GB2026485A

GB2026485A - Thiopropanoylamino acid derivatives

Info

Publication number: GB2026485A
Application number: GB7925259A
Authority: GB
Original assignee: ER Squibb and Sons LLC
Current assignee: ER Squibb and Sons LLC
Priority date: 1978-07-27
Filing date: 1979-07-19
Publication date: 1980-02-06
Also published as: GB2026485B; IT7924614A0; JPS5520795A; CA1109475A; DE2930605A1; FR2432019A1; IT1122310B

Abstract

New thiopropanoylamino acid derivatives which have the formula <IMAGE> wherein R3 and R5 each is lower alkyl; R is hydrogen or lower alkyl; and R4 is hydrogen, lower alkanoyl or benzoyl; may be used as hypotensive agents and can be incorporated into pharmaceutical compositions.

Description

SPECIFICATION Thiopropanoylamino acid derivatives This invention provides new thiopropanoylamino acid derivatives which have the formula

In formula land throughout this specification the symbols have the meanings described below.

R3 and R5 each is lower alkyl; R is hydrogen or lower alkyl; R4 is hydrogen, lower alkanoyl or benzoyl.

The lower alkyl groups are straight or branched chain hydrocarbon radicals having up to seven carbon atoms, e.g., methyl, ethyl, propyl, isopropyl, butyl, sec.butyl and the like. The C1 -C4 and especially C1-C2 alkyl groups are preferred.

The lower alkanoyl groups are the acyl radicals of the lower (C2-C7) fatty acids, e.g., acetyl, propionyl, butyryl, isobutyryl and the like. The members mentioned, and especially acetyl, are preferred.

The compounds of formula I are produced from amino acid compounds having the formula (11)

by reacting such an acid with a halopropanoyl halide having the formula (Ill) R3 X-CH2-C Co-X R5 wherein each Xis halogen, preferably chlorine or bromine, to obtain an intermediate having the formula

Treatment of this intermediate with a mercaptan (V) R4SH (wherein R4 is other than hydrogen) vields a Droduct havina the formula

R4 in this instance is other than hydrogen, i.e., the acyl groups lower alkanoyl or benzoyl. By treating the acyl derivative of formula IV with ammonia or concentrated ammonium hydroxide, a compound of formula VI wherein R4 is hydrogen is derived.

Alternatively, by treating the intermediate of formula IV with an alkali metal bisulfide like sodium bisulfide, a product of formula VI wherein R4 is hydrogen is directly obtained.

Additional experimental details can be found in the illustrative examples below.

The compounds of this invention are angiotensin converting enzyme inhibitors and may be used as hypotensive agents, particularlyforthe reduction of angiotensin dependent hypertension. By administering a composition containing one or a combination of angiotensin converting enzyme inhibitor of this invention to a hypertensive mammal, it intervenes in the angiotensinogen < (renin) < angiotensin i --, angiotensin II sequence and the hypertension is reduced or alleviated.

A single dose, or preferably two to four divided daily doses, provided on a basis of about 1 to 1000 mg. per kilogram per day and especially about 10 to 200 mg. per kilogram per day is appropriate to bring about a reduction in elevated blood pressure. The animal model experiments described by Engel et al., Proc. Soc.

Exp. Biol. Med. 143,483 (1973) provide a valuable guide.

The composition is preferably administered orally, but it can also be administered subcutaneously, intramuscularly, intravenously or intraperitoneally. The compound or compounds of formula I can be formulated as tablets, capsules or elixirs for oral administration. Sterile solutions or suspensions can be used for patenteral use.

The invention thus extends to pharmaceutical compositions comprising compounds of this invention and a pharmaceutical carrier.

About 50 to 1500 mg. of a compound or compounds of formula I can be compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., in a conventional unit dosage form as called for by accepted pharmaceutical practice. The amount of active substance is selected so as to provide a dosage in the range indicated.

The following Example is illustrative of the invention and represents a preferred embodiment. All temperatures are in degrees Celsius.

Example 1-(3-Mercap to-2,2-dimethyl- 1-oxopropyl-L-proline a) 1-(3-Chloro-2,2-dimethyl- 1-oxopropyl)-L-prollne L-proline (1.15 g.) is dissolved in 11.8 ml. of 0.85 N sodium hydroxide with vigorous stirring in an ice-bath.

To this solution 5 ml. of 2N sodium hydroxide is added, followed immediately by p-chloro-pivalic acid chloride and 2 ml. of ether. After 3.5 hours, the ninhydrin test is almost negative. To this reaction mixture 12.9 ml. of 0.85 N sodium hydroxide and 820 mg. of thiolacetic acid are added and stirred overnight at room temperature. This is acidified with concentrated hydrochloric acid and extracted with ethyl acetate. This material is dissolved in a mixture of ether-hexane (1 :10) and the crystalline product that separates (0.4 g., m.p. 116-118", tic identical to mother liquors) is filtered and the filtrate is concentrated to dryness in vacuo and utilized without further purification.

b) 1-(3-Mercapto-2,2-dimethyl- 1-oxopropyl)-L-proline The ss-chioropivaloyl prolinefrom part a (1.15 g.) is dissolved in 5 ml. of water and 920 mg. of sodium bisulfide-H2O under a continuous stream of nitrogen. The mixture is heated on the steam cone for one hour, acidified with concentrated hydrochloric acid and extracted with ethyl acetate, yield 1.1 g. The product is purified by silica gel chromatography with benzene-acetic acid (7:1). The product 1 -(3-mercapto-2,2- dimethyl-1-oxopropyl)-L-proline is then crystallized from ethyl acetate and hexane, yield 180 mg., m.p.

94-96".

Claims

1. Acompound oftheformula

wherein R3 and Rg each is lower alkyl; R is hydrogen or lower alkyl; and R4 is hydrogen, lower alkanoyl or benzoyl.

2. A compound as in Claim 1 wherein R4 is acetyl.

3. A compound as in Claim 1 wherein R and R4 each is hydrogen and R3 and R5 each is lower alkyl.

4. A compound as in Claim 3 wherein each lower alkyl group is methyl.

5. A compound as in any preceding claim for use as a hypotensive agent.

6. A pharmaceutical composition comprising a compound as in any one of claims 1 - 4 and a pharmaceutical carrier.

7. A composition as in claim 6, in the form of a tablet, capsule, elixir, or sterile injectable preparation.

8. A composition as in Claim 6 or 7, including an excipient, binder, preservative, stabiliser or flavor.