WO1987006934A1

WO1987006934A1 - Nitric esters of benzothiazepinones

Info

Publication number: WO1987006934A1
Application number: PCT/CH1987/000053
Authority: WO
Inventors: Pierre Baudet
Original assignee: Pierre Baudet
Priority date: 1986-05-09
Filing date: 1987-05-08
Publication date: 1987-11-19
Also published as: EP0267924A1

Abstract

Nitric esters of benzothiazepines useful in cardiovascular therapy, and their synthesis methods.

Description

Benzothiazepinone nitric esters.

The nitric esters of the invention have coronary vasodilatory properties useful for the treatment of angina of various types, relieving pain and improving the blood supply to ischemic heart tissue.

The oxy-acyl derivatives of benzothiazepines currently in use as vasodilators, such as iazem, hydrolyze relatively easily in the digestive tract and by hepatic metabolism, so that bioavailability, e.g. 2- (4-methoxyphenyl) -3-oxy-acetyl -5 (2-dimethylamino-ethyl) -2, 3 dihydro-1,5 benzothiazepine-4 (5H) -one is only about 10%.

The basic property of this benzothiazepine, although relatively weak, does not, however, allow good intraepidermal penetration as new galenic preparations would allow. The oxy-nitro derivatives of the invention such as: 2- (4-methoxyphenyl) -3-oxy-nitro-5 (2-dimethylamino-ethyl) 2,3 dihydro-1,5 benzothiazepine-4 (5H) - they have great stability in biological media and good diffusion through the epidermis through which they reach the bloodstream for a prolonged period. They can be used by trans-epidermal administration techniques.

Example:

1.- Cis (+) - 3- (4methoxyphenyl) -3-oxy-nitro-5 (2-dimethylamino-ethyl) -2,3 dihydro-1,5benzothiazepine-4 (5H) -one.

To the mixture of 2.74 g, acetic anhydride and 1.77 g. 100% NO ₃ H, cooled to -5 -0 ° (prepared by adding dropwise drops of nitric acid in acetic anhydride cooled to -5º) added in several servings 3.72 g. of 2- (4-methoxyohényl) -3-oxy-5 (2-di _. methylamino-ethyl) -2,3 dihydro-1,5 benzothiazenine-4 (5H) -one.

After 60 minutes, the reaction medium is removed from the ice-salt mixture and the reaction continues with magnetic stirring until the medium becomes homogeneous.

The solution in 50 ml of methylene chloride from the medium is extracted twice with 100 ml of CO ₃ HNa at 5% and then twice with 100 ml of water. The evaporation residue from the organic solution is taken up in ethyl acetate. This solution is extracted twice with 150 ml of water. The organic solution is dried over magnesium sulfate and the solvent evaporated under reduced pressure.

The amorphous residue is crystallized from water, mp 76-77 °, recrystallized. in ether at -18 °, F. 86-87 °, recrystallization in EtOH at -18 °, F.86-87 °.

ccm silica G-60 F ₂₅₄ : Rf Solvents

0.85 n-butanol-H-O / ac. acétiπue

(5.1 2.5 vol.)

0.70 ethyl acetate

0.50 ethyl acetate / n-hentane

(3.1 vol.)

0.18 ethyl acetate / n-heptane

(1.1 vol.)

a) 1R (nujol) 1670 (F), 1640 (F), 1610 (m), 1560 (f), 1525 (F), 1400 (f), 1280 (F), 1180 (F), 1090 (m) , 1040 (m), 1020 (F), 850 (F), 765 (F), 727 (f) cm ^-1

intensity: F = strong f = weak m = medium b)

= + 153.2 (C = 1% ethyl acetate)

Claims

1.- Therapeutically active nitrinue esters of formula I

in which, R represents a phenyl residue which is unsubstituted or substituted by an alkyl group of 1 to 3 atoms or by several lower alkyl groups or by an alkoxy group or by several alkoxy groups or by a halogen atom or several halogen atoms in which R ₁ and R ₂ are lower alkyl groups, Y is an alkylene group of 2 to 3 carbon atoms, X is a hydrogen atom or a halogen atom.

The configuration of carbons 2 and 3 can be 2S, 3R 2R, 3S 2S, 3S or 2R, 3R or the racemates.

The property, although weakly basic, of these compounds allows the formation of pharmaceutically acceptable acid addition salts.

The therapeutic actions of the benzothiazepine derivatives of formula I are particularly notable in the field of coronary vasodilation or as an anti-depressant, this particularly for the following derivatives:

a) 2- (4-methylphenyl) -3 oxy nitro-5 (2-dimethylamino-ethyl) -2,3 dihydro1,5 benzothiazenine-4 (5H) -one, b) 2- (4-methoyphenyl) -3-oxynitro-5- (2-dimethylamino-ethyl) -2,3-dihydro-1,5-benzothiazepine-4 (5H) -one. c) 2- (4-chlorophenyl) -3-oxynitro-5- (2-dimethylamino-ethyl) -7-chloro-2.3-dihydo-1,5-benzothiazepine-4 (5H) -one, d) 2- ( 4-methoxyphenyl) -3-oxynitro-5- (2-dimethylamino-ethyl) -7-chloro-2,3-dihydro-1,5-benzothiazepine-4 (5H) -one, d) 2- (4-methoxyphenyl ) -3-oxynitro-5- (3-dimethylamino-propyl) -7-chloro-2,3-dihydro-1,5-benzothiazepine-4 (5H) -one.

Z.- Therapically active nitric esters of formula II or Intermediate for the synthesis of compounds of formula I,

in which R and X have the same meaning as in formula I. 3.- Process for the preparation of the nitric benzothiazepine esers of the formula

characterized by the reaction of the product from the mixture of acetic anhydride and 100% or 96% nitric acid, prepared extemporaneously, with a corresponding alcohol of the benzothiazepines of formula I. The molar ratio of the reactants can be 1/1 or 2/1 or higher. The reaction temperature is initially between -5 ° and 0 °, then at room temperature until the medium is homogeneous. The solution in methylene chloride of the reaction medium is extracted with an aqueous solution of CO ₃ HNa , then washed with evaporation residue is dissolved in ethyl acetate, this solution is extracted with dried water and the solvent evaporated under reduced pressure. The residue crystallizes in water as the base of the nitric ester of a benzothiazepine of formula I.

The nitric esters of the compounds of formula I can, if necessary, be purified by absorption on silica G 60230 at 400 mesh. then eluted with ethyl acetate.

4.- Process for the preparation of the benzrihiazepine nitriou ester of formula II, characterized by the reaction of the reaction product of acetic anhydride and nitric acid from 100 to 96%, prepared immediately, with the corresponding alcohol of benzothiazepine of formula II.

5.- Therapeutic property of the benzothiazenines of formula I, characterized by a vasodilatory action, in particular coronary.

6.- Therapeutic property of the benzothiazenines of formula I, characterized by an anti-depressant action.

7.- Therapeutic property of the benzothiazepines of formula I, characterized by trans epidermal administration.