GB2048863A

GB2048863A - Tetrahydroisoquinoline-3-carboxylic Acids

Info

Publication number: GB2048863A
Application number: GB8012431A
Authority: GB
Original assignee: Morton Norwich Products Inc
Current assignee: ATK Launch Systems LLC
Priority date: 1979-05-16
Filing date: 1980-04-15
Publication date: 1980-12-17
Also published as: JPS55153769A; GB2116542B; DE3018545A1; NL8002828A; FR2456733B1; IT1133009B; GB2116542A; FR2456733A1; BE883320A; IT8048675A0; GB2048863B

Abstract

The compounds, which are Angiotensin I-converting enzyme inhibitors, are of the formula: <IMAGE> wherein R1 is hydrogen, acetyl or benzoyl, R2 and R3 are each hydrogen or methoxy, n is 1 or 2 and m is 0 or 1.

Description

SPECIFICATION Tetrahydroisoquinoline-3-carboxylic acids This invention is concerned with certain novel tetrahydroisoquinoline-3-carboxylic acids.

According to the invention, there are provided, as novel compounds, 2-[mercapto- 1 oxo(lower alkyl)]-1 ,2,3,4,-tetrahydroisoquinoline-3- carboxylic acids of the formula:

wherein R, is hydrogen, acetyl or benzoyl, R2 and R3 are hydrogen or methoxy, n is 1 or 2, and m is Oor 1.

These compounds are potent inhibitors of the enzyme responsible for converting the decapeptide Angiotensin I to the octapeptide Angiotensin II. 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 compound of Formula (I) and an inert, pharmaceutically acceptable carrier.

Of late, it has been recognized that a substance capable of interrupting the pathway whereby Angiotension II 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 inhibiting Angiotension i converting enzyme. Thus, in in vitro 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 10-8 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 antihypertensive effect. Such oral dosage as, for example, a suspension in 0.5% methylcellulose solution to achieve and ED30 (calculated oral dosage for a reduction of 30 mm Hg in mean arterial blood pressure) is about 16200 mg/kg.

The compounds according to the invention can be prepared by condensing a tetrahydroisoquinoline-3-carboxylic acid, or an ester thereof, of the formula:

in which R2 and R3 have the above-stated meanings and R4 is hydrogen or an ester-forming group, with an acid or acid halide of the formula

in which X is -OH or a- halogen atom, and R1, n and m have the abovestated meanings. When the compound of formula 11 is an ester, the product is then hydrolysed to the corresponding acid and when R, is acetyl or benzoyl, the product may be hydrolysed to the corresponding compound in which R, is hydrogen.

In order that the invention may be more fully understood, the following examples are given by way of illustration only. All temperatures are inoC.

Example 1 (S)( + )-2-(3-Benzoylthio-1 -oxopropyl)- 1,2,3,4-tetrahydroisoquinoline-3-carboxylic Acid (S)(-)- 1 2,3,4-Tetrahyd roisoquinoli ne-3- carboxylic acid (35 g, 0.197 mole) was suspended in 197.5 ml of 1N NaOH in a one-litre three-neck round-bottomed flask which was equipped with two addition funnels, a mechanical stirrer and cooled in an ice-water bath. To this cooled suspension were added simultaneously 3bromopropionyl chloride (33.86 g, 0.197 mole) and 98.76 ml of 2N NaOH, by means of the two addition funnels, with rapid stirring. The reaction mixture was stirred at ambient temperature for 3.5 hours.After this time, a solution of potassium thiobenzoate (34.82 g, 0.197 mole) in 175 ml of water was added, dropwise with rapid stirring, and the reaction mixture was stirred at room temperature overnight.

The reaction mixture was cooled in an icewater bath and acidified with 6N HCI to a pH of about 2. A thick residue precipitated from the aqueous solution. This residue was extracted from the aqueous layer with 3x250 ml of chloroform.

The chloroform extracts were combined, washed with 3x150 ml 10% HCI,3x150 ml H2O, dried over MgSO4, filtered to remove the drying agent, and evaporated under reduced pressure to a thick oil which was placed under high vacuum for about 30 minutes to remove any excess solvent.

The thick oil was heated on a steam bath, under hexane, and a solid was formed. The solid was removed by filtration and triturated for 1 hour under ether. The solid was removed by filtration, washed with ether and dried to a final wt. of 37.73 g, 51%; m.p. 137--1410.

Analysis: Calculated for C20H1gNO4S C=65.02%; H=5.18%; N=3.79% Found: C=64.61%; H=5.21%; N=3.71%.

Example 2 (S)( +)-2-(3-Mercapto-1 -oxopropyl) 1,2,3,4-tetrahydroisoquinoline-3-carboxylic Acid (S) (+)-2-(3-Benzoylthio- 1 -oxopropyl)- 1,2,3,4tetrahydroisoquinoline-3-carboxylic acid (7.3 g) was slurried in concentrated ammonium hydroxide (21.4 ml) and water (200 ml). The resulting suspension was stirred at 0 for one hour under nitrogen and then at room temperature for four hours. After this time, the resulting solution was washed three times with ethyl acetate (150 ml). The aqueous solution was then cooled to 0 and acidified to pH 2 with 6N HCI in the presence to a second layer of ethyl acetate. The layers were separated and the aqueous layer extracted three times with ethyl acetate (100 ml).The combined latter ethyl acetate washings were dried with magnesium sulphate and concentrated in vacuo to a viscous oil which solidified upon trituration with ether, yield 4.2 g. Recrystallization from ethyl acetate and hexane gave a product which melted at 151155 ; Rf 0.59 (silica gel; toluene, acetic acid; 75:25); [a!]20 +29.6 (c, 0.5, MeOH).

Example 3 (S)(+)-2-Bromoacetyl-1 .2,3,4- tetrahydroisoquinoline-3-carboxyl ic Acid (intermediate for compound according to the invention) (S)(-)-1 ,2,3,4-Tetrahydroisoquinoline-3- carboxylic acid (20 g) was dissolved in a solution of 1N NaOH (113 ml) and water (150 ml). The resulting solution was cooled in an ice-water bath and bromoacetyl bromide (22.78 g) and 2N NaOH (56.5 ml) were added simultaneously with rapid stirring. After stirring at ambient temperature for three hours, the reaction mixture was cooled with an ice-water bath and acidified with 6N HCI until pH 2. After stirring for 1 5 minutes, the solid was filtered and washed with ether. This product was dissolved in ethyl acetate and washed with 10% HCI, brine, and water.After drying over magnesium sulphate, the ethyl acetate solution was filtered and evaporated to dryness in vacuo.

The residue was recrystallized from ethyl acetate/hexane to give 6.2 g of product; m.p.

145--1470; Rf 0.52 (silica gel; toluene, acetic acid; 75:25); [cu]2+13.70 (c, 1, DMF).

Example 4 (S) 2-Benzoylthioacetyl-1 .2,3,4- tetrahydroisoquinoline-3-carboxylic Acid (S) (+)-2-Bromoacetyl- 1,2,3,4- tetrahydroisoquinoline-3-carboxylic acid (19.78 g) was dissolved in dimethylformamide (100 ml).

A solution of potassium thiobenzoate (11.7 g) in dimethylformamide (100 ml) was added dropwise over 1 5 minutes and the resulting solution was stirred at ambient temperature for three hours.

After this time, the reaction mixture was concentrated in vacuo and the residue twice azeotroped with xylenes (150 ml) to give a viscous oily product weighing 21 g; Rf 0.70 (silica gel; CHCl3, Me OH; 9:1). The product was further characterised as its dicyclohexylamine salt. (S)2- Benzoylth ioacetyl- 1 2,3 ,4-tetrahydroisoquinoline- 3-carboxylic acid (24 g) was dissolved in acetonitrile (100 ml) and with stirring dicyclohexylamine (12.33 g) was added dropwise.

After stirring the reaction mixture for 30 minutes, it was cooled at 50 overnight. The product was filtered and recrystallized from acetonitrile; yield 19.5 g; m.p. 142144c; Rf 0.43 (silica gel; CHCl3, MeOH; 9:1); [a:]2g+9.1 (c, 1,toluene).

Example 5 (S)(+)-2-Mercaptoacetyl-1 .2,3,4- tetrahydroisoquinoline-3-carboxylic Acid (S) 2-Benzoylthioacetyl- 1,2,3,4tetrahydroisoquinoline-3-carboxylic acid (21 g) was dissolved in a solution of concentrated ammonium hydroxide (50 ml) and water (40 ml).

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 ml). The aqueous phase was then brought to pH 2 with 6N HCI and extracted with ethyl acetate three times (100 ml). These latter ethyl acetate extracts were combined, dried with magnesium sulphate, and concentrated in vacuo producing 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. 1451480; Rf 0.50 (silica gel; toluene, acetic acid; 75:25); [aj%0+29.90 (c, 0.5, MeOH).

Example 6 (5)1 ,2,3,4Tetrahydrnisoquinoline-3- carboxylic Acid tert. Butyl ester (intermediate for compound according to the invention) (S)(-)-1 ,2,3,4-Tetrahydroisoquinoline-3- carboxylic acid (96 g) was dissolved in a mixture of water (1200 ml) and 2N NaOH (330 ml). This solution was cooled with an ice-water bath and with rapid stirring benzyl chloroformate (94.2 ml) and 2N NaOH (330 ml) were added dropwise.

When addition was complete, the reaction mixture was stirred two hours at 0 and two hours at room temperature. The resulting solution was extracted four times with ether (250 ml), and the aqueous layer acidified to pH 2 with 6N HCI in the presence of a second layer of ethyl acetate.

The layers were separated and aqueous layer extracted three times with 300 ml of ethyl acetate. The combined extractions were washed three times with 100 ml of brine, dried with magnesium sulphate, and concentrated in vacuo to an oil which solidified upon standing at 50 overnight, yield 162 g. The product was recrystallized from ethyl acetate and hexane; m.p.

1 40--1 42 0; Rf 0.42 (silica gel; toluene, acetic acid; 9:1); [a]20+23.80 (c, 1.0, EtOH).

A mixture of the resulting (S)(+)-1,2,3,4tetra hydro-2-phenyl-methoxy-carbonyl-3- isoquinoline carboxylic acid (124.5 g), methylene chloride (1700 ml), and concentrated sulphuric acid (6 ml) 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 g) and water (500 ml) 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 ml), 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) 1,2,3,4tetra hydro-2-phenyl-methoxycarbonyi3isoquinoline carboxylic acid tert. - butyl ester (122 g),10% palladium on carbon catalyst (5.0 g), and ethanol (800 ml) 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 ml) and to this solution was added a solution of phosphorous acid (26.2 g) in ether (1000 ml) and water (700 ml). The layers were separated and the aqueous layer was treated with sodium hydroxide (22.4 g). It was then extracted with ether (250 ml) 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) 1,2,3,4- tetrahydroisoquinoline-3-carboxylic acid tert.

butyl ester, yield 30 g; b.p. 1 58-1 590 (3.0 mm); Rf 0.65 (silica gel; CHCI3, MeOH, acetic acid; 8.5:1.0:0.5.

Example 7 (3S)( + )-2-(3-Acetylthio-2-methyl-1 oxopropyl)-l ,2,3,4-tetrahydroisoquinoline-3- carboxylic Acid. tert.-Butyl Ester (intermediate for compound according to the invention) To a stirred solution of dicyclohexyl carbodiimide (22.7 g) and (S) 1,2,3,4 tetrahydroisoqui noli ne-3-carboxylic acid tert.butyl ester (25.7 g) in methylene chloride (180 ml) was added at 00, 3-acetylthio-2methylpropanoic acid (17.8 g) over a period of five minutes. The resulting mixture was stirred for one hour at 0 and 16 hours at room temperature. After this time, the precipitate was filtered and washed three times with 100 ml of methylene chloride.The filtrate and washings were combined and washed twice with 100 ml of 10% citric acid, 100 ml of brine, twice with 100 ml of 5% sodium bicarbonate solution; and once again with 100 ml of brine. After drying with magnesium sulphate and concentrating in vacuo, a viscous oil was obtained, yield 42g; Rf 0.59 (silica gel; EtOH, CHCI3; 5:95); [a]0+0.960 (c, 1, MeOH).

Example 8 (33)(-)-2-(3-Acetylthio-2-methyl-1 oxopropyl)-1 ,2,3,4-tetrahydroisoquinoline-3- carboxylic Acid A solution of anisole (180 ml) and trifluoroacetic acid (375 ml) was added to (3S) (+)-2-(3-acetylthio-2-methyl- 1 -oxopropyl) 1 ,2,3,4-tetrahydroisoquinoline-3-carboxylic acid tert.-butyl ester (32 g). The resulting solution was stirred periodically while standing at room temperature for one hour 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 ml) and 5% sodium bicarbonate solution (250 ml). 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 viscous oil, yield 27.4 g; Rf: two overlapping spots at 0.35 and 0.45 (silica gel; ethanol, CHCl3; 1:9); [a]2-1 3.00 (c, 1, MeOH).

This product was further characterised as its dicyclohexylamine salt. The viscous oil (23.4 g) obtained above was dissolved in ether (1 50 ml) and with stirring a solution of dicyclohexylamine (13.75 ml) in ether (50 ml) was added dropwise at 00. After stirring for one hour at 00, the reaction mixture was cooled at 50 for 28 days.

The product was filtered, yield 14 g; m.p. 166- 1690 (dec.); Rf 0.71 (silica gel; n-butanol, methanol, water; 2:1:1); [a]0-30.4 (c, 0.5, MeOH).

Example 9 2-( Benzoylthioacetyl)- 1 2,3,4-tetrahydro- 6,7-dimethoxyisoquinoline-3-carboxylic Acid 1,2,3,4-Tetrahydro-6,7 dimethoxyisoquinoline-3-carboxylic acid hydrochloride (21.0 g) was dissolved in 1N NaOH (154 ml) and then mechanically stirred with chloroacetyl chloride (8.83 g) and 2N NaOH (38.4 ml). The reaction mixture was stirred for three hours at room temperature and then potassium thiobenzoate (13.5 g) in water (168 ml) was added and the resulting mixture stirred for 1 8 hours at room temperature. This solution was acidified with 6N hydrochloric acid (17 ml) to pH 2, stirred for 10 minutes and then filtered. After washing the product with water and drying at room temperature, a yellow solid was obtained.

this product was recrystallized from ethyl acetate, yield 15.3 g; m.p. 1 70--1 72 0; Rf 0.58 (silica gel; chloroform, acetic acid, methanol; 57:1:3).

Claims

1. A compound of the formula:

wherein R, is hydrogen, acetyl or benzoyl; R2 and R3 are each hydrogen or methoxy; n is 1 or 2; and m is 0 our 1.

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

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

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

5. (3S)(-)-2-(3-Acetylthio-2-methyl-l- oxopropyl)-1 ,2,3,4-tetrahydroisoquinoline-3- carboxylic acid.

6.2-Benzoylthioacetyl- 1,2,3,4-tetrahydro- 6,7-dimethoxy-isoquinoline-3-carboxylic acid.

7. A pharmaceutical composition comprising at least one compound according to any of claims 1 to 6 and an inert, pharmaceutically acceptable carrier.