IE55092B1 - New bicyclic aminoacids as intermediates and processes for their preparation - Google Patents

Description

The invention relates to compounds of the formula III, (III) in which H the H atoms on the C atoms 3a and 7a have the cis configuration relative to one another and the group ~ -COgV cnC atom 2 is oriented exo or endo to the bicyclic ring system and wherein • V denotes hydrogen, (C, to cg)-alkyl or (Cy or Cg)-aralkyl.

These compounds serve according to the invention as starting materials for the synthesis'of compounds of the formula I* CO.R (U 2*n Y I X R denotes hydrogen, (C^ to Cg}-alkyl or aralkyl having 7 to 9 C atoms, R* denotes hydrogen or (C^ to Cg)-alkyl, which can optionally be substituted by amino, (C^ to C^J-acyl-amino, or benzoylamino, (C2 to Cg)- 3 alkenyl, (¾ to Cg)-cycloalkyl, (¾ to Cg)-cycloalkenyl, (Cg to (^)- " cycloalkyl-(C1 to C^)-alkyl, (Cg-C10)-aryl or partially hydrogenated «W -aryl, which each can be substituted by (C^ to C^)-alkyl, (C1 or ty"*11*0*? or halogen, (Cg-C^J-aryl-^ to C4)-alkyl Or (C7-C11) -arcyl-Ci-alkyl, of which can be substituted in the aryl radical as defined in the aforegoing, a monocyclic' or bicycllc heterocyclic radical having 5 to 7 or 8 to 10 ring atoms respectively, of which 1 or 2 ring atoms represent sulfur or oxygen atoms and/or of which 1 to 4 ring atoms represent nitrogen atoms, or a side chain of a naturally occurring “ -aminoaeid, R2 denotes hydrogen, to Cg)-alkyl, (C2 to Cg)-alkenyl or aryl-iC^ to C^J^alkyl, Y denotes hydrogen or hydroxyl, t Z denotes hydrogen or V 4 Y and Ζ together denote oxygen and X denotes (C^ to Cg)-alkyl, (C2 to Cg)-alkenyl, (Cj to Cg)-cycloalkyl, (Cg-C^J-aryl, which can be mono-, di- or trisubstituted by (C^ to C^)-alkyl, (C1 5 to C^)-alkoxy, hydroxyl, halogen, nitro, amino, (C-^ to C^)-alkylamino, di-(C^ to C^)-alkylamino or methylene-dioxy or 3-indolyl, and their physiologically acceptable salts.

Particularly suitable Baits are alkali metal and 1o alkaline earth metal salts,. salts with physiologically tolerated amines and salts with inorganic or organic acids, such as, for example, HC1, HBr, HgSO^, maleic acid or fumaric acid.

In this context and the following text, aryl is 15 to be understood preferably as optionally substituted phenyl or naphthyl. Alkyl can be straight-chain or branched.

Two possible configurations of the carboxyl group are suitable in the preferred configuration of the H atoms on C-3a and C-7a of the bicycle, namely those in-20 the exo position (part formula la) and the endo position (part formula lb) of the carboxyl group.

The endo position of the carboxyl group on C-2 is defined such that the carboxyl group is turned towards the direction of the 6-membered ring of the bi-25 cycle, i.e. the concave side of the bicycle (part formula lb).

Accordingly, the exo position of the carboxyl group on C-2 is defined^ such that the carboxyl group is 5 oriented in the direction of the relevant bridgehead H atoms (part formula la). Η H Compounds of the formula I have chiral C atoms 5 ..in positions C-2, C-3a, C-7a and in the C atoms in the side chain marked with an asterisk. Hie canpounds of the formula I can thus be present as optical isomers, as diastereomers as racemates or as mixtures of these. However, the compounds of the formula I are preferred in which the C atom 2 in 10 the bicydic ring system and the C atoms in the side chain marked with an asterisk (*) have the S configuration.

The compounds of the formula I can be prepared by reacting, by the known methods of amide formation in peptide chemistry, a can-pound of the formula II, Y (II) HO-C-CH-NH-CH-(CH,) -C-X Z i 2 n i 5 wherein 12 n, R , R, X, y and Z have the meanings as in formula I, with a compound of the formula III, H J3a III in which H ¥ denotes hydrogen,· (C1 to cg) -alkyl or (C7 or c8)-aralkyl, in particular a tert.-butyl radical, and then optionally splitting off the radical V by acid treatment and optionally also splitting off the radical R by additional acid or base- treatment, the free carboxylic acids being obtained in each case. 7 The compounds according to the of the Invention, formula III can, be prepared by the following procedure: Compounds of the formula IX, in which A | R denotes (Cj to Cg)-alkyl or (C^ to Cg)~ aralkyl, are reacted with acylating agents, which transfer the group -CO-R^, wherein the radical R^ represents (C-^ to Cg)-alkyl, (C,- to Cg)-cycloalkyl, (Cg to Cg)-alkenyl, (C^ to Cg)-alkoxy, aryl, aryloxy, aryl-fc^ to C^)-alkyl or aryl-(C^ to C^)-alkoxy, to give compounds of the formula X, (X) C°2R * COR ο» * ia which R and R have the foregoing meaning, the latter are cyelized to give a mixture of stereoisomeric compounds of the formula XI, » * L3 Ot 1 in which R and R-' have the foregoing meaning and the hydrogen atoms on the bridgehead C atoms have the cis configuration, ίο (XI) this mixture of stereoisomers, in which pairs of diastereomers are present, depending on whether the starting compounds of the formula IX . had the R or S configuration or were racemic, of the formulae Xlb and d or XTa end c, or mixtures, of the formulae XIa-d, respectively, 15 CO-R 0^1^"'"COR2 **3 COR (XI b) CORJ (XI a) Ch "i,CO_R Η 1 3 2 COR (xi a> 2* 91 X In which R and R each have the foregoing meaning, ia hydrolyzed, optionally after previous separation into enantiomers, pairs of diastereomers or racemates, to give compounds of the formula III, in which V represents hydrogen, and the latter are optionally esterif led to give compounds of the formula III, in which V represents (C1 to Cg)-alkyl or (C? or Cg)-aralkyl.

The synthesis of compounds of the formula IX starts from an allylglycine ester of the formula XII, 91 wherein R is (C^ to Cg)-alkyl or (Cy ’or Cg)-aralkyl, preferably (C^ to C^)-alkyl or benzyl. The allylglycine ester can be employed in the synthesis as the racemic compound or as optically pure R or S form. The synthesis of the racemic allylglycine is described in Monatshefte der Chemie 8g, 1071 (1954); that of the R and the S compounds in Jlblol.Chem.225. page 40 (1955). The esterification is carried out by known methods of organic chemistry. The preparation of the ethyl ester is described in the article in Monatshefte der ..Chemie.

The compound of the formula XII is reacted with crotonaldehyde in an organic solvent, with separation out of water, to give the Schifffe base of the formula IX. The reaction is carried out at temperatures in the range from -40° to +80°C, preferably at +20°C. Aprotic 1.0 solvents, such as, for example, benzene, toluene, carbon tetrachloride or chloroform are- used. The water of reaction is removed from the reaction equilibrium with a water-binding agent, such as, for example, MgSO^, 5 NagSO^, molecular sieves or an organic auxiliary, such as, for example, orthoformates or by means of azeotropic separation out of water.

The Schiff's base is preferably acylated in an aprotic solvent, such as, for example, methylene chlo-10 ride, chloroform, toluene or dimethylformamide, in the presence of a base, such as, for example, triethylamine, collidine, pyridine or other amines, with an acylating agent, such as, for example, an acid chloride, to give the dienamide of the formula X. The reaction is 15 carried out at temperatures in the range from -80° to +40°C. Preferably,· the reaction is started at -80°C and completed at 20°C. 3h the acylating agent which transfers the group -CO-R^, preferably denotes phenyl, tert.-butoxy, 20 methyl, methoxy or ethoxy. The compound of the formula X is preferably heated in a high boiling organic solvent and cydized, in an intramolecular OLels-ALder reaction, to give the bicyclic amino acid derivatives XIa-d, which are produced as a mixture of stereoisomers. 25 Those solvents can be used which boil In a tem perature range between 80 and 250°C, such as, for example, toluene, xylene or dichlorobenzene. The ther-- molysis is also possible with a lower boiling solvent in a pressure apparatus. Preferably, the thermolysis 11 3 . is carried out in a temperature range between 100 and 180°C under normal pressure. In order to deactivate the glass surface of the reaction vessel, If appropriate, bistrimethylsilylacetamide or customary deactivating compounds or acid traps and a radical trap such as, for example, tert.'-butylcatechol to suppress radical side reactions are added.

The endo-cis compounds XIa and Xlb and the exo-cis compounds XIc and Xld are each present as racemates when the racemic allylglycine ester XII is used. On using the allylglycine ester with the S configuration as the starting compound, the aminoacid derivatives XIa having the cis-endo-S configuration and XIc having the cis-exo configuration are obtained, the S configuration relating to the C atom 2, Correspondingly, ou using the allylglycine ester with the R configuration, the aminoacid derivatives Xlb and Xld having the R configuration at carbon 2 are obtained. The racemates XIa/XIb and Xlc/XId or the diastereomers XIa and XIc or Xlb and Xld can be separated, for example, by fractional crystallization or by column chromatography on silica gel by customary methods. The racemates or the optically pure diastereomers can be employed in the further reactions.

The aminoaclds of the formula III, wherein V denotes hydrogen, are obtained by acid or alkaline hydrolysis. The aminoacids can optionally be esterified. The preferred tert.-butyl esters of the aminoacids of the formula III (V = tert.-butyl) are obtained by the IS sethods customary in peptide chemistry, such .as, for example, by reaction of the acids with isobutylene in an inert organic solvent (for example dloxane) in the presence of acids (such as, for example, sulfuric acid).

The following process has been found to be particularly advantageous: ' the appropriate aminoacid is acylated on the nitrogen with a group which can be split off by base, such as, for example, the methylsulfonylethoxycar-bonyl group (= MSC), Tesser, Balvert-Geers, Int.J.Pept. 10 Protein Res. 2,295 (1975). The carboxylic acid is reacted, in the neutral to weakly basic pH range, with tert.-butanol in an organic solvent, such as, for example, pyridine, in the presence of propylphosphonic anhydride to give the corresponding tert.-butyl ester.

The tert.-butyl ester of the formula III (W = tert.-butyl) is obtained by splitting off the MSC protective group in the strongly alkaline pH range with alkali in an aqueous solvent.

The compounds of the formula II, with n being 1, 20 Y and Z being hydrogen, R being methyl and R being methyl or ethyl and X being phenyl, used as starting materials for the preparation of the compounds of the formula I, are known (European Patent Application No. 37,231). - 13 The reaction of a compound of the formula II with a compound of the formula III to prepare a compound of the formula I is carried out in accordance with a condensation reaction known in peptide chemistry, dicy-clohexylcarbodiimlde and 1-hydroxybenzotriazole,for example, being added as the condensing agent. On subsequently splitting off the radical W with acid, trifluoroacetic acid or hydrogen chloride are preferably employed as the acids.

In the reactions for the preparation of the compounds of the formulae III and I, described above, the configurations of the intermediate products at the bridgehead C atoms 3a and 7a are retained in each case.

The compounds of the formula III obtained according to the procedure described above are produced as a mixture and can be separated from one another, for example, by recrystallization or by chromatography.

The compounds of the formula III are produced as racemic mixtures and can be employed as such in the further syntheses described above. However, they can also be employed as the pure enantiomers after separation of the racemates into the optical antipodes using customary methods, for example via salt formation with optically active bases or acids. The pure enantiomers can also be obtained. id .The following examples serve to illustrate the invention, •t The % .KMR data reported in the following examples were found by measurement in CDCI^ and are re-5 ported in 6 (ppm).

Example 1 · 1- [H-(lS-carboethoxv-3-phenvlpropyl)-S-alanvll- cls-2.5.3a. 4,5.7 a-hexahydro Γ IHl lndole-2R,S-endo-carboxy-lic acid 10 a) Ethyl ester of N-benzoyl-N-(1.3-butadienyl)-Rt S-allyl-glycine 28.6 g of RsS—allylglycine ethyl ester.were dissolved in 140 ml of toluene, and 14.0 g of crotonaldehyde were added. After adding 30 g of anhydrous.magnesium sulfate, 15 the mixture was stirred at room temperature for 3 hours. The magnesium sulfate v/as then filtered off with suc-. tion and the toluene was removed in vacuo.

Residues 44.4 g of oil. 750 ml of methylene chloride were cooled down to -?0°C and 44.4 g of triethylamine and 28.1 g of benzoyl chloride were added. To this were added the 44.4 g of Schiff's base obtained above. The mixture was stirred at -75°C for 2 hours. It was then 25 allowed to warm to 0°C. · The solvent was removed in •a rotary evaporator at room temperature. The residue was then taken up in toluene, washed with water, IS dried and the toluene vaa removed in a rotary evaporator. She residue was filtered through a short column of silica gel (500 ml). Methylene chloride was used to elute. After evaporating off the methylene chloride, 5 49 g of ethyl ester of N-benzoyl-N- (1,3-butadienyl)-R, S- allylglycine were obtained· -½ NMR data: 1.1 - 1.4 (t, 3H), . . - 2.7 - 3.1 (η, 2H), 10 4.0 - 4.5 (m, 3H), 4.8 - 6.8 (m, 8H), 7.3 - 7.6 (s, 5H). b) Ethyl N-benzovl-cis-2.5.3a.4.5.7a-hexahvdro ΓlH]indole-2R .S-endo-carboxylate 15 49 g of N-benzoyl-N-(l,3-'butadienyl)-R,S-allyl- glycine. ethyl ester were dissolved in 1,000 ml of xylene, and 6.1 g of tert.-butylcatechol and 5 drops of bistrioethyl-silylacetamide were added. The mixture was heated to reflux under nitrogen for 6 hours, a further 0.1 g 20 of tert.-butylcatechol and 5 drops of bistrimethylsilyl-acetamide being added after 3 hours. The xylene was removed in a rotary evaporator and 43 g of an oily residue remained. 70 g of oil were chromatographed on silica gel 25 with toluene/ethyl acetate 4:1. 53 g of ethyl N- benzoyl-cis-2,3,3a, 4,5,7a-hexahydro [ 1H] indole-2R, S-endo-carboxylate (Rf: 0.18) were obtained as an oil and 7.5 • g of ethyl N-benzoyl-cis-2,3,3a,4,5,7a-hexahydro[lH]in-dc0e-2R,S-exo-carboxylate (Rf: 0.26, melting point: 96- 16 .98®C) were obtained.

Both compounds.are in the form of racemates.

¢) Cls-2.3.3a.4.5.7a-hexahvdrprIHlindole-2R.S-endo-carboxvllc acid 5 1.5 g of ethyl N-benzoyl-cis-2,5>3a»4,5>7a-hexa- hydro[lH]indole-2-endo-R,S-carboxylate were dissolved in 10 elL of ethanol. 0.35 g of potassium hydroxide dissolved in 5 ml of water was added to this. The mixture was stirred at room temperature for 2½ hours, dill 0 luted with water and extracted with ethyl acetate.

The aqueous solution was acidified with 2N hydrochloric acid and again extracted with ethyl acetate. After drying and evaporation on a rotary evaporator, 0.9 g of N-benzoyl-cis-2,3,3a, 4,5,7a-hexahydro [ 1H] indo3s-2-endo-15 carboxylic acid of melting point 153-154°C was obtained. 13.4 g of the N-benzoyl carboxylic acid were dissolved in a mixture of 200 ml of 2K hydrochloric acid and 67 ml of ethanol and heated under nitrogen at a bath temperature of 110°C for 22 hours. The alcohol 20 was removed in vacuo and the aqueous phase was extracted with methylene chloride. The .pH was then adjusted to 7.0 with concentrated sodium hydroxide solution and the solution was evaporated to dryness in vacuo. . The residue was taken tip in methylene chloride/methanol, Yield 25 salt was removed by filtration, the filtrate was evaporated and recrystallized from ethanol/ether. 7.0 g, melting point: 220°C (decomposition). ir Example 2 Tert.-butyl cls-2.5.3a.4.5,7a-hexahvdroriHllndole-2R.S-endo-carboxvlate 3.35 g of cis-2,3,3a,4,5,7a-hexahydro[lH]indole-5 2R,S-endo-carboxylic acid were dissolved in 50 ml of dimethylformamide, and 5.3 g of methylsulfonylethyl succinimidocarbonate and 2.3 g of ethylmorpholine were added. The mixture was allowed to stand at room temperature for 12 hours, the solvent was evaporated 10 off in vacuo and the residue was dissolved in ethyl acetate. The ethyl acetate solution was extracted by shaking with saturated sodium bicarbonate solution, this was adjusted to pH 3.5 with 2N hydrochloric acid, and extracted several times with ethyl acetate. After 15 drying, the combined ethyl acetate solutions were evaporated. The residue obtained was 8.5 g of N-methyl-sulfonylethyloxycarbonyl-cis-2,3,3a,4,5,7a-hexahydro[1H] indole-2R,S-endo-carboxylic acid, which was dissolved in 10 ml of pyridine. .To this were added, at 0°C, 10 ml 20 of tert.-butanol and 12 ml of a 50$ strength solution of propylphosphonic anhydride in methylene chloride.

The mixture was stirred at 40°C for 6 hours, 200 ml of ethyl acetate were added and potassium bisulfate solution •was added until a pH of 3.5 was reached. The mixture was extracted with ethyl acetate, the ethyl acetate 25 18 solution was trashed with water, dried and evaporated in vacuo. The oil remaining wa's purified on silica gel, eluting with ethyl acetate. The tert.-butyl ester was obtained as an oil.

HHR data·. 1.4 (s, 9H), 1.0 - 2.8 (a, 1H), 2.9 (s, 3H), 3.1 - 3.5 (m, 2H>, 10 3.7 - 4.8 (m, 4H), 5.6 - 5.9 (m, 2H), • 1.35 g of tert.-hutyl ester was dissolved in 15 ml of methanol and 1.5 ml of water. The pH was adjusted to 13 with 2N sodium hydroxide solution and the 15 mixture was stirred at room temperature for 2 hours.

It was then neutralized with 2N hydrochloric acid, the methanol was evaporated in vacuo, the aqueous phase was extracted with ethyl acetate, and the ethyl acetate solution \*ras washed with water, dried and evaporated.

The oily residue was purified on silica gel, eluting with ethyl acetate. 0.3 g of tert.-butyl cis-2,3,3a,4,5,7a-hexahydro [lH]indole--ai^-endp-carboxylate was thus obtained as an oil. 1H NMR, data! 1.4 (s, 9H), 1.0 - 2.7 (m, 8H), 3.2 - 4.9 (m, 2H), 5.8 (d, 2H). 19 Example 3.

Tert.-butyl cis-2.3.3a.4.5.7a-hexahvdroflHlindole-2R.S-exo-carboxylate This compound was prepared from cis-2,3r3a,4,5,7a-5 hexahydro[lH] indole-2R,S-exo- carboxylic acid in analogy to the process described in Example 2. ' NMR data: 1.1 - 2.8 (m, 8H) 1.4 (s, 9H) 10 3.3 - 4.9 (m, 2H) 5.8 (m, 2H).

Example 4 . t- fN- (IS-c arbo ethoxy- 3-phen ylpropyl) -S-al anvil -cls-2.3.3a.4.5.7a-hexahYdroriHllndole~25-endo-carboxvlic acid a) Ethyl ester of S-allvlglvcine The preparation was carried out in the manner as described in Monatshefte der Chemie 85, 1071 (1954). bX Ethyl ester of N-benzoyl-N-(l,3-butadienyl)- 20 S-allvl glycine Shis compound was prepared in analogy to the process described in Example la. 1H MR data: - 5 1.1 - 1.4 (tr, 3H) 2.7 - 3.1 (m, 2H) 4.0 - 4.5 (m, 3H) 4.8 - 6.8 (m, 8H) 7.3 - 7.6 (s, 5H) 10 e) Ethyl H«-benzovl-cis-2.3«5a.4.5.7a-hexahvdro riHlindole-25-endo-carboxvlate and ethyl N-benzovl-cis-2.3.5a. 4,5,7 a-hexahydro Γ1H1 indolle-25- exo-carboxylate • This mixture of diastereomers was prepared from the compound from Example 4h . in analogy to the process 15 described in Example lb. The mixture was separated on silica gel using toluene/ethyl acetate 4:1. Rf value of the endo compound: 0.18; Rf value of the exo compound: 0.26.

HMR data: 20 . 0.8 - 2.8 (a, 10H) i 5.8 - 4.8 (m, 4H) 5.5 - 5.9 (broad s, 2H) 7.4 (s, 5H) d) Gis-2.3.5a. 4,5.7a-hexahydrofIHl indole-2S-endo-25 carboxylic acid This compound was prepared from the compound from Example 4c in analogy to the process described in Example lc. •hi MR data: 21 (d2o) 1.1 - 2.9 (m, 7H) 3.9 - 4.4 (m, 2H) 5.5 -.6.4 (m, 2H) Example 5 Tert.-butyl cls-25.3a.4.5.7a-hexahvdroΓ1H1Indole-2S-endo-carboxvlate 10 This compound was prepared from the compound from Example 4 In analogy to the process described in Example 2. ΧΗ MMR data: 1.4 (s, 9H) 1.0 - 2.7 (m, 8H) 3.2 - 4.9 (m, 2H) 15 5.8 (d, 2H).

Example 6 20 1 - [K-(lS-carboethoxy-3-Phenylpropyl)-S-alanyll'-cls 2,3,3a, 4,5,7a-hexahvdror 1H1 indole-25- exo-carboxvllc acid Qs-2.3.3a, 4.5.7a-hexahvdrpr lHllndo3e-2S-exo-carboxylic acid This compound was prepared from the exo compound from Example .4c in analogy to the process described in Example lc. 1 H NMR data: 0>2o) 1.0 - 2.8 (m, 1H) 3.6 - 4.4 (m, 2H) 5.5 - 6.4 (m, 2H) 25 23 Example 7 Tert„-butyl cls-23,3a,4.5. 7a-hexahvdrof 1H1 indole-2S-exo-carboxylate 5 This compound was prepared from the compound from Example 6. in analogy to the process described in Example 2. 1H MMR data: 1.4 (s, 9H) 0.9 - 2.8 (m, 8H) ^o 5.3 - 4.9 (m# 2H) 5.4 - 5.8 (m, 2H)

Claims (7)

1. A compound of the formula III, 5 the H atoms on the C atoms 3a and 7a have the cis configuration relative to one another and the group -COgW on the C atom 2 Is oriented exo or endo to the bi- cyclic ring system and wherein W( denotes hydrogen, (C1 to Cgi-alkyl or (C? or Cg)-aralkyl. 10

2. A process for the preparation of a compound of the formula III as claimed In claim .1., which comprises reacting a compound of the formula IX, a*3VVllNjA^CH2 (ix) C02R2’ in which 15 R2' denotes (C^ to Cg)-alkyl or (Cy or Cg)-aralkyl, with an acylating agent, which transfers the group -CO-R^, wherein the radical represents to Cg)-alkyl, (C^ to C^)-cycloalkyl, (C2 to Cg)-alkenyl, (Cj to Cg)-alkoxy, aryl, aryloxy, aryl-iC^ to C^J-alkyl or aryl-iC^ to C^J-alkoxy, to give a compound.of the formula X, (X) 20 34 10 15 in which R^S and have the foregoing meanings, icyclizlng this compound to give a mixture of stereoisomerio compounds of the formula XI, H H. CO"3 02r (XI) in vMch, · U,3R R2’ and R^ have the foregoing meanings and the hydrogen atoms on the bridgehead C atoms have the cis configuration, hydrolyzing this mixture of stereoisomers, in which pairs of diastereomers are present, depending on whether the starting compound of the formula IX had the R or S configuration or was racemic, of the formulae Xlb and d or XIaandc, or -a. mixture of the formulae XIa-d, re spectively H ^^r^CO..R2 co2R‘ CO„R2 I CORJ COR (XI b) (XI d) (XI c) in which Ol * R and R each have the foregoing meanings, hydrolyzing, if appropriate, after previous separation into enantiomers, pairs of diastereomers or racemates, to give a compound of the formula III as claimed in claim 1, in which V represents hydrogen and if appropriate, esterifying the latter to give a compound of the formula III in which V represents, (C1 to Cg) -alkyl or (C^ or Cg),-aralkyl.

3. The use of a compound as claimed in claim 1 for the preparation of a compound of the formula I, in which h denotes 0 or 1, R denotes hydrogen, (Cj, to Cg)-alkyl or aralkyl' having 7 to 9 C atoms, R* denotes hydrogen or (C^ to Cg)-alkyl, which can optionally be substituted by amino, (C^ to C^)-acyl-amino or benzoylamino, (Cg to Cg)-alkenyl, (C^ to Cg)-cycloalkyl, (C^ to Cg)-cycloalkenyl, (C5 to C^)-cycloalkyl- (C1 to C^)-alkyl, (Cg-C1(J) -aryl or partially hydrogenated (Cg-C^)-aryl, which each can be substituted by (C^ to c^)-alkyl CC1 or C2)-alkoxy or halogen, (Cg-C^-aryl-tc, to C4)-alkyl or {C7“C1^)-aroyl-Cl-alkyl, both of which can be substituted in the aryl radical as defined in the aforegoing, a monocyclic or bicyclic heterocyclic radical having 5 to 7 or 8 to 10 ring atoms respectively, of which 1‘ or 2 ring atoms represent sulfur or oxygen atoms and/or of which 1 to 4 ring atoms represent nitrogen atoms, or a side chain of a naturally occurring aminoacid, R2 denotes hydrogen, (C^ to Cg)-alkyl, (C2 to Cg)-alkenyl or aryl-(C^ to C^)-alkyl, Y denotes hydrogen or hydroxyl 2 denotes hydrogen or Y and Z together denote oxygen and X denotes (C^ to Cg)-alkyl, (C2 to Cg)-alkenyl, (C5 to Cj)-cycloalkyl, (Cg-C1())-aryl, vhidi can be mono—, di- or. trisubsfcituted by (Cj to C^)-alkyl, tCj^ t® C^)-alkoxy, hydroxyl, halogen, nitro, amino, (C^ to C^)-alkylamino, di-»(C^ to C^J-alkylamino or methylene-dloxy, or 3-indolyl, or a physiologically acceptable salt thereof.

4. A compound of the formula m given and defined in claim 1, ‘substantially as· hereinbefore described and exemplified.

5. A process for the preparation of a compound of the formula nr given and defined in claim 1, substantially as hereinbefore described and exemplified. 2 7

6. A compound of the formula III given and defined in claim 1, whenever prepared by a process claimed in claim 2 or 5. Dated this the 11th day of January, 1990, P. R. KELLY & CO. BY: EXECUTIVE.

7. 27 Clyde Road, Ballsbridge, Dublin 4. AGENTS FOR THE APPLICANTS.