GB2116542A - Tetrahydroisoquinoline-3- carboxylic acids - Google Patents

Abstract

The novel compounds according to the invention are: 1. (S)(+)-2-Mercaptoacetyl- 1,2,3,4-tetrahydroisoquinoline-3- carboxylic acid; and 2. (3S)(-)-2-(3-Acetylthio-2- methyl-1-oxopropyl)-1,2,3,4- tetrahydroisoquinoline-3-carboxylic acid. The compounds are Angiotensin I- converting enzyme inhibitors and are therefore useful in combatting hypertension.

Description

1 GB 2 116 542 A 1

SPECIFICATION Tetrahydroisoquinoline-3-carboxylic acids

This invention is concerned with certain novel tetra hyd roisoq u inol i ne-3-ca rboxyl ic acids.

According to the invention there are provided, as novel compounds, (S)(+)2-mercaptoacetyl 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid and (3S) (-)-2-(-3- acetylth io-2-m ethyl- 1 -oxopropyl)- 5 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

These compounds are potent inhibitors of the enzyme responsible for converting the decapeptide Angiotensin I to the octapeptide Angiotensin IL The latter is the powerful pressor agent implicated as the causative agent in some forms of hypertension. The present invention also comprises a pharmaceutical composition comprising at least one of the compounds according to the invention and 10 an inert, pharmaceutically acceptable carrier.

Of late, it has been recognized that a substance capable of interrupting the pathway whereby Angiotensin 11 is produced, that is, the conversion referred to above, presents a useful and effective means of combatting hypertension associated with that pressor agent.

As already stated, we have found that the compounds of this invention have substantial activity in 15 inhibiting Angiotensin I converting enzyme. Thus, in in v1tro techniques designed to evince such activity these compounds are highly effective. For example, they inhibit the pure converting enzyme isolated from rabbit lung tissue at a level of about 3.1 to 13 x 10-1 moles per litre. Similar activity has also been observed in in vivo tests. Thus, oral administration of the compounds to rats subject to acute aortic coarctation hypertension shows that they have a dose dependent anti hypertensive effect. Such oral 20 dosage as, for example, a suspension in 0.5% methyl cellulose solution to achieve an ED30 (calculated oral dosage for a reduction of 30 mm Hg in mean arterial blood pressure) is about 16-200 mg/kg.

The compounds according to the invention can be prepared by a method as described in U.K.

Application 8012431 (Specification No. 2048863), from which the present application has been divided.

In order that the invention may be more fully understood, the following Examples of preparation of compounds according to the invention are given by way of illustration only. All temperatures are in 1C.

EXAMPLE 1 (S)(+)-2-Mercaptoacetyi-1,2,3,4-tetrahydroisoquinoline-3-carboxylic Acid (S) 2-Benzoyithioacety]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (21 9) was dissolved in a 30 solution of concentrated ammonium hydroxide (50 mi) and water (40 m]). The resulting solution was stirred under N2 while cooling in an ice-water bath for one hour and then at room temperature for one hour. After this time, the benzamide was removed by filtration and the filtrate was washed three times with ethyl acetate (75 mi). The aqueous phase was then brought to pH 2 with 6N HCl and extracted with ethyl acetate three times (100 m]). These latter ethyl acetate extracts were combined, dried with 35 magnesium sulphate, and concentrated in vacuo produci ng a solid product which was triturated with ether and dried to yield 12.2 g of product. Recrystallization from acetonitrile gave a crystalline solid; m.p. 145-1481; Rf 0.50 (silica gel; toluene; acetic acid; 75:25); [a],')0 + 29.91 (c, 0.5, MeOH).

EXAMPLE 2 (S) 1,2,3,4-Tetrahydroisoquinoline-3-carboxylic Acid tert. Butyl ester (intermediate for compound 40 according to the invention) (S)(-)-1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid (96 9) was dissolved in a mixture of water (1200 mi) and 2N NaOH (330 mi). This solution was cooled with an ice- water bath and with rapid stirring benzyl chloroformate (94.2 m]) and 2N NaOH (330 mi) were added dropwise. When addition was complete, the reaction mixture was stirred two hours at 0' and two hours at room temperature. 45 The resulting solution was extracted four times with ether (250 m[), and the aqueous layer acidified to pH 2 with 6N HCl in the presence of a second layer of ethyl acetate. The layers were separated and aqueous layer extracted three times with 300 mi of ethyl acetate. The combined extractions were washed three times with 100 mi of brine, dried with magnesium sulphate, and concentrated in vacuo to an oil which solidified upon standing at 511 overnight, yield 162 g. The product was recrystallized from 50 ethyl acetate and hexane; m.p. 140-1420; Rf 0.42 (silica gel; toluene, acetic acid; 9:1); [a] 20 + 23.8' D (c, 1.0, ROH).

A mixture of the resulting (S)(+)-1,2,3,4-tetrahydro-2-phenyi-methoxycarbonyi-3-isoquinoline carboxylic acid (124.5 g), methylene chloride (1700 mi), and concentrated sulphuric acid (6 mi) was stirred and saturated with isobutylene gas over a seven hour period. The mixture was then stirred overnight at ambient temperature. After this time a solution of sodium carbonate (60 9) and water (500 mi) was added at a rapid drop rate. When addition was complete, the layers were separated and the methylene chloride layer was washed three times with water (500 mi), dried with magnesium sulphate, and concentrated in vacuo to give the product as a viscous oil; yield 121.8 g, Rf 0.52 (silica gel; toluene, acetic acid, 9:1).

A stirred mixture of the resulting (S) 1,2,3,4-tetrahydro-2-phenylmethoxycarbonyi-3-isoquinoline carboxylic acid tert.-butyl ester (122 g), 10% palladium on carbon catalyst (5.0 g), and ethanol (800 mi) 2 GB 2 116 542 A 2 was stirred in a hydrogen atmosphere at room temperature for 24 hours. After this time, the catalyst is filtered and evaporated in vacuo to a viscous oil. This oil was dissolved in ethanol (500 mO and to this solution was added a solution of phosphorous acid (26.2 g) in ether (1000 mi) and water (700 mi). The layers were separated and the aqueous layer was treated with sodium hydroxide (22.4 g). It was then extracted with ether (250 m11) three times. The combined ether washes were dried with magnesium sulphate and then concentrated in vacuo. The resulting residue was vacuum distilled to give the product, (S) 1,2,3,4tetrahydroisoquirioline-3-carboxylic acid tert. butyi ester, yield 30 g; b.p. 158-1591 (3.0 mm); Rf 0.65 (silica gel; CI-IC13, Me01-1, acetic acid; 8.5:1.0:0.5.

EXAMPLE 3 (3S)(+)-2-(3-Acetyithio-2-methyi-l-oxopropyi)-1,2,3,4tetrahydroisoquinoline -3-carboxylic Acid. tert.-10 Butyl Ester (intermediate for compound according to the invention) To a stirred solution of dicyciohexylcarbodiimide (22.7 g) and (S) 1,2,3, 4-tetrahydroisoquinoline3-carboxylic acid tert.-butyl ester (25.7 g) in methylene chloride (180 mO was added at 01, 3acety[thio-2-methylpropanoic acid (17.8 g) over a period of five minutes. The resulting mixture was stirred for one hour at 01 and 16 hours at room temperature. After this time, the precipitate was filtered15 and washed three times with 100 mi of methylene chloride. The filtrate and washings were combined and washed twice with 100 mi of 10% citric acid, 100 mi of brine, twice with 100 mI of 5% sodium bicarbonate solution; and once again with 100 m] of brine. After drying with magnesium sulphate and concentrating in vacuo, a viscous oil was obtained, yield 42 g; Rf 0.59 (silica gel; EtOH, CHCla; 5:95); [a] 20 D + 0.96' (c, 1, MeOH).

EXAMPLE 4 (3S) (-)-2-(3-Acetyith io-2-m ethyl- 1 -oxopropyi)-1,2,3,4tetrahydroisoquinoline-3-carboxylic Acid A solution of anisole (180 ml) and trifluoroacetic acid (375 mi) was added to (3SA+)-2-Q acetylthio-2-m ethyl- 1 -oxopropyi)-1,2,3,4-tetrahydroisoquinoline-3- carboxylic acid tert.-butyl ester 25. (32 g). The resulting solution was stirred periodically while standing at room temperature for one hour 25 protected from moisture by a drying tube. After this time, the reaction solution was evaporated in vacuo to an oil, which was dissolved in ethyl acetate (400 m]) and 5% sodium bicarbonate solution (250 m[).

The mixture was shaken well and the layers were separated. The aqueous layer was acidified with 6N HCI to pH 2 in the presence of a second layer of ethyl acetate while chilling in an ice-water bath. This ethyl acetate layer was separated, dried over magnesium sulphate, and evaporated in vacuo to give a 30 viscous oil, yield 27.4 g; Rf: two overlapping spots at 0.3 5 and 0.45 (silica gel; ethanol, CI-IC13; 1: 9); lall) - 13.00 (c, 1, Me01-1).

This product was further characterized as its dicyclohexylamine salt. The viscous oil (23.4 g) obtained above was dissolved in ether (150 mO and with stirring a solution of dicyclohexylamine (13.75 ml) in ether (50 mi) was added dropwise at 00. After stirring for one hour at 01, the reaction 35 mixture was cooled at 51 for 28 days. The product was filtered, yield 14 g; m.p. 166-1690 (dec.); Rf 0.71 (silica gel; n-butanol, methanol, water; 2:11:11); [d] 20 - 30.41 (c, 0.5, MeOH).

D

Claims (3)

1. (S)(+)-2-Mercaptoacetyi-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

2. M) (-)-2-Q -Acetylthio-2-m ethyl- 1 -oxopropyi)-1,2,3, 4tetrahydroisoquinoline-3-carboxylic 40 acid.

3. A pharmaceutical composition comprising a compound according to claim 1 or 2 and an inert, pharmaceutically acceptable carrier.

Printed for Her Majesty's Stationery Office by the Courier Press, Leamington Spa, 1983. Published by the Patent Office Southampton Buildings, London, WC2A lAY, from which copies may be obtained.

f i