Lactam-substituted dicarboxylic acids and use thereof
View Patent ↗The present application relates to novel lactam-substituted dicarboxylic acid derivatives, processes for their preparation, their use for the treatment and/or prophylaxis of diseases, and their use for producing medicaments for the treatment and/or prophylaxis of diseases, especially for the treatment and/or prevention of cardiovascular disorders.
1. A compound of the formula (I)
in which
A represents a group of the formula 1
in which
* represents the point of attachment to group E,
R 4 represents (C 1 -C 6 )-alkyl or phenyl,
x represents the number 0, 1 or 2,
where if the substituent R 4 occurs twice, its meanings may be identical or different,
and
y represents the number 2, 3 or 4,
where a CH 2 group may be replaced by —O— or >N—R 4A in which
R 4A is hydrogen, (C 1 -C 6 )-alkyl or phenyl,
E represents (C 2 -C 6 )-alkanediyl, (C 2 -C 6 )-alkenediyl or (C 2 -C 6 )-alkynediyl, each of which may be mono- or polysubstituted by fluorine,
m represents the number 1 or 2,
R 1 , R 2 and R 3 independently of one another represent a substituent selected from the group consisting of halogen, (C 1 -C 6 )-alkyl, trifluoromethyl, (C 1 -C 6 )-alkoxy, trifluoromethoxy, cyano and nitro,
and
n, o and p independently of one another each represent the number 0, 1 or 2,
where, if R 1 , R 2 or R 3 is present more than once, their meanings may in each case be identical of different,
or a salt thereof.
2. The compound of the formula (I) as claimed in claim 1 , in which
A represents a group of the formula
in which
* represents the point of attachment to group E,
R 4 represents (C 1 -C 4 )-alkyl or phenyl,
x represents the number 0, 1 or 2,
where if the substituent R 4 occurs twice, its meanings may be identical or different,
and
y represents the number 2 or 3,
where a CH 2 group may be replaced by —O— or >N—R 4A in which
R 4A represents (C 1 -C 4 )-alkyl or phenyl,
E represents (C 2 -C 6 )-alkanediyl or (C 2 -C 6 )-alkenediyl,
m represents the number 1 or 2,
R 1 represents a substituent selected from the group consisting of fluorine, chlorine, bromine, methyl, trifluoromethyl, methoxy and trifluoromethoxy,
R 2 and R 3 each represent fluorine,
and
n, o and p independently of one another each represent the number 0 or 1,
or a salt thereof.
3. A compound of the formula (I-A)
in which
A represents a group of the formula
in which
* represents the point of attachment to group E,
E represents 1,2-ethylene, 1,3-propylene, 1,4-butylene or 1,5-pentylene,
m represents the number 1 or 2,
and
R 1 represents hydrogen or fluorine,
or a salt thereof.
4. The compound of the formula (I-A) as claimed in claim 3 , in which
A represents a group of the formula
in which
* represents the point of attachment to group E,
E represents 1,2-ethylene, 1,3-propylene or 1,4-butylene,
m represents the number 1 or 2,
and
R 1 represents hydrogen or fluorine,
or a salt thereof.
5. A process for preparing a compound of the formula (I) or (I-A) as defined in claim 1 , wherein the compounds of the formula (II)
in which R 2 , R 3 , m, o and p each have the meanings given in claim 1 and
T 1 and T 2 are identical or different and represent (C 1 -C 4 )-alkoxycarbonyl,
are either
[A] converted in an inert solvent in the presence of a base with a compound of the formula (III-A)
in which A, E, R 1 and n each have the meanings given in claim 1 and
L represents phenyl or o-, m- or p-tolyl
and
X represents halide or tosylate,
into compounds of the formula (IV-A)
in which A, E, R 1 , R 2 , R 3 , m, n, o, p, T 1 and T 2 each have the meanings given above,
or
[B] converted in an inert solvent in the presence of a base with a compound of the formula (III-B)
in which R 1 , n, L and X each have the meanings given above,
initially into compounds of the formula (IV-B)
in which R 1 , R 2 , R 3 , m, n, o, p, T 1 and T 2 each have the meanings given above, and these are then alkylated in an inert solvent in the presence of a base with a compound of the formula (V)
A-E-Q (V),
in which A and E have the meanings given in claim 1 and
Q represents a leaving group, such as, for example, halogen, tosylate or mesylate,
to give compounds of the formula (IV-C)
in which A, E, R 1 , R 2 , R 3 , m, n, o, p, T 1 and T 2 each have the meanings given above,
and the resulting compounds of the formula (IV-A) or (IV-C) are converted by hydrolysis of the ester groups T 1 and T 2 into the dicarboxylic acids of the formula (I) and the compounds of the formula (I) are separated where appropriate by methods known to the skilled person into their enantiomers and/or diastereomers, and/or where appropriate reacted with the appropriate (i) solvents and/or (ii) bases or acids to give the or a salt thereof.
6. The compound as defined in claim 1 for the treatment of diseases.
7. A pharmaceutical composition comprising a compound as defined in claim 1 in combination with one or more inert, non-toxic, pharmaceutically suitable excipients.
8. The pharmaceutical composition of claim 7 , further comprising one or more further active ingredients selected from the group consisting of organic nitrates, NO donors, cGMP-PDE inhibitors, stimulators of guanylate cyclase, agents having antithrombotic activity, agents lowering blood pressure, and agents altering lipid metabolism.
9. The pharmaceutical composition as claimed in claim 7 for the treatment of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemias, vascular disorders, thromboembolic disorders and arteriosclerosis.
10. A method for the treatment of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemias, vascular disorders, thromboembolic disorders and arteriosclerosis in humans and animals by administration of an effective amount of at least one compound as defined in claim 1 .
11. A method for the treatment of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemias, vascular disorders, thromboembolic disorders and arteriosclerosis in humans and animals by administration of an effective amount of the pharmaceutical composition of claim 7 .