BENZIMIDAZOLE AND PYRAZOLOPYRIDINE DERIVATIVES FOR TREATING AND/OR PREVENTING CARDIOVASCULAR DISEASES
The present application relates to novel fused, heteroatom-bridged pyrazole and imidazole derivatives, to processes for their preparation, to their use, alone or in combination, for the treatment and/or prevention of diseases and to their use for preparing medicaments for the treatment and/or prevention of diseases, in particular for the treatment and/or prevention of cardiovascular disorders.
1 . Compound of the formula (I)
L-A-M-Q (I),
in which
A represents O, S, —S(═O)—, S(═O) 2 — or NR′,
where
R 1 represents hydrogen or (C 1 -C 4 )-alkyl,
L represents (C 5 -C 7 )-cycloalkyl, phenyl, pyridyl, pyrimidinyl, furyl, thienyl, thiazolyl, oxazolyl, isothiazolyl or isoxazolyl,
where phenyl, pyridyl, pyrimidinyl, furyl, thienyl, thiazolyl, oxazolyl, isothiazolyl and isoxazolyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of halogen, cyano, (C 1 -C 4 )-alkyl, trifluoromethyl, chloromethyl and (C 2 -C 4 )-alkynyl
and
where (C 5 -C 7 )-cycloalkyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine and (C 1 -C 4 )-alkyl,
M represents a bicyclic heteroaryl group of the formula
where
* represents the point of attachment to group A,
** represents the point of attachment to group Q,
T, U, V and W each represent CR 2 or N,
with the proviso that at most two of the ring members T, U, V and W simulataneously represent N,
and
in which
R 2 represents hydrogen, halogen, cyano, (C 1 -C 4 )-alkyl, trifluoromethyl, amino, (C 1 -C 4 )-alkoxy or trifluoromethoxy,
and
in which, if the substituent R 2 occurs more than once, its meanings may be identical or different
and
Q represents an unsaturated 5- or 6-membered heterocycle or a 5- or 6-membered heteroaryl,
where the 5- or 6-membered heterocycle and the 5- or 6-membered heteroaryl may be substituted by 1 to 4 substituents independently of one another selected from the group consisting of halogen, azido, nitro, cyano, oxo, thioxo, —R 3 , —C(═O)—R 3 , —C(═O)—OR 3 , —C(═O)—NR 3 R 4 , —O—(C═O) n —R 3 , —O—C(═O)—OR 3 , —O—C(═O)—NR 3 R 4 , —S(O) p —R 3 , —SO 2 —OR 3 , —SO 2 —NR 3 R 4 , —NR 3 —(C═O) n —R 4 , —NR 3 —SO 2 —R 4 , —NR 3 —C(═O)—OR 4 , —NR 5 —C(═O)—NR 3 R 4 and —NR 5 —SO 2 —NR 3 R 4
in which
n represents a number 0 or 1,
p represents a number 0, 1 or 2,
R 3 , R 4 and R 5 each independently of one another represent hydrogen, (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 3 -C 8 )-cycloalkyl, (C 3 -C 8 )-cycloalkenyl, (C 6 -C 10 )-aryl, 4- to 8-membered heterocyclyl or 5- to 10-membered heteroaryl,
in which R 3 , R 4 and R 5 for their part may be substituted by 1 to 5 substituents independently of one another selected from the group consisting of halogen, azido, nitro, cyano, trifluoromethyl, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkylcarbonyl, (C 1 -C 6 )-alkylcarbonyloxy, hydroxycarbonyl, (C 1 -C 6 )-alkoxycarbonyl, amino-carbonyl, mono-(C 1 -C 6 )-alkylaminocarbonyl, di-(C 1 -C 6 )-alkylaminocarbonyl, hydroxyl, trifluoromethoxy, (C 1 -C 6 )-alkoxy, oxo, mercapto, (C 1 -C 6 )-alkylthio, amino, mono-(C 1 -C 6 )-alkylamino, di-(C 1 -C 6 )-alkylamino, formylamino, (C 1 -C 6 )-alkylcarbonylamino, alkoxycarbonylamino, (C 3 -C 8 )-cycloalkyl, (C 3 -C 8 )-cyclo-alkenyl and 4- to 8-membered heterocyclyl,
or
R 3 and R 4 together with the radical to which the two are attached form a 4- to 8-membered heterocycle,
or
R 3 and R 5 together with the radical to which the two are attached form a 4- to 8-membered heterocycle,
or an N-oxide, salt, or salt of an N-oxide thereof.
2 . Compound of the formula (I) according to claim 1 in which
A represents O, S or NR 1 ,
where
R 1 represents hydrogen,
L represents phenyl, thienyl, pyridyl or pyrimidinyl,
where phenyl, thienyl, pyridyl and pyrimidinyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, chlorine, cyano, methyl, ethyl and trifluoromethyl,
M represents a bicyclic heteroaryl group of the formula
in which
* represents the point of attachment to group A,
** represents the point of attachment to group Q,
T 1 , U 1 , V 1 and W 1 each represent CR 2A or N,
where at most two of the ring members T 1 , U 1 , V 1 and W 1 simultaneously represent N
and
where
R 2A represents hydrogen or fluorine,
where at most two of the radicals R 2A represent fluorine
and
where, if the substituent R 2A occurs more than once, its meanings may be identical or different,
T 2 , U 2 , V 2 and W 2 each represent CR″ or N,
where at most two of the ring members T 2 , U 2 , V 2 and W 2 simultaneously represent N
and
where
R 2B represents hydrogen or fluorine,
where at most two of the radicals R 2B represent fluorine
and
where, if the substituent R 2B occurs more than once, its meanings may be identical or different,
and
Q represents a group of the formula
where
# represents the point of attachment to group M,
D represents CH or N,
J represents CR 8 , N or N + —O − ,
in which
R 8 represents halogen, nitro, cyano, —R 3 , —C(═O)—R 3 , —C(═O)—OR 3 , —C(═O)—NR 3 R 4 , —O—(C═O) n —R 3 , —O—C(═O)—OR 3 , —O—C(═O)—NR 3 R 4 , —S(O) p —R 3 , —SO 2 —OR 3 , —SO 2 —NR 3 R 4 , —NR 3 —(C═O) n —R 4 , —NR 3 —SO 2 —R 4 , —NR 3 —C(═O)—OR 4 , —NR 5 —C(═O)—NR 3 R 4 or —NR 5 —SO 2 —NR 3 R 4 ,
in which
n represents a number 0 or 1,
p represents a number 0 or 2,
R 3 , R 4 and R 5 each independently of one another represent hydrogen, (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 3 -C 7 )-cycloalkyl, (C 3 -C 7 )-cycloalkenyl, phenyl, 5- to 7-membered heterocyclyl or 5- or 6-membered heteroaryl,
in which R 3 , R 4 and R 5 for their part may be substituted by 1 to 3 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, trifluoromethoxy, oxo, amino, mono-(C 1 -C 4 )-alkylamino and di-(C 1 -C 4 )-alkylamino,
or
R 3 and R 4 together with the radical to which the two are attached may form a 5- to 7-membered heterocycle,
or
R 3 and R 5 together with the radical to which the two are attached may form a 5- to 7-membered heterocycle,
R 9 represents hydrogen, (C 1 -C 6 )-alkyl or (C 3 -C 7 )-cycloalkyl, where (C 1 -C 6 )-alkyl may be substituted by 1 to 5 substituents independently of one another selected from the group consisting of (C 3 -C 7 )-cycloalkyl, hydroxyl, (C 1 -C 4 )-alkoxy, trifluoromethoxy, (C 1 -C 4 )-acyloxy, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino, (C 1 -C 4 )-acylamino, hydroxycarbonyl, (C 1 -C 4 )-alkoxycarbonyl, aminocarbonyl, mono-(C 1 -C 4 )-aminocarbonyl, di-(C 1 -C 4 )-alkylaminocarbonyl and a 5- or 6-membered heterocycle,
or an N-oxide, salt, or salt of an N-oxide thereof.
3 . Compound of the formula (I) according to claim 1 in which
A represents S or NR',
where
R 1 represents hydrogen,
L represents phenyl, pyridyl or pyrimidinyl,
where phenyl may be substituted by 1 or 2 fluorine substituents,
M represents a bicyclic heteroaryl group of the formula
in which
* represents the point of attachment to group A,
** represents the point of attachment to group Q,
and
T 1 represents CH or N,
U 1 represents CH,
W 1 represents CH,
V 1 represents CR 2A
in which
R 2A represents hydrogen or fluorine,
Q represents a group of the formula
where
# represents the point of attachment to group M,
J represents CR 8 or N
in which
R 8 represents hydrogen, fluorine, (C 1 -C 4 )-alkyl, (C 3 -C 7 )-cycloalkyl, phenyl, pyridyl, —NR 3 —(C═O) n —R 4 , —NR 3 —C(═O)—OR 4 or —NR 5 —C(═O)—NR 3 R 4
in which
n represents the number 0 or 1,
R 3 represents hydrogen or (C 1 -C 4 )-alkyl
in which (C 1 -C 4 )-alkyl for its part may be substituted by a substituent selected from the group consisting of fluorine, trifluoromethyl, hydroxyl and methoxy,
R 4 represents hydrogen, (C 1 -C 4 )-alkyl or (C 3 -C 7 )-cycloalkyl,
in which (C 1 -C 4 )-alkyl for its part may be substituted by a substituent selected from the group consisting of fluorine, trifluoromethyl, hydroxyl and methoxy,
R 5 represents hydrogen or (C 1 -C 4 )-alkyl,
or
R 3 and R 4 together with the radical to which the two are attached may form a 5- to 7-membered heterocycle,
R 6 represents hydrogen or amino,
R 7 represents hydrogen or amino,
or an N-oxide, salt, or salt of an N-oxide thereof.
4 . Process for preparing compounds of the formula (I), as defined in claim 1 characterized in that
[A] a compound of the formula (II)
in which A, L, T 1 , U 1 , V 1 and W 1 each have the meanings given in claim 1
is reacted in an inert solvent in the presence of a palladium catalyst and a suitable base with a compound of the formula (III)
in which D, J, R 6 and R 7 each have the meanings given in claim 1
and
X 1 represents a suitable leaving group such as, for example, halogen, mesylate, tosylate or triflate
to give a compound of the formula (I-A)
in which A, D, J, L, T 1 , U 1 , V 1 , W 1 , R 6 and R 7 each have the meanings given in claim 1 ,
or
[B] a compound of the formula (IV)
in which A, L, T 2 , U 2 , V 2 and W 2 each have the meanings given in claim 1
are, in an inert solvent, converted with a halogenating agent into a compound of the formula (V)
in which A, L, T 2 , U 2 , V 2 and W 2 each have the meanings given in claim 1
and
X 2 represents halogen, in particular bromine,
and then converted by standard methods into a tin species (VI)
in which A, L, T 2 , U 2 , V 2 and W 2 each have the meanings given in claim 1
and
R 10 represents (C 1 -C 4 )-alkyl,
which is then reacted in an inert solvent in the presence of a palladium catalyst and a suitable base with a compound of the formula (III)
to give a compound of the formula (I-B)
in which A, D, J, L, T 2 , U 2 , V 2 , W 2 , R 6 and R 7 each have the meanings given in claim 1 ,
or
[α] a compound of the formula (VII)
in which A, L, T 2 , U 2 , V 2 and W 2 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 (VIII)
in which J and R 6 each have the meanings given in claim 1 ,
to give a compound of the formula (I-C)
in which A, J, L, T 2 , U 2 , V 2 , W 2 and R 6 each have the meanings given in claim 1
and the resulting compounds of formulae (I-A), (I-B) or (I-C) is, optionally, converted with the appropriate (i) solvent and/or (ii) base or acid into a salt thereof.
5 . (canceled)
6 . (canceled)
7 . (canceled)
8 . A pharmaceutical composition comprising a compound of the formula (I) as defined in claim 1 in combination with an inert, non-toxic, pharmaceutically suitable excipient.
9 . The pharmaceutical composition of claim 8 , further comprising an active ingredient selected from the group consisting of an organic nitrates, an NO donor, a cGMP-PDE inhibitor, an agent having antithrombotic activity, an agent lowering blood pressure, and an agent altering lipid metabolism.
10 . (canceled)
11 . A method for the treatment and/or prevention of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemias, vascular disorders, thromboembolic disorders and arteriosclerosis comprising administering to a human or animal in need thereof an effective amount of at least one compound of claim 1 .