NL8000097A - DEHYDROPROLINE DERIVATIVE. - Google Patents

Description

N.O. 28,573 -

Dehydroproline derivative

The invention relates to 1 - [(3) -3-raercapto-2-methyl-propanoyl] -L-3-dehydroproline of the formula 1 and its salts with a base.

1 - [(S) -3-mercapto-2-methylpropanoyl] -L-3. -Dehydroproline 5 and its salts with a base are obtained according to the invention by the addition of a) in a compound of the formula 2 wherein R an alkyl group with a small number of carbon atoms, a phenyl group or a phenylalkyl group with a small number of carbon atoms in the alkyl radical represents the acyl group of the formula R -CO-, or b) a compound of the formula 3 wherein R is an alkyl group with represents a small number of carbon atoms in the corresponding free acid conversion and, if desired, converts the obtained 1 - [(S) -3-mercapto-2-methylpropanoyl] -L-3,4-dehydroproline with a base to a salt.

The cleavage of the acyl group of the formula R-CO- to obtain a compound of the formula 2 is carried out by methods known per se, expediently by ammonolysis or basic hydrolysis. Preferably, a compound of the formula II is suitably treated at about room temperature with ammonia containing alcohol or ammonia, preferably with ammonia containing alcohol or concentrated ammonia.

The conversion of a compound of the formula III into the corresponding free acid is also carried out by methods known per se. Preferably, a compound of formula 3 wherein R represents a tert-butyl or tert-amyl group is treated with trifluoroacetic acid and anisole at about room temperature. If R in formula 3 represents another alkyl group, the conversion to the free acid can be carried out by basic hydrolysis, expediently with an alkali metal hydroxide, preferably sodium hydroxide. If the conversion of a compound of the formula III to the free acid is carried out by basic hydrolysis, racemization can occur in the 3 · 1 -1 dehydroproline residue.

The compounds of formulas 2 and 3 are also within the subject of the present invention. The compounds of the formula II can be obtained, for example, by obtaining an L-3.4-dehydroproline derivative of the formula k in which R represents a hydrogen atom or an alkyl group with a small number of carbon atoms 800 0 0 97 2 <, according to known per se converts methods with a haloalkanoic acid of the formula VI wherein X represents a halogen atom, preferably a chlorine or bromine atom, wherein the acid of the formula 5 is activated, or for the reaction thereof with the compound having the formula k by forming a mixed anhydride, a symmetrical anhydride, an acid chloride or an activated ester, either using the Woodward reagent K or N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (ESDC ), dicyclohexylcarbodiimide and the like.

According to the mentioned conversion, a compound of the formula II is obtained in which X and R have the meanings mentioned, which are subsequently reacted with the anion of a thio acid of the formula VII in which R has the meanings mentioned. Thereby 1 2, a compound of the formula 8 is obtained in which R and R have the meanings mentioned.

According to another method, the compounds of the formula (8) can also be obtained by first reacting a thioic acid of the formula (6) with methacrylic acid of the formula (9) to form an acylthioalkanoic acid of the formula (10) in which R has the stated meanings. In a second step, the acylthioalkanoic acid obtained is then reacted with an L-3 "if" dehydroproline derivative of the formula k to form the desired compound of the formula 8.

In another method, the methacrylic acid 25 is first reacted with a L-3 ** dehydroproline derivative of the formula k into a compound of the formula 11 wherein R has the meanings stated. This compound is then converted to the desired compound of formula 8 with a thioic acid of the formula VI.

In another process, an L-3 .beta. -Dehydropro-30 line derivative of the formula ^ is reacted with a haloalkanoyl halide of the formula X wherein X and X 'are the same or different and represent halogen atoms, preferably chlorine or bromine atoms.

This reaction is carried out in a basic reaction medium, for example, in a dilute alkali metal hydroxide, an alkali metal hydrogen carbonate or an alkali metal carbonate solution, at a reduced temperature, conveniently at about 0-15 ° C.

The reaction product is then reacted with the anion of a thioic acid of the formula VI also under basic reaction conditions kO, preferably in an alkali metal carbonate solution, and then worked up according to conventional methods, with the desired compound having the obtains formula 8.

In another method, an L-3-dehydroproline derivative of the formula k wherein R represents an alkyl group with a small number of carbon atoms, preferably a tert-butyl group, at a temperature from about 0 ° C to about room temperature in an anhydrous solvent, such as tetrahydrofuran, dioxane, dichloromethane and the like, with α-methyl-p-propiothiolactone in 2

the desired compound of the formula 8 are converted wherein R

10 represents an alkyl group with a small number of carbon atoms.

2

The compounds of the formula wherein R represents an alkyl group z θ 1 £ de with a small number of carbon atoms can be converted in the manner into the corresponding free acids, which is the same as the above-mentioned process, wherein a compound of the formula 3 in the 1 - [(S) -3-mercapto-2-methyl-propanoyl] -L-3> hydroproline of the formula 1 is reacted.

In the stated embodiment, the method of obtaining a compound of the formula 8, with the exception of the method using methacrylic acid, the racemate or the desired enantiomer can be used as the starting product.

If a racemic starting product is used, a mixture of two epimers is obtained, which must be separated at an appropriate place from the synthesis by conventional chromatography or fractional crystallization. Preferably, a compound of formula 8 wherein R represents a hydrogen atom is treated with a suitable base, preferably dicyclohexylamine, and the salt thus obtained is separated by fractional crystallization.

It is clear that the compounds of formula II fall within the definition of formula VIII.

The compounds of the formula III can be prepared according to a method which is in accordance with the method for the preparation of the compounds of the formula 2. However, it is clear that this is based on an L-3 * -dehydroproline derivative. Dishes of the formula k wherein R represents an alkyl group with a small number of carbon atoms and in the last step of the preparation "1 the acyl group of the formula R -CO- is cleaved. The cleavage can be carried out according to a procedure which is the same to the process indicated for the conversion of a compound JfO of formula 2 into the desired end product of formula 1.

80 0 0 0 97 ** b 1- [(S) -3-mercapto-2-methylpropanoyl] -L-3if-dehydroproline of the formula I forms salts with various inorganic and organic bases, which are also the subject of the present invention. Such salts include preferred ammonium and alkali metal-3 language salts, such as the sodium and potassium salt, alkaline earth metal salts such as the calcium and magnesium salt, organic base salts such as dicyclohexylaraine, benzothine, N-methyl-D-glucamine, hydrabamine, or salts with amino acids such as arginine, lysine and the like. The non-toxic, physiologically unsafe salts are preferred, although other salts are also valuable, for example for the isolation and purification of the product.

The salts are conventionally obtained by reacting the free acid of the formula I with one or more equivalents of 13 with a suitable base, the desired cation being placed in a solvent or reaction medium in which the salt is insoluble. The salt formation can also be carried out in water, after which the water is removed by freeze-drying. By neutralizing the salts with an insoluble acid, such as a cation exchange resin in the H + form (for example, a polystyrene sulfonic acid resin, such as Dowex 50) or with an aqueous acid and subsequent extraction with an organic solvent, such as ethyl acetate , dichloromethane and the like, the corresponding free acid can be obtained and optionally converted to another salt.

Further experimental details appear from the examples relating to a preferred embodiment of the invention.

According to the invention, "alkyl group with a small number of carbon atoms" means straight or branched chain saturated hydrocarbon radicals with 1-7 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl groups and the like. Preference is given to groups having 1 to carbon atoms, in particular methyl groups and ethyl groups. The phenylraethyl group is the preferred phenylalkyl group. According to the invention, "halogen" is understood to mean the halogens fluorine, chlorine, bromine and iodine, chlorine and bromine being preferred.

1- [(S) -3-mercapto-2-methylpropanoyl] -L-3if "dehydroproline 40 and its salts inhibit the conversion of the decapeptide 80 0 0 0 97. 5 angiotensin I in angiotensin IX and thereby cause the reduction or elimination of high blood pressure caused by angiotensin. The action of the enzyme renin on angiotensinogen, a pseu-globulin in the blood plasma, causes the formation of angiotensin I. This angiotensin is converted into angiotensin II by the angiotensin converting enzyme (ACE). The latter angiotensin is an active blood pressure-increasing compound, which is considered to be the cause of a number of forms of high blood pressure in different types of mammals, such as, for example, rats and dogs. 10 1 - [^ - O-mercapto-S-methylpropanoyl ^ LJ. ^ - dehydroproline and its salts intervene in the sequence of conversions renin -> angiotensin I - angiotensin II, namely by inhibiting the angiotensin converting enzyme , and reduce or prevent the formation of the blood pressure-increasing compound angiotensin 15 II. For example, administration of a pharmaceutical composition containing 1- [(S) -5-mercapto-2-methylpropanpyl] -L-3.iJ-dehydroproline or a physiologically harmless salt thereof can reduce angiotensin-induced high blood pressure in mammals. A single dose, or preferably a dose divided into 2-k doses, of one day should contain about 0.02-100 mg / kg active compound. 1- [(Sj-J-mercapto-methyl-propanoyl-LJ. -Dehydroproline and its salts are preferably administered orally, but may also be administered parenterally and also subcutaneously, intramuscularly, intravenously or intraperitoneally, 1- (S 5-mercapto-2-methylpropanoyl] -L-5-dehydroproline and its salts can be used to lower blood pressure, namely in the form of pharmaceutical preparations such as tablets, capsules or elixirs for oral administration or sterile solutions or suspensions for parenteral administration.

Thereby, about 1 - 500 mg of 1 - [(S) -3-mercapto-2-methylpro-panoyl] -L-3.if-dehydroproline or a physiologically harmless salt thereof with a physiologically harmless carrier, binder, preservative, stabilizer , flavoring, etc., in a dosage form according to conventional methods for the preparation of pharmaceutical preparations. The amount of active compound in these pharmaceutical preparations is chosen to provide an appropriate dose in the indicated range.

Examples of auxiliaries that can be used in tablets, capsules and the like are: as binders tragacanth, ifO acacia, corn starch or gelatin; as carrier dicalcium phosphate, as 80 0 0 0 97 & breaker maize starch, potato starch, alginic acid and the like; as a lubricant magnesium stearate; as a sweetener sucrose, lactose or saccharin; as a flavoring peppermint oil, wintergreen oil or cherry. When the active compound is introduced into a capsule, the capsule may contain, in addition to the stated components, a liquid carrier such as an oil. Various other substances may also be present, for example coating agents or substances which in a certain way affect the physical properties of the preparation during administration. For example, tablets can be coated with shellac, sugar or both. A syrup or an elixir may contain, in addition to the active compound, sucrose as a sweetener, methyl and propyl paraben as a preservative, a coloring agent and a flavoring such as cherry or citrus.

Sterile solutions for injection can be prepared by conventional methods of preparing pharmaceutical preparations, namely by dissolving or suspending the active compound in a carrier, such as water, vegetable oils, such as sesame oil, coconut oil, groundnut oil, cottonseed oil, etc. or a synthetic fat-like carrier such as ethyl oleate and the like. Buffers, preservatives, antioxidants and the like may optionally also be present.

The following examples illustrate the invention. The examples illustrate the preparation of 1 - [(S) -3-mercapto-2-methyl-propanoyl] -L-3'-dehydroproline by the following method: Thioacetic acid and methacrylic acid are formed at 100 ° C to form (RS 3-acetylthio-2-methylpropionic acid. L-3-dehydroproline is prepared according to the method of Roeske, J. Org. Chem., 28, 1251 (1963) converted to the corresponding tert-butyl ester. By coupling the two compounds mentioned by the dicyclohexylcarbodiimide-30 method, 1 - [(RS) -3-acetylthio-2-methylpropanoyl] -L-3 .if-dehydroproline t-butyl ester is obtained in excellent yield.

The tert-butyl ester group is selectively removed by trifluoroacetic acid. After the conversion into the dicyclohexylaramonium salt, the separation of the two epimers is carried out. The 1 - [(5) -3-33 acetylthio-2-methylpropanoyl] -1-3-dehydroproline dicyclohexyl ammonium salt is recrystallized until the rotation is constant; the salt is then converted to the free acid and finally deacylated with ammonia in methanol. The final product is purified by chromatography on an ion exchanger. The absolute configuration of the structure is determined by X-ray analysis.

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Example I

Preparation of (RS) -3-acetylthio-2-methylpropionic acid

A mixture of 32.5 g (0.378 mol) of methacrylic acid and 25 g (0.323 mol) of thioacetic acid was refluxed on a steam bath for 2 hours. The unreacted reactants were removed by distillation (under the reduced pressure of a water jet pump) and the residual oil was crystallized from petroleum ether. Recrystallization from petroleum ether gave 3.3 g (65.8%) (RS) -3-acetylthio-2-methylpropionic acid as a white crystalline product, mp 34-37 ° C. Example II

Preparation of L-3-dehydroproline t-butyl ester

Mixtures each consisting of 2.83 g (0.023 mol) of L-3-dehydroproline and 50 ml of dioxane were introduced into five pressure vessels. While stirring, 5 ml of concentrated sulfuric acid were first added in portions, followed by 30 ml of isobutene. Then stirring was continued at 25 ° C for 16 hours. The reaction mixtures were added to 800 ml of cooled 1 N sodium hydroxide solution. The reaction mixture was extracted with ether (3 x 100 ml) and the organic phase was washed with water (3 x 50 ml), dried over magnesium sulfate and evaporated. The resulting residue was further heated until all volatile components were removed. 9.77 g (6 6.2%) of a viscous colorless oil consisting of L-3 ^ -dehydroprolin tert-butyl ester were obtained.

The 1,3-dehydroproline tert-butyl ester was converted to the corresponding hydrochloride by reaction with hydrogen chloride in ether. By recrystallization from isopropanol / ether, a white crystalline product with a melting point decomposing 122 DEG-128 DEG C. was obtained; [α] 25187.0 ° (c, 2% by volume ethanol).

Example III

Preparation of 1-Γ (RS) -3-acetylthio-2-methylpropanoyl-L-3. -Dehydroproline tert-butyl ester

A mixture of 9.77 g (0.0577 mol) Ιι-3. *) ~ Dehydroprolin t-butyl ester and 10.3 g (0.0635 mol) (RS) -3-acetylthio-2-methyl-35-propionic acid in 80 ml of dichloromethane was cooled to 0 ° C and coupled in the presence of 13.1 g (0.0635 mol) of dicyclohexylcarbodiimide. The reaction mixture was then stirred at 0 ° C for 1 hour and at 25 ° C for 3 hours. The reaction mixture was filtered, then with 1 molar citric acid (3 x 50 ml), a saturated NaKO trichloride solution (3 x 50 ml) and a 10 wt% sodium 800 0 0 97 ✓ o hydrogen carbonate solution (3 x 50 ral ) extracted, dried over magnesium sulfate and evaporated, yielding 16.8 g (92.9%) of a viscous oil; [α] 25-9.2 ° (c, 1.3 wt. ethanol).

Example IV

5 Preparation of 1- (S) -3-acetylthio-2-raethylpropanoyl ~ L--5.it ~ dehydro-proline-dicyclohexylammonium salt 16.8 g (0.0536 mol) 1 - [(BS) -3-acetylthio- 2-Methylpropanoyl] -L-3 · *! - clehydroprolin tert-butyl ester under nitrogen at 25 ° C for 1 hour with a mixture of trifluoroacetic acid, anisole and mercapto-10 ethanol (200 ml: 100 ml: 0.5 ral) treated. The reaction mixture was then evaporated to dryness, the residue obtained was taken up in ethyl acetate and extracted 3x with a 10% sodium bicarbonate solution by weight. The aqueous phase was acidified with 6 molar hydrochloric acid and extracted 3x with ethyl acetate, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residual oil (11.85 g, A4.9 mmol) was dissolved in 75 µl ethyl acetate and 8.8 ml (4 4.9 mmol) of dicyclohexylamine were added to the solution. The mixture was kept at 0 ° C for 18 hours to obtain a crystalline product. By recrystallization from acetonitrile, 0.91 g of 1- [(S)] - 3-acetylthio-2-methylpropanoyl] -L-3, zide-dehydroproline dicylohexyl ammonium salt as white crystalline product, m.p. 5 ° C; [α] 208.7 ° (c, 1.1 wt% ethanol). The melting point and the rotation remained unchanged even after further crystallization.

Example V

Preparation of 1-f (S) -3-cetylthio-2-methylpropanoyl] -L-5. ^ -Dehydro-proline ^ 9 g (10.2 mmol) 1 - [(S) -3 ** acetylthio- 2-Methylpropanoyl] -30 L-3.if-dehydroproline-dicyclohexylammonium salt was added to 50 ml of a 5% strength potassium hydrogen sulfate solution and extracted 3 times with 30 ml each of ethyl acetate. The organic phase was again extracted with 5% potassium hydrogen sulfate solution, washed with water, dried over magnesium sulfate and evaporated under reduced pressure to obtain 2.03 g (77 $) of a viscous colorless oil ; [α] 25D -297.3 ° (c, 1 wt% ethanol).

Example VI

Preparation of 1-Γ (S) -5-mercanto-2-methylpropanoyl] -L-3'-dehydro-kO proline 800 0 0 97 9 s 1.71 g (6.65 mmol) 1 - [) S 3-acetylthio-2-methylpropanoyl] -L-3,5-dehydroproline was dissolved in 1 * f, 5 ml (89.9 mmol) of a freshly prepared 6.2 molar ammonia solution in methanol and the solution 2 stirred at 25 ° C for hours. The reaction mixture was evaporated to dryness under reduced pressure and the resulting residue was filtered through a column (1.5 x 17.5 cm) filled with Dowex 50-7X2 (H + form) and eluted with water (0.01 molar in mercaptoethanol, 50 drops per fraction). Fractions 7-25 were combined, lyophilized, triturated with water (0.01 molar in mercaptoethanol), and crystallized from ethyl acetate / petroleum ether to yield 0.72 g (50.2%) 1 - [(S) -3- aercapto-2-methylpropanoyl] -L-3. melting point 122-12k ° C; [cc] ^ -3 ^ 0.9 ° (c, 1.76 wt. ethanol). The infrared spectrum and the NMR spectrum were consistent with the assumed structure. The X-ray analysis on the structure confirmed the absolute configuration (o) - (L).

Example A

Tablets of the following composition:. Mg / tablet 1 - [(S) -3-mercapto-2-methylpropanoyl-L-3 .if-dehydroproline 1 5 10 25 lactose 221 217 212 181 microcrystalline cellulose k5 ^ 5 h5 55 direct pressable starch 30 30 30 35 magnesium stearate 3 3 3 ^ 25 weight of the tablets 300 mg 300 mg 300 mg 300 mg can be prepared in the following way:

The active compound was mixed well with an equal amount of lactose. Then the microcrystalline cellulose, the directly pressable starch and the remaining amount of lactose were added and mixed well. The magnesium stearate was added and mixed for 3 minutes, after which the resulting mixture was processed into tablets in a suitable presser.

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Example B

Tablets of the following composition: mg / tablet 1 - [(S) -3-me]> capto-2-methylpropatoyl-LO-dehydroproline 15 30 60 lactose 207 192 162 microcrystalline cellulose b5 b5 b5 directly pressable starch 30 30 Magnesium stearate 333 10 weight of the tablets 300 mg 300 mg 300 mg can be obtained in the following manner:

The active compound was mixed well with an equal amount of lactose. Subsequently, the microcrystalline cellulose, the directly pressable starch and the remaining amount of lactose were added and mixed well. The magnesium stearate was then added and the mixture was mixed for 3 minutes. The resulting mixture was processed into tablets in a suitable press device.

Example C

20 Tablets of the following composition: _mg / tablet_ 1 - [(S) -3-mercapto-2-methylpropanoyl] -L-3 »if-dehydroproline 100 250 500 lactose 147.5 100 97.5 25 pregelatinized starch 25 30 60 modified starch 25 50 60 corn starch 25 50 60 magnesium stearate 2.5 5 7.5 weight of the tablets 325 mg ^ 85 mg 7Ö5 mg 30 can be obtained in the following way:

The first five ingredients were mixed in a suitable mixer. Granulated with water, dried in a suitable oven for the next day and ground in a suitable mill. The magnesium stearate was added and the resulting mixture was processed into tablets in a suitable presser.

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Example D

Tablets of the following composition: mg / tablet _____ 1 - [(S) -3-fflercapto-2-, ethyl-5-propanoyl] -L-3,4-dehydro-proline 1 3 15 30 60 lactose 202 198 188 173 188 modified starch 25 25 25 25 30 pregelatinized starch 20 20 20 20 20 distilled water qs q.s. q.s. q.s. q.s.

magnesium stearate 22 2 2 2 weight of the tablets 250 mg 250 mg 250 mg 250 mg 300 mg can be obtained in the following manner: The first four ingredients were mixed in a suitable mixing device. The mixture was mixed with an amount of water sufficient to obtain a suitable consistency and the mixture was granulated. The granulate was ground and dried in a suitable drying oven. The magnesium stearate 20 was added and the whole was mixed for 3 minutes. The resulting mixture was processed into tablets in a suitable press device.

Example E

Capsules of the following composition: 25 mg / capsule_ 1 - [(S) -3-mercapto-2-methyl-propanoyl] -L-3 »4-dehydropropoline 1 5 15 30 60 lactose 203 199 239 224 194 30 starch 30 30 30 30 30 talc 15 15 15 15 15 magnesium stearate 11 1 1 1 fill weight of the capsules 250 mg 250 mg 300 mg 300 mg 300 mg can be obtained in the following way: 35 The first three ingredients were mixed in a suitable blender after which the appropriate amount of talc and the appropriate amount of magnesium stearate were added. The resulting product was then mixed for a short time. Capsules were filled with the product obtained in a suitable filling device.

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Id s

Example F

Capsules of the following composition: mg / cansule_ 1 - [(S) -3-raercapto-2-methylpropanoyl] -L-3 »4— dehydroproline 100 500 lactose 99 corn starch 20 50 57 talc 5 10 15 magnesium stearate 1 2 Fill weight of the capsules 225 rag ms can be obtained in the following manner

The first three ingredients were mixed well in a suitable mixer and then ground with a suitable mill. Then the appropriate amount of talc and the appropriate amount of magnesium stearate were added and mixed well. Capsules were then filled with the resulting mixture in a suitable filling device.

800 0 0 97

Claims (7)

13 ^ 1. 1- [(3) -3-mercapto-2-methylpropanoyl] -L-3'-ithydroproline and its salts with a base. 2. A compound of the formula 13 wherein R 4 represents a hydrogen atom and R represents a group of the formula R -CO-, wherein R represents an alkyl group with a small number of carbon atoms, a phenyl group or a phenylalkyl group with a small number carbon atoms in the alkyl radical, or wherein R 1 represents an alkyl group having a small number of carbon atoms and R represents a hydrogen atom. 3- 1- [(S) -3-mercapto-2-methylpropanoyl] -L-3'-ii-dehydroproline and its physiologically harmless salts with a base as pharmaceutically active compounds. 4. 1- [CS) -3-mercapto-2-methylpropanoyl] -L-3 'i) -dehydroproline and physiologically harmless salts thereof with a base as 13 antihypertensive active compounds. 3) Process for the preparation of 1 - [(S) -3-mercapto-2-methyl-propanoyl] -L-3 -dehydroproline and its salts with a base, characterized in that a) in a compound with the formula 2 wherein R represents an alkyl group with a small number of carbon atoms, a phenyl group or a phenylalkyl group with a small number of carbon atoms in the alkyl radical, cleaves the acyl group of the formula R -CO- or b) a compound of the formula 3 wherein R is a alkyl group with a small number of carbon atoms, converts to the corresponding free acid and optionally converts the obtained 1 - [(S) -3-mercapto-2-methyl-propanoyl] -L-3,4-dehydroproline with a base to a salt. 6. Pharmaceutical preparation; containing 1 - [(S) -3-mercapto-2-methylpropanoyl] -L-3,4-dehydroproline or a physiologically harmless salt thereof with a base. 7 · Antihypertensive active pharmaceutical composition, containing 1 - [(S) -3-mercapto-2-methylpropanoyl] -L-3,4-dehydroproline or a physiologically harmless salt thereof with a base. 8. Use of 1 - [(S) -3-mercapto-2-methylpropanoyl] -L-3 "dehydroproline or a physiologically harmless salt thereof with a base to combat or prevent diseases. 9. Use of 1 - [(S) -3-mercapto-2-methylpropanoyl] -L-3,4-dehydroproline or a physiologically harmless salt thereof with a base to combat high blood pressure. * * * * * * 800 0 0 97 -L JL JL S. \ ^ COOH. / \ «EcOOH f Y-« COOR r Ή N) / nH XfKS (H3Ci ^ C ^ 0 H3C ^ Aq ¥ ^ Λο <% ch2 ch2 ^ SH N '^ SH, K' ^ o A. == \ - ( ^ X-COOR2 / \ -eCOOR2 · ^ H3 ^ 'H' Ή X-CH.-CH-COOH LH 2 HjC ^ / S i_ JL c ^ x * - * - «ζν ™! AJ! L_ H3CfH3 0 CM I CH «CH-COOH i II I 3 RCS-CHn-CH-COOH SA ^ _LL fA j / V -— COOR4 S / ^ Γ fH3 H3C ^ Y ^ 0 X-CH £ -CH-COX jjH H3C ^ Y ^ 0 ^ SR4 cn2 80 0 0 0 97