NO834352L - NEW DERIVATIVES OF CYCLOALKA (C) PYRROL CARBOXYLIC ACID, PROCEDURE FOR THEIR PREPARATION, SUBSTANCES CONTAINING THESE AND THEIR USE, AND NEW CYCLOALKA (C) PYRROLE CARBOXYL CARROCYRO FOR THEIR FIRST. - Google Patents

Description

The present invention relates to new derivatives of bicyclic amino acids with the formula I

in which the hydrogen atoms of the bridgehead C atoms 4 and (7+n) are cis- or trans-configured to each other, whereby the carboxyl group of C-atom 1 can be oriented to the hydrogen atom of C-atom 7+n in cis- or trans- position and in which

n = 1/2 or 3,

R"^ = hydrogen, (C^-Cg)-alkyl, which may optionally be substituted with amino, (C^-C^)-acylamino, preferably (Ci-C4)-alkanoylamino or benzoylamino, (C2--C6) -alkenyl, (C5~C9)-cycloalkyl, (C5-Cg-cycloalkenyl, (C5~C7)-cycloalkyl-(C^-C^ )-alkyl, (C<g-C>^Q)-aryl or partially hydrogenated (C 8 -C 10 )-aryl, each of which may be substituted with (C 1 -C 2 )-alkyl, (C 1 -C 2 )-alkyl, (C 1 -C 2 )-alkyl or halogen, (C 8 -C 2 Q)-aryl-(C^-C^)-alkyl, which as defined above may be substituted in the aryl residue, a mono- or bicyclic heterocyclen residue with 5 to 7 or 8 to 10 ring atoms, of which 1 to 2 ring atoms are sulfur or oxygen atoms and/or of which 1 to 4 ring atoms are nitrogen atoms, or a side chain of a naturally occurring amino acid,

2

R = hydrogen, (C-1-C8)-alkyl, (C2-C8)-alkenyl or

(C 6 -C 10 )-aryl-(C 1 -C 4 )-alkyl,

Y = hydrogen is hydroxy,

Z = hydrogen or

Y and Z = combined oxygen,

X = (C1-C8)-alkyl, (C2-C8)-alkenyl, (C5-C8)-dichloroalkyl,

(Cg-C^Q9-aryl, which may be mono-, di- or tri-substituted with (C^-C^)-alkyl, (C1-C4)-alkoxy, hydroxy, halogen, nitro, amino, (C-^ -C 1 -alkylamino, di-(C 1 -C 4 )-alkylamino or methylenedioxy

or means indol-3-yl,

as well as their physiologically acceptable salts.

As salts, alkali and alkaline earth salts, salts with physiologically acceptable amines and salts with inorganic or organic acids such as e.g. HC1, HBr, H2S04'maleic Acid'fumaric acid.

Here, as below, aryl preferably means phenyl or naphthyl. Alkyl can be straight chain or branched.

Compounds of formula I have chiral C atoms in the positions C-1, C-4, C-(7+n), as well as in the C atoms in the side chain marked with an asterisk. Both the R and S configurations of all centers are subject to the present invention. The compounds of formula I can therefore exist as optical isomers, as diastereomers, as racemates or as mixtures of these. Preferred are the compounds of formula I, in which the C atom 1 in the bicyclic ring system as well as the C atoms of the side chain marked with an asterisk have the S configuration.

Preferred compounds of formula I are those in which

R"*" means hydrogen, (C^-C^)-alkyl, (C2~C3)-alkenyl, benzyl

4-amino-butyl, 4-methoxybenzyl or 4-ethoxybenzyl R 2 means hydrogen, (C1~C4)-alkyl or benzyl and

X means phenyl, which may be mono- or di-substituted or

in the case of methoxy trisubstituted by (C 1 -C 2 )-alkyl, (C 1 -C 2 )-alkyl, hydroxy, fluorine, chlorine,

bromine, amino, (C 1 -C 4 )alkylamino, di-(C 1 -C 4 )alkylamino, nitro or methylenedioxy.

Particularly preferred are such compounds of formula I,

in which n means 1 or 2, R"<*>" means methyl, 4-methoxybenzyl or 4-ethoxybenzyl and X means phenyl, whereby those in which R 2 means hydrogen or ethyl are preferred.

The invention further relates to the method for producing the compounds of formula I. A method variant is characterized by reacting a compound of formula II

1 2 in which R , R , X, Y and Z have the meanings as in formula I, with a compound of formula III,

in which the configuration of said bicyclic ring system and the substituent of C-1 is the same as in formula I and wherein n means 1, 2 or 3 and

W means a hydrogenolytic or acidic cleavable residue,

in particular a benzyl or a tert.-butyl residue,

according to known amide formation methods from peptide chemistry and then split off by catalytic hydrogenation or acid treatment the residue W and optionally by further acid or base treatment also split off the residue R 2 , whereby the free carboxylic acids are always obtained.

Further synthesis methods for the preparation of compounds of formula I, in which Y and Z together represent hydrogen, consist in reacting a compound of formula IV,

in which the configuration of the bicyclic ring system and of the substituent of C-1 is the same as in formula I and wherein n and R"*" have the meanings as in formula I and W has the meaning as in formula III, with a compound of formula

W,

in which R 2 and X have the meanings as in formula I, in a known manner by a Michael reaction (Organikum, 6th edition, p. 492, 1967) and split off the residue W and optionally the residue R 2 as described above, or that one reacts a compound of the above formula IV with a compound of the general formula VI, in which R 2 has the meaning as in formula I, and reacts with a compound of the general formula VII

wherein X has the meaning as in formula I, in a known manner by a Mannich reaction (s. Bull.Soc.Chim. France 1973, p. 625) and then splits off the residue W and possibly the residue R 2 as described above to form the free carboxy groups.

Furthermore, compounds of formula I can be prepared with

Y and Z = hydrogen also in the way that one reacts a compound with the above-mentioned formula IV according to that in J.Amer. Chem. Soc. 9_3, 2897 (1971) described method with a compound of formula VIII

in which R 2 and X have the meanings as in formula I, the prepared Schiff's bases are reduced and then the residue W and possibly the residue R 2 is split off as described above, forming the free carboxy groups, or that a compound of formula I formed according to the methods specified above is reduced , in which Y and Z together mean hydrogen. Preferred is the catalytic hydrogenation. The reduction of the Schiff bases can take place catalytically, electrolytically or with reducing agents such as, for example, complex borates, preferably sodium borohydride or sodium cyanoborohydride.

Compounds of formula I with Y = hydroxy and Z = hydrogen can, for example, also be obtained by reduction of a compound I formed according to the above-mentioned methods with Y and Z = together oxygen. This reduction can take place catalytically with hydrogen or with another reducing agent such as, for example, complex boranates, preferably sodium boron

hydride.

Subject matter of the present invention are also compounds of formula III',

in which the C atoms 1, 4 and (7+n) have the same configurations as in formula III, n means 1, 2 or 3 and W has the meaning of W in formula III and also means hydrogen. According to the invention, these compounds serve as starting materials in the synthesis of the compound of formula I and can be prepared according to the invention according to the following methods. In a synthesis variant, one starts from a compound of formula IX

in which the H atoms of the C atoms 4 and (7+n) are cis- or trans-oriented to each other and n means the number 1, 2 or 3.

Compounds of formula IX with n=1 are known from R.Griot, Heiv.Chim.Acta _42' 67 (1959), those with n=2 are known from

C. M. Rice et al., J. Org. Chem. 21, 1687 (1955)

These compounds of formula IX are acylated in a known manner,

whereby an aliphatic or aromatic acyl residue, preferably an acetyl or benzoyl residue, is attached to the nitrogen atom, and the formed N-acylated compounds are anodically oxidized in an aliphatic alcohol, preferably an alkanol with 1 to 4 C atoms, especially methanol, in the presence of a light salt, preferably at temperatures in the range from 0° to +40°C to form a compound of formula X, in which n means 1, 2, 3 and

R 3 means (C^-C^)-alkyl, (analogously: Liebigs Ann. Chem. 1978,

p. 1719).

The formed compound with the general formula X is reacted with trimethylsilyl cyanide according to Tetrahedron Letters 1981, p. 141 in an aprotic organic solvent such as in a hydrocarbon, halohydrocarbon, in ether or in THF at temperatures in the range from -60°C to +20° C, preferably -40°C to -0°C in the presence of a Lewis acid such as for example ZnCl2, SnCl2, SnCl4, TiCl4, BF3-etherate, preferably BF^-etherate, and the formed compound of formula XI,

in which the H atoms of the C atoms 4 and 7+n are oriented in the cis or trans position to each other, whereby the CN group is in the cis position to the H atom of the C atom (7+n) and in which n has the meaning mentioned above, after purification and separation from by-products by means of recrystallization or column chromatography under the action of acids or bases in a known manner, the formed compound esterifies to a compound of formula III with W = hydrogen and the latter is optionally esterified. In the acidic hydrolysis of the nitrile group, HC1 or HBr is particularly used as acid. The esterification is carried out here subsequently according to the methods common in amino acid chemistry. Compounds of the general formula III' can also be prepared by transferring a compound of the formula XII,

in which the H atom of the C atoms 4 and (7+n) is cis- or trans-configured and n has the above-mentioned meaning,

in a Beckmann rearrangement by reaction with a mineral acid such as sulfuric acid or polyphosphoric acid or with benzenesulfonyl chloride or p-toluenesulfonyl chloride and a base such as triethylamine in a compound of formula XIII, in which

n has the meaning mentioned above, and halogenates this to a compound of formula XIV

in which n has the above-mentioned meaning and Hal means a halogen atom, preferably chlorine or bromine. Examples of halogenating agents include inorganic acid halides such as PCI, -, SO2C12, POC13, SOC12, PBr^ or halogens such as bromine. It is advantageous to use PC1b C or P0C1j-,

in combination with S02C12. As an intermediate, an imide halide is first formed which reacts further with the aforementioned halogenating agents and subsequent hydrolysis under basic conditions, preferably with aqueous alkali carbonate, to a compound of formula XIV.

The compounds of formula XIV are subsequently catalytically reduced in a polar protic solvent such as an alcohol, preferably ethanol, or in a carboxylic acid such as acetic acid with the addition of an acid acceptor such as sodium acetate or triethylamine to a compound of formula XV

in which n and Hal have the above meanings.

As a catalyst, for example, Raney nickel or palladium or platinum on animal charcoal.

Compounds of formula XV can also be prepared directly by halogenation of compounds of formula XIII using smaller amounts of the above-mentioned halogenating agents.

Compounds of formula XV are reacted according to the known Favorskii reaction in the presence of a base to a compound of formula III' with W'= hydrogen and this is optionally esterified. The above-mentioned Favorskii reaction is carried out in an alcoholic solvent such as methanol, ethanol or tert-butanol or in water or in mixtures thereof at temperatures in the range from 20°C to 140°C, preferably between 60°C and 100° C. Alkali or alkaline earth hydroxides such as sodium, potassium or barium hydroxide or alkali alcoholates such as sodium methylate or potassium tert-butanolate are suitably used as the base.

The intermediates of formula XIII can also be prepared according to Can.J.Chem. 38.' 557 (1960) of unsaturated nitriles of the formula XVI

in which n has the above meaning, by reaction with maleone esters in a Michael addition followed by reductive cyclization, saponification and decarboxylation. The compounds of formula II with Y and Z = hydrogen, R 1 ' methyl and R<2> = methyl or ethyl and X = phenyl used as starting materials for the preparation of compounds of formula I are known (European patent application no. 37,231). The compounds of formula II can be prepared by various methods. In a synthesis variant, one starts from a ketone of the above-mentioned formula VII which is reacted according to known methods in a Mannich reaction with a compound of the above-mentioned formula VI together with amino acid esters of the formula XVII

in which R and W have the above-mentioned meanings, to a compound of formula XVIII, in which R 2 , R 2 , X and W have the above-mentioned meanings, with the restriction that if W means a hydrogenolytically cleavable residue, especially benzyl, R 2 does not have the meaning of W. If the residue W is cleaved off hydrogenolytically with the help of, for example, palladium, compounds of formula II with Y and Z =■ hydrogen are obtained. If the residue W is split off with acids such as trifluoroacetic acid or hydrochloric acid in an inert organic solvent such as dioxane, compounds of formula II are obtained with Y and Z together = oxygen.

Compounds of formula XVIII are also available by Michael addition of a compound of the above-mentioned formula V with a compound of the above-mentioned formula XVII according to known methods. Preferably, this method is suitable for the production of such compounds with

1 2

formula XVIII, in which R is methyl, R is ethyl and

X means aryl.

The compounds of formula XVIII are obtained as diastereomer mixtures. Preferred diastereomers of formula XVIII are those in which the chiral C atoms marked with an asterisk have the S configuration. These can be separated by recrystallization or by chromatography, for example on silica gel. In a subsequent cleavage of the residue W, the configurations of the chiral C atoms are maintained.

The compounds of the above-mentioned formula IV used as starting materials for the preparation of the compounds of formula I are obtained by known methods from the compounds of the above-mentioned formula III by reaction with an N-protected 2-aminocarboxylic acid of the formula XIX,

wherein V means a protecting group and R has the above meaning. As protective group V, which is cleaved off again after the reaction has been completed, examples include the groups benzyloxycarbonyl or tert.-butoxycarbonyl.

The starting materials of formula XII are obtained in the usual way

the known ketones of formula XX

whereby the H atoms of the bridgehead carbon atoms can be in the cis or trans position and n has the above meaning. Compounds of formula XX with n = 1 are known from S.Dev, J.Indian Chem. Soc. 30, 815 (1953), those with n =2 from

A. Kandiah, J. Chem. Soc. 922 (1931) and such with n - 3 are known from A.M. Islam. RAW. Raphael, J. Chem. Soc. 315 (1955).

The reaction of a compound of formula II with a compound of formula III to produce a compound of formula I takes place according to one of the condensation reactions known in peptide chemistry, whereby for example dicyclohexylcarbodiimide and 1-hydroxy-benzotriazole are added as condensation agents. In the subsequent hydrogenolytic cleavage of residue W, palladium is preferably used as catalyst, while in the acidic cleavage of residue W, trifluoroacetic acid or hydrogen chloride is preferably used as acids.

In the above-described reactions for preparing the compounds of the formulas III', IV and I, the configurations of the intermediates of the bridgehead atoms 4 and (7+n) are always maintained. The starting materials of the formulas IX,

XII and XIII are formed during the synthesis either as pure diastereomers or as mixtures of the possible diastereomers,

which can optionally be separated by chromatography or crystallization.

The compounds of formula III' formed according to the methods described above are obtained as racemic mixtures and can be used as such in the syntheses described above. But they can also be used as pure enantiomers after separation of the racemates by usual methods, for example via salt formation with optically active bases or acids in the optical antipodes.

If the compounds of formula I are obtained as racemates, these can also be cleaved according to the usual methods such as, for example, via salt formation with optically active bases or acids in their enantiomers.

The compounds of formula I according to the invention are present

as internal salts. As amphoteric compounds, they can form salts with acids or bases. These salts are prepared in the usual way by reaction with an equivalent acid or

base.

The compounds of formula I and their salts have a long-acting, intensive blood pressure-lowering effect. They are strong inhibitors of angiotensin-converting enzymes (ACE inhibitors). They can be used to reduce high blood pressure in different ways

species. Their combination with other blood pressure lowering, vasodilating or diuretic active compounds is also possible. Typical representatives of this effect class are described e.g. in Erhardt-Ruschig, Arzneimittel, 2nd edition, Weinheim. 1972. It can be administered intravenously, subcutaneously or orally.

The dosage for oral administration is 1-100 mg, preferably 1-40 mg for each individual dose in an adult patient of normal weight, this is approx. 0.013-1.3 mg/kg/day, preferably 0.013-0.5 3 mg/kg/day. In more serious cases, the doses can also be increased, as toxic properties have not been demonstrated so far. A reduction in the dose is also possible and especially appropriate when diuretics are administered at the same time.

The compounds according to the invention can be administered orally or parenterally in corresponding pharmaceutical preparations. For an oral application form, the active compounds are mixed with the usual additives such as carriers, stabilizers or inert diluents, and brought by usual methods into suitable administration forms, such as tablets, dragees, suppositories, aqueous, alcoholic or oil-containing suspensions or aqueous, alcoholic or solutions containing oil. As inert carriers can be used e.g. gum arabic, magnesium carbonate, potassium phosphate, milk sugar, glucose or starch, especially corn starch. Thereby, the production can take place both as dry or wet granules. For example, plant oils and animal oils, such as sunflower oil or cod liver oil, are considered as oil-containing carriers or solvents.

For subcutaneous or intravenous application, the active compounds or their physiologically acceptable salts,

if desired with the therefore usual substances such as dissolution agents, emulsifiers or further auxiliaries brought into solution, suspensions or emulsions. Examples of solvents for the new active compounds and the corresponding physiologically acceptable salts are: water, physiological saline solutions or alcohols, e.g. ethanol, propanediol or glycerin, besides also sugar solutions such as glucose or mannitol solutions, or also a mixture of the various solvents mentioned.

The unusually strong effect of the compounds according to formula I is evident from the pharmacological data in the following table:

Intraduodenal (i.d.) or intravenous (i.v.) administrations to anesthetized rats, 50% inhibition of 310 ng angiotensin I triggered pressor reaction 30 min. after application at the dose ...... = ED^Q

The symbols n, X, Y, Z, R 1 and R 2 refer to the compounds of formula I.

The following examples serve as an illustration of the invention without this being limited to the compounds mentioned.

Example 1

(-)-( IS, 4S, 8S )- octahydrocyclopenta[ c ] pyrrole- 1- carboxylic acid

a) N-acetyl-cis-octahydrocyclopenta[c]pyrrole

To a solution of 3 g of octahydrocyclopenta[c]pyrrole and

4.2 ml of triethylamine in 30 ml of dry tetrahydrofuran are added dropwise at 0°C to 2.1 ml of acetyl chloride. After 15 min. stirring at 0°C, dilute with 150 ml of water, make acidic with 1N hydrochloric acid and extract with methylene chloride. The organic phase

is dried and evaporated. The raw product is distilled in high vacuum.

Yield: 2.4 g; boiling point 71°C/o.2 mm.

b) N-acetyl-2-methoxy-cis-octahydrocyclopenta[c]pyrrole 2.4 g N-acetyl-cis-octahydrocyclopenta[c]pyrrole is oxidized

anodic in methanol with the addition of tetramethylammonium tetrafluoroborate according to the indications in Liebig's Ann.Chem. 1978, page 1719. The solvent is removed, the residue is taken up in ether, filtered and the filtrate is evaporated.

<1>H-NMR data: 3.33 + 3.27 (2s,OCH3)

2.12 + 2.06 (2s,COCH3)

c) (-)-( 1S, 4S, 8S)- N- acetyl- octahydrocyclopenta[ e]- pyrrole- 1-carboxylic acid

To a solution of 2.4 g of N-acetyl-2-methoxy-cis-octahydrocyclopenta[c]pyrrole in 15 ml of methylene chloride, 1.31 g of trimethylsilyl cyanide in 3 ml of methylene chloride is added at -40°C. 1.88 g of boron trifluoride etherate is then added dropwise, whereby the temperature rises to -30°C. After 2 hours at -20°C and 2 hours at 0°C, water is added and extracted three times with methylene chloride. The organic phase is washed with sodium carbonate solution and water and saturated sodium chloride solution, dried and evaporated. 2.2 g of the title compound is obtained as a colorless oil.

d) (-)-( IS, 4S, 8S)- octahydrocyclopenta[c] pyrrole-1- carboxylic acid 2.2 g (-)-(1,S,4S,8S)-N-acetyl-octahydrocyclopenta[c]- 1-carboxylic acid-nitrile is boiled for 2 hours in 8 ml of concentrated hydrogen bromine. After the hydrogen bromide has been distilled off, the residue is stirred with a little acetone and suctioned off. An aqueous solution of the product is adjusted with a weak basic ion exchanger to a pH value of 6.0. After filtration, the solution is evaporated and the residue is filtered over silica gel with a mixture of methylene chloride, methanol, glacial acetic acid and water in the ratio 20:10:0.5:0.5. The eluate is evaporated and the residue is stirred with diiso-

propyl ether.

Yield: 1.6 g, Melting point 190 - 195°C.

If one works analogously to the methods described in example 1, the following compounds mentioned in example 2 and example 3 are obtained: Example 2

(-+)-( IS, 4S, 8S)- octahydro- 2H- cyclohexa[ c]- pyrrole- l- carboxylic acid

a) N-acetyl-cis-octahydro-2H-isoindole

b) N-acetyl-1-methoxy-cis-octahydro-2H-isolndole

in

c) N- acetyl- l- cyano- cis- octahydro- 2H- isoindole d) (-)-( IS, 4S, 9S)- octahydro- 2H- cyclohexa[c]- pyrrole- 1-carboxylic acid

Example 3

(-)-( IS, 4S, lOS)- decahydro- cyclohepta[ c] pyrrole- 1- carboxylic acid

a) N-acety1-cis-decahydrocyclohepta[c]pyrrole

b) - N- acetyl- l- methoxy- cis- decahydrocyclohepta[ c] pyrrole c) N- acetyl- l- cyano- cis- decahydrocyclohepta[ c] pyrrole d) (-)-( lS, 4S, lOS)- decahydrocyclohepta [c] pyrrole-l-carboxylic acid

Example 4

(-)-( IS, 4S, 9S)- octahydro- 2H- cyclohexa-'[c] pyrrole-l- carboxylic acid

a) cis-octahydro-2H-isoquinolin-3-one

To a mixture of 33.6 g (0.22 mol) of cis-hexahydro-indan-2-one-oxime and 300 ml of 5 N sodium hydroxide solution, 41 g (0.24 mol) of benzenesulfonyl chloride are added, whereby the temperature is kept below 50°C. One hour after the addition is complete, extract with methylene chloride, dry and evaporate, the residue is sublimed at 100-110°C/ 20 mm, Yield: 20 g, Melting point 149 - 151°C.

b) 4, 4-dichloro-cis-octahydro-2H-isoquinolin-3-one A solution of 23 g of cis-octahydro-2H-isoquinolin-3-one in

350 ml of anhydrous chloroform are added with 28.8 g of phosphorus pentachloride at room temperature. To this, 43.1 g of sulphuryl chloride in 45 ml of anhydrous chloroform are added dropwise over the course of 30 minutes at 20 to 30°C and the reaction mixture is stirred at the boiling point temperature. After standing overnight, the mixture is neutralized with an aqueous potassium carbonate solution cooled at 0°C. The aqueous phase is extracted twice with methylene chloride. The combined organic phases are dried over sodium sulfate and evaporated. The residue is recrystallized from ethanol with the addition of activated carbon. You get 32 g of pale yellow crystals.

c) 4-chloro-cis-octahydro-2H-isoquinolin-3-one

15.9 g of 4,4-chloro-cis-octahydro-2H-isoquinolin-3-one is hydrogenated

in one liter of ethanol with the addition of 10 ml of triethylamine and Raney nickel at 20 to 25°C under normal pressure until uptake of one molar equivalent of hydrogen. After filtration, the solution is evaporated, the residue is taken up in vinegar, the solution is extracted twice with water and dried over sodium sulphate. After removal of the solvent, the product is stirred with diisopropyl ether and suctioned off. Colorless crystals of the title compound are obtained.

d) (-)-( IS, 4S, 9S)- octahydro- 2H- cyclohexa[ c] pyrrole- l- carboxylic acid

3.75 g of 4-chloro-cis-octahydro-2H-isoquinolin-3-one is added to a boiling solution of 6.63 g of barium hydroxide octahydrate in 120 ml of water. After 3.5 hours of heating under reflux, the reaction mixture is added with 0.9 ml conc. sulfuric acid, boil for a further hour and then leave overnight for coagulation.

The precipitate that has formed is suctioned off and the filtrate adjusted to a pH value of 6.5 is evaporated to dryness. The residue is extracted with boiling ethanol, evaporated and brought to crystallization.

Yield: 3.1 g (identical to the compound described in example 2d).

Example 5

(-)-( IS, 4R, 9S )- octahydro- 2H- cyclohexa[ c ] pyrrole- l- carboxylic acid

a) trans-octahydro-2H-isoquinolin-3-one

Analogously to example 4a), 14.1 g of trans-hexahydroindan-2-one-oxime are reacted with 17.2 g of benzenesulfonyl chloride to give 8 g of the title compound,

Melting point: 165 - 167°C.

b) 4, 4-dichloro-trans-octahydro-2H-isoquinoliri-3-one Analogously to example 4b), 7.1 g of trans-octahydro-2H-isoquinolin-3-one is converted by reaction with 8.9 g of phosphorus pentachloride and 14 ml sulfuryl chloride to 11 g of the title compound:

pale yellow crystals, melting point 133 - 137°C.

c) 4-chloro-trans-octahydro-2H-isoquinolin-3-^one

Analogously to example 4c), 8 g of 4,4-dichloro-trans-octahydro-2H-isoquinolin-3-one are transferred by hydration in 5 g of the title compound.

d) (-)-( IS, 4R, 9S )- octahydro- 2H- cyclohexa[ c] pyrrole- l- carboxylic acid

Analogously to example 4d), 4.2 g of 4-chloro-transoctahydro-2H-isoquinolin-3-one gives 3.4 g of the title compound as colorless, amorphous powder.

The amino acids listed below can be prepared analogously to the methods described in examples 4a) to d).

Example 6

(-)-( 1S, 4S, 8S)- octahydro- cyclopenta[ c] pyrrole- 1- carboxylic acid Colorless crystals, melting point 190 - 195°C (identical to the compound described in example 1d). Example 7 (-)-(1S, 4R, 8S)-octahydrocyclopenta[c]pyrrole-1-carboxylic acid Colorless, amorphous powder. Example 8 (-) - ( IS , 4S , 10S ) - decahydro- cyclohepta [ c ] pyrrole- l - carboxy- 1 acid Colorless amorphous powder. Example 9 (-)-(IS, 4R, 10S)-decahydro-cyclohepta[c]pyrrole-l-carboxylic acid Colorless amorphous powder.

Example 10

(-)-( IS, 4S, 8S )- octahydrocyclopenta[ c3pyrrole- l- carboxylic acid benzyl ester hydrochloride

To a solution prepared at -40°C of 0.7 ml of thionyl chloride

0.7 g of (-)-(IS,4S,8S)-octahydro-cyclopenta[c]pyrrole-1-carboxylic acid is added to 7 ml of benzyl alcohol at -5°C. After a reaction time of 20 hours at room temperature, the benzyl alcohol is removed and the residue is stirred with diisopropyl ether. 0.84 g of the title compound is obtained as colorless crystals with a melting point of 120-122°C.

Analogous to the method described in example 10, lar

the following benzyl ester derivatives from examples 11 to 15 are prepared:

Example 11

(-) -( 1S, 4S, 9S )- octahydrocyclohexa[ c ] pyrrole- 1- carboxylic acid benzyl ester hydrochloride

Example 12 (-)- (IS, 4S, 10S)-decahydrocyclohepta[c]-1-carboxylic acid benzyl ester hydrochloride Example 13 (-)-CIS, 4R, 8S)-octahydrocyclopenta[c] pyrrole-l-carboxylic acid benzyl ester -hydrochloride Example 14 (-)-( IS, 4R, 9S)- octahydrocyclohexa[ c] pyrrole- 1- carboxylic acid benzyl ester hydrochloride Example 15 (-) -( IS, 4R, 1OS)- decahydrocyclohepta[ c] pyrrole- l - carboxylic acid benzyl ester hydrochloride

Example 16

(-+)- (IS, 4S, 8S)- octahydrocyclopenta[c] pyrrole-l- carboxylic acid-tert-butyl ester- hydrochloride

10 ml of conc. sulfuric acid and 50 g of isobutylene. The reaction mixture is heated in an autoclave *slowly to 20 to 25°C and stirred for 20 hours at this temperature.

The mixture is added to ice-cold 50% aqueous sodium hydroxide solution and extracted with methylene chloride. The combined organic phases are washed with water, dried with sodium sulphate and evaporated. The residue is taken up in ether and adjusted using ethereal hydrogen chloride to a pH value of 2.0 to 3.0. It is evaporated to dryness and the product is stirred with diisopropyl ether. After suction, 7.3 g of the title compound are obtained.

The tert-butyl esters in the subsequent examples 17 to 19 can be prepared analogously: Example 17 (-)-( IS, 4S, 9S)- octahydrocyclohexa[c] pyrrole-l-carboxylic acid tert-butyl ester hydrochloride Example 18 (-) -( IS, 4R, 8S)- octahydrocyclopenta[ c3 pyrrole- l- carboxylic acid-tert.- butyl ester- hydrochloride Example 19 (*)—( IS, 4R, 9S)- octahydrocyclohexa[ c] pyrrole- l- carboxylic acid-tert. -butyl ester hydrochloride

Example 20

N-(1S-carbethoxy-3-phenyl-propyl)-S-alanyl-1S,4S,8S-octahydrocyclopenta[c]pyrrole-1-carboxylic acid benzyl ester (=diastereomer. A 20) and N-(1S-carbethoxy-3- phenyl- propyl)- S-alanyl- 1R, 4R, 8R- octahydrocyclopenta[c] pyrrole- 1- carboxylic acid benzyl ester ( = diastereomer B 20)

0.82 g N-(1S-carbethoxy-3-phenyl-propyl)-S-alanine, 0.39 g 1-hydroxy-benztriazole, 0.82 g {-)-(1S,4S,8S)-octahydrocyclopenta [ c]pyrrole-1-carboxylic acid benzyl ester hydrochloride, 0.5 ml of N-ethylmorpholine and 0.59 g of dicyclohexylcarbodiimide are added at 20°C in 4 ml of dimethylformamide. It is stirred for 3 hours, diluted with 50 ml of acetic acid, extracted twice with water, dried over sodium sulphate and evaporated.

A mixture of the above-mentioned diastereomers A 20 is obtained

and B 20, which are separated over silica gel with a mixture of cyclohexane/acetic ester (2:1).

The compounds in the following examples 21 to 29 are prepared in an analogous way, as described in example 20: Example 21 N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-1S,4R,8S-octahydrocyclopenta[c ] pyrrole-l-carboxylic acid benzyl ester ( = diastereomer A 21)

Example 22 N-(1-S-carbethoxy-3-phenyl-propyl)-S-aianyl-1S,4S,9S-octahydrocyclohexa[c]pyrrole-1-carboxylic acid benzyl ester (=diastereomer A 22)

Example 23

N- (l- S- carbethoxy- 3- phenyl- propyl)- S- alanyl- 1S, 4R, 9S- octahydrocyclohexa[c] pyrrole- l- carboxylic acid- benzyl ester

( = diastereomer A 23)

Example 24

N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-1S,4S,10S-decahydrocyclohepta[c]pyrrole-1-carboxylic acid benzyl ester

(=diastereomer A 24)

Example 25

N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-1S,4R,10S-ocyclohepta[c]pyrrole-1-carboxylic acid benzyl ester

( = diastereomer A 25)

Example 2 6

N- (1- S- carbethoxy- 3- phenyl- propyl)- S- alanyl- 1S, 4S, 8S- octahydrocyclopenta[ c 3 pyrroi- 1- carboxylic acid- tert.- butyl ester

( = diastereomer A- 26)

Example 27

N- ( 1- S- carbethoxy- 3- phenyl- propyl)- S- alanyl- 1S, 4S, 9S- octahydrocyclohexa[c] pyrrole- 1- carboxylic acid- tert.- butyl ester

(- diastereomer A 27)

Example 28

N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-1S, 4R, 8S- octahydrocyclopenta[c] pyrrole-1- carboxylic acid tert. butyl ester

( = diastereomer A 28)

Example 29

N- (1- S- carbethoxy- 3- phenyl- propyl)- S- alanyl)- 1S, 4R, 9S-octahydrocyclohexa[c] pyrrole- l- carboxylic acid- tert-butyl ester

( = diastereomer A 29)

Example 30

N-(l- S- carbethoxy- 3- phenyl- propyl)- S- alanyl- 1S, 4S, 8S- octa-hydropenta[c] pyrrole- l- carboxylic acid hydrochloride

Method A:

0.7 g of diastereomer A 20 from Example 20 is hydrated in 25 ml of ethanol with 100 mg of palladium-animal charcoal (10%) at 20 to 25°C under atmospheric pressure. After separation of the catalyst, 0.5 n ethanolic hydrogen chloride is added to the solution until an acidic reaction. The solution is evaporated in vacuo and the residue is stirred with diisopropyl ether. 400 mg of the title compound are obtained as amorphous powder.

Method B:

A solution of 0.8 diastereomer A 26 from Example 26 i

5 ml of methylene chloride is saturated with dry chlorine hydrogen gas and left to stand for 16 hours at 20 to 25°C. The solution is evaporated in vacuo, the residue is stirred with diisopropyl ether and filtered off with suction.

Yield: 550 mg.

Example 31

N-(1- S- carbethoxy- 3- phenyl- propyl)- S- alanyl- 1R, 4R, 8R- octahydrocyclopenta[c] pyrrole- 1- carboxylic acid hydrochloride

This compound is obtained from diastereomer B 20 from example 20 in an analogous way to method A from example 30.

Colorless crystals with melting point 185 - 188°C.

Example 32

N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-1S,4R,8S-octahydrocyclopenta[c]pyrrole-1-carboxylic acid hydrochloride

This compound is obtained from the diastereomers A 21 from example 21 by a method analogous to method A in example 30.

Example 33

N-(1-S-carbethoxy-3-phenyl-propyl-S-alanyl-1S,4S,9S)-octahydrocyclohexa[c]pyrrole-1-carboxylic acid hydrochloride

This compound is obtained from the diastereomers A 22 from example 22 by a method analogous to method A in example 30.

Example 34

N-(l- S- carbethoxy- 3- phenyl- propyl)- S- alanyl- 1S, 4R, 9S- octa-hydrhexa[c] pyrrole- l- carboxylic acid hydrochloride

This compound is prepared from the diastereomers A 23 from example 23 analogously to method A, which is described in example 30.

The compounds from examples 32 to 34 can also be prepared from the diastereomers A 26 to A 28 according to the method B described in example 30.

Example 35

N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-1S,4S,10S-decahydrocyclohepta[c]pyrrole-1-carboxylic acid hydrochloride

This compound is prepared from the diastereomer A 24 from example 24 analogously to the method A described in example 30.

Example 36

N-( 1- S- carbethoxy- 3- phenyl- propyl)- S- alanyl- 1S, 4R, 10S- decahydrocyclohepta[c] pyrrole- 1- carboxylic acid hydrochloride

This compound is prepared from the diastereomer A 25 from example 25 analogously to the method A described in example 30.

Example 37

N-(l- S- carboxy- 3- phenyl- propyl)- S- alanyl- 1S, 4S, 8S- octahydrocyclopenta[c] pyrrole- l- carboxylic acid

A solution of 1 g of N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-1S,4S,8S-octahydrocyclopenta[c]pyrrole-1-carboxylic acid hydrochloride in 10 ml of water is added to two equivalents of potassium hydroxide and a 10% excess of 4n-potassium hydroxide solution. After stirring for 8 hours at 20 to 25°C, the reaction solution is adjusted with 2n-hydrochloric acid to a pH value of 4.0 and evaporated in vacuo. The residue is taken up in vinegar, filtered off from the secreted salt. The acetic ester solution is evaporated, the residue is stirred with diisopropyl ether and suctioned off.

Yield: 0.6 g

Example 38

N-(l- S- carboxy- 3- phenyl- propyl)- S- alanyl- 1S, 4R, 8S- octahydrocyclopenta[c] pyrrole- l- carboxylic acid

This compound is prepared from the compound from example 32 analogously to the method described in example 37.

Example 39

N-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-1S, 4S, 9S- octa-. hydrocyclohexa[c]pyrrole-l-carboxylic acid

This compound is prepared from the compound from example 33 analogously to the method described in example 37.

Example 40 ( cKÅaJ^ din,) N-( 1- S- carboxy- 3- phenyl- propyl)- S- alanyl)- IS , 4R, 9S- alcyclo-hexa[c] pyrrole-l- carboxylic acid

This compound is prepared from the compound from example 34 analogously to the method described in example 37.

Example 41

N-(l- S- carboxy- 3- phenyl- propyl)- S- alanyl- 1S, 4S, lOS- deca hydrocyclohepta[c] pyrrole- l- carboxylic acid

This compound is prepared from the compound from example 35 analogously to the method described in example 37.

Example 42

N-(l- S- carboxy- 3- phenyl- propyl)- S- alanyl- 1S, 4R, 10S- decahydrocyclohepta[c] pyrrole- l- carboxylic acid

This compound is prepared from the compound from example 36 analogously to the method described in example 37.

Example 4 3 N-(1-S-carbethoxy-3-phenyl-3-oxo-propyl)-S-alanyl-1S,4S,8S-octahydrocyclopenta[c]pyrrole-1-carboxylic acid benzyl ester 2.5 g N-(1-S -carbethoxy-3-phenyl-3-oxo-propyl)-S-alanine is added together with 1.2 g of 1-hydroxybenztriazole, 2.5 g of (-)-IS,4S,8S-octahydrocyclopenta[c]pyrrole-l- carboxylic acid benzyl ester hydrochloride, 1.25 ml of N-ethylmorpholine and 2 g of dicyclohexylcarbodiimide in 20 ml of dimethylformamide. The mixture is stirred for 1 hour at 0°C and then for 12 hours at 20 to 25°C.

The reaction solution is diluted with 25 ml of acetic acid, secreted urea is suctioned off. After evaporation in vacuo, the residue formed is taken up in ether and the ethereal solution is washed with saturated aqueous sodium bicarbonate solution and with water, dried and evaporated. 3 g of the title compound are obtained as a mixture of diastereomers. The diastereomer mixture can be separated over silica gel with cyclohexane-acetic acid ester as eluent in the optically pure compounds.

Examples 44 to 50

The compounds indicated below in examples 44 to 50 can be prepared by a method which is analogous to that indicated in example 4 3 using the corresponding bicyclic carboxylic acid ester compounds.

Example 44

N-(1-S-carbethoxy-3-phenyl-3-oxo-propyl)-S-alanyl-1S,4R,8S-octahydrocyclopenta[c]pyrrole-1-carboxylic acid benzyl ester

Example 45

N-(1-S-carbethoxy-3-phenyl-3-oxo-propyl)-S-alanyl-1S,4S,9S-octahydrocyclohexa[c]pyrrole-1-carboxylic acid benzyl ester

Example 46 N-(1-S-carbethoxy-3-phenyl-3-oxo-propyl)-S-alanyl-1S, 4R, 9S-g^U^^ cyclohexa[c] pyrrole-1-carboxylic acid benzyl ester Example 4 7 N- ( l- S- carbethoxy- 3- phenyl- 3- oxo- propyl) - S- alanyl- lS , 4S , 8S- ^txJ^oL-o cyclopenta[ c] pyrrole- l- carboxylic acid- tert. - butyl ester

Example 48

N-(1-S-carbethoxy-3-phenyl-3-oxo-propyl)-S-alanyl-1S,4R,8S-octahydrocyclopenta[c]pyrrole-1-carboxylic acid tert-butyl ester

Example 49 N-(1-S-carbethoxy-3-phenyl-3-oxo-propyl)-S-alanyl-1S,4S,9S-octahydrocyclohexa[c]pyrrole-1-carboxylic acid-tert-butyl ester Example 50 N- (l- S- carbethoxy- 3- phenyl- 3- oxo- propyl)- S- alanyl- 1S, 4R, 9S-octahydrocyclohexa[c] pyrrole- l- carboxylic acid- tert-butyl ester

Example 51

N-(l-S-carbethoxy-3-phenyl-3-oxo-propyl)-S-alanyl-lS,4S,8S-octahydrocyclopenta[c]pyrrole-l- carboxylic acid

0.9 g of the compound from example 4 7 is stirred in 6 ml of trifluoroacetic acid for 2 hours at 20°C. Evaporate in a vacuum, stir with diisopropyl ether and filter with suction.

Yield: 0.4 g

Analogous to the method described in example 51, the compounds in examples 52 to 54 can be prepared below: Example 52 N-(1-S-carbethoxy-3-phenyl-3-oxo-propyl)-S-alanyl-1S, 4R, 8S-octahydrocyclopenta[c]pyrrole-l-carboxylic acid Example 53 N-(l-S-carbethoxy-3-phenyl-3-oxo-propyl)-S-alanyl-lS,4S,9S-octahydrocyclohexa[c]pyrrole-l - carboxylic acid

Example 54

N-(1-S-carbethoxy-3-phenyl-3-oxo-propyl)-S-alany1-1S,4R,9S-octahydrocyclohexa[c]pyrrole-1-carboxylic acid

Example 55

N-( l- S- carboxy- 3- phenyl- 3- oxo- propyl)- S- alanyl- 1S, 4S, 8S-octahydrocyclopenta[c] pyrrole- l- carboxylic acid

To prepare this compound, 0.5 g of N-(1-S-carbethoxy-3-phenyl-3-oxo-propyl)-S-alanyl-1S,4S,8S-octahydrocyclopenta[c]pyrrole-1-carboxylic acid is reacted analogously to that in example 37 described method with potassium hydroxide:

Example 56

N-(l- S- carbethoxy- 3- phenyl- 3- hydroxy- propyl)- S- alanyl- 1S, 4S, 8S- octahydrocyclopenta[c] pyrrole- l- carboxylic acid

1 g of N-(1-S-carbethoxy-3-phenyl-3-oxo-propyl)-S-alanyl-1S,4S,8S-octahydrocyclopenta[c]pyrrole-1-carboxylic acid is dissolved in 50 ml of anhydrous ethanol and hydrated with 50 mg of palladium / coal at 20 to 25°C under atmospheric pressure with 1 mole equivalent of hydrogen. After filtering off the catalyst, the solution is evaporated. The residue is stirred with diisopropyl ether and suctioned off.

Yield: 0.7 g

Example 57

S- alanyl- 1S, 4S, 8S- octahydrocyclopenta[c] pyrrole- 1- carboxylic acid benzyl ester

a) N- tert.- butoxycarbonyl- S- alanyl- 1S, 4S, 8S- octahydrocyclopenta[c] pyrrole- 1- carboxylic acid benzyl ester

To a solution of 19 g of BOC-ala-OH in 100 ml of DMF is added

13 ml of N-ethylmorpholine, 13.5 g of 1-hydroxy-benzotriazole and 29.6 g of 1S,4S,8S-octahydrocyclopenta[c]pyrrole-1-carboxylic acid benzyl ester hydrochloride. The mixture is cooled in an ice bath and 21 g of dicyclohexylcarbodiimide are added. The mixture is stirred for 15 hours at 20 to 25°C. The precipitated urea is suctioned off, the filtrate is evaporated in a vacuum and taken up in vinegar. The organic phase is extracted 3 times with aqueous potassium hydrogen sulfate solution, 3 times with aqueous potassium hydrogen carbonate solution and aqueous sodium chloride solution, dried and evaporated. The residue is chromatographed on silica gel with ethyl acetate/cyclohexane (1:3). The first fraction contains the desired product.

Yield: 21 g

b) S-alanyl-1S, 4S, 8S- octahydrocyclopenta[c] pyrrole-1-carboxylic acid r e- benzyl ester

20.5 g of N-tert.-butoxycarbonyl-5-alanyl-1S,4S,8S-octahydrocyclopenta[c]pyrrole-1-carboxylic acid benzyl ester were dissolved in 50 ml of trifluoroacetic acid. After a reaction time of 10 min.

the solution is evaporated in a vacuum, the residue is stirred several times with diisopropyl ether and this is dried in a vacuum. Yield: 12.5 g.

Examples 58 to 62

These compounds are prepared analogously to the methods described in example 57 under a) and b): Example 58 S-alanyl-1S, 4R, 8S- octahydrocyclopenta[c] pyrrole-1-carboxylic acid benzyl ester Example 59 S-alanyl-1S, 4S, 9S- octahydrocyclohexa[c] pyrrole-1-carboxylic acid benzyl ester

Example 60

S- alanyl- 1S, 4R, 9S- octahydrocyclohexa[c] pyrrole- 1- carboxylic acid benzyl ester

Example 61 S- alanyl- lS, 4S, lOS- decahydrocyclohepta[ c] pyrrole- l- carboxylic acid benzyl ester Example 62 S- alanyl- lS, 4R, lOS- decahydrocyclohepta[ c] pyrrole- l- carboxylic acid benzyl ester Example 6 3 N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-1S,4S,8S-octahydrocyclopenta[c]pyrrole-1-carboxylic acid a) N-(1-S-carbethoxy-3 - phenyl- propyl)- S- alanyl- 1S, 4S, 8S-octahydrocyclopenta[c]pyrrole-l- carboxylic acid- benzyl ester 10 ml mol S-alanyl-1S,4S,8S-octahydrocyclopenta[c]pyrrole-1-carboxylic acid- benzyl ester is dissolved in 30 ml of anhydrous ethanol. The solution is adjusted to a pH value of 7.0 using ethanolic potassium hydroxide and 1 g of powdered molecular sieve (4Å) and then 10 mmol of 2-keto-4-phenyl-butyric acid ethyl ester are added. A solution of 1 g of sodium cyanoborohydride in 10 ml of anhydrous ethanol is slowly added dropwise.

After a reaction time of 20 hours at 20 to 25°C, the reaction solution is filtered and the solvent is distilled off. The residue is taken up in vinegar/water. After evaporation of the acetate phase, the residue is chromatographed on silica gel with acetate/cyclohexane (1:4). H-NMR data agree with the data of the compounds from example 20. b) The compound prepared above is further reacted as described in example 30, method A, to the desired compound. Example 64 N-(1-S-carbethoxy-3-phenyl-3-oxo-propyl)-S-alanyl-1S,4S,9S-octahydrocyclohexa[c]pyrrole-1-carboxylic acid benzyl ester 10 mmol S-alanyl-1S ,4S,9S-octahydrocyclopenta[c]pyrrole-1-carboxylic acid benzyl ester is dissolved together with 10 mmol of 3-benzoyl acrylic acid ethyl ester and 10 mmol of triethylamine in 100 ml of anhydrous ethanol and the mixture is stirred for 24 hours at 20 to 25°C. Neutralize with 1 N hydrochloric acid, evaporate to dryness and take up the residue with vinegar/water. The acetic ester phase is dried, evaporated and chromatographed on silica gel. Example 65 N-(1-S-carbethoxy-3-oxo-3-phenyl-propyl)-IS,4S,10S-decahydrocyclohepta[c]pyrrole-1-carboxylic acid benzyl ester 10 mmol acetophenone, 10 mmol glyoxylic acid ethyl ester and 10 mmol S -alanyl-1S,4S,10S-decahydrocyclohepta[c]pyrrole-1-carboxylic acid benzyl ester is heated in 30 ml of glacial acetic acid for 36 hours at 45°C. After evaporation in vacuo, make alkaline with aqueous sodium bicarbonate solution and extract with acetic acid. The acetic ester phase is evaporated and chromatographed on silica gel.

Example 66

N-(l-S-carbethoxy-3-phenyl-propyl)-O-ethyl-S-tyrosyl-lS,4S,8S-octahydrocyclopenta[c]pyrrole-l-carboxylic acid

a) N-(1- R, S- carbethoxy- 3- phenyl- propyl)- O- ethyl- S- tyrosyl-, benzyl benzyl ester

One reacts 24 g of benzoyl acrylic acid ethyl ester in 100 ml of ethanol with 30 g of O-ethyl-S-tyrosine benzyl ester in the presence of 0.5 ml of triethylamine and after evaporating the solution and stirring the residue with diethyl ester/petroleum ether (1:1) and drying in vacuo 42 g of the title compound.

b) N-(1-R,S-carbethoxy-3-phenyl-propyl)-o-ethyl-S-tyrosine

40 g of the compound prepared according to example 66a is hydrated in 800 ml of glacial acetic acid with 4 g of Pd/C (10%) at 100 bar and room temperature. After chromatography on silica gel with ethyl acetate/cyclohexane (1:3) as eluent and drying of the evaporation residue, 25 g of the thin-layer chromatographically almost uniform title compound are obtained, melting point 205-213°C.

c) N-(1-S-carbethoxy-3-phenylpropyl)-0-ethyl-S-tyrosyl-1S,4S,8S- octahydrocyclopenta[c]pyrrole-1-carboxylic acid

Analogous to the method described in example 20, 1.5 g of the benzyl ester described in example 10 is reacted with 2.5 N-(1-R,S-carbethoxy-3-phenyl-propyl)-0-ethyl-S-tyrosine,

1.3 dicyclohexylcarbodiimide and 0.8 g 1-hydroxybenztriazole. Chromatography of the crude product on silica gel with cyclohexane/acetic ester (1:1) as eluent gives 1 g of the title compound as a colorless oil.

'''The H-NMR data and mass spectrum are consistent with the given structure.

The benzyl ester is hydrogenolyzed analogously to the method described in example 30. 0.6 g of the title compound is obtained as a colorless amorphous powder.

Example 67

N-(l-S-carbethoxy-3-phenyl-propyl)-O-methyl-S-tyrosyl-lS,4S,8S-octahydrocyclopenta[c]pyrrole-l-carboxylic acid

The title compound is obtained analogously to the method described in example 66 using O-methyl-tyrosine benzyl ester instead of O-ethyl tyrosine benzyl ester in the 66a) analogous step.

Example 68

N-(1-S-carbethoxy-3-phenyl-propyl)-O-ethyl-S-tyrosyl-1S,4S,9S-octahydroisoindole-1-carboxylic acid

Prepared analogously to the method described in example 6 6 of the amino acid described in example 2. ^"The H-NMR data is consistent with the given structure.

Example 69

N-( 1- S-( carbethoxy- 3- phenyl- propyl)- 0- methyl- S- tyrosyl- 1S, 4S, 9S- octahydroisoindole- 2- carboxylic acid

Prepared analogously to the method described in example 68 using the amino acid described in example 2. "'"The H-NMR data is consistent with the given structure.

Example 70

N-(1- S- carbethoxy- 3- phenyl- propyl)- O- ethyl- S- tyrosy1- 1S, 4S, 8R-octahydrocyclopenta[c] pyrrole- 2- carboxylic acid

Prepared analogously to the method described in example 6 6 using the amino acid described in example 7.

Example 71

N-(l-S-carbethoxy-3-phenyl-propyl)-O-methyl-S-tyrosyl-lS,4S,8R-octahydrocyclopenta[c]pyrrole-l-carboxylic acid

Prepared analogously to the procedure described in example 67 using the amino acid described in example 7. The ^H-NMR data is consistent with the given structure.

Example 72

N-(l- S- carbethoxy- 3- phenyl- propyl)- O- ethyl- S- tyrosyl- lS, 4S, 9R-octahydrocyclohexa[c] pyrrole-l- carboxylic acid

Produced analogously to the method described in example 66. The analytical data are consistent with the stated structure.

Example 73

N-(1-S-carbethoxy-3-phenyl-propyl)-O-methyl-S-tyrosyl-1S,4S,9R-octahydrocyclohexa[c]pyrrole-1-carboxylic acid

Produced analogously to the method described in example 67. The analytical data are consistent with the stated structure.

Claims (2)

1. Compound of formula III' in which the C atoms 1, 4 and (7+n) have the same configuration as in formula III, and in which n means 1, 2 or 3, W means hydrogen or a hydrogenolytic or acidic cleavable residue. 2. Process for the preparation of compounds of formula III' according to claim 1, characterized by) that a compound of formula IX is acylated, in which the H atoms of the C atoms 4 and (7+n) are cis- or trans-configured to each end and in which n means the number 1, 2 or 3, then anodically oxidizes the formed compound with an alcohol in the presence of a lead salt of a compound of formula X wherein n has the above meaning and R 3 means (C 1 -C 2 )-alkyl, reacts this with trimethylsilyl cyanide in the presence of a Lewis acid to a compound of formula XI, in which the H atoms of the C atoms 4 and (7+n) are cis- or trans-configured to each other and whereby the CN group is in the cis position to the H atom of the C atom (7+n) and in which n has the aforementioned meaning, and this is hydrolysed by the action of acids or bases to a compound of formula III' with W=hydrogen and optionally esterified the latter compound, orb) that one reacts a compound of formula XII in which the H atoms of the C atoms 4 and (7+n) are cis- or trans-configured and n has the above meaning, in a Beck- mann rearrangement to a compound of formula XIII wherein n has the above-mentioned meaning, this halogenates to a compound of formula XIV, wherein n has the above meaning and Hal means a halogen atom, reduces this to a compound of formula XV, in which n and Hal have the meanings mentioned above, and then converts this under the influence of a base into a compound of the formula III <1> with W'=hydrogen, and optionally esterifies this.