1,4-dihydropyridine derivatives and their use in therapy

Details 1,4-dihydropyridine derivatives and their use in therapy 1,4-dihydropyridine derivatives and their use in therapy

1999-07-08

2000-12-26

Fan, Jane

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

514343, 546194, 5462784, A61K 314545, C07D40112

Patent

active

061660353

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 PCT/FR98/00042, Jan. 12, 1998 now WO 9,831,680.
The present invention relates to novel 1,4-dihydropyridine derivatives.
Various 1,4-dihydropyridine derivatives have already been described. Thus, various esters of 2,6-dimethyl-4-(3-nitrophenyl)-5-methoxycarbonyl-1,4-dihydropyridine-3-car boxylic acid and in particular the 2-[methyl(phenylmethyl)amino]ethyl ester known under the name nicardipine, have already been described, in particular in FR 2,218,107.
Other 1,4-dihydropyridine derivatives have moreover been described in EP-A-0,494,816, these derivatives containing in position 3 a chain of the type: ##STR2## in which: A represents a group chosen from the groups of formula: ##STR3## and R.sub.2 represents a group chosen from 2,4,6-trimethoxyphenyl, 2-thienyl and phenyl groups.
The present invention is directed towards providing novel 1,4-dihydropyridine derivatives which have a better therapeutic range than that of compounds corresponding to the formula described in EP-A-0,494,816.
A subject of the present invention is thus compounds of formula: ##STR4## in which: n=1 or 2, and 2-pyrrolyl groups,
The subject of the present invention is, more particularly, (4S,3'R)(-)N-[4-(2-thienoyl)butyl]-piperid-3'-yl 2,6-dimethyl-4-(3-nitrophenyl)-5-methoxycarbonyl-1,4-dihydropyridine-3-car boxylate, (4S,3'R)(-)N-[4-(2,4,6-trimethoxybenzoyl)butyl]pyrrolidin-3'-yl 2,6-dimethyl-4-(3-nitrophenyl)-5-methoxycarbonyl-1,4-dihydropyridine-3-car boxylate and (4S,3'R)(-)N-[5-(1H-2-pyrrolyl)-5-oxopentyl]piperid-3'-yl 2,6-dimethyl-4-(3-nitrophenyl)-5-methoxycarbonyl-1,4-dihydropyridine-3-car boxylate, and the addition salts thereof with pharmaceutically acceptable acids.
The expression "addition salts with pharmaceutically acceptable acids" denotes salts which give the biological properties of the free bases, without having an undesirable effect. These salts can be, in particular, those formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid or phosphoric acid; acidic metal salts, such as disodium orthophosphate and monopotassium sulphate, and organic acids.
The compounds of formula I can be obtained by reaction of the acid of formula: ##STR5## with an alcohol of formula ##STR6## in which n and R.sub.1 have the meaning given above.
The addition salts are conventionally obtained by reaction of the compound of formula I with a pharmaceutically acceptable acid in a suitable solvent. Conversely, the bases can be obtained from addition salts by treatment with a strong base.
The acid of formula II can be prepared as described in EP-A-0,494,816 or as described in EP-A-0,680,952.
The alcohols of formula III can be obtained by reaction of a compound of formula: ##STR7## with a chloro derivative of formula ##STR8##
The examples which follow illustrate the preparation of the compounds according to the invention.


EXAMPLE 1

Preparation of (4S,3'R)(-)N-[4-(2-thienoyl)-butyl]piperid-3'-yl 2,6-dimethyl-4-(3-nitrophenyl)-5-methoxycarbonyl-1,4-dihydropyridine-3-car boxylate (CRL 42249) ##STR9##
a) Preparation of 2-(5-chloropentanoyl)thiophene
16 g (0.120 mol) of aluminium chloride are introduced portionwise over 15 min into a solution, maintained at about +5.degree., of 20.2 g (0.240 mol) of thiophene and 15.5 g (0.100 mol) of 5-chlorovaleryl chloride and the mixture is stirred for 5 h at room temperature. After removal of the supernatant by means of separating the phases by settling, the reaction medium is taken up in 120 ml of 3N hydrochloric acid solution and extracted with chloroform.
The organic phase is washed with water and dried over dry sodium sulphate and the solvent is evaporated off to give 16.5 g of an orange-brown oil.
Yield: 81.65%.
b) Preparation of (R)-2-[5-(3-hydroxypiperidinopentanoyl]thiophene hydrochloride
A solution of 20.3 g (0.10 mol) of the compound obtained in a) in 10 ml of acetonitrile is added over 45 min to a refluxing suspension of 8.1 g (0.08 mol) of (R)-3-hydroxypiperidine, prepared as described by H. Siertsson et al. (J. Med. Chem. 15, 1085,

REFERENCES:
patent: 5250543 (1993-10-01), Lafon et al.

Affiliated with

Also associated with

Rating

1,4-dihydropyridine derivatives and their use in therapy does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with 1,4-dihydropyridine derivatives and their use in therapy, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and 1,4-dihydropyridine derivatives and their use in therapy will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-995187