which R 1 and R 2 each have the meanings given above,
ring Q represents a group of the formula
where
* represents in each case the point of attachment to the C2 atom,
# represents in each case the point of attachment to the C3 atom,
R 6 represents hydrogen, (C 1 -C 4 )-alkyl or allyl,
in which (C 1 -C 4 )-alkyl may be substituted by a substituent selected from the group consisting of hydroxycarbonyl, (C 1 -C 4 )-alkoxycarbonyl and amino,
R 7 represents hydrogen or (C 1 -C 4 )-alkyl, and either
i) R 8A and R 8B represent hydrogen, or
ii) R 8A together with R 8B forms an oxo group, or
[D] reacting a compound of the formula (V) in an inert solvent in the presence of a base with a compound of the formula (VIII)
in which R 1 has the meaning given in claim 1
to give compounds of the formula (I-D)
in which R 1 and R 2 each have the meanings given in claim 1 , and
ring Q represents a group of the formula
where
* represents in each case the point of attachment to the C2 atom,
# represents in each case the point of attachment to the C3 atom,
R 6 represents in each case hydrogen, (C 1 -C 4 )-alkyl or allyl,
in which (C 1 -C 4 )-alkyl may be substituted by a substituent selected from the group consisting of hydroxycarbonyl, (C 1 -C 4 )-alkoxycarbonyl and amino,
R 7 represents hydrogen or (C 1 -C 4 )-alkyl, and either
i) R 8A and R 8B represent hydrogen, or
ii) R 8A together with R 8B forms an oxo group, or
[E] reacting a compound of the formula (IX)
in which R 2 and R 6 each have the meanings given in claim 1 ,
is reacted in an inert solvent in the presence of a suitable base with a compound of the formula (VII) to give a compound of the formula (I-E)
in which R 1 , R 2 and R 6 each have the meanings given in claim 1 , or
[F] converting a compound of the formula (IX) in an inert solvent in the presence of a suitable base with an alkyl halide into a compound of the formula (X)
in which R 2 and R 6 each have the meanings given in claim 1 , and
R 12 represents (C 1 -C 4 )-alkyl,
and reacting the compound of formula (X) in an inert solvent in the presence of a suitable base with a compound of the formula (VIII) to give a compound of the formula (I-F)
in which R 1 , R 2 and R 6 each have the meanings given in claim 1 , or
[G] reacting a compound of the formula (XI)
in which R 2 , R 9A and R 9B each have the meanings given in claim 1 , in an inert solvent in the presence of a suitable base with a compound of the formula (VII) and optionally with addition of a suitable oxidizing agent to give a compound of the formula (I-G)
in which R 1 , R 2 , R 9A and R 9B each have the meanings given in claim 1 , or
[H] converting a compound of the formula (XI) in an inert solvent in the presence of a suitable base with an alkyl halide into a compound of the formula (XII)
in which R 2 , R 9A and R 9B each have the meanings given in claim 1 , and
R 12 represents (C 1 -C 4 )-alkyl,
and reacting the compound of formula (XII) in an inert solvent in the presence of a suitable base with a compound of the formula (VIII), optionally with addition of a suitable oxidizing agent to give a compound of the formula (I-H)
in which R 1 , R 2 , R 9A and R 9B each have the meanings given in claim 1 ,
any protective groups present are then cleaved off and the resulting compounds of the formulae (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G) and (I-H) are optionally converted with the appropriate (i) solvents and/or (ii) bases or acids into their salts.
6. A medicament comprising a compound of the formula (I) as defined in claim 1 in combination with an inert nontoxic pharmaceutically suitable auxiliary.
7. A medicament comprising a compound of the formula (I) as defined in claim 1 in combination with one or more further active ingredients selected from the group consisting of lipid metabolism-altering active ingredients, antidiabetics, antihypertensive drugs and antithrombotic drugs.
8. A method for the treatment of coronary heart disease, acute coronary syndrome, angina pectoris, heart failure, myocardial infarction, atrial fibrillation and hypertension in humans and animals comprising the step of administering an effective amount of at least one compound of the formula (I) as defined in claim 1 .
9. A method for the treatment of diabetes, metabolic syndrome and dyslipidemias in humans and animals comprising the step of administering an effective amount of at least one compound of the formula (I) as defined in claim 1 .