NL8002828A - 2- (MERCAPTO-1-OXOALKYL) -1,2,3,4-TETRAHYDROISOQUINOLINE -3-CARBONIC ACIDS AND THEIR DERIVATIVES. - Google Patents

Description

; S 'VO 315

Title: 2- (mercapto-1-oxoalkyl) -1,2,3,1-tetrahydroisoquinoline-3-carboxylic acids and their derivatives.

The invention relates to 2- (mercapto-1-oxoalk: yl) -1,2,3 Λ-tetrabyro-isoquinoline-3-carboxylic acids of the formula 1 of the formula sheet, wherein R 1 is hydrogen, acetyl or benzoyl, Rg and 1 3 hydrogen or methoxy, n is 1 or 2 and m is 0 or 1, as well as their salts or esters.

These compounds are good inhibitors of the enzyme responsible for the conversion of the decapeptide Angiotensin I to the octapeptide Angiotensin II. The latter is a substance that causes some forms of high blood pressure.

It has recently been discovered that a substance which interrupts the reaction producing Angiotensin II, ie the above conversion, is a useful and effective agent for combating hypertension caused by said substance.

It has been discovered that the present compounds have a clear activity in inhibiting the enzyme that converts Angiotensin I. For example, in vitro tests show that the activities of these compounds are very high. They brake e.g. the pure conversion enzymes isolated from rabbit lung tissues already at a concentration of

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3 to 13 x 10 "moles per liter. So they are good inhibitors of Angiotensin I-converting enzymes.

The present compounds are not all-active in vitro.

When administered orally, a dose-dependent antihypertensive effect was observed in rats with hypertension due to acute aortic astringent. Such oral doses, e.g. a suspension in a 0.5-200% Methocel solution of 16-200 mg / kg was found to have a clear ED (qi) (calculated oral dose for a reduction in mean arterial blood pressure by 30 mm Hg).

The following examples further illustrate the invention.

Example I

(S) (+) -2- (3-Benzoylthio-1-oxopropyl) -1,2,3, l-tetrahydric isoquinoline- 3-carboxylic acid ______ (S) (-) - 1,2,3, tetrahydroisoquinoline- 3-carboxylic acid (35g, 0.197 µmole) was suspended in 197.5 cm 1 l sodium hydroxide solution in a 1 liter three-necked flask fitted with two dropping funnels, a mechanical stirrer and cooled in an ice-water bath. 33.86 g was added to this cooled solution

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35 (0.197 mol) 3-bromopropionyl chloride and 98.76 cm 2 N caustic soda equal- 8 0 0 2 8 23 -2-. ƒ r added from both dropping funnels in good time with good stirring. The reaction mixture was then stirred at room temperature for 3.5 hours. After this, a solution of potassium thiobenzoate (3 ^, 82 g,

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0.197 mol) in 175 cm of water and this is stirred dropwise under good stirring, after which the reaction mixture is stirred overnight at room temperature.

This reaction mixture was cooled in an ice-water bath and brought to pH 2 with 6 N hydrochloric acid. A thick residue precipitated from the aqueous solution. This residue was extracted from the water layer with o 10 3 x 250 cm chloroform. The chloroform extracts were combined, washed with 3 x 150 cm ^ 10 #'s HCl J3 X 150 cm ^ HgO, dried with magnesium sulfate, filtered and the filtrate evaporated to dryness under reduced pressure to a thick oil for about 30 minutes below.

high vacuum / held cm to remove residual solvent.

The thick oil was heated on a steam bath under hexane to form a solid. This solid material was filtered off and triturated with ether for 1 hour. Then filtered again, the precipitate was washed with ether and dried to a final weight of 37.73 g (51 *) with m.p. 137-100 ° C.

20 Anal. ber. for C ^ H ^ NO ^ S: C = 65.02 *; H - 5.18 *; N = 3.79 *.

found: C = 6k, 6l%; H = 5.21 *; N = 3.71 *.

Example II

(S_) (+) -2- (3-mercapto-1-oxopropyl) -1,2,3, wfcetrahydroisoquinoline-3-carboxylic acid 25 (S_) (+) - 2- (3-benzoylthio-1-oxopropyl) - 1,2,3 U-tetrahydroiso

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quinoline-3-carboxylic acid (7.3 g) was suspended in 21 cm3 concentrated ammonia and 200 cm3 of water. The resulting suspension was stirred at 0 ° C under nitrogen for 1 hour and then at room temperature for 1 hour. The resulting solution was then washed three times with 150 ml of ethyl acetate. The aqueous solution was then cooled to 0 ° C and acidified with 6 N hydrochloric acid at pH 2 in the presence of a second layer of ethyl acetate. The layers were separated and the water - 3.

layer extracted three times with 100 cm ethyl acetate. The combined ethyl acetate liquids were dried with magnesium sulfate and concentrated in vacuo to a viscous oil, which solidified at 302 288.

-3- rubbing with ether; yield k, 2 g. Crystallization from ethyl acetate and hexane gave a product, mp 151-155 ° C.

Rf 0.59 (silica gel ·; toluene, acetic acid; 75:25); $ / p ° + 29.6 ° (c, 0.5,

MeOH).

Example III

(SO (+) - 2-bromoacetyl-1,2,3,4-tetrahydrois oquinoline-3-carboxylic acid (S_) (-) - 1,2,3, Wtetrahydroisoquinoline-3-carboxylic acid (20 g), 3 3 were dissolved in a solution of 113 cm IN sodium hydroxide solution and 150 cm of water.

This solution was cooled in an ice-water bath and 22.78 g of bromoacetyl bromide and 2 N sodium hydroxide (56.5 cm) were added simultaneously with good stirring. After stirring at room temperature for 3 hours, the reaction mixture was cooled in an ice-water bath and acidified to pH 2 with 6 N hydrochloric acid.

After stirring for an additional 15 minutes, the precipitate was filtered off and washed with ether. This product was dissolved in ethyl acetate and washed with 10 # hydrochloric acid, brine and water. After drying with magnesium sulfate, the ethyl acetate solution was filtered and evaporated to dryness in vacuo. The residue was recrystallized from ethyl acetate / hexane to 6.2 g of product with mp. 1 ^ 5-1 ^ 7 ° C; Rf 0.52 (silica gel; toluene, acetic acid; 75:25); 8 ° C + 13.7 ° (c, 1, DMF).

20

Example IV

(S) 2-benzoylthioacetyl-1,2,3, k-tetrahydroisoquinoline-3-carboxylic acid (_S) (+) -2-bromoacetyl-1,2,3, wfc hydrate oisoquinoline-3-carboxylic acid.

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(19.78 g) was dissolved in 100 cm of dimethylformamide. A solution of 11.7 g of aluminum thiob and about 100 ml of dimethylformamide was added dropwise over 15 minutes and the resulting solution stirred at room temperature for 3 hours. After this, the reaction mixture was concentrated in vacuo and the residue was azeotropically distilled twice with 3 .... .

150 cm xylene to give a 21 g viscous oily product; Rf 0.70 (silica gel; C 1 Cl 2, MeOH; 9 Ί). This product was further characterized as its dicyclohexylamine salt. (S) 2-Benzoylthioacetyl-1,2,3, Wtetrahydroisoquinoline-3-carbonic acid (2h g), 3 m of 100 ml of acetonitrile were dissolved for this purpose and 12.33 g of dicyclohexylamine were added dropwise therewith with stirring. After stirring the reaction mixture for 30 minutes, it was cooled to 5 ° C and thus 800 2 8 28 overnight

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ί -U- saved. Filtering and recrystallizing from acetonitrile, 19.5 g of product were obtained; m.p. 1H2-1Hk0C; Rf 0.13 (silica gel; CECl 4, MeOH; 9: 1); 9-1 ° (c., 1, toluene).

Example V

5 (£) (+) - 2-mercaptoacetyl-1,2,3, H-tetrahydroisoquinoline-3 ”carboxylic acid (S) 2-benzcylthioacetyl-1,2,3, H-tetrahydroisoquinoline-3-carboxylic acid 3 (21 g ) was dissolved in a solution of 50 cm concentrated ammonia and Ho cm water. The resulting solution was stirred under nitrogen while cooling with an ice-water bath, then stirring for an additional 1 hour at room temperature. The benzamide 3 formed was then filtered off and the filtrate washed three times with 75 cm ethyl acetate.

The aqueous phase was then brought to pH 2 with 6 N hydrochloric acid and extracted with 3 three 100 ml portions of ethyl acetate. These ethyl acetate extracts were dried with magnesium sulfate and concentrated in vacuo to a solid product which was triturated with ether and dried to 12.2 gm product. Recrystallization from acetonitrile provided a crystalline material with a melt. from IH5-IH80; Rf 0.50 (silica gel; toluene, acetic acid; 75:25); ^ί ^ + 29.9 ° (c., 0.5

MeOH).

Example VI

(S) 1,2,3, H-tetrahydroisoquinoline-3-carboxylic acid t-butyl ester (S) (-) -1,2,3, k-tetrahydroisoquinoline-3-carboxylic acid (96 g), 3 3 was dissolved in a mixture of 1200 cm water and 330 cm 2 N caustic soda.

This solution was cooled in an ice-water bath and added dropwise with stirring, with good stirring, 9 cm, 2 cm benzyl chloroformate and 330 cm 2 N sodium hydroxide. At the end of this, the reaction mixture was stirred at 0 ° C for 2 hours and at room temperature for 2 hours. The resulting solution was

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extracted four times with 250 ml ether and the aqueous layer with 6 l hydrochloric acid. adjusted to pH 2 in the presence of a second layer of ethyl acetate. The layers were separated and the water layer extracted three times with 300 cm ethyl acetate. The combined extracts were washed three times with 100 cm brine, dried with magnesium sulfate and concentrated in vacuo to an oil which solidified overnight at 5 ° C; yield 162 g. This product was recrystallized from ethyl acetate and hexane; m.p. 1Ho-1H2 ° C; Rf 0.12 (silica gel; toluene, acetic acid; 9: 1); 23.8 ° (c., 1.0, EtOH).

800 2 8 28 3 s

A mixture of the "obtained (S) (+) -1,2,3, k-tetrahydro-2-phenyl; methoxycarbcm] yl-3-isoquinoline carboxylic acid (12.5 g), 1700 cm

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methylene chloride and 6 cm concentrated sulfuric acid were stirred and saturated with isobutylene gas for a period of 7 hours.

The mixture was then post-cured overnight at room temperature.

At the end of this, a solution of 10 g of sodium carbonate and 500 cm of water was added dropwise quickly. After this, the layers were separated and the methylene chloride layer three times with

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Washed 500 cm water, dried with magnesium sulfate and concentrated in vacuo to a viscous oil; yield 121.8 g, Rf 0.52 (silica gel; toluene, acetic acid; 9: 1)

A stirred mixture of the obtained (S) 1,2,3, k-tstrahydro-2-phenyl-methoxycarbcmyl-3-isoquinoline carboxylic acid t-butyester (122 g), 10% palladium on carbon catalyst (5.0 g) and 800 cm ethanol was stirred at room temperature in a dust atmosphere for 2b hours. At the end of this, the catalyst was filtered off and the filtrate evaporated in vacuo to a viscous oil. This oil was dissolved in 500 ml of ethanol and a solution of 26.2 g was added to this solution. "3 3 phosphonic acid in 1000 cm ether and 700 cm water added. The 20 layers were separated and the water layer treated with 22, k g sodium hydroxide. It was then extracted three times with 3,250 cm3 of ether. The combined ether liquors were dried with magnesium sulfate and then concentrated in vacuo.

The resulting residue was distilled in vacuo to (S_) 1,2,3,15-tetrahydroisoehinoline-3-carboxylic acid t, butyl ester (30 g yield), bp. 158-159 ° C (3.0 mm); Rf 0.65 (silica gel; CHCl 3, MeOH, acetic acid; 8.5: 1.0: 0.5.

Example VII (3S) (+) - 2- (3-acetylthio-2-methyl-1-oxopropyl) -1,2,3, U-tetrahydro-isocholine-3-carboxylic acid t-butyl ester_

To a stirred solution of 22.7 g of dicyclohexylcarbo-diimide and (S) 1,2,3, k-tetrahydroisoquinoline-3-carboxylic acid t-butyl ester (50.7 g) in 180 ml of methylene chloride was added at 0 ° C 17.3 g of 3-acetylthio-2-methylpropanoic acid are added over 5 minutes. The resulting mixture was heated at 0 ° C for 1 hour and at room temperature for 300 hours. . . ? stirred. The precipitate was then filtered off and washed three times with 100 cm of methylene chloride. The filtrate and washings were combined and washed twice with 100 cm 10% citric acid, 100 cm 3 brine, twice with 100 cm 5% sodium bicarbonate solution and another 3 times with 100 cm brine solution. After drying with magnesium sulfate and concentrating in vacuo, a viscous oil was obtained; it weighed 1 + 2 g; Hf 0.59 (silica gel; EtOH, CHCl 3; 5:95); 0.96 ° (c, 1,

MeOH).

Example VIII

10 (3j3) (-) - 2- (3-ace ty lthi o-2-methyl 1-1-oxopr opyl) -1,2,3,1 + tetr abydroisoquinoline-3-carbanic acid_ 3 3

A solution of 180 cm anisole and 375 cm trifluoroacetic acid was added to 32 g (3S) (+) - 2- (3-acetylthio-2-methyl-1-oxoprcpyl) -1,2,3,1 + -tetrahydroisoquinoline-3- carboxylic acid t-butyl ester. The resulting solution was periodically stirred while left at room temperature for 1 hour and protected from air moisture by a drying tube. The reaction mixture was then added

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evaporated in vacuo to an oil in 1 + 00 cm ethyl acetate and

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5% sodium bicarbonate solution (250 cnr) was dissolved. The mixture was shaken well and the layers separated. The water layer was acidified with 6 L hydrochloric acid to pH 2 in the presence of a second layer of ethyl acetate while cooling in an ice-water bath. The ethyl acetate layer was separated, dried with magnesium sulfate and evaporated to a viscous oil; yield 27.1+ g. Rf: two overlapping spots at 0.35 and 0.1 + 5 (silica gel; ethanol, CHCl 3; 1: 9); ~ 13.0 ° (c, 1.1MeOH).

This product was further characterized in the form of its dicyclohexylamine salt. 23.1+ g of the viscous oil 3 obtained above were dissolved with 150 cm of ether and a solution of 13.75 80 0 2 8 28 -7- 2- (¾enzoyIthioacety1) -1,2,3, Wfcetrahydr0-6 with stirring 7-dime thoxy is oquinoline-3-carboxylic acid 1,2,3-tetrahydro-6,7-dimetlioxyisoquinoline-3-carboxylic acid-

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hydrochloride (21.0 g) was dissolved in 1 U caustic soda (15¼ cm) and then treated with mechanical stirring with 8.83 g chloroacetyl chloride and 2 N caustic soda (38.1 cm cm). The reaction mixture was stirred at room temperature for 3 hours and then 13.5 g of potassium thiobenzoate in 168 cm of water was added and the resulting mixture for 18 hours

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stirred at room temperature. This solution was acidified to pH 2 with 17 cnr 6 II 10 hydrochloric acid, stirred for 10 minutes and then filtered. After washing with water and drying at room temperature, a yellow solid material was obtained. This product was recrystallized from ethyl acetate; yield 15.3 g; m.p. 170-172 ° C; Rf 0.58 (silica gel; chloroform; acetic acid, methanol; 57: 1: 3).

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Claims (3)

1. Compounds of the formula I of the formula sheet, wherein R 1 is hydrogen, acetyl or benzoyl; Rg and Rl hydrogen or methoxy; n is 1 or 2 and m is 0 or 1 proposals as well as their salts and esters. 2. 5 2. (S-) (+) - 2- (3-Benzoylthio-1-oxopropyl) -1,2,3jiv-tetrahydroisoquinoline-3-carboxylic acid. 3. (S_) (+) - 2- (3-mercapto-1-oxopropyl) -1,2,3, U-tetrahydroi soquinoline-3-carboxylic acid. 1 *. (j3) (+) - 2-mercaptoacetyl-1,2,3 Wcetrahydroisoquinoline-3-carboxylic acid. (3S) (-) -2- (3-Acetylthio-2r-methyl-1-oxopropyl) -1,2,3 U-tetrahydroisoquinoline-3-carbonic acid. 6. 2-Benzoylthioacetyl-1,2,3 Msetrahydro-7,7-dime thoxyis oquinoline-3-carboxylic acid. Medicament containing a compound according to claims 1-6. 800 2 8 28