Substituted 6-phenylnicotinic acids and their use
View Patent ↗The present application relates to novel substituted 6-phenylnicotinic acid 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 prophylaxis of cardiovascular disorders, in particular dyslipidaemias, arteriosclerosis and heart failure.
1. A compound of the formula (I)
in which
A represents N and D represents CH,
R 1 isobutyl,
R 2 represents trifluoromethyl,
R 3 represents hydrogen,
R 4 represents hydrogen,
R 5 represents chlorine,
R 6 represents hydrogen,
and its salts.
2. A process for preparing compounds of the formula (I) as defined in claim 1 , characterized in that a compound of the formula (II)
in which A,D, R 2 , R 3 , R 4 , R 5 and R 6 have the meanings given in claim 1 ,
X 1 represents a suitable leaving group, such as, for example, halogen, in particular chlorine
and
R 8 represents (C 1 -C 4 )-alkyl,
is either
[A] reacted in an inert solvent in the presence of a base and a suitable palladium catalyst with a compound of the formula (III-A)
R 1A —X 2 (III-A),
in which
R 1A represents isobutyl,
and
X 2 represents a group of the formula —B(OR 9 ) 2 or -ZnHal,
where
Hal represents halogen, in particular chlorine, bromine or iodine,
and
R 9 represents hydrogen or (C 1 -C 4 )-alkyl
or
both radicals R 9 together form a —C(CH 3 ) 2 —C(CH 3 ) 2 bridge,
to give compounds of the formula (IV-A)
in which A, D, R 1A , R 2 , R 3 , R 4 , R 5 , R 6 and R 8 each have the meanings given above,
and these are converted by basic or acidic hydrolysis into the carboxylic acids of the formula (I-A)
in which A,D, R 1A , R 2 , R 3 , R 4 , R 5 and R 6 have the meanings given above,
or
[B] reacted in an inert solvent in the presence of a base with a compound of the formula (III-B)
R 1B —H (III-B),
in which
claim 1 ,
to give compounds of the formula (IV-B)
in which A, D, R 1B , R 2 , R 3 , R 4 , R 5 , R 6 and R 8 each have the meanings given above,
and these are converted by basic or acidic hydrolysis into the carboxylic acids of the formula (I-B)
in which A,D, R 1B , R 2 , R 3 , R 4 , R 5 and R 6 have the meanings given above.
3. A process for preparing compounds of the formula (I) as defined in claim 1 and in which A represents CH and D represents N, characterized in that a compound of the formula (XI)
in which R 2 , R 3 , R 4 , R 5 , and R 6 have the meaning given in claim 1
and
R 11 represents (C 1 -C 4 )-alkyl or benzyl,
is reacted in an inert solvent under Mitsunobu conditions with a compound of the formula (III-C)
R 1C —H (III-C),
in which
where R c has the meaning given in claim 1
in which R 1C , R 2 , R 3 , R 4 , R 5 , R 6 and R 11 each have the meanings given above,
and these are converted by basic or acidic hydrolysis into the carboxylic acids of the formula (I-C)
in which R 1C , R 2 , R 3 , R 4 , R 5 and R 6 have the meanings given above.
4. A process for preparing the compounds of the formula (I) as defined in claim 1 and in which A represents CR 7 and D represents N, characterized in that a compound of the formula (XIV)
in which R 2 and R 7 have the meaning given in claim 1 ,
R 1A represents isobutyl
R 8 represents (C 1 -C 4 )-alkyl,
and
X 6 represents a suitable leaving group, such as, for example, halogen, in particular chlorine,
is, in an inert solvent in the presence of a suitable transition metal catalyst and, if appropriate, a base, coupled with a compound of the formula (VI)
in which R 3 , R 4 , R 5 and R 6 have the meanings given above,
X 4 represents the group —B(OR 9 ) 2 , -ZnHal or -MgHal,
where
Hal represents halogen, in particular chlorine, bromine or iodine,
and
R 9 represents hydrogen or (C 1 -C 4 )-alkyl
or
both radicals R 9 together form a —C(CH 3 ) 2 —C(CH 3 ) 2 bridge,
to give compounds of the formula (IV-D)
in which R 1A , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 each have the meanings given above,
and these are converted by basic or acidic hydrolysis into the carboxylic acids of the formula (I-D)
in which R 1A , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 have the meanings given above.
5. A medicament, comprising a compound of the formula (I) as defined in claim 1 in combination with an inert nontoxic pharmaceutically suitable auxiliary.
6. A medicament, comprising a compound of the formula (I) as defined in claim 1 in combination with one or more further active compounds selected from the group consisting of HMG-CoA reductase inhibitors, diuretics, beta-receptor blockers, organic nitrates and NO donors, ACE inhibitors, angiotensin All antagonists, aldosterone and mineralocorticoid receptor antagonists, vasopressin receptor antagonists, platelet aggregation inhibitors and anticoagulants.
7. The compound of claim 1 , wherein the salt is a sodium salt.