SU1148560A3 - Method of obtaining substituted acul derivative of 1,2,3,4-tetrahydroisoquinoline--3-carboxylic acid or pharmaceutically accepted salts - Google Patents

Abstract

The method of obtaining a substituted acyl derivative of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid of the general formula 1 COOR RI O 1 II CH-c-1 where X and Y have the indicated meanings; Rj is a lower alkyl or benzyl ester is subjected to. Interaction with the N-substituted amino acid of formula (III) Ar-CHj — CHg — CH — W — CH-COOH COORj where Ar, R, R., have the indicated values, with division of the target product or with a sequential length by removing the blocking group and isolating the target product in free form or in the form of a pharmaceutically acceptable salt.

Description

1148560 .J

The invention relates to a method for isoquinoline-3-carboxylic acid for the preparation of a new substituted acyloxy formula (I) derivative 1,2,3., 4-tetrahydro

,

SNG 1

COOR lower alkyl, lower alknl, hydrogen-, X and Y - lower alkoxy, vODORD-, phenyl; hydrogen, lower alkyl or benzyl, or to its pharmaceutically acceptable salts possessing biological activity. The peptide bond is known to react by reacting a carboxyl group with an N-protected amino group in an organic solvent medium using a dehydrating agent 1J. The purpose of the invention is the synthesis of new compounds with valuable physiological properties. The goal is achieved by the fact that according to the method for producing the substituted acyl derivative 1,2,3, D-tetrahydroisoxynol-3-carboxylic acid of the indicated general formula (I), based on the peptide bond formation reaction, compounds of the formula (II where X and Y RJ is lower alkyl or benzyl ester, is reacted with an N-substituted amino acid of formula 2 - CHj - W-CH CH-COOH, where Ar, Rj, R have the indicated values, and product or with subsequent removal of the block

COOR

incineration group and the selection of the target product in free form or in the form of a pharmaceutically acceptable salt. Example 1. 2- (2 {(1- (ethoxycarbonyl) -3-phenylpropyl) amino-1-oxopropyl) -1,2,3,4-tetrahydro-6, 7-dimethoxy-3-isoquinoline carboxylic acid, hydrochloride , hydrate (S, S, S). 0,0079 mol of hydrochloride 2- (2- {(1- (ztoxycarbonyl) -3-phenylpropyl) -amino -1-oxopropp) -1,2,3,4-tetrahydro-6, 7-dimethoxy-3-isoquinoline-carboxyl bonic acid, phenylmethyl ester (SSS) dissolved in too ml of tetrahydrofuran, is subjected to catalytic debenzylation by hydrogen under low pressure in the presence of 0.5 g of 20% palladium on carbon. The catalyst is then filtered and the product is precipitated as a relatively non-hygroscopic solid by adding 10 times the amount of disulfide ether (3.7 g, 58% yield) with mp 120-140 ° C, thin layer chromatographic treatment (mixture of 20% methanol with chloroform on silica dvuoxide): one spot, Rf - 0.50, 7, (alpha) 2 +31.6 (0.05% ethanol). Found,%: C 58.59, H N N 5.06. C.Hj.N.O. Calculated,%: C 58.63; H 6.74; N 5.07. . A noncrystalline diester hydrochloride starting material is obtained by treating 5.54 g (0.0079 mol) of the maleate salt (prepared as in Example 5) with an excess of sodium bicarbonate solution, by extracting the free base with 50% diethyl ether and ethyl acetate, (t1 (this

solution of excess hydrogen chloride and concentrating the mixture under reduced pressure.

Example 2. 2- (2 - {(1- (ethoxycarbonyl) -3 Fensch1propid) amino t 5 -oxopropyl) -1,2,3, D-tetrahydro-3-isoquinrline carboxylic acid, hydrochloride, hydrate, ().

Procedure A. De-benzylation.

2- (2- {(1 - (Ethoxycarbonyl) -3-phenyl-10 propyl) -amino -1-oxoprrpyl) -1,2, 3,4-tetrahydro-3-isoquinolinecarboxylic acid, phenylmethyl ether, maleate (S, ), obtained in accordance with Example 6, are subjected to t5 catalytic de-distillation of Example 1, as a result of which, with the achievement of 56% yield, a product is obtained with mp. 105-120С, fine-: layer chromatographic processing (20% of methanol in a mixture with chloroform on silica); one spot, R, 6, (alpha) d "10.9 ° (1.03% ethanol).

Found%: C 6t, 00, H 6.37 / 25 N 5.59 ..

C Hj N Oy-HCIH O

Calculated,%: C 60.90; H 6.75, N 5.58.

Procedure B. Cleavage of 1,1-dn-JQ methyl ethyl ether. To 11.6 g (0.023 mol) of 2- (2 - {(1-ethoxycarbonyl) -3-phenylpropyl) -a: 1ino -1-oxoprpryl) -1,2,3,4-tetrahydro-3 ishirhinolincarboxylic 35 acid, 1, the t-dimethyl ethyl ester () obtained in Example 7 is added with 100 g of trifluoroacetic acid. Next, the mixture is stirred at room temperature 40 until a solution is formed, and then another 1 hour. Most of the trifluoroacetic acid is removed in a rotary evaporator, and the remaining traces are removed successively by adding and 50 ml of tetrahydrofuran in a rotary evaporator. . The residual oil is dissolved in approximately 400 ml of dry diethyl ether 50 and the hydrochloride is precipitated by adding

a solution of 1.0 g (excess) of dry diethyl ether. After filtration and washing with dry diethyl ether, the filter cake is dissolved 55 into approximately 250 ml of water. This

the solution is filtered through pelite and dried by freezing to obtain 10.0 g (yield) of the product as a partial hydrate with a melting point of 113-120 ° C.

Found,%: C 61.51; H 6.49; N 5.70.

C25.H N20j-HCI-3/4

Calculated,% from 61.55; H 6.70; N 5.74 ..

Example 3. 2- (2-f (1-Kap6oKsi-3-phenylpropyl) -aminoJ-1-oxopropyl) -1,2,3,4-tetrahydro-6,7-d1-tethoxy-3-isoquinoline carboxylic acid, hydrochloride, hydrate (

A solution of 0.553 g (0.001 mol) of 2- (2- (1- (ethoxycarbonate I) -3-phenylpropyl) -amino5 -1-okraspoh l) -t, 2, 3, 4-tetrahydro-6,7-dimethoxy-3- isoquinolinecarboxylic acid, hydrochloride, hydrate (S.), prepared according to example 1, in 4 ml (0.004 mol) of 1N sodium hydroxide solution and 4 ml of methanol are kept quiet at room temperature for 20 hours. Then this the reaction solution is added to 5 ml of 1N. hydrochloric acid under reduced pressure. The residual amount of water is removed by two successive additions and removing under reduced pressure 25 ml portions of ethanol. The organic portion of the residue is dissolved in 0.5 ml of methanol. Next, 30 ml of chloroform is added and the solution is dried over sodium sulfate, treated with charcoal, filtered and concentrated to obtain 0.45 g of product. This amorphous product is dissolved in 20 ml of tetrahydrofuran and then 100 MP of diethyl ether is added, resulting in The precipitate drops out 0.4 g of a practically white solid with mp. 145-170 ° C (80% recovery), thin layer chromatography (mixture of 20% methanol with chloroform, on silica) i

RI - 0.1 (alpha) j5 +37.8 (1.09% methanol).

Found,%: C 57.17 g; H 6.10 N 5.51

CjsHjoNjQ -HCI-HjO

Calculated,% :. C 67.10 H 6.34; N 5.34.

PRI me R 4. 2-2 {(1-carboxy-3-phenylprosh) -aminou-1-oxopropyl) -1,2,3,4-tetrahydro-3-isoh S nolincarboxylic acid, hydrochloride, hemihydrate () . 2 (2- {(1- (ethoxycarbonyl) -3-phenylpropyl) -amino V-1-olcconpopyl) -1,2,3,4-tetrahydro-3-Ioquinolinecarboxylic acid, hydrochloride, hydrate () is treated according to an example 3, with the result that with the addition of 39% vkod get a product with so pl. 140-170 ° C, (alpha) 23 +14.5 (1.08% methanol). Found,%: C 60.68; H 6.04; N 5.89J and 7.04. C23HigN205-HCe- 1/2 H, 0 Calculated,%: C 60.59; H 5.97; N 6.15; every 7,77. Example 5. 2- (2- (1- (ethoxycarbonyl) -3-phenylpropyl) -amino1-1-oxopropyl) -1,2,3,4-tetrahydro-6, 7-dimethoxy-3-isoquinolinecarboxylic acid, phenylmethyl ether, maleate (). A stirred solution of 5.0 g (0.0158 mol) of ethyl-alpha- (1-carboxyethyl) -amino) -beneol-butanoate hydrochloride (), prepared in Example 8, is subsequently processed in 200 ml of methylene chloride in succession to 1.60 (0.0188 mol 3) triethylamine, 2.14 g (0.0158 mol) of 1-hydroxybenzotriazole, 5.16 g (0.0158 mol) of 1,2,3,4-tetra hydro-6,7-dimethoxy-3-isoquinolinecarboxylic acid, free by basing the phenylmethyl complex effu (S-form) obtained in Example 9, and then 3.26 g (0.0158 mol) of dicyclohexylcarbodiimide in 10 ml of methylene dichloride. Gradually withdraw dicyclohexyl urea. The mixture was then allowed to stand overnight at room temperature, 300 ml of hexane was added and the urea was filtered off. The filtrate is washed with 250 ml of saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated to remove the solvent. The viscous residue is triturated in 50 ml of diethyl ether and filtered to remove insoluble components. The filtrate is concentrated to give 9.2 g (99% yield) of a crude base. Preparation of the maleate salt. The solution of 9.0 g (0.015 mol) of the above crude base in 50 ml of ethyl acetate is treated with a warm (at 40 ° C) solution of 1.86 g (0.016 mol) of maleic acid in 50 ml of ethyl acetate. As a result, white crystals were obtained in the amount of 7.2 g (65% yield) with m.p. 139-14GS, thin-layer chromatography of the ecology treatment of the base (obtained by treating the salt with sodium bicarbonate followed by extraction with ethyl acetate) indicates the presence of one spot, R / -0.7 (ethyl acetate, on silica). Recrystallization from ethylene acetate gives a pure product with the same melting point, (alpha) +3.4 (1.05% ethanol). Found,%: C 64.48; H 6.30; N 3.99. , N20yC H404 Calculated,%: C 64.74-, H 6.29) N 3.98. Example 6. 2- (2 - {(1-ethoxycarbonyl) -3-phenylpropyl) -amine 1-oxopropyl) -1,2,3,4-terahydro-3-isoquinoline carboxylic acid, phenylmethyl ether, maleate (S.,) . Ethyl-alpha (1-carboxymethyl) -amino) -benzene-butanoate hydrochloride () prepared according to example 8 is reacted with 1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid, free base of phenstmethyl ester (S-form ), obtained in example 10, in accordance with example 5, with the result that with the achievement of 61% yield get a product with so pl. 151-153 ° C (after recrystallization from ethyl acetate), (alpha) 5 11.7 (1.0% methanol). Found: C G5,58-, H 6.09; N 4.25 C3 HjjNj05-C4H404 Calculated,%: C 67.07; H 6.25; N 4.35. Example 7. 2- (2- (1-ethoxycarbonyl) -3-phenylpropyl) -amino J-1-oxoprphenyl) -1,2,3,4-tetrahydro-3-yoquinoline carboxylic acid, 1,1-dimethylether ester ( SiS, S). A mixture of 8.38 g (0.03 mol) of ethyl alpha- (1-car6oxyethyl) amino) benzenebutanoate (free amino acid) (SS) prepared in Example 8, 8.09 g (0.03 mol) 1, 2,3,4-tetrahydro-3-isoquinolinecarboxylic acid, 1,1-dimethyl ethyl ester hydrochloride (S-form) obtained in Example 11, 4.05 g (0.03 mol) of 1-hydroxy-benzotriazole with 250 ml tetrahydrofuran is cooled in a bath with ice to 3-5 ° C. While stirring, J, 04 g (0.03 mol) of triethylamine is added, and then a solution of 6.92 g (0.0335 mol) of dicyclohexane carbrdiimide in 30 ml of tetrahydrofuran is added dropwise over 20 minutes. The reaction mixture was stirred at 3-5fC for 1 hour. Next, without the ice bath, the reaction mixture was stirred for another 3 hours. The resulting mixture of triethylamine hydrochloride with dicyclohexyl urea was removed by filtration and washing with tetra-hydrofuran. The filtrate is evaporated in a rotary evaporator in order to remove all volatile components. The resulting gummy mass is dissolved in approximately 300 ml of ethyl acetate. After filtration through a zeolite, the ethyl acetate solution is subjected to extraction. The treatment is carried out with two 100 ml portions of a saturated solution of sodium bicarbonate, one 75 ml portions 2 n. a solution of citric acid with one SO-milliliter portion of a saturated solution of sodium bicarbonate and one 100-ml-liter portion of a saturated solution of sodium chloride. After drying over anhydrous magnesium sulphate and filtering, ethyl acetate is removed on a rotary evaporator to give 16. 9 g of light brown resinous material, which is dissolved in 350 mp of boiling goxane and decanted through zeolite. The hexane solution is cooled on ice, seeded with a crystallization seed and stirred until intensive crystallization is achieved. Then the product is filtered, washed with cold hexane and dried to obtain 11.6 g (78% yield) of the substance with mp. 68 ,, (alpha) -12.2 (2% methanol). M.p. pure product 71-72 C, (alpha) 5 -12.6 ° (2% methanol). M.p. maleate salt 127.5-128, (alpha) J, +46.4 (2% methanol).

Example 8. Ethyl alpha- (t-carboxyethyl) -amino) -benzoylbenanate hydrochloride (SyS).

A solution of 2.0 g of tert-butylanania (S-form) and 3.78 g of ethyl-2-bromo-4-phenylbutanoate in 25 ml of dimethylformanide is treated with 1.8 ml of triethylamine and held at 70 ° C for 18 hours. The solvent is removed under reduced pressure and the residue is mixed with water, followed by extraction treatment with diethylBbw ether. The organic layer is washed with water and dried over magnesium sulfate. Concentration to remove the solvent under reduced pressure affords an oil-like tert-butyl ester intermediate, which, as established by gas-liquid chromatographic processing, is sufficiently pure for subsequent use. The solution of 143.7 g of this tert-butyl ester in 630 mp trifluoroacetic acid is stirred at 1 hour at room temperature. The solvent is removed under reduced pressure and the residue is dissolved in diethyl ether, followed by repeated evaporation. This operation is then repeated. The ether solution is then treated by adding dropwise a solution of gaseous hydrogen chloride in diethyl ether until the precipitation stops. The solid product collected by filtration is a mixture of diastereoisomers with m.p. 152-165C, (alpha)) +3.6 (1% methanol).

In order to preserve the preferred S S-isomer, a suspension of 10.0 g of this mixture in 200 ml of methylene chloride is stirred at room temperature for 5 minutes, followed by filtration. The solid product is washed with an additional amount of methylene chloride and finally diethyl ether. M.p. one of the isomers 202-208 0 (with decomposition), (alpha) -29, (1% methanol) g and this isomer was a diastereoisomer having the R, S-KOH configuration (the S symbol is the portion of the molecule obtained by L-ananine ). The preferred S-S-diastereoisomer is removed from the filtrate after concentration and trituration of the residue in diethyl ether. M.p. this substance 137-139 C, (alpha) +31.3 (1% methanol).

The free amino acid (S 8-form) is obtained by treating the aqueous solution of the hydrochloride with a saturated solution of sodium acetate. The resulting product is filtered, washed intensively with cold water and recrystallized from ethyl acetate. M.p. product 149-1SlC (alpha) 1 +29, (U 0.1 and hydrochloric acid).

Example 9.1,2,3,4-tetrahydro-6, 7-dimethoxy-3-isoquinoline carboxylic acid, phenylmethyl complex, hydrochloride (S-form).

A mixture of 1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylic acid, hydrochloride (S-form) with 600 ml of benzyl alcohol is saturated with gaseous hydrogen chloride. The temperature of the mixture is increased to. This mixture is then stirred at room temperature for 3 days. A relatively small amount of solid is then filtered and the filtrate is treated with approximately 2 liters of diethyl ether, with the result that 37.5 g of crude product is obtained with an achievement of 83% yield. The latter is purified by treating with an excess amount of a saturated sodium bicarbonate solution, extracting the base with ethyl acetate and precipitating the hydrochloride salt with gaseous hydrogen chloride. As a result of recrystallization from a mixture of methanol and diethyl ether, a pure product of m.p. 255-260C, (alpha) p -81, (1.0% methanol), thin-layer chromatography (20% methanol, mixture with chloroform on silica) - one spot Rp 0.8.

Found,%: C 62.54i H 5.99; N 4.00.

Ci, H2iN04-HCe

Calculated,%: C 62.72; H 6.10; N 3.85.

Example 1.0 1,2,3,4-tetrahydro-3-isoquinoline carboxylic acid, phenylmethyl ester, hydrochloride (S-form) 750. ml of benzyl alcohol is treated with 150 g of technical polyphosphoric acid, followed by heating the mixture to 90 s and stirring at this temperature until it forms a homogeneous mixes. Next, add to

a mixture of 165.2 g of solid 1,2,3,4-tetra-. hydro-3-isoquinolinecarboxylic acid (S-form). The mixture is then stirred for 4 hours at 95-105 ° C, followed by

rest in a calm state at room temperature for 18 hours. Next, 18.5 g of hydrogen chloride gas in 2.5 liters of anhydrous diethyl ether and the product are added.

0 is gradually separated with cooling overnight. Filtration gives crude benzyl-1,2,3,4-tetrahydro-3-isoquinoline carboxylate hydrochloride. Last

5 double recrystallization from ethanol to obtain the product with t, sh1. 190.5-19iCj (alpha), -83.3 (1% mixture of methanol with 1N hydrochloric acid in the ratio 1: t).

0 Example 11. 1,2,3,4-tetrahydro-3-isoquinoline carboxylic acid, 1,1-dimethyl ester, hydrochloride (S-form).

This compound is obtained by passing 447 g of isobutylene through a cooled to a solution of 63.5 g of 1,2,3, 4-tetrahydro-3-isoquinolinecarboxylic acid S-form) in 650 ml of dry

dioxane and 65 ml of concentrated sulfuric acid (in a stream of nitrogen). The reaction vessel is then closed and its contents shaken for 17 hours at room temperature. Next, the reaction vessel is opened and the mixture is poured into 25 liters of cold 2 n. sodium hydroxide solution. The resulting product is extracted with diethyl ether. The ethereal solution is washed with water, vomited and concentrated to a residual volume of approximately 500 ml. The latter is treated with 6 Hi of an isopropanol hydrochloric acid solution to precipitate the product, which is separated by filtration. A sample purified by recrystallization from a mixture of ethanol and diethyl ether has mp. 190-192С (with decomposition) .-, (alpha) -88.7 (2%

methanol).

Example 12: 1000 tablets, each of which contains 100 mg of 2 - ((ethoxycarbonyl) -3-phenylpropyl) -3-phenylpropyl) -amino -1-oxopropyl) -1,2,3,4-tetrahydro-6, 7-dimethoxy-3-isoquinoline carboxylic acid, hydrochloride, hydrate (SS; S), molded using the following components, g; 2- (2- (1- (Ethoxycarbonyl) -3-phenylpropyl) -aMHHoj-1-OKco-propyl) -1,2,3,4-tetrahydro-6, 7-dimethoxy-3-isoquinoline carboxylic acid, hydrochloride, hydrate , (S :,) 100 Corn starch 50 Gelatin Avicel (microcrystalline cellulose) 25 Magnesium stearate 2.5 2- (2- (1- (ethoxycarbonyl) -3-fensch1propyl) .- amino -1-oxopropyl) -1, 2 , 3,4-tetrahydro-6,7-dimethoxy) -3-isoquinoline carboxylic acid, hydrochloride, hydrate (), and corn starch are mixed with an aqueous solution of gelatin. Then this mixture is dried and ground to a fine powder. Next with granulnrova Avisel. The product is then mixed with magnesium stearate. After this mass, the tablet is compressed into a tablet form, thus 1000 tablets, each containing 100 mg of active ingredients each. Example 13: 1000 tablets, each of which includes 200 mg of 2- (2- (1- (ethoxycarbNYL) -3-phenylpropyl) -amino -1-oxopropyl) -1,2,3,4-tetrahydro-6. , 7-di-methoxy-3-isoquinolinecarboxylic acid, hydrate hydrochloride (formed using the following components, g: 2- (2- (1- (Ethoxycarbonyl) -3-phenylpropyl) -amino-1-oxopropyl) -1, 2, 3,4-tetrahydro-6,7-dimethoxy-3-isoquinoline carboxylic acid, hydrochloride, hydrate, () 200 Lactose 100 Product Avisel 150 Cornstarch 50 Magnesium stearate 5 2- (2- (1- (ethoxycarbonlo)) -3-fesch lppropyl) amino j -1-oxopropyl) -1,2,3,4-tetrahydro-6,7-dimethoxy-3 -isoquinoline carboxylic acid, hydrochloride, hydrate () lactose and Avicel product are mixed. 012 is then mixed with corn starch. Then the magnesium stearate is added to the mixture. The dry mixture is compressed into a tablet machine, resulting in a molding of 1000 tablets weighing 505 mg each. each, each of these tablets contains 200 mg of the active ingredient each, and then the tablets are coated with a solution of Metosel E 15 (methyl cellulose), which includes a colorful varnish containing yellow dye No. 6. Example 14. Dual-element gelatin capsules No. 1, each of which includes 250 mg of 2- (2- (1- (ethoxycarbonyl) -3-phenyl) amino--1-oxopropsh1) -1,2,3,4-tetrahydro-6, and 7 dimethoxy-3-isoquinoline carboxylic acid, hydrochloride, padrat () is filled with the mixture of the following components, mg: 2- (2- (1-Ethoxycarbonyl) -3-phenylpropyl) -aminoj-1-exopropyl) -1, 2,3, 4-tetrag1odro-6, 7-dimethoxy-3-isoquinoline carboxylic acid, hydrochloride, hydrate (5.8., S) 250 Magnesium stearate 7 Lactose USP193 Example 15. The solution for injection contains the following components: 2- (2- (1 -Etoxycarbonyl) -Z-phenylpropyl) -amino J-1-oxopropyl) -1,2,3,4-tetrahydro -6,7-dimethoxy-3-isoquinoline carboxylic acid, hydrochloride, hydrate (, S) 500 g Methyl paraben 5 g Propyl paraben. 1 g Sodium hydroxide 25 g Water for injection in an amount up to 5 liters The active ingredient, onservants and sodium chloride are dissolved in 3 liters of water for injection, and the total solution volume is brought to 5 liters with water. Then the solution is filtered through a sterile filter and aseptic conditions are packaged in sterilized tubes, after which they are closed with sterilized caps. Each tube contains 5 ml of solution with the concentration of the active ingredient in 100 ml per ml of injection. Under the action of the enzyme renin on angiotensinogen pseudoglobulin in the blood plasma, decapeptide angiotensin I is formed. Under the action of the angiotensin-converting enzyme (ACE), angiotensin I is converted to the octapeptide angiotene ZIN II. The latter is an active pressor substance that serves as an agent that causes various types of hypertension in mammals, such as rats and dogs. The compounds of the present invention interfere with the course of the renin-angiotensin-1-angiotensin II sequence, by suppressing the activity of the enzyme, which causes the conversion of angiotensin I, and by reducing or completely suppressing the formation of a fresh substance, such as angiotensin II, with the result that such compounds can be used to relieve or treat hypertension. It is recommended that the proposed composition be administered to the body in a single dose or from two to four fractional dosages per daily from 0, 1 to

/ CHoCH, CH-NHCH

// i

COOR

sn

CO OR 00 mg / kg, preferably from 1 to 50 mg / kg / day. The proposed drugs are administered orally or by subcutaneous, intramuscular, intravenous and intraperitoneal injections. In vitro testing. APF. The ACE inhibitory effect is determined by conducting an experiment with serum ACE of a guinea pig in the presence and absence of the test compound. Before adding the labeled substrate ZN-hippurylglycylglu-uin ACE to the guinea pig, the test compound is subjected to preincubation for 10 min. After a 60-minute incubation, the reaction is stopped by the addition of 0.1 and. hydrochloric acid. The ACE cleaves the hippuryl-glycyl link to form depiptidglycyl-glycine and 3H-hippuric acid. Next, HH-hippuric acid is extracted with ethyl acetate and the ACE of this sample is calculated as the amount of leached HH-hippuric acid. The table shows the acyl derivatives of 1,2,3,4-tetrahydroisoquinol-3-carboxylic acids (S S S-configuration) and their inhibitory activity when acting on ACE, defined in vitro.

Table continuation