3-aryl-substituted imidazo[1,2-A]pyridines and their use
The present application relates to novel 3-aryl-substituted imidazo[1,2-a]pyridines, to processes for preparation thereof, to the use thereof, alone or in combinations, for treatment and/or prophylaxis of diseases, and to the use thereof for production of medicaments for treatment and/or prophylaxis of diseases, especially for treatment and/or prophylaxis of cardiovascular disorders.
1. A compound having the structure of formula (I)
in which
A represents CH 2 ,
R 1 represents cyclohexyl or phenyl,
where phenyl is substituted by 1 to 3 fluorine substituents,
or
represents a pyridyl group of the formula
where
# is the attachment site to A,
and
R 10 represents fluorine,
R 2 represents methyl or ethyl,
R 3 represents phenyl,
where phenyl is optionally substituted by 1 or 2 substituents selected from the group consisting of fluorine, bromine, chlorine, cyano, trifluoromethyl, difluoromethyl, methyl, ethyl, —(C═O)NR 7 R 8 , amino, hydroxycarbonyl, methylsulphonyl, ethylsulphonyl, methoxy, ethoxy, trifluoromethoxy, difluoromethoxy and cyclobutyl,
in which methyl and ethyl is optionally substituted by 1 or 2 substituents selected from the group consisting of trifluoromethoxy, —(C═O)NR 7 R 8 , methoxy, ethoxy, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, hydroxy and amino,
in which amino is optionally substituted by 1 or 2 substituents independently of one another selected from the group consisting of (C 1 -C 4 )-alkyl, methylcarbonyl, ethylcarbonyl, methylsulphonyl, ethylsulphonyl and methoxyethyl,
in which cyclobutyl is optionally substituted by amino or hydroxy,
in which amino is optionally substituted by 1 or 2 substituents independently of one another selected from methyl, ethyl, methylcarbonyl, ethylcarbonyl, methylsulphonyl or ethylsulphonyl,
and in which
R 7 and R 8 independently of one another represent hydrogen, methyl, ethyl or cyclopropyl,
or
represent represents a group of the formula
where
* represents the point of attachment to the imidazopyridine,
n represents a number 1 or 2,
R 9a represents (C 1 -C 6 )-alkyl, phenyl, pyridyl or cyclopropyl,
where (C 1 -C 6 )-alkyl is optionally substituted by 1 or 2 substituents selected from the group consisting of fluorine, cyano, trifluoromethyl, difluoromethyl, methylcarbonyl, methoxycarbonyl, ethoxycarbonyl, hydroxycarbonyl, —(C═O)NR 7 R 8 , —O(C═O)NR 7 R 8 , methylsulphonyl, ethylsulphonyl, methoxy, phenyl, pyridyl, 1H-pyrazolyl, 1H-tetrazolyl, 1,2-oxazolyl, hydroxy, amino, (C 3 -C 5 )-cycloalkyl, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, thiomorpholinyl 1,1-dioxide and azetidine,
in which 1H-pyrazolyl, 1H-tetrazolyl and 1,2-oxazolyl is optionally substituted by 1 or 2 methyl or ethyl substituents,
in which piperidinyl is optionally substituted by 1 to 2 fluorine substituents,
in which azetidine is optionally substituted by hydroxyl,
and
in which piperazinyl is optionally substituted by methyl,
where cyclopropyl is optionally substituted by 1 to 2 substituents independently selected from the group consisting of methyl, ethyl, methoxycarbonyl, ethoxycarbonyl and hydroxycarbonyl,
where phenyl and pyridyl is optionally substituted by 1 or 2 fluorine substituents,
and in which
R 7 and R 8 independently of one another represent hydrogen, methyl, ethyl or cyclopropyl,
R 9b represents hydrogen or (C 1 -C 4 )-alkyl,
R 9c represents hydrogen or (C 1 -C 4 )-alkyl,
R 9d represents hydrogen, (C 1 -C 6 )-alkyl, trifluoromethyl, methoxy, ethoxy, amino, methoxycarbonyl, ethoxycarbonyl, hydroxycarbonyl, —(C═O)NR 7 R 8 , phenyl, pyridyl, pyrimidyl, 1,3-thiazolyl, tetrahydrothiophenyl 1,1-dioxide or cyclopropyl,
where (C 1 -C 6 )-alkyl is optionally substituted by 1 or 2 substituents selected from the group consisting of trifluoromethyl, difluoromethyl, (C 1 -C 4 )-alkoxy, 2-oxopyrrolidin-1-yl, phenyl, pyridyl, pyrimidyl, 1H-1,2,4-triazolyl, hydroxy and amino,
in which 1H-1,2,4-triazolyl is optionally substituted by 1 or 2 methyl or ethyl substituents,
and
in which amino is optionally substituted by (C 1 -C 4 )-alkyl,
where amino is optionally substituted by (C 1 -C 4 )-alkyl,
where phenyl, pyridyl, pyrimidyl and 1,3-thiazolyl can each be substituted by 1 or 2 methyl or ethyl substituents,
and where
R 7 and R 8 each independently of one another represent hydrogen, methyl, ethyl or cyclopropyl,
R 4 represents hydrogen,
R 5 represents hydrogen, chlorine, fluorine, methyl, ethyl, difluoromethyl or cyclopropyl,
R 6 represents hydrogen,
and the N-oxides, salts, solvates, salts of the N-oxides and solvates of the N-oxides or salts thereof.
2. The compound according to claim 1 in which
A represents CH 2 ,
R 1 represents cyclohexyl,
or
represents a phenyl group of the formula
where
## represents the point of attachment to A,
and
R 11 , R 12 and R 13 independently of one another represent hydrogen or fluorine,
with the proviso that at least two of the radicals R 11 , R 12 , R 13 are different from hydrogen,
or
represents a pyridyl group of the formula
where
# represents the attachment site to A,
and
R 10 represents fluorine,
R 2 represents methyl or ethyl,
R 3 represents phenyl,
where phenyl is optionally substituted by 1 or 2 substituents selected from the group consisting of fluorine, chlorine, cyano, amino, trifluoromethyl, difluoromethyl, methyl, —(C═O)NR 7 R 8 , methoxy, piperidinyl and cyclobutyl,
in which methyl is optionally substituted by 1 or 2 substituents selected from the group consisting of —(C═O)NR 7 R 8 , methoxy, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, hydroxy and amino,
in which amino is optionally substituted by 1 or 2 substituents independently of one another selected from methyl, ethyl and methoxyethyl,
in which amino is optionally substituted by 1 or 2 substituents independently of one another selected from methyl, ethyl, methylcarbonyl, ethylcarbonyl, methylsulphonyl or ethylsulphonyl,
in which cyclobutyl is substituted by amino,
and in which
R 7 and R 8 each independently of one another represent hydrogen, methyl, ethyl or cyclopropyl,
or
represents a group of the formula
where
* represents the point of attachment to the imidazopyridine,
R 9a represents (C 1 -C 6 )-alkyl, phenyl, pyridyl or cyclopropyl,
where (C 1 -C 6 )-alkyl is optionally substituted by fluorine, cyano, trifluoromethyl, difluoromethyl, methylcarbonyl, methoxycarbonyl, ethoxycarbonyl, hydroxycarbonyl, —(C═O)NR 7 R 8 , —O(C═O)NR 7 R 8 , methylsulphonyl, ethylsulphonyl, methoxy, ethoxy, trifluoromethoxy, difluoromethoxy, phenyl, pyridyl, 1H-pyrazolyl, 1H-tetrazolyl, 1,2-oxazolyl, hydroxy, amino, cyclopropyl, cyclobutyl, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, thiomorpholinyl 1,1-dioxide or azetidine,
in which 1H-pyrazolyl, 1H-tetrazolyl and 1,2-oxazolyl is optionally substituted by 1 or 2 methyl or ethyl substituents,
in which piperidinyl is optionally substituted by 1 to 2 fluorine substituents,
in which azetidine is optionally substituted by hydroxyl,
and
in which piperazinyl is optionally substituted by methyl,
where cyclopropyl is optionally substituted by methoxycarbonyl, ethoxycarbonyl or hydroxycarbonyl,
where phenyl and pyridyl is optionally substituted by 1 or 2 fluorine substituents,
and in which
R 7 and R 8 independently of one another represent hydrogen, methyl, ethyl or cyclopropyl,
R 9b represents hydrogen or methyl,
R 9c represents hydrogen or methyl,
R 9d represents hydrogen, (C 1 -C 6 )-alkyl, trifluoromethyl, methoxy, ethoxy, amino, methoxycarbonyl, ethoxycarbonyl, hydroxycarbonyl, —(C═O)NR 7 R 8 , phenyl, pyridyl, pyrimidyl, 1,3-thiazolyl, tetrahydrothiophenyl 1,1-dioxide or cyclopropyl,
where (C 1 -C 6 )-alkyl is optionally substituted by 1 or 2 substituents selected from the group consisting of trifluoromethyl, difluoromethyl, (C 1 -C 4 )-alkoxy, 2-oxopyrrolidin-1-yl, phenyl, pyridyl, pyrimidyl, 1H-1,2,4-triazolyl, hydroxy and amino,
in which 1H-1,2,4-triazolyl is optionally substituted by 1 or 2 methyl or ethyl substituents,
and
in which amino is optionally substituted by (C 1 -C 4 )-alkyl,
where amino is optionally substituted by (C 1 -C 4 )-alkyl,
where phenyl, pyridyl, pyrimidyl and 1,3-thiazolyl may each be substituted by 1 or 2 methyl or ethyl substituents,
and in which
R 7 and R 8 each independently of one another represent hydrogen, methyl, ethyl or cyclopropyl,
R 4 represents hydrogen,
R 5 represents hydrogen, chlorine, fluorine, methyl, ethyl, difluoromethyl or cyclopropyl,
R 6 represents hydrogen,
and the N-oxides, salts, solvates, salts of the N-oxides and solvates of the N-oxides or salts thereof.
3. A process for preparing the compound according to claim 1 , comprising
[A] converting a compound of the formula (II)
in which A, R 1 , R 2 , R 4 , R 5 and R 6 are each as defined in claim 1 and
T 1 represents (C 1 -C 4 )-alkyl or benzyl,
in an inert solvent in the presence of a suitable base or acid to a carboxylic acid of the formula (III)
in which A, R 1 , R 2 , R 4 , R 5 and R 6 each have the meanings given above,
and converting the carboxylic acid of the formula (Ill) in the presence of a suitable acid into an imidazo[1,2-a]-pyridine of the formula (IV)
in which A, R 1 , R 2 , R 4 , R 5 and R 6 each have the meanings given above,
and converting the imidazo[1,2-a]-pyridine of the formula (IV) with a halogen equivalent into a compound of the formula (V)
in which A, R 1 , R 2 , R 4 , R 5 and R 6 are each as defined above and
X 1 represents chlorine, bromine or iodine,
and reacting the compound of the formula (V) in an inert solvent, in the presence of a suitable transition metal catalyst, with a compound of the formula (VI)
in which
R 3A has the meanings given in claim 1 for R 3 and
T 2 represents hydrogen or (C 1 -C 4 )-alkyl, or the two T 2 radicals together form a —C(CH 3 ) 2 —C(CH 3 ) 2 — bridge,
to give a compound of the formula (I-A)
and if R 3A represents
reacting the compound of the formula (I-A) in an inert solvent in the presence of a suitable base with a compound of the formula (VIII)
R 14 —X 1 (VIII),
in which
X 1 represents a suitable leaving group,
and
R 14 represents (C 1 -C 6 )-alkyl,
where (C 1 -C 6 )-alkyl can be substituted by 1 to 3 substituents selected from the group consisting of fluorine, cyano, trifluoromethyl, difluoromethyl, (C 1 -C 4 )-alkylcarbonyl, (C 1 -C 4 )-alkoxycarbonyl, hydroxycarbonyl, —(C═O)NR 7 R 8 , —O(C═O)NR 7 R 8 , (C 1 -C 4 )-alkylsulphonyl, (C 1 -C 4 )-alkoxy, trifluoromethoxy, difluoromethoxy, phenyl, 1H-pyrazolyl, 1H-1,2,4-triazolyl, 1H-tetrazolyl, 1,2-oxazolyl, tetrahydrothiophenyl 1,1-dioxide, hydroxy, amino, (C 3 -C 7 )-cycloalkyl, morpholinyl, piperidinyl, pyrrolidinyl, 2-oxopyrrolidin-1-yl, piperazinyl, tetrahydrothiophenyl 1,1-dioxide, thiomorpholinyl 1,1-dioxide and azetidine,
in which 1H-pyrazolyl, 1H-1,2,4-triazolyl, 1H-tetrazolyl and 1,2-oxazolyl is optionally substituted by 1 or 2 methyl or ethyl substituents,
in which piperidinyl is optionally substituted by 1 or 2 fluorine substituents,
in which phenyl is optionally substituted by 1 or 2 fluorine substituents,
in which piperazinyl is optionally substituted by methyl,
and in which
R 7 and R 8 each independently of one another represent hydrogen, methyl or cyclopropyl,
or
R 7 and R 8 together with the carbon atom to which they are attached form a 3- to 5-membered carbocycle,
to give a compound of the formula (I-B)
in which A, R 1 , R 2 , R 4 , R 5 , R 6 and R 14 each have the meanings given above and
removing any protecting groups present, and optionally converting the resulting compounds of the formula (I-B) with the appropriate (i) solvents and/or (ii) acids or bases into the solvates, salts and/or solvates of the salts thereof,
or
[B] converting the compound of the formula (II) in the presence of hydrazine hydrate into a compound of the formula (IX)
in which A, R 1 , R 2 , R 4 , R 5 and R 6 each have the meanings given above,
and subsequently reacting the compound of the formula (IX) in an inert solvent under amide coupling conditions with a carboxylic acid of the formula (X)
in which R 15 represents (C 1 -C 6 )-alkyl,
where (C 1 -C 6 )-alkyl is optionally substituted by 1 to 3 substituents selected from the group consisting of trifluoromethyl, difluoromethyl, hydroxy and amino,
to give a compound of the formula (XI)
in which A, R 1 , R 2 , R 4 , R 5 , R 6 and R 15 each have the meanings given above,
and converting the compound of the formula XI with 2,4-bis(4-methoxyphenyI)-1,3,2,4-dithiadiphosphetane-2,4-disulphide [Lawesson's reagent] into a compound of the formula (I-C)
in which A, R 1 , R 2 , R 4 , R 5 , R 6 and R 15 each have the meanings given above,
then detaching any protecting groups present, and optionally converting the resulting compounds of the formula (I) with the appropriate (i) solvents and/or (ii) acids or bases to the solvates, salts and/or solvates of the salts thereof.
4. A medicament comprising the compound according to claim 1 in combination with an inert, non-toxic, pharmaceutically suitable excipient.
5. A medicament comprising the compound according to claim 1 in combination with a further active ingredient selected from the group consisting of organic nitrates, NO donors, cGMP-PDE inhibitors, antithrombotic agents, hypotensive agents and lipid metabolism modifiers.
6. A method for treatment of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorders, renal insufficiency, thromboembolic disorders and arteriosclerosis in humans and animals comprising administering an effective amount of at least one compound according to claim 1 to a patient in need thereof.
7. A method for treatment of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorders, renal insufficiency, thromboembolic disorders and arteriosclerosis in humans and animals comprising administering an effective amount of the medicament according to claim 4 to a patient in need thereof.
8. A method for treatment of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorders, renal insufficiency, thromboembolic disorders and arteriosclerosis in humans and animals comprising administering an effective amount of the medicament according to claim 5 to a patient in need thereof.