SE426819B - Derivatives of pyrrolidine carboxyaldehyde and piperidine carboxyaldehyde, together with intermediates for their preparation - Google Patents

Abstract

The invention relates to derivatives of pyrrolidine carboxyaldehyde and piperidine carboxyaldehyde, together with intermediates for their preparation, having the general formula <IMAGE> where R is a hydrogen atom, a lower alkanoyl group or a group with the formula <IMAGE> where R1 is a hydrogen atom or a lower alkyl group, R2 is a hydrogen atom or a hydroxyl group, R3 is a hydroxymethyl group, a di-(lower alkoxy)-methyl group or a formyl group, and n has the value of 1 or 2, together with their bisulphite addition compounds. The above products can be used as antihypertensive agents.

Description

R1 is hydrogen or lower alkylg R2 is hydrogen or hydroxy; R 3 is hydroxymethyl, di (lower alkoxy) methyl or formyl and n is 1 or 2, - and their bisulfite addition products.

In formula I above, the asterisks indicate asymmetric carbon atoms.

In its broadest aspect, the invention relates to derivatives of pyrrolidine-2-carboxaldehyde and piperidine-2-carboxaldehyde and intermediates for their preparation.

Preferred compounds of formula I are those wherein R is acetyl, R 1 is hydrogen or lower alkyl, especially hydrogen or methyl, R 2 is hydrogen, R 3 is hydroxymethyl or formyl, in particular formyl, and n is 1 or 2, in particular l.

The L-configuration of the pyrrolidine- or piperidine-substituted group is particularly preferred.

The lower alkyl groups represented by R 1 include straight and branched chain hydrocarbon groups from methyl to heptyl, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl and the like. The C1-Cu groups, especially the C1 and C2 groups, are preferred.

The lower alkanoyl groups are those which contain the acyl group of lower (C2-G7) fatty acids, for example acetyl, propionyl, butyryl and the like. Likewise, such lower alkanoyl groups having up to Å carbon atoms and especially acetyl are preferred.

A preferred method for the synthesis of the compounds of formula I involves oxidation of an alcohol intermediate of formula 7903300-7 3 (II) R. R 1 -CH 2 -CH-co-r: - - cH-cnzo fl wherein R, B1, R2 and n have the meanings given above, with manganese dioxide, dimethylsulfoxide dicyclohexylcarbodiimide, chromium trioxide / pyridine, etc. The preferred oxidation process utilizes dimethyl sulfoxide / dicyclohexylcarbodiimide.

The intermediates of formula II are synthesized by coupling an acid of formula (III) R 11 RS-CH 2 -CH-COOH with an amino alcohol of formula R (IV), 2 CH // \\\ Hzíc (ICHZM HN ---- ---- CH-CH OH 2 by a method which can be used to form amide bonds, see for example "Methoden der Organischen Chemie" (Houben-Weyl) Part I, page 756 ff, Part II, page 1 In the preferred method, an active ester, for example the nitrophenyl ester, is used.

According to an alternative method, according to the formula (V) CH 2 (ïH 2) n Hn .______- cH-cH (o R 4) 2 wherein Ru is lower alkyl and R 2 has the meaning given above, with an acid of the formula III to produce a compound of the formula (VI) fz ca: \ R cuz (cH2) n 1 l | In R-s-cH2-cH-co-N ---- ca-ca (oR4) 2 A compound of formula VI can be hydrolyzed to a compound of formula I, wherein R3 is formyl. A compound of formula VI can also be prepared from a compound of formula I (R 3 is formyl) by acetalization with a lower alkanol and acid.

The compounds of formula II, wherein R is a group of formula 79033 00-7 R | 2 CH / \ R1 cnz (CH2) n III sægz-c fl-co-n - ~ - cz-x-cnz-o fl are obtained by oxidation of a compound of formula II, wherein R is hydrogen, with iodine.

The aldehydes of formula I, i.e. where R 3 is formyl, bisulfite addition products form with metal bisulfites, especially alkali metal bisulfites such as sodium bisulfite, potassium bisulfite, etc. These can be illustrated by the formula (VII) R, 2 CH 2 n cn ïl 2? (I 2) n OH - I. i R-s-'caz-CH-Co-N --- cH - CH I so 'Met + wherein Met is a metal ion, for example a sodium or potassium ion. Although these bisulfite addition products also exhibit the hypotensive effects listed below, they are mainly useful for isolating the aldehydes in pure form and for characterizing the products.

As mentioned above, the products of formula I have asymmetric carbon atoms, which are indicated by asterisks. The compounds thus exist in stereoisomeric forms or in racemic mixtures thereof. All of these fall within the scope of the present invention. The syntheses described above may use the racemate or any of the enantiomers as starting materials.

When a racemic starting material is used in the synthesis process, the stereoisomers obtained in the product can be separated by conventional chromatographic methods or by fractional crystallization. In general, the L-isomer with respect to the carbon in the heterocycle constitutes the preferred isomeric form.

The compounds of the present invention are useful as hypotensive agents. They inhibit the conversion of decapeptide-angiotensin I to angiotensin II and are therefore useful in reducing or alleviating angiotensin-related hypertension. The action of the enzyme renin on angiotensinogen, a pseudoglobulin in blood plasma, produces angiotensin I. Angiotensin I is converted by angiotensin-converting enzyme (ACE) to angiotensin II. The latter is an active compressor substance, which has been shown to be the active agent for inducing various forms of hypertension in various mammalian species, emmmeh räs straight and dog. The compounds of the present invention intervene in the reaction sequence angiotensiogen- + (renin) -e angiotensin I-, (ACE) - »angiotensin II by inhibiting the angiotensin converting enzyme and reducing or eliminating the formation of the pressor substance angiotensin II. Thus, by administering a composition containing a compound of formula I or a combination of such compounds or a physiologically acceptable salt thereof, the angiotensin-dependent hypertension of mammalian species suffering therefrom is alleviated. A single dose or preferably two to four divided daily doses, administered on a basis of about 0.1 - 100 mg per kg per day, preferably about 1-50 mg per kg per day, are suitable for reducing blood pressure, as determined by the animal experiments described by SL Engel, T.R. scnaeffer, M. H. waugh and R. Rubin 1 Páoc. soc. Exp.

Biol. With. lüš, (1973) H83. The substance is preferably administered orally, but parenteral modes of administration may also be used, such as subcutaneous, intramuscular, intravenous or intraperitoneal administration. The alcohols according to formula II show this activity but are not potent compounds and are useful when it is desired to use only mildly active compounds in dosages corresponding to the upper limit in the above-mentioned dosage ranges. They are therefore essentially useful as intermediates or for the preparation or isolation of a compound of formula I.

The compounds of the invention may be used to achieve a reduction in blood pressure by formulation in compositions such as tablets, capsules, tinctures or mixtures for oral administration or in sterile solutions or suspensions for parenteral administration. Approximately 10 to 500 mg of a compound or mixture of compounds of formula I is compounded with a physiologically acceptable carrier, excipient, binder, preservative, stabilizer, flavoring agent, etc., in unit dosage form as required by standard pharmaceutical practice. The amount of active substance in these compositions or preparations is such that a suitable dosage will be obtained within the above ranges.

The invention is further illustrated by the following exemplary embodiments, in which the temperature indications refer to Uelsius degrees.

Example 1 3- (Acetylthio) propanoic acid p-nitrophenyl ester To 75 ml of a stirred ice-cold solution of ethyl acetate containing 7, H g (50 mmol) of 3- (acetylthio) propanoic acid and 8, M g (60 mmol) of p-nitrophenyl ester nitrophenol was added 10.3 g (50 mmol) of dicyclohexylcarbodiimide portionwise. After 30 minutes, the ice bath was removed and the solution was stirred at room temperature overnight. The precipitated dicyclohexylurea was filtered off, the ethyl acetate was evaporated and the residue was dissolved in ethanol. The 3- (acetylthio) -propanoic acid p-nitrophenyl ester crystallized out in a yield, .alpha .-. .j un m \ (JJ m CD (D I -1 of 8.6 g (63.7%) with a melting point of 71 - 730).

Example 2 1- (3-Acetylthiopropanoyl) -2-L- (hydroxymethyl) -pyrrolidine L-prolinol was prepared by the method described in J. Org. Chem. 52 (1967) 2388.

A solution of 2.25 g (22.5 mmol) of L-prolinol and 6.3 g (25 mmol) of 3- (acetylthio) propanoic acid p-nitrophenyl ester in 45 ml of dimethylformamide was stored for 6 hours at room temperature. The dimethylformamide was evaporated and the remaining 1- (3-acetylthiopropanoyl) -2-L- (hydroxymethyl) pyrrolidine was chromatographed on silica gel (H00 g, Mallinckrodt, SilicAR CC-7) using a 1: 9 mixture of benzene and acetone for elution. The yield was ü, 6 g (88%); Rf = 0.17, silica gel, Äzl mixture of benzene and acetone.

Example 3 1- (3-Acetylthiopropanoyl) -2-L-pyrrolidinecarboxaldehyde To a solution of 1,8 g of 1- [3-acetylthiopropanoyl-2-L- (hydroxymethyl) pyrrolidine in 10.6 ml of dimethyl sulfoxide was added 10 ml of a benzene solution containing 0.64 ml of pyridine and 0.32 ml of trifluoroacetic acid. 9696 g of dicyclohexylcarbodiimide was added portionwise to this mixture. After the solution was stored at room temperature for 16 hours, it was diluted with 200 ml of ether, followed by the addition of 5 ml of a solution of 2.2 g of oxalic acid in methanol. After 20 minutes, the solution was filtered to remove precipitated dicyclohexylurea.

The ether solution was concentrated and redissolved in 10 ml of toluene to give a small portion of oil. The toluene-soluble material was chromatographed on silica gel (150 g; Mallinckrodt, SilicAR CC-7) using 7% acetone in toluene for elution. The yield of 1- (3-acetylthiopropanoyl) -2-L-pyrrolidine-1-carboxaldehyde was 1.2 g; Rf = 0.33, silica gel, Uzl mixture of benzene and acetone; [d] 25-1030 (c = 1.5, CHCl 3). D Example H 5- (Acetylthio) -2-methylpropanoic acid p-nitrophenyl ester By substituting 3-acetylthio-2-methylpropanoic acid 3-acetylthio-2-methylpropanoic acid p-nitrophenyl ester for the procedure of Example 1} -acetylthiopropanoic acid ; Rf = 0.66, silica gel, chloroform.

Example 5 1- (3-Acetylthio-2-methylpropanoyl) -2-L-hydroxymethylpyrrolidine By replacing the 3-acetylthiopropanoic acid p-nitrophenyl ester with the 3-acetylthio-2-methylpropanoic acid p-nitrophenyl ester in the procedure of Example 2 1- (3-acetylthio-2-methylpropanoyl) -2-L-hydroxymethylpyrrolidine was obtained; Rf = 0.17, silica gel, üzl mixture of toluene and acetone; Idls-36,10 (c = 0.83, MeOH Example 6 1 * (3-acetylthio-2-methylpropanoyl) -2-L-pyrrolidinecarboxaldehyde By substituting 1- (3-acetylthiopropanoyl) in the procedure of Example 3 - The 2-L-hydroxymethylpyrrolidine with 1- (3-acetylthio-2-methylpropanoyl) -2-L-hydroxymethylpyrrolidine was obtained 1- (3-acetylthio-2-methylpropanoyl) -2-L-pyrrolidine carboxaldehyde; Rf = 6, HO, silica gel, Hzl mixture of toluene and acetone; methylphosphine (c = 1, cyclic). 79D3ÉÛÛ-7 Example 7 1- (5-acetylthiopropanoyl) -2-DL-hydroxymethylpiperidine By substituting in the procedure described in Example 2 L -prolinol with 2-DL-hydroxymethylpiperidine (prepared starting from DL-pipecolic acid by the procedure for the preparation of L-prolinol in J. Org. Chem. 32 (1976) 2388) was obtained 1- (5-acetylthiopropanoyl) -2-DL-hydroxymethylpiperidine.

Example 8 1- (3-Acetylthiopropanoyl) -2-DL-piperidinecarboxaldehyde By substituting 1- (3-acetylthiopropanoyl) -2-L-hydroxymethylpyrrolidine for 1- (3-acetylthiopropanoyl) -2 in the procedure of Example 3 -DL-hydroxymethylpiperidine obtained 1- (3-acetylthiopropanoyl) -2-DL-piperidinecarboxaldehyde.

Example 9 1- (3-Butanoylthiopropanoyl) -2-DL-pyrrolidinecarboxaldehyde By replacing the 3- (acetylthio) propanoic acid with 3- (butanoylthio) propanoic acid in the procedure of Example 1, 1- (butanoylthio) propanoic acid p- nitrophenyl ester. By using this product in the procedure of Example 2 and replacing the L-prolinol with DL-prolinol and then applying the procedure of Example 3, 1- (3-butanoylthiopropanoyl) -2-DL-pyrrolidinecarboxaldehyde was obtained. _ - .., ._............_. Example 10 1- (3-acetylthiopropanoyl) -2-L-pyrrolidinecarboxaldehyde sodium bisulfite adduct A solution of 172 mg of sodium bisulfite in 15 ml of water was added to N00 mg of 1 - (3-acetylthiopropanoyl) -2-L-pyrrolidinecarboxaldehyde and the suspension was stirred for 16 hours at room temperature. A practically clear solution was obtained. The solution was filtered and upon lyophilization 510 mg of a white powder were obtained. NMR analysis of this material showed the absence of aldehyde protons but the presence of a new doublet at H, 9 [a] D = -BSJ? (c = 1, ü, H 2 O).

Example 11 1- (3-Mercaptopropanoyl) -2-L- (hydroxymethyl) pyrrolidine Ig 1- (3-acetylthiopropanoyl) -2-L-hydroxymethylpyrrolidine was dissolved in 6 ml of 5.5 M ammonium hydroxide and the solution was stored at room temperature for 50 minutes. under argon. The mixture was then concentrated in vacuo, passed through a column of Dowex 50 ion exchange resin (hydrogen form) and washed with water. The water was removed by freeze-drying; yield 770 mg; Rf = 0.5, silica gel, 9: 1 mixture of ~ CHCl 3 and MeOH; [dlSs-55.3 (0.1, CHCl3).

Example 12 1,1 '- [dithiobis (3-propanoyl)] - bis-2-L- (hydroxymethylpyrrolidine 0.95 g of 1- (3-mercaptopropanoyl) -2-L-hydroxymethylpyrrolidine was dissolved in 20 ml of water and pH was adjusted to 6.5 with 1 N sodium hydroxide, an ethanol solution of iodine was added dropwise until a permanent yellow color was obtained, the dye was removed with a drop of sodium thiosulfate and the solution was passed through a column of Dowex 50 ion exchange resin.-The aqueous solution was concentrated to dryness to give 1,1 '- [dithiobis (3-propanoyl)] - bis-2-L- (hydroxymethyl) pyrrolidine.

Example 13 1,1 '- [Dithiobis- (3-propanoyl)] - bis-2-L-pyrrolidinecarboxaldehyde By replacing 1- (3-acetylthiopropanoyl) -2- (L-hydroxymethyl) -pyrrolidine in the procedure of Example 3 with 1,1 '- [dithio-bis (3-propanoyl) -1-bis-2-L-hydroxymethylpyrrolidine was obtained 1,1' - [dithiobis- (5-propanoyl) -1-bis-2-L-pyrrolidinecarboxaldehyde. Example 1a 1- (3-Mercaptopropanoyl) -2-L-pyrrolidinecarboxaldehyde 1 g of 1- (3-acetylthiopropanoyl) -2-L-pyrrolidinecarboxaldehyde was dissolved in a mixture of 5 ml of methanol and 5 ml of 2N sodium hydroxide under argon. After 50 minutes, the reaction mixture was diluted with 20 ml of 2N hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated to dryness in vacuo to give 1- (3-mercaptopropanoyl) -2-L-pyrrolidinecarboxaldehyde. This material should be used immediately after manufacture as it is unstable.

Example 15 1,1'e [dithiobisr (2-methyl-3-propanoyl)] phbis-2-L-pyrrolidinecarboxaldehyde * By substituting 1- (3-acetylthiopropanoyl) -2-L- (hydroxymethyl) pyrrolidine for the procedure of Example 11 with 1- (3-acetylthio-2-methylpropanoyl) -2-L- (hydroxymethyl) pyrrolidine and then subjecting the product to the procedure of Examples 12 and 13, 1,1 '- [dithiobis- (2 -methyl-3-propanoyl)] - bis-2-L-pyrrolidinecarboxaldehyde. .....- a. ___ _ .. _ ._.._.,., _. _ .. _. Example 16 1- (3-Mercapto-2-methylpropanoyl) -2-L-pyrrolidinecarboxaldehyde By substituting 1- (3-Acetylthiopropanoyl) -2-L-pyrrolidinecarboxaldehyde In the procedure of Example 1a with 1- (5-acetylthio-2-methylpropanoyl) -2-L-pyrrolidinecarboxaldehyde, 1- (3-mercapto-2-methylpropanoyl) is obtained. -2-L-pyrrolidinecarbozaldehyde.

Example 17 1-Benzyloxycarbonyl-β-benzyl-2-L-pyrrolidinecarboxaldehyde dimethylacetal a) N, 55 g 1-benzyloxycarbonyl-H-benzyloxy-L-proline [prepared from β-benzyloxyproline [Biochem. Biophys.

Acta 303 (1975) 198] and benzyloxycarbonyl chloride] and 1.5 g of 3,5-dimethylpyrazole were dissolved in 200 ml of chloroform. 2.06 g of dicyclohexylcarbodiimide was added and the mixture was stirred in an ice-salt bath for 1 hour and at room temperature for 16 hours. The precipitate was filtered and the filtrate was concentrated to dryness. The residue was dissolved in ethyl acetate and washed with 1N hydrochloric acid and water. The organic layer was dried and concentrated to dryness in vacuo to give 1-benzyloxycarbonyl---benzyloxy-L-proline-5,5-dimethylpyrazolide. b) 5.3 g of dimethylpyrazolide, dissolved in 200 ml of tetrahydrofuran, were added to a suspension of 20 mmol of lithium aluminum hydride in 200 ml of tetrahydrofuran over a period of 1 hour, keeping the temperature between -15 ° and -200 °. After stirring for an additional 1 hour at this temperature, 12 ml of 2N hydrochloric acid was added slowly at -200 with slow addition of a stream of argon. The aluminum hydroxide precipitate was centrifuged and the solvent was removed in vacuo. The residue was dissolved in ether, washed with water and evaporated. The residue was dissolved in absolute methanol and 0.02 ml of concentrated hydrochloric acid was added. The mixture was stored at room temperature for 3 days and then concentrated to dryness, the residue was dissolved in ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate and water. The organic phase was dried and concentrated to dryness in vacuo to give 1-benzyloxycarbonyl-H-benzyl-2-L-pyrrolidinecarboxaldehyde dimethylacetal.

Example 18 1- (3-Acetylthiopropanoyl) -α-hydroxy-2-L-pyrrolidinecarboxaldehyde a) 4.8 g of 1-benzyloxycarbonyl-H-benzyl-2-L-pyrrolidinecarboxaldehyde dimethylacetal were dissolved in 150 ml of methanol, then 500 g mg l0 fi palladium on charcoal was added. The mixture was stirred under a stream of hydrogen until carbon dioxide no longer developed. The catalyst was filtered off and the filtrate was concentrated to dryness in vacuo. The residue and 2.8 g of 3- (acetylthio) propanoic acid p-nitrophenyl ester were dissolved in 20 ml of dimethylformamide and the mixture was stored at room temperature for 16 hours. The solvent was removed in vacuo and the residue was chromatographed on a silica gel column using gradient elution using benzene acetone to give 1- (3-acetylthiopropanoyl) -α-hydroxy-2-L-pyrrolidinecarboxaldehyde aldehyde dimethyl acetal. b) The dimethylacetal from section a) above was suspended in 0.1N hydrochloric acid and the mixture was stirred at room temperature until the acetal had been completely hydrolyzed. The aqueous mixture was extracted with ethyl acetate and the organic phase was washed with water, dried over magnesium sulfate and concentrated to dryness to give 1- (3-acetylthiopropanoyl) -α-hydroxy-2-L-pyrrolidinecarboxaldehyde. Example 19 1- (3-Acetylthio-2-methylpropanoyl) -α-hydroxy-2-L-pyrrolidinecarboxaldehyde By replacing 3-acetylthiopropanoic acid The p-nitrophenyl ester in the procedure of Example 18 with 3-acetylthio-2-methyl-propanoic acid p-nitrophenyl ester gave 1- (3-acetylthio-2-methyl-propanoyl) -H-hydroxy-2-L-pyrrolidinecarboxaldehyde.

Example 20 1- (3-Acetylthiopropanoyl) -2-L-pyrrolidinecarboxaldehyde dimethyl acetal A solution of 1- (1--acetylthiopropanoyl) -2-L-pyrrolidinecarboxaldehyde in 10 ml of absolute methanol and 0.02 ml of concentrated row of hydrochloric acid was stored for 3 days at room temperature. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate and washed with sodium bicarbonate and water.

The organic layer was dried and concentrated to dryness to give 1- (3-acetylthiopropanoyl) -2-L-pyrrolidinecarboxaldehyde dimethylacetal.

Example 21 1- (5-Acetylthio-2-methylpropanoyl) -2-L-pyrrolidinecarboxaldehyde dimethylacetal By replacing 1- (5-acetylthiopropanoyl) -2-L-pyrrolidinecarboxaldehyde in the procedure of Example 20 with 1- (3- acetylthio-2-methylpropanoyl) -2-L-pyrrolidinecarboxaldehyde was obtained 1- (3-octylthio-2-methylpropanoyl) -1H-pyrrolidinecarboxaldehyde. Example 22 1- (3-Mercapto-2-methylpropanoyl) -2-L-pyrrolidinecarboxaldehyde dimethylacetal Ig 1- (3-acetylthio-2-methylpropanoyl) -2-L-pyrrolidinecarboxaldehyde dimethylacetal was dissolved in a mixture of 5 ml of methanol and 5 ml of 2N sodium hydroxide- After 60 minutes, the mixture was diluted with 30 ml of water. The pH was adjusted to 5 and the mixture was extracted with ethyl acetate. The organic layer was washed, dried and concentrated to dryness to give 1- (3-mercapto-2-methylpropanoyl) -2-L-pyrrolidinecarboxaldehyde dimethylacetal.

The following products were prepared by the parentheses using the corresponding pipecolic acid and 2- (hydroxymethyl) piperidine derivatives as starting material: Example 23 1- (3-mercaptopropanoyl) -2-L- (hydroxymethyl) -piperidine ( Example 11) ZH 1,1 '- [dithiobis- (3 * propanoyl)]' bis-2-L- (hydroxymethyl) piperidine (Example 12) 1,1 '- [dithiobis- (3-propanoyl)] bis-2-L-piperidinecarboxaldehyde (Example 13) 26 1- (3-mercaptopropanoyl) -2-L-piperidinecarboxaldehyde (Example 1 fl) 27 1,1 '* [dithiobis- (2-methyl-3- propanoyl)] - bis-2-L-piperidinecarboxaldehyde (Example 15) 28 1- (3-mercapto-2-methylpropanoyl) -2-L-piperidinecarboxaldehyde (Example 16) 29 1- (3-acetylthiopropanoyl) -5- hydroxy-2-L-piperidinecarboxaldehyde (Example 1-18) 1- (3-acetylthio-2-methylpropanoyl) -5-hydroxy-2-L-piperidinecarboxaldehyde (Example 19) 79033 00-7 17 Example 51 1 - (3-acetylthiopropanoyl) -2-L-piperidinecarboxaldehyde dimethylacetal (Example 20) 52 1- (3-acetylthio-2-methylpropanoyl) -2-L-piperidinecarboxaldehyde -dimethylacetal (Example 21) 33 1- (3-mercapto-2-methylpropanoyl) -2-L-piperidinecarboxyldehyde dimethylacetal (Example 22) BH 1- (3-butanoylthiopropanoyl) -2-DL-piperidinecarboxaldehyde (Example 9) 1- (3-Acetylthiopropanoyl) -2-L-piperidinecarboxaldehyde sodium bisulfite additive product (Example 10) 1,1 '- [dithiobis- (3-propanoyl) -1-bis-2-L-pyrrolidinecarboxaldehyde sodium bisulfite addition product By replacing 1- (3-acetylthiopropanoyl) -2-L-pyrrolidinecarboxaldehyde in the procedure of Example 10 with 1 , 1'- [dithiobis- (3'propanoyl) -1-bis-2-L-pyrrolidinecarboxaldehyde was obtained 1,1 '~ [dithiobis ~ (3'propanoyl)] - bis-2-L-pyrrolidinecarboxaldehyde sodium bisulfite addition product .

Example 38 1,1 '- [dithiobis- (2-methyl-5-propanoyl)] - bis-2-pyrrolidinecarboxaldehyde sodium bisulfite addition product By replacing 1- (3-acetylthiopropanoyl) -2-L-pyrrolidinecarboxylate in the process according to Example 10 with 1,1 '- [dithiobis- (2-methyl-3-propanoyl)] - bis-2-L-pyrrolidinecarboxaldehyde was obtained 1,1' - {dithiobis- (2-methyl-3-propanoyl) ] ~ bis-2-pyrrolidinecarboxaldehyde sodium bisulfite addition products. Example 39 1,1 '- [dithiobis- (2-methyl-5-propanoyl)] - bis-2-L-piperidinecarboxaldehyde-sodium bisulfite addition product By replacing 1- (3-acetylthiopropanoyl) -2-L-pyrrolidine The carboxaldehyde in the procedure of Example 10 with 1,1'- [dithiobis- (2-methyl-3-propanoyl)] - bis-2-L-piperidinecarboxaldehyde was obtained 1,1 '- [dithiobis- (2-methyl- 3-propanoyl) -bis-2-L-piperidinecarboxaldehyde sodium bisulfite addition product.

Claims (10)

1. Compounds of the formula R '2 CH R H 2 O (cH 2) n ¶. 1 II RS-CH 2 -CH-CO-N - CH-R 3 wherein R is hydrogen, lower alkanoyl having 2- 7 carbon atoms or a group of the same formula ln E1 is hydrogen or lower alkyl having 1-7 carbon atoms, R 2 is hydrogen or hydroxy, R B is hydroxymethyl, di (lower alkoxy) methyl or formyl and n is 1 or 2, and monovalent metal bisulfite addition products thereof, when R 3 is formyl. Compounds according to claim 1, characterized in that n is l. Compounds according to claim 1, characterized in that n is 1 and H 3 is formyl. 7903300-7 20 Ä. Compounds according to claim 1, characterized in that R is acetyl, R 1 is hydrogen or lower alkyl, R 3 is formyl and n is 1 or 2. Compounds according to claim 1, characterized in that R is acetyl, B1 is hydrogen or lower alkyl, R3 is hydroxymethyl and n is 1 or 2. Compounds according to claim 1, characterized in that n is 1, R is acetyl and R1 is methyl. The compound 1- (3-acetylthiopropanoyl) -2-L-pyrrolidinecarboxaldehyde according to claim 1. The compound 1- (3-acetylthio-2-methylpropanoyl) -2-L-pyrrolidinecarboxaldehyde according to claim 1. The compound 1- (3-mercaptopropanoyl) -2-L-pyrrolidinecarboxaldehyde according to claim 1. The compound 1- (3-mercapto-2-methylpropanoyl) -2-L-pyrrolidinecarboxaldehyde according to claim 1. 7903300-7 Summary The invention relates to derivatives of pyrrolidinecarboxaldehyde and piperidinecarboxaldehyde and to intermediates for their preparation according to the general formula * '12 / CH 2 III H 2 C (CH 2) n 11 R 5 -cnz-cn-co-N-š- cH 113 wherein R is hydrogen, lower alkanoyl or a group of the formula R 1z CH 1: 1 H 2? \ (cïHz) n -s-c fl z-c fl-co-N CH H3; B1 is hydrogen or lower alkyl, R2 is hydrogen or hydroxy, R5 is hydroxymethyl, di (lower alkoxy) methyl or formyl and n is 1 or 2, and their bisulfite addition products. These compounds are useful as hypotensive agents.