SE426698B - New therapeutically active derivatives of 3,4- dehydroproline - Google Patents

Abstract

New compounds with the general formula <IMAGE> where R1 is a hydrogen atom or a lower alkanoyl group, R2 is a hydrogen atom or a lower alkyl group, and n has the value of 0 or 1, together with basic salts thereof, for use as antihypertensive agents.

Description

7901316-5 to heptyl, for example methyl, ethyl, propyl, isopropyl, butyl, 10-butyl, t-butyl, pentyl, isopentyl and the like. The C1-C4 groups, especially the C1 and C2 groups, are most suitable.

The lower alkanoyl groups are those having acyl groups of lower (C2-C7) fatty acids; for example, acetyl, propionyl, butyryl, iso- Similarly, the lower alkanoyl groups are most suitable. butyryl and the like. having up to 4 carbon atoms and especially acetyl. The products of formula I can be prepared by various synthetic methods.

In general, these compounds can be synthesized by coupling the acid of formula (II) R 2 R 1 -S- (CH 2) n -CH-COOH or its chemical equivalent to the cyclic amino acid of formula I § (III) H ac / š Hzc CH I 1 _ HN --- ca. coon by any method that can be used to form amide bonds. See, for example, "Methoden der Grganischem Chemie" (Houben ~ Weyl), Part 1, p. 735 et seq., Part II, p. The following (1974). According to one method, an acid or ester of formula III is coupled to a haloalkanoic acid of formula I and (IV} TX - (cH2) n-CH-coon wherein X is a halogen, preferably chlorine or bromine, through one of the known processes according to which acid IV is activated before the reaction with acid III, comprising the formation of a mixed anhydride, symmetrical anhydride, acid chloride, active ester or the use of Woodward reagent K, EEDQ (N-ethoxycarbonyl-2-ethoxy-1,2) (Dihydroquinoline) or similar.

The product of this reaction is a compound of the formula H (v) C \\\ H c. cn 132 21 i x- (ca) -cn-- c - N cn 2 II l 0 coon This product is reacted with the anion of a thioacid of formula (VI) R 3 -CO-5H wherein R 3 is lower alkyl, which gives a product of the formula H WII) c / \ ~ c RS-CO-S- (CH 2) èfCH * C _ * N which can be transferred to the product (wine) H HS- (CH 3 u 7901316-5 by ammonolysis or alkaline When OR is an ester group (for example R is lower alkyl) the ester group can be removed in the usual way, for example when R is tert-butoxy or tert-amyloxy the treatment of the ester of formula VII or VIII with trifluoroacetic acid and anisole gives the corresponding free acid When other alkoxy groups are present, alkaline hydrolysis of the compound of formula VII or VIII gives the free acid.

When an acid of formula III is used as starting material or when the final product is obtained as free carboxylic acid, "this acid can be converted into its ester, for example by esterification with a diazoalkane, such as diazomethane, 1-alkyl-3-p-tolyl-triazene, such as 1-n-butyl-3-p-tolyltriazen or the like.

According to another variant, an ester is preferably treated with the methyl or t-butyl ester of formula III in an anhydrous medium such as dichloromethane, tetrahydrofuran, dioxane or the like, with an acylthioalkanoic acid of formula R (IX) | 2 R --- cos- (CH 2) n - cH-coon 3 wherein R 3 is lower alkyl, in the presence of dicyclohexylcarbodiimide, N, N'-carbonylbisimidazole, ethoxyacetylene, diphenylphosphoryl azide or similar coupling substances at a temperature in the range 0-110 ° C. The ester group can then be removed, for example, by treatment with trifluoroacetic acid and anisole at about room temperature to give the free acid (R = H).

Alternatively, an ester of formula III (for example R is lower alkyl, especially t-butyl) may be reacted with a thiolactone, for example β-propiotiolactone, armethyl-β-propiotiolactone or the like in an anhydrous solvent such as tetrahydrofuran, dioxane, methylene chloride or similar at about 0 ° C to approximately room temperature. The ester group can be removed with anisole and trifluoroacetic acid as described above. 7901316-5 The products of formula I have an asymmetric carbon atom and two if R2 represents a group other than hydrogen. These carbon atoms are marked with an asterisk in formula I. The compounds thus exist in stereoisomeric forms or racemic mixtures thereof.

All of these are within the scope of the invention. The synthesis described above can use the racemate or one of the enantiomers as starting material. When the racemic starting material is used in the synthesis process, the stereoisomers obtained in the product can be separated by conventional chromatography or fractional crystallization. In general, with respect to the carbon atom of the amino acid, the L-isomer constitutes the preferred isomeric form.

The compounds according to the invention form basic salts with various inorganic and organic bases, which are also within the scope of the invention. Such salts include ammonium salts, alkali metal salts such as sodium and potassium salts (which are most suitable), alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salt, benzatin, N-methyl -D-glucamine, hydrabamine, salts with amino acids such as arginine, lysine and the like. The non-toxic, physiologically acceptable salts are preferred; nevertheless, other salts are also useful, for example in isolating or purifying the product.

The salts are formed in a conventional manner by reacting the free acid form of the product with one or more equivalents of the appropriate base, which gives the desired cation in a solvent or medium in which the salt is insoluble or in water and removes the water by freeze-drying. By neutralizing the salt with an insoluble acid, such as a cation exchange resin in hydrogen form (for example, polystyrene sulfonic acid resin, such as Dowex 50) or with an aqueous acid, and extraction with an organic solvent, for example ethyl acetate, dichloromethane or the like, the free acid form can be obtained another salt is formed. 7901516-5 Further experimental details are shown in the examples, which constitute suitable embodiments and also serve as models for the preparation of other units of the group.

The compounds of the invention are useful as hypotensive agents. They prevent the conversion of decapeptide angiotensin I to angiotensin II and are therefore useful in reducing or alleviating hypertension due to angiotensin. The action of the enzyme renin on angiotensinogen, a pseudoglobulin in blood plasma, produces angiotensin I. Angiotensin I is converted via angiotensin converting enzyme (ACE) to angiotensin II.

The latter is an active compressor substance present, which has been reported as the causative agent in various forms of hypertension in various animal species, for example rats and dogs.

The compounds of the invention intervene in the angiotensinogen-β (renin) -γ angiotensin I-ä (ACE) -7 angiotensin II series by preventing the angiotensin converting enzyme and reducing or eliminating the formation of the pressor substance angiotensin II.

Thus, by administering a composition containing one or a combination of compounds of formula I or physiologically acceptable salts thereof, angiotensin-dependent hypertension in the animal species suffering therefrom is reduced. A single dose or preferably two to four divided daily doses, prepared on the basis of about 0.1 to 100 mg / kg / day, preferably about 1-50 mg / kg / day are suitable for reducing blood pressure as indicated in animal model experiments. described by S.LÄ Engel, TR

Schaeffer, M.H. Waugh and B. Rubin, Proc. Soc. Exp. Biol. With. låå, 483 (l973). The substance is preferably administered orally, but parenteral administration, such as subcutaneous, intramuscular, intravenous or intraperitoneal, may also be used.

The compounds of the invention may be used to achieve a reduction in blood pressure by the preparation of compositions such as tablets, capsules or elixirs for oral administration or in sterile solutions or suspensions for parenteral administration. About 10 to 500 mg of a compound or mixture of compounds of formula I or physiologically acceptable salts thereof are mixed with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavoring agent, etc. in a unit dosage form which is acceptable according to the practice of the pharmaceutical industry. The amount of active substance in these compositions or mixtures is such that a suitable dose within the range indicated above is obtained.

The invention is further illustrated by the following examples and constitutes particularly suitable embodiments. Temperatures are given in degrees Celsius.

Example Gel 1. 1- (3-Acetylthiopropanoyl) -DL-3,4-dehydroproline methyl ester 3.75 g of DL-3,4-dehydroproline methyl ester are dissolved in 40 ml of dichloromethane and the solution is cooled on an ice-water bath. A solution of 6.18 g of dicyclohexylcarbodiimide in 21 ml of dichloromethane is added and then 4.45 g of 3-acetylthiopropanoic acid are added immediately.

After stirring for 15 minutes on the ice-water bath and 16 hours at room temperature, the precipitate is filtered off and the filtrate is concentrated to dryness in vacuo. The residue is dissolved in ethyl acetate and washed until neutral. The organic layer is dried over magnesium sulfate and concentrated to dryness to give the 1- (3-acetylthiopropanoyl) -DL-3,4-dehydroproline methyl ester.

Example 2. 1- (3-mercotopropanoyl) -DL-3,4-dehydroproline 2.5 g of 1- (3-acetylthiopropanoyl) -DL-3,4-dehydroproline methyl ester are dissolved in a mixture of 10 ml of methanol and 20 ml of normal sodium ~ hydroxide. The mixture is stirred at room temperature under a blanket of nitrogen for 2 hours, diluted with water and extracted with ethyl acetate. The aqueous layer is acidified and extracted with ethyl acetate.

The organic layer is dried over magnesium sulfate and concentrated to dryness to give 1- (3-mercaptopropanoyl) -DL- -3,4-dehydroproline, m.p. 160-1630 (sintering 1430) as a dicyclohexylamine salt; Rf 0.33, silica gel, ethyl acetate: pyridineacetic acid water (45: 20: 6: 11). Example 90 3. 1- (3-Acetylthiopropanoyl) -DL-3,4-dehydroproline 5 g of 3-acetylthiopropanoyl chloride and 1.5 ml of ZN sodium hydroxide are added to a solution of 3.4 g of DLr3,4-dehydroproline in 30 ml of normal sodium hydroxide , cooled in an ice water bath. After stirring for three hours at room temperature, the mixture is extracted with ether, the aqueous phase is acidified and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate and evaporated to dryness to give 1- (3-acetylthiopropanoyl) -DL-3,4-dehydroproline, m.p. 175-1580 (sintering 1520) as a dicyclohexylamine salt. Rf 0.38; silica gel; ethyl acetate: pyridine: acetic acid: water (45: 20: 6: 11).

Example 4. 2-Ethyl-3-acetylticpropanoic acid 6.61 g of thiolacetic acid, 6.25 g of ethyl acrylic acid and a few crystals 2,2 '-azobis- (2-methylpropionitrile) are refluxed for four hours and the mixture is then allowed to stand at room temperature. - tour 48 hours. The reaction mixture is concentrated to dryness and the residue is re-evaporated twice from toluene to give 7.88 g of 2-ethyl-3-acetylthiopropanoic acid.

Example Gel 5. 2-Ethyl-3-acetylthiopropanoyl chloride 7.88 g of 2-ethyl-3-acetylthiopropanoic acid are dissolved in 6.14 g of thionyl chloride and the solution is stirred at room temperature for 18 hours.

Distillation gives 2-ethyl-3-acetylthiopropanoyl chloride as a clear yellow oil, yield 4.8 g, b.p. 50-600 (0.04 mm Hg). Example Gel 1- 1- (3-Acetylthio-2-ethylnropanoyl) -L-3,4-dehydroproline 3.4 g of L-anis-ahyaroproline are dissolved in normal sodium hydroxy and the solution is cooled on an ice-water bath. 5.84 g of 3-acetylthio-2-ethylpropanoyl chloride and 15 ml of 2N sodium hydroxide are added and the solution is stirred at room temperature for three hours.

The mixture is extracted with ether, acidified and extracted with ethyl acetate. The organic phase is dried over magnesium sulphate and evaporated to dryness to give 1- (3-acetylthio-2-ethylpropanoyl) -L-3,4-dehydroproline.

Example 1 1- (2-ethyl-3-mercaptooropanoyl) -L-3,4-dehydroproline 3 g of 1- (3-acetylthio-2-ethylpropanoyl) -L-3,4-dehydroproline are dissolved in a mixture of 10 ml water and 10 ml of concentrated ammonia under a blanket of nitrogen. After 25 minutes, the reaction mixture is acidified and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate and evaporated to dryness to give 1- (2-ethyl-3-mercaptopropanoyl) -L-3,4-dehydroproline.

Example 8. 1- (2-Acetylthiopropanoyl) -L-3,4-dehydroproline 5.65 g of L-3,4-dehydroproline are dissolved in 50 ml of 1N aqueous sodium hydroxide and the solution is cooled on an ice-water bath with stirring. 5 ml of ZN sodium hydroxide and 8.57 g of 2-bromopropanoyl chloride are added. The mixture is stirred at room temperature for 1 hour. A mixture of 4.18 g of thioacetic acid and 4.8 g of potassium carbonate in 50 ml of water is added and the mixture is stirred at room temperature for 18 hours. After acidification, the mixture is extracted with ethyl acetate.

The organic layer is dried over magnesium sulfate and concentrated to dryness in vacuo to give 1- (2-acetylthiopropanoyl) -L-3,4-dehydroproline.

ExemEel_â. 1- (2-Mercaptopropanoyl) -L-3,4-dehydrooroline By replacing 1- (2-acetylthiopropanoyl) -L-3,4-dehydroproline with 1- (3-acetylthio-2-ethylpropanoyl) -L-3, 4-dehydroproline In the procedure of Example 7, 1- (2-mercaptopropanoyl) -L-3,4-dehydroproline is obtained. ïå = § @ 1 ”- * f> §l_l9 ..-_ 1,1 '~ [dithiobis- (2-methyl-3-propanoyl)] - bis-L-3,4-dehydroproline 1 g l- (3 -mercapto-2-methylpropanoyl) -L-3,4-dehydroproline is dissolved in water and the pH is adjusted to 6.5 with 1N sodium hydroxide.

An ethanolic solution of iodine is added dropwise while maintaining a pH between 6 and 7 by careful addition of 1N sodium hydroxide. When a permanent yellow tar is obtained, the addition of iodine is stopped and the paint is removed with sodium thiosulfate. The reaction mixture is acidified and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate and evaporated to dryness to give 1,1 '- [dithiobis- (2-methyl-3-propanoyl) -1-bis-L-3,4-dehydroproline.

Exemgel ll. 1- (3-Mercapto-2-methylpropanoyl) -L-3,4-dehydroproline By replacing L-3,4-dehydroproline with 4,5-dehydropiperidine-2-carboxylic acid in the procedure of Example 10 and then subjecting the product to the procedure according to Example 7, 1- (3-mercapto; 2-methylpropanoyl) -L-3,4-dehydroproline is obtained. In Example Gel 12. 1- (3-Mercapto-2-methylpropanoyl) -L-3,4-dehydroproline sodium salt A solution of 1- (3-mercapto-2-methylpropanoyl) -L-3,4-dehydroproline in water is neutralized with 1N sodium hydroxide and the water is then removed by lyophilization to give 1- (3-mercapto--2-methylpropanoyl) -L-3,4-dehydroproline sodium salt.

Example Gel 13. 1- (3-Mercapto-2-methylpropanoyl) -L-3,4-dehydroproline-dicyclogoylammonium salt To a solution of 1- (3-mercapto-2-methylpropanoyl) -L-3,4-dehydro- proline in ethyl acetate is added an equimolar amount of dicyclohexylamine.

The precipitate formed is isolated by centrifugation to give 1- (3-mercapto-2-methylpropanoyl) -L-3,4-dehydroproline dicyclohexylammonium salt.

Example Gel 14. 1- (3-Acetylthiopropanoyl) -DL-3,4-dehydroproline 1.02 g of DL-3,4-dehydroproline was dissolved in 9 ml of 1N aqueous sodium hydroxide and cooled on an ice bath. To this solution was added 1.5 g of acetylthiopropionyl chloride in 3 ml of ether. 4.8 ml of 2N sodium hydroxide was added gradually while maintaining a pH of about 8.0. The aqueous solution was extracted with ethyl acetate. The aqueous solution is brought down to a pH of 1.5 whereby an oil precipitates which is removed.

The aqueous solution was washed with ethyl acetate and the ethyl acetate wash was added to the separated oil. The solvent was removed and the residue was dissolved in 7 ml of acetonitrile. 1.9 ml of dicyclohexylamine (DCHA) was added followed by 20 ml of ether. The title product (DCHA salt) was separated as crystals (2.5 g), m.p. 156-1580.

C22H3SN2U4S Calculated: c 62.38 H 3.33 N 6.61 s 7.57 Found: C 62.05 H 8.47 N 6.61 S 7.57 Example gel 15. 1 «(3-acetylthiopronanoyl) -DL- 3,4-dehydroproline A mixture of 800 mg of DL-3,4-dehydroproline, 2.45 g of acetylthiopropionic acid β-nitrophenyl ester and 1.1 ml of triethylamine in 30 ml of dimethylformamide and 8 ml of water was stirred for 72 hours. The solvents were removed and the residue was chromatographed on silica gel (Baker, 200 g) using the solvent system: ethyl acetate; pyridine: acetic acid: water (60: 20: 6: 11) to give 1.27 g of product, m.p. 156-1580 (DCHA salt). 1- (3-Mercaptonylpanoyl) -DL-3,4-dehydroproline 3,0- (3- Acetylthiopropanoyl) -DL-3,4-dehydroproline was dissolved in 15 ml of 5.5N methanol-containing ammonia and kept at room temperature. for 45 minutes. The solvent was removed and the residue was dissolved in water, passed through AG-50 resin, lyophilized and chromatographed on silica gel (50 g) using the solvent system: benzene: acetic acid (8: 2) to give 0.8 g of product. melting point 16l ~ l63 ° (sintering 1430) in the form of DCHA ~ salt.

WH NG S "8 ll 3 Calculated: C 47.7ê H 5.51 N 6.96 S 15.93 Found: C 48.09 H 5.73 N 6.86 S 15.65 7901316-5 12 Example 17. 1- [D-3- (acetylthio) -2-methylpropanoyl] -DL-3,4-dehydroproline 3.39 g of DL-3,4-dehydroproline were dissolved in aqueous sodium carbonate and cooled on an ice bath. To this was added 5.5 g of D-3-acetyl-thio--2-methylpropionyl chloride in 10 ml of ether in two portions. 16 ml of 4N sodium carbonate solution was added over 15 minutes while maintaining the pH at about 7.5. The solution was then stirred for one hour, extracted with ethyl acetate (discarded), acidified to pH 2, saturated with sodium chloride and extracted with ethyl acetate. The ethyl acetate extract was concentrated, added to a silica gel column (300 g) and eluted with benzene acetic acid (10: 2) to give 5.7 g of product, [α] D 25 = -69.10 (c = 2, CH 3 OH). Rf = 0.34 (silica gel, benzene: acetic acid 7: 2).

C 11 H 15 NO 4 S · H 2 O Calculated: C 47.99 H 6.22 N 5.09 S 11.69 Found: C 48.20 H 6.29 N 4.91 S 11.34 Example 18. 1- [D-3- ( acetylthio) -2-methylpropanoyl] -L-3,4-dehydronroline To a stirred solution of 4.7 g of the product of Example 22 in 100 ml of acetonitrile was added 4 ml of dicyclohexylamine (DCHA). The solution was kept cooled overnight and the crystallized material was filtered and recrystallized from acetonitrile to give 2.8 g of product, in the form of DCHA salt, [d] α5 = -z22 ° (c = z, cnaon), melting point (ncHA side) 1ss-19o °. 2.7 g of DCHA salt were dissolved in 25 ml of water and treated with AG-50 (H +) resin (bed volume 90 ml) and filtered. The bartset was washed thoroughly with water (200 ml), methanolic water (1: 1, 100 ml) and 200 ml of methanol. The washings were combined and evaporated to dryness to give 1.45 g of the title product, Ialšs = 32326 ° (c = 1, CH 3 OH). Rf = 0.36, silica gel, benzene: acetic acid (7: 2).

C 11 H 15 NO 4 S: Calculated: C 51.35 H 5.88 N 5.44 S 12.46 Found: C 51.30 H 6.20 N 5.43 S 12.16 - 7901316-5 13 Example 19. 1- (D -3-mercapto-2-methylpropanoyl) -L-3,4-dehydroproline A sample of the title product from Example 23 (1.2 g) was dissolved in 10 ml of methanol and to this was added (under argon atmosphere) 8 ml of aqueous ammonium hydroxide (13.5N ). The solution was kept at room temperature for 35 minutes, evaporated, dissolved in 20 ml of water and acidified to pH 1.5, and extracted with ethyl acetate. The ethyl acetate extract was evaporated to give 629 mg of the product, m.p. 121-1240 (sintering 166 °), [q] δ = -352 ° (C = 1.2, cH 30 H).

C9H13NO3S Calculated: C 50.22 H 6.09 N 6.51 S 14.89 FHn fl @ t = C 49.93 H 5.84 N 6.28 s 14.87

Claims (6)

1. 7901316-5 11+ PATENT CLAIM 1. Compound of the formula HCHC / \\ C "a 2 n FZ | [_ R -s--" H) cH-cN-ca l (k 2 n = H * å 'O OOH wherein R 1 represents hydrogen or lower alkanoyl, R 2 represents hydrogen or lower alkyl, and n is 0 or 1, and basic salts thereof. A compound according to claim 1, characterized in that R1 represents acetyl. - A compound according to claim 1, characterized in that R 1 represents hydrogen and n is 1, A compound according to claim 1, characterized in that R1 represents acetyl and n is l. A compound according to claim 1, characterized in that R 1 represents hydrogen, R 2 represents methyl and n is 1. A compound according to claim 1, characterized in that R 1 and R 2 each represent hydrogen and n is 1. 7901316-5 Abstract New compounds of the general formula H _ c / \\ .Rz - H2? wherein R 1 represents hydrogen or lower alkanoyl, R 2 represents hydrogen or lower alkyl, and n is 0 or 1; and basic salts thereof, useful as hypotensive agents.