DE3151690A1 - Novel derivatives of bicyclic amino acids, process for their preparation, compositions containing them and their use, and also novel bicyclic amino acids as intermediates and process for their preparation - Google Patents

Abstract

The invention relates to cis, exo- and trans-compounds of the formula I <IMAGE> in which n denotes 0, 1 or 2, R1 denotes hydrogen, alkyl which can optionally be substituted by amino, acylamino or benzoylamino, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl or partially hydrogenated aryl, which in each case can be substituted by alkyl, alkoxy or halogen, arylalkyl which can be substituted in the aryl radical as defined above, a mono- or bicyclic S- or O- and/or N-heterocycle radical or a side chain of a naturally occurring amino acid, R2 denotes hydrogen, alkyl, alkenyl or arylalkyl, Y denotes hydrogen or hydroxyl, Z denotes hydrogen or Y and Z together denote oxygen and X denotes alkyl, alkenyl, cycloalkyl, aryl which can be mono-, di- or trisubstituted by alkyl, alkoxy, hydroxyl, halogen, nitro, amino, alkylamino, dialkylamino or methylenedioxy, or indol-3-yl, and their physiologically acceptable salts, a process for their preparation, compositions containing them and their use, and also novel bicyclic amino acids as intermediates and a process for their preparation.

Description

New derivatives of bicyclic amino acids, method too

their preparation, agents containing them and their use, as well as new bicyclic amino acids as intermediates and processes for their preparation. The present invention relates to new derivatives of the bicyclic amino acids of the formula I, in which the hydrogen atoms on the bridgehead carbon atoms 3 a and (6 + n) a are cis or trans configured to one another, in the case of the cis configuration the carboxy group on carbon atom 2 is oriented exo to the bicyclic ring system and where n = 0,1 or 2, R1 = hydrogen, (C1-C6) -alkyl, which may optionally be substituted by amino, (C1-C4) -acylamino or benzoylamino, (C2-C6) -alkenyl, (C5- Cg) -cycloalkyl, (C5-C9) -cycloalkenyl, (C5-C7) -cycloalkyl- (C1-C4) -alkyl, aryl or partially hydrogenated aryl, each represented by (C1-C2.) -Alkyl, (C-C2 ) -Alkoxy or halogen, aryl (C1-C4) alkyl, the aryl radical of which, as defined above, can be substituted, a mono- or bicyclic heterocycle radical with 5 to 7 or 8 to 10 ring atoms, of which 1 up to 2 ring atoms are sulfur or oxygen atoms and / or of which 1 to 4 ring atoms represent nitrogen atoms, or a side chain of a naturally occurring amino acid, R2 = hydrogen, (C1-C6) -alkyl, (C2-C6) -alkenyl or aryl- (C1-C4) -alkyl, Y = hydrogen or hydroxy, Z = hydrogen or Y and Z = together oxygen, X = (C1-C6) -alkyl, (C2-C6) -alkenyl, (C5-Cg ) -Cycloalkyl, aryl, substituted by (C1-C4) -alkyl, (C1-C4) -alkoxy, hydroxy, halogen, nitro, amino, (C1-C4) -alkylamino, di- (C1-C4) -alkylamino or methylenedioximono can be di- or trisubstituted, mean indole bonded via carbon atom 3, as well as their physiologically harmless salts.

Particularly suitable salts are alkali and alkaline earth salts, Salts with physiologically acceptable amines and salts with inorganic or organic Acids such as HCl, HBr, H2S04, maleic acid, fumaric acid.

Here, as in the following, aryl is to be understood as meaning phenyl or naphthyl. Alkyl can be straight-chain or branched.

In the case of the trans configuration of the H atoms at C-3a and C- (6 + n) a two possible configurations of the bicycle come into consideration, namely the 2B, 3ad, (6 + n) aß-configuration (formula residue Ib) as well as the 3B, 3ass, (6 + n) a «-configuration (Formula residue Ic), while in the case of the cis configuration of the H atoms, the carboxy group must be oriented in the exo position (= B position).

The exo position (= B position) of the carboxy group at C72 is defined as that the carboxy group is oriented in the direction of the relevant H atoms, i.e.

facing away from the concave side of the bicycle, for example in accordance with the formula radical Ia. (For the definition of and B see also Fieser and Fieser, Steroide, p. 2, 1961) Compounds of the formula I have chiral carbon atoms in positions C-2, C-3a, C- (6 + n) a, and in the carbon atoms of the side chain marked with an asterisk. Both the R and S configurations at all centers are the subject of the invention. The compounds of the formula I can therefore exist as optical isomers, as diastereomers, as racemates or as mixtures thereof.

Preference is given to the compounds of the formula I in which the carbon atom 2 in the bicyclic ring system, as well as the carbon atoms marked with an asterisk in the Side chain have S configuration.

Preferred compounds of the formula I are those in which R1 = hydrogen, (C1-C3) -alkyl, (C2-C3) -alkenyl, benzyl, 4-amino-butyl, R2 = hydrogen, (C1C4) -alkyl, Benzyl X = phenyl, which is replaced by (C1-C2) -alkyl, (C1-C2) -alkoxy, hydroxy, fluorine, chlorine, Bromine, amino, (C1-C4) -alkylamino, di- (C1-C) alkyl-amino, nitro or methylenedioxy, mono- or can be disubstituted or, in the case of methoxy, trisubstituted.

Particularly preferred are those compounds of the formula I in which R1 = methyl and X = phenyl and those in which R2 = hydrogen 'or Mean ethyl.

The invention also relates to processes for the preparation of the compounds of the formula I. A variant of the process is characterized in that a compound of the formula II, wherein R1, R2, X, Y and Z have the meanings as in formula I, with a compound of formula III, in which the H atoms on the carbon atoms 3 a and (6 + n) a are cis-pder trans -configured to one another, in the case of the cis configuration the group -CO2W is oriented exo to the bicyclic ring system, and where n = 0, 1 or 2 and W = a hydrogenolytically or acidically cleavable radical, in particular a benzyl or tert-butyl radical, converted by known amide formation methods of peptide chemistry and then converted by catalytic hydrogenation or acid treatment to the radical W and if appropriate, by additional acid or base treatment, the radical R2 is also split off, the free carboxylic acids being obtained in each case.

Further synthetic processes for the preparation of the compounds of the formula I, in which Y and Z together denote oxygen, consist in that a compound of the formula IV, wherein the H atoms on the carbon atoms 3a and (6 + n) a are cis or trans configured with respect to one another, wherein in the case of the cis configuration the -CO2W group is oriented exo to the bicyclic ring system, and wherein n and R1 have the meanings as in formula I and W has the meaning as in formula III, with a compound of the formula V, R202C-CH = CH-CO-X V wherein R2 and X have the meanings as in formula I in a known manner in a Michael reaction (Organikum, 6th edition, SO 492, 1967) converts and splits off the radical W and optionally the radical R2 as described above or that a compound of the above formula IV with a compound of the general formula VI, in which R2 is as in formula I, and with a compound of the general formula VII OHC-CO2R2 X-CO-CH3 VI VII in which X has the same meaning as in formula I, in a known manner in a Mannich reaction (Bull.Soc.Chim.

France 1973, p.625) and then the remainder W and possibly splitting off the radical R2 as described above with formation of the free carboxy groups.

Furthermore, compounds of the formula I where Y, Z = hydrogen can also be prepared in such a way that a compound of the above formula IV is prepared according to the method described in J. Amer. Chem. Soc. 93 2897 (1971) described procedure with a compound der'Formel VIII in which R2 and X have the meanings as in formula I, the Schiff bases obtained are reduced and then the radical W and optionally the radical R2 as described above are split off with formation of the free carboxy groups, or one obtained according to the above procedures Compound of the formula I in which Y and Z together denote oxygen, catalytically reduced with hydrogen. The Schiff bases can be reduced catalytically, electrolytically or with reducing agents such as sodium borohydride or sodium cyanoborohydride.

Compounds of the formula I with Y = hydroxy and Z = hydrogen can for example also by reducing a obtained according to the above procedures Compound I with Y and -Z = together oxygen. This reduction can be catalytic with hydrogen or with another reducing agent such as Sodium borohydride.

The invention also relates to compounds of the formula III ', where C-2, C-3a and C- (6 + n) a have the same configurations as in formula III, n = 0, 1 or 2 and W 'has the meaning of W in formula III and additionally denotes hydrogen . According to the invention, these compounds serve as starting materials in the synthesis of compounds of the formula I and can be prepared according to the invention by the following procedures.

One synthesis variant is based on a compound of the formula IX, in which the H atoms on the carbon atoms 3a and (6 + n) a are cis or trans configured with respect to one another and in which n is the number 0, 1 or 2.

Compounds of formula IX with n = 0 are from Booth et al., J. Chem. Soc. 1959 p. 1050, those with n = 1 from King et al., J. Chem. Soc. 1953es. 250, 253 and those with n = 2 from Ayerst et al., J. Chem. Soc. 1960, p. 3445 known.

These compounds of the formula IX are acylated in a known manner, an aliphatic or aromatic acyl radical, preferably an acetyl or benzyl radical, being bonded to the nitrogen atom, and the M-acylated compounds obtained in an aliphatic alcohol, preferably an alkanol 1 to 4 carbon atoms, in particular methanol, in the presence of a conductive salt, preferably at temperatures in the range from 0 ° to + 409C with the formation of a compound of the formula X in which n = 0, 1 2 and R3 = (C1-C4) -alkyl, anodically oxidized (analogous: Liebigs Ann. Chem. 1978, p. 1719).

The resulting compound of the general formula X is hydrogenated with trimethylsilyl cyanide according to Tetrahedron Letters 1981, p. 141 in an aprotic organic solvent such as, for example, in a hydrocarbon, halocarbon, in ether or in THF at temperatures in the range from -600C to + 200C, preferably - 400C to + 0 ° C in the presence of a Lewis acid such as ZnCl2, SnCl2, SnCl4, TiCl41 BF3 etherate, preferably BF3 etherate, reacted and the resulting compound of the formula XI, wherein the H atoms on the carbon atoms 3 a and (6 + n) a are cis or trans configured with respect to one another, wherein in the case of the cis configuration the group -CN is oriented exo to the bicyclic ring system and wherein n has the abovementioned meaning, after purification and removal of by-products by means of recrystallization or column chromatography by the action of acids or bases hydrolyzed in a known manner to give a compound of the formula III with W '= hydrogen and the latter optionally esterified. In the acidic hydrolysis of the nitrile group, HCl or HBr in particular is used as the acid. The esterification is carried out here as in the following in accordance with the procedures customary in amino acid chemistry.

Compounds of the general formula III 'can also be prepared by adding a compound of the formula XII in which the H atoms on the carbon atoms 3 a and (6 + n) a are cis or trans configured and n has the meaning given above in a Beckmann rearrangement analogous to Helv. Chim. Acta 46, 1190, (1963) to a compound of the formula XIII, in which n is as defined above converts and this to a compound of formula XIV, where n has the abovementioned meaning and Hal is a halogen atom, preferably chlorine or bromine, halogenated. Possible halogenating agents are, for example, inorganic acid halides such as PCl5, SO2Cl2, POCl3, SOCl2, PBr3 or halogens such as bromine. The use of PCl5 or POCl3 in combination with SO2Cl2 is advantageous. As an intermediate, an imide halide is initially formed which reacts further with the halogenating agents mentioned and subsequent hydrolysis under basic conditions, preferably with aqueous alkali metal carbonate, to form a compound of the formula XIV.

The compounds of the formula XIV are subsequently in a polar protic solvent such as an alcohol, preferably ethanol, or a carboxylic acid such as acetic acid with the addition of an acid acceptor such as sodium acetate or triethylamine to give a compound of the formula XV, in which n and Hal have the meanings given above, catalytically reduced. For example, Raney nickel or palladium or platinum on charcoal can be used as the catalyst.

Compounds of the formula XV can also be prepared directly by halogenation of the compounds of the formula XIII when using smaller amounts of the abovementioned Halogenating agents are produced.

Compounds of formula XV are made according to the known Favorskii reaction in the presence of a base to a bond of the formula III 'with W '= hydrogen reacted and this optionally esterified. The aforementioned Favorskii reaction is 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 ° to 140 "C, preferably between 600 and 100" C carried out. As bases are appropriate Alkali or alkaline earth hydroxides such as sodium, potassium or barium hydroxide or alkali alcoholates such as sodium methylate or potassium tert-butoxide are used.

Furthermore, the compounds of the formula III ', in which the H atoms on the carbon atoms 3a and (6 + n) a are cis-configured, from the compound of the formula XVI, in which n = 0.1 or 2, can be produced by following these according to Ann. Chim. 62 200 (1972) reduced by means of platinum oxide / acetic acid to a compound of the above formula XIII and this is further reacted according to the procedures described above. Compounds of the formula XVI are from J. Org.

Chem. 29 2780- (1964) known.

tCompounds of the formula III ', in which the H atoms on the C atoms 3a and (6 + n) a can also have trans configuration from a compound of the above Formula XVI can be prepared by this according to Bull. Soc. Chim. Belg. 85 11 (1976) with sodium formate / formic acid to a compound of the formula XIII reduced and this further implemented according to the procedures described above.

Furthermore, the trans-configured compounds of the formula III starting from an N-acylated B-haloalanine ester of the formula XVII (free amino compound s: Helv. Chim. Acta 40, 1541 (1957)), in which Hal is a halogen atom, preferably chlorine, Bromine, acyl, an aliphatic or aromatic acid radical, in particular an acetyl or benzoyl radical, and R4 = (C1 - C4) -alkyl, especially methyl, are based on an acylated aminoacrylic ester of the formula XVIII (Chem. Ber. 91, 2427 ( 1958)).

wherein acyl and Ra has the meaning given above, are prepared by combining one of the two compounds of the formula XVII or XVI II mentioned with a compound of the formula XIX (Organikum, 6th edition, p. 370, 1967), in which n has the meaning given above, and A is a chemical bond, a methylene group or an oxygen atom, to a compound of the formula XX, in which n, acyl and R4 have the abovementioned meanings in a known manner, these react with a mineral acid, preferably HCl, HBr to form a compound of the formula XXI, in which n has the abovementioned meaning, cyclized, this reduced to a compound of the formula III 'with W' = hydrogen and this optionally esterified. The reduction of the compound of the formula XXI can be carried out catalytically with hydrogen under the usual conditions or with a reducing agent such as sodium borohydride.

The compounds of formula II with Y, Z = hydrogen, R1 = methyl and R2 = methyl eder ethyl and X = phenyl used as starting materials for the preparation of the compounds of the formula I are known (European patent application No. 37 231). The compounds of the formula II can be prepared by various procedures. One synthesis variant is based on a ketone of the above formula VII which, according to known procedures, in a Mannich reaction with a compound of the above formula VI together with amino acid esters of the formula XXII, in which R1 and W have the meanings given above, to a compound der'Formel XXIII, in which R1, R2, X and W have the meanings mentioned above, with the restriction that in the case of W = a hydrogenolytically cleavable radical, in particular benzyl, R2 does not Meaning of W may have, implements.

If you split the remainder W hydrogenolytically with the help of, for example From palladium, compounds of the formula II with Y, Z = hydrogen are obtained. Is the remainder W with acids such as trifluoroacetic acid or hydrochloric acid split off in an inert organic solvent such as dioxane, one obtains compounds of the formula SI with Y and Z together = oxygen.

Compounds of Formula XXIII are also one by Michael addition Compound of the above formula V with a compound of the above formula XXII accessible by known procedures. This method is particularly suitable for the preparation of compounds of the formula XXIII in which R1 = methyl, R2 = ethyl and X = aryl.

The compounds of the formula XXIII fall as mixtures of diastereomers at. Preferred diastereomers of the formula XXIII are those in which the with a Asterisk marked chiral carbon atoms each have the S configuration.

This can be done by recrystallization or by chromatography, for example on silica gel. In the subsequent cleavage of the remainder W remain the configurations of the chiral carbon atoms are preserved.

The compounds of the abovementioned formula IV used as starting materials for the production of the compounds of the formula I are obtained from the compounds of the abovementioned formula III by reaction with an N-protected 2-aminocarboxylic acid of the formula XXIV in which V is a protective group and R1 has the abovementioned meaning, obtained by known procedures. As protective group V, which is split off again after the reaction has ended, for example the groups benzyloxycarbonyl or tert. -Butoxycarbonyl in question.

The reaction of a compound of the formula II with a compound ' of the formula III for the preparation of a compound of the formula I is carried out according to a condensation reaction known in peptide chemistry, being used as a condensation agent for example dicyclohexylcarbodiimide and 1-hydroxy-benzotriazole can be added.

In the subsequent hydrogenolytic cleavage of the residue W becomes Palladium is preferably used as the catalyst, while in the acidic cleavage of the radical W preferably used as acids trifluoroacetic acid or hydrogen chloride will.

In the reactions described above for the preparation of the compounds of formulas III '. , IV and I remain the configurations of the intermediates, respectively obtained at the bridgehead carbon atoms 3a and (6 + n) a. In the case of the trans configuration of the H atoms on the C atoms 3a and (6 + n) a are the compounds in question partly obtained as pure diastereomers, partly as mixtures of diastereomers, the as stated above, the 2ß-3aoc, (6 + n) aß or the 2B, 3aß, (6 + n) ao <-configuration exhibit. These isomers can be easily identified by recrystallization or chromatography be separated.

Are for the preparation of the compounds of the formulas III ', IV or I corresponding starting materials with cis configuration of the H atoms at C-3 a and C- (6 + n) a used, the exo (or B) isomers are obtained almost exclusively, Which by recrystallization or by chromatography of small proportions of the isomers can be freed.

The compounds obtained according to the procedures described above of the formula III 'are obtained as racemic mixtures and can be used as such in the other syntheses described above are used. But you can also after separation of the racemates using customary methods, for example via salt formation with optically active ones Bases or acids can be used as pure enantiomers in the optical antipodes.

If the compounds of the formula I are obtained as racemates, they can also this according to the usual methods such as, for example, via salt formation with optical active bases or acids are split into their enantiomers.

The compounds of the formula I according to the invention are internal Salts before. As amphoteric compounds, they can form salts with acids or bases. These salts are prepared in the usual way by reacting with one equivalent of acid or Base made.

The compounds of formula I and their salts have long lasting, - intense antihypertensive effect.

They are powerful angiotensin converting enzyme (ACE) inhibitors. They can be used to combat high blood pressure of various origins. Also their combination with other antihypertensive, vasodilator or diuretic effective connections is possible. Typical representatives of these activity classes are e.g.

in Erhardt-Ruschig, Arzneimittel, 2nd edition, Weinheim, 1972, described. It can be used intravenously, subcutaneously or orally.

The dosage for oral administration is 1-100 mg, preferably at 1-40 mg per single dose for an adult patient of normal weight. ^ It can in severe cases it can also be increased, since toxic properties have not yet been observed became. A reduction in the dose is also possible and is particularly appropriate if if diuretics are administered at the same time.

The compounds according to the invention can be administered orally or parenterally in appropriate pharmaceutical preparation are administered. For oral use the active compounds with the usual additives such as carriers, Stabilizers or inert diluents and mixed by conventional methods brought into suitable dosage forms, such as tablets, coated tablets, push-fit capsules, aqueous, alcoholic or oily suspensions or aqueous, alcoholic or oily suspensions Solutions. Examples of inert carriers are gum arabic, magnesium carbonate, potassium phosphate, Milk sugar, glucose or starch, especially corn starch, can be used. Included the preparation can be done either as dry or wet granules. As oily Carriers or solvents come, for example, of vegetable and animal origin Consider oils such as sunflower oil or cod liver oil.

The active compounds are used for subcutaneous or intravenous administration or their physiologically acceptable salts, if desired with those customary therefor Substances such as solubilizers, emulsifiers or other auxiliaries in solution, Suspensions or emulsions brought.

As a solvent for the new active compounds and the corresponding Physiologically compatible salts come into question, for example: water, physiological saline solutions or alcohols, e.g. ethanol, propanediol or glycerine, as well as sugar solutions such as glucose or mannitol solutions, or a mixture of the various solvents mentioned.

The extraordinarily strong effectiveness of the compounds according to formula I is demonstrated by the pharmacological data in the tables below: Intraduodenal administration to the anesthetized rat, 50% inhibition of the presser reaction triggered by 310 μg angiotensin I 30 minutes after administration in the dose ..... = ED50: Table I (H atoms at C-3a and C- (6 + n) a in formula I have cis configuration) n XYZ R2 R1 ED50 (ijg / kg) O <22 HH C2H5 CH3 40 3 ' OOHHH CH3 700 OHH C2H5 CH3 50 HOHHH CH3 600 2 OHH C2H5 CH3 230 2 (3 HHH CH3 840 1 - 0 ° ~ C2H5 CH3 390 The symbols n, X, Y, Z, R1 and R2 relate to the compounds of the formula I.

Table II H atoms at C-3a and C- (6 + n) a have the trans configuration; X = phenyl, R1 = methyl n Y Z R2 configuration of the ED50 (µg / kg) BiCYCLUS 0 H H H 2S, 3aR, 6aS 700 0 H H C 2H5 2S, 3aR, 6aS 40 1 H H H 2S, 3aR, 7aS 800 1 H H C2H5 2S, 3aR, 7aS 55 1 H H H 2S, 3aS, 7aR 850 1 H H C 2H5 2S, 3aS, 7aR 65 2 H H H 2S, 3aR, 8aS 1080 2 H H C2H5 2S, 3aR, 8aS 110 1 - 0 - C 2H5 25, 3aR, 7aS 180 The symbols n, X, Y, Z, R1 and R2 relate to the compounds of the formula I.

The following examples serve to illustrate the invention, without restricting these to the representative compounds: example 1 2β, 3ass, 7ass-octahydroindole-2-carboxylic acid a) N-acetyl-3ass, 7ass-octahydroindole 3.5 g of platinum oxide are added to a solution of 77 g of indole in 700 ml of glacial acetic acid. The mixture is hydrogenated first for 16 hours at 20 to 250 ° C. under 100 atmospheres and then at 20 to 25 ° C under normal pressure until the hydrogen uptake has ended. Of the The catalyst is filtered off with suction and the solvent is distilled off in vacuo. The residue is taken up in water and made alkaline with saturated potassium carbonate solution. After saturation with sodium chloride, the aqueous phase is washed four times with methylene chloride extracted and the organic phase dried and evaporated.

The residue is taken up in 250 ml of pyridine, with 93 ml of acetic anhydride added, after which the mixture is allowed to react at 20 to 250C for 12 hours.

After the pyridine has been distilled off, water is added to the residue and with conc. watery Sodium hydroxide made alkaline. The aqueous is extracted Phase with methylene chloride, the organic phase obtained is washed with 2N hydrochloric acid and then with water. After drying and concentrating the solution, the residue becomes distilled.

Yield: 85 g; Bp: 91 to 950C / 0.2 mm Hg b) N-acetyl-2-methoxy-3ass, 7ass-octahydroindo 54 g of N-acetyl-3aB, 7ass-octahydroindole are dissolved in methanol with the addition of tetramethylammonium tetrafluoroborate according to the Anyaben in LiebigsAnn Chem. 1978, page 1719 anodic oxidized. The solvent is distilled off and the residue over 500 g of silica gel filtered using ethyl acetate. After evaporation, the ethyl acetate solution becomes 53.6 g of the above product were obtained. Rf value (thin layer chrome.): 0.33 (silica gel, Ethyl acetate).

c) N-Acetyl-2ß, 3aß, 7aß-octahydroindole-2-carboxylic acid nitrile to one Solution of 49.8 g of N-acetyl-2-methoxy-3ass, 7ass-octahydroindole in 250 ml of methylene chloride 25 g of trimethylsilyl cyanide in 50 ml of methylene chloride are added dropwise at -400C. Then 35.9 g of boron trifluoride etherate are added dropwise so that the temperature of the reaction mixture does not exceed -200C. After a reaction time of 2 hours -200C, the temperature is slowly increased to OOC, stirred overnight at OOC and then another hour at 20 to 250C. Add water and stir for 10 min.

The aqueous phase is extracted three times with methylene chloride. the combined organic extracts are dried, concentrated and the residue triturated with diisopropyl ether.

Yield: 47 g; Fp .: 1280 to 1300C.

d) 2ß, 3ass, 7ass-Octahydroindole-2-carboxylic acid 10 g of acetyl-2ß, 3ass , 7ass-octahydroindole-2-carboxylic acid nitrile are concentrated in 30 ml. Hydrogen bromide two hours to. Boiling heated. After the hydrogen bromide has been distilled off, the The residue is stirred with a little acetone and filtered off with suction.

An aqueous solution of the product is weakly basic Ion exchanger set to a pH of 6.0. After filtration, the solution becomes evaporated and the residue over silica gel with a mixture of methylene chloride, Methanol, glacial acetic acid and water in a ratio of 20: 10: 0.5: 0.5 filtered.

The eluate is concentrated and the residue is triturated with diisopropyl ether.

Yield: 7.6 g * H-NMR spectrum: 1.0-2.5 (m, 11H); 3.4-3.9 (m, 1H); 4.0-4.5 (m, 1H); 7.5-8.3 (s-wide, interchangeable with D20) Proceed in the same way as Procedures described under Example 1, one obtains the under Example 2 and Example 3 in the following compounds: Example 2 2ß, 3aß, 6aß-Octahydrocyclopenta / b 7-pyrrole-2-carboxylic acid a) N-acetyl-cis-octahydrocyclopenta [b] -pyrrole 1H-NMR data: 1.0 to 2.3 (m, 9H); 2.0 (d. 3H); 3.3 to 4.2 (m, 3H) b) N-acetyl-2-methoxy-cis-octahydrocyclopenta / 7-pyrrole 1 H NMR data: 0.9 to 2.6 (m, 9H); 2.1 (s, 3H); 3.3 (s, 3H); The H-NMR data were determined here as in the following in CDCl3 and are here as in the following given in ppm.

3.8-4.3 (m, 1H) 4.7-5.5 (m, 1H).

c) N-Acetyl-2-cyano-cis-octahydrocyclopenta [b] pyrrole H-NMR data: 1.0-3.0 (m, 9H); 2.1 (d, 3H) 3.5-4.1 (m, 1H); 4.4-4.7 (m, 1H).

d) 2β, 3aß, 6aß-Octahydrocyclopenta [b] pyrrole-2-carboxylic acid H-NMR data: 1.0-2.3 (m, 9H); 3.5-3.9 (m, 1H) 4.0-4.6 (m, 1H); 7.7 - 8.4 (s-wide, with D2O exchangeable) Example 3 2β, 3ass, 8ass-Decahydrocyclohepta [b] pyrrole-2-carboxylic acid a) N-acetyl-cis-decahydrocyclohepta / b-7pyrrole 1 H NMR data o 0.9-2.5 (m, 13H); 2.1 (s, 3H) 3.1-4.1 (m, 3H).

b) N-acetyl-2-methoxy-cis-decahydrocyclohepta [b] pyrrole 1 H-NMR data: 0.9-2.7 (m, 13H) 2.1 (s, 3H) 3.2 (s! 3H) 3.7-4.2 (m, 1H); 4.7-5.3 (m, 1H) c) N-acetyl-2-cyano-cis-decahydrocyclopenta / b-7pyrrole 1 H-NMR data: 0.9-3.1 (m, 13H); 2.1 (s, 3H); 3.5-4.1 (m, 1H); 4.3-4.7 (m, 1H) d) 213.3ass, 8ass-D.ecahydrocylohepta / -b 7-pyrrole-2-carboxylic acid 1 H-NMR data: 0.8-2.4 (m, 13H); 3.5-3.9 (m, 1H); 4.1-4.6 (m, 1H); 7.6- - 8.3 (s-wide, interchangeable with D2O) Example 4 2B, 3ass, 7ass-Octahydroindole-2-carboxylic acid a) 3,4,5,6, 7,8-Hexahyd'ro-1H-quinolin-2-one 392 g of cyclohexanone and 212 g of acrylonitrile are together with 20 g of cyclohexylamine, 4 g of glacial acetic acid and 0.4 g of hydroquinone for 4 hours heated under reflux to a final temperature of 2000C. After distillation at 100 to 1500C / 0.5 mm Hg will be the residue left that is the desired Recrystallized from n-hexane.

The distillate is heated to 200 ° C. for 2 days with 10 ml of 10% acetic acid heated. After cooling, further product is obtained, which is obtained from methanol / water crystallized.

A total of 460 g of the title compound, m.p .: 143-1440C are obtained.

b) Cis-Octahydro-1H-quinolin-2-one A solution of 80 g of 3,4,5,6,7,8-hexahydro-1H-quinolin-2-one is mixed with one gram of platinum (IV) oxide and at 20 to 250C under normal pressure hydrogenated.

After filtration of the reaction solution this is evaporated and the The residue is fractionally crystallized from n-hexane. 35 g of cis-octahydro-1H-quinolin-2-one are obtained of m.p. 123 to 1260C.

c) 3,3-dichloro-cis-octahydro-1H-quinolin-2-one A solution of 23 g of cis-octahydro-1H-quinolin-2-one in 350 ml of anhydrous chloroform is 28.8 g phosphorus pentachloride added. For this purpose, 43.1 g of sulfuryl chloride in 45 ml of anhydrous Chloroform added dropwise within 30 min. At 20 to 30 ° C and the reaction mixture Stirred for 5 'hours at boiling temperature. After standing overnight, the mixture becomes neutralized with aqueous potassium carbonate cooled to OOC. The aqueous phase.

is extracted twice with methylene chloride. The united organic Phases are dried over sodium sulfate and concentrated. The residue will be off Recrystallized ethanol with the addition of activated charcoal. 32 g of pale yellow crystals are obtained from Fp.

176 to 1770C.

d) 3-chloro-cis-octahydro-1H-quinolin-2-one 15.9 g 3,3-dichloro-cis-octahydro-1H-quinolin-2-one are in one liter of ethanol with the addition of 10 ml of triethylamine and Raney nickel at 20 to 25 "C under normal pressure up to the absorption of one molar equivalent of hydrogen hydrogenated. After filtration, the solution is evaporated and the residue in ethyl acetate added, the solution extracted twice with water and over Dried sodium sulfate. After removing the solvent, the product is with Triturated diisopropyl ether and sucked off. There are colorless crystals with a melting point of 1850C obtain.

e) 2β, 3ass, 7ass-Octahydroindol-2-carboxylic acid 3.75 g of 3-chloro-cis-octahydro-1H-quinolin-2-one are in a boiling solution of 6.63 g of barium hydroxide octahydrate in 120 ml of water given. After refluxing for 3.5 hours, the reaction mixture is with 0.9 ml conc. Added sulfuric acid, heated to boiling for a further hour and then left to stand overnight.

The deposited precipitate is filtered off with suction and that with 1N sodium hydroxide the filtrate, which has been adjusted to a pH value of 6.5, is evaporated to dryness. The residue is extracted with boiling ethanol, concentrated and crystallized.

Yield 3.1 g In a manner analogous to that described in Example 4, The compounds 2B-cis-octahydrocyclopenta / 7pyrrole-2-carboxylic acid can also be used (corresponds to compound from Example 2d) and 2ß, 3aß, 8aß-Decah'ydrocyclohepta / b 7pyrrole-2-carboxylic acid (corresponds to connection in example 3 d).

Example 5 2B, 3aB, 7aB-Octahydroindole-2-carboxylic acid benzyl ester hydrochloride 3 ml of thionyl chloride are added dropwise to 25 ml of benzyl alcohol. For this purpose 3'g 2β, 3ass, 7ass-octahydroindole-2-carboxylic acid hydrochloride added. You leave that Reaction mixture Stand at 5 ° C for 2 days, after which a clear solution forms. After evaporation the residue obtained is mixed with diisopropyl ether and filtered off with suction. You get 3.8 g of the title compound, m.p. 1500C (dec.).

In a manner analogous to that described in Example 5, the produce the following ester compounds of Examples 6 and 7: Example 6 2ß, 3aß 6ass-Octahydrocyclopenta / b 7pyrrole-L-carboxylic acid benzyl ester hydrochloride 1H-NMR data: 1.0-2.3 (m, 9H); 3.4-3.9 (m, 1H); 4.1-4.6 (m, 1H); 5.1 (s, 2H); 7.2 (s, 5H) example 7 2β, 3ass, 7-pyrrole-2-carboxylic acid benzyl ester hydrochloride 1 H-NMR data: 0.9-2.3 (m, 13H) 3.5-3.9 (m, 1H); 4.2-4.7 (m, 1H); 5.2 (s, 2H) 7.2. (s, 5H) Example 8 2B, 3ass, 7ass-Octahydroindole-2-carboxylic acid tert-butyl ester hydrochloride to a solution, cooled to -10 ° C., of 10 g of 2β, 3ass, 7ass-octahydroindole-2-carboxylic acid in 100 ml of dioxane, 10 ml of conc. Sulfuric acid and 50 g of isobutylene.

The reaction mixture is slowly heated to 20 ° to 250 ° C. in the autoclave and stirred at this temperature for 20 hours.

The mixture is poured into ice-cold 50% strength aqueous sodium hydroxide and extracted with methylene chloride.

The combined organic phases are washed with water, with Dried sodium sulfate and concentrated.

The residue is taken up in ether and treated with ethereal hydrogen chloride Adjusted to its own pH value of 2.0 to 3.0. It is concentrated to dryness and rubbed in the product with diisopropyl ether. After filtering off with suction, 7.3 g of the title compound are obtained obtain.

1 H NMR data: 1.0-2.5 (m, 11H); 1.3 (s, 9H); 3.4-3.9 (m, 1H) 4.0 - 4.5 (m, 1H).

The following ester compounds of Examples 9 and 10 can analogously to Procedure described in Example 8 are prepared: Example 9 2ß, 3aß , / pyrrole-2-carboxylic acid tert. butyl ester hydrochloride 1 H NMR data: 1.0-2.7 (m, 9H); 1.3 (s, 9H) 3r4-3.9 (m, 1H); 4.0-4.5 (m, 1H).

Example 10 2β, 3aß b 8ass-Decahydrocyclohepta (b] pyrrole-3-carboxylic acid tert-butyl ester hydrochloride 1 H-NMR data: 0.8-2.9 (m, 13H); 1.3 (s, 9H); 3.4-3.9 (m, 1H) 4.0-4.5 (m, 1H).

Example 11 N- (1 S-Carbethoxy-3-phenyl-propyl) -5- alanyl-2S, 3aR, 7aR-octahydroindole-2-carboxylic acid benzyl ester (= diastereomer A 11) and N- (1S-carbethoxy-3-phenyl-propyl) -S- alanyl-2R, 3aS, 7aS-octahydroindole-2-carboxylic acid benzyl ester (= diastereomer B 11).

2.5 g N- (1 SCarbethoxy-3-phenyl-propyl) -S- alanine, 1.22 g 1-Hydroxi-benzotriazole, 2.5 g (d, l) -2β, 3aB, 7ass-octrahydroindole-2-carboxylic acid benzyl ester hydrochloride, 1.25 ml of N-ethylmorpholine and 2 g of dicyclohexylcarbodiimide are in 20 ml of dimethylformamide at 0 ° C given.

The mixture is stirred for 1 hour. at OOC, the mixture slowly warms to room temperature and stir overnight at 20 to 250C.

25 ml of ethyl acetate are added to the reaction mixture; more unusual Urea is sucked off. After evaporating the solution, the residue obtained becomes taken up in 50 ml of ether, the ethereal solution using saturated aqueous sodium hydrogen carbonate and water washed, dried and concentrated. It becomes a mixture of the above Diastereomers A 11 and B 11 obtained, which over silica gel with a mixture is separated from cyclohexane / ethyl acetate (4: 1).

Rf value for diastereomer A 11: 0.36 R value for diastereomer B 11: 0.34 The following compounds of Examples 12 to 16 are in a procedure analogous to how Described in Example 11, obtained: Example 12 N- (1-S-Carbethoxy-3-phenyl-propyl) -5- alanyl-2S, 3aR, 7aR-octahydroindole-2-carboxylic acid-tert. butyl ester (= diastereomer A 12).

H-NMR data: 1.25 (d + t, 6H); 1.35 (s, 9H); 1.3-3.6 (m, 18H); 4.2 (q, 2H) 4.4 (m, 1H); 7.3 (s, 5H).

Example 13 N- (1-S-Carbethoxy-3-phenyl-propyl) -5- alanyl-2S, 3aR, 6aR-octahydrocyclopenta / b ~ / pyrrole-2-carboxylic acid benzyl ester (= diastereomer A 13).

H-NMR data: 1.1 (d, 3H); 1.3 (t, 3H) 1.3-2.4 (m, 10H); 2.3-3.4 (m, 6H); -4.1 (q, 2H); 4.55 (d. 1H); 5.2 (s, 2H); 7, .2 (s, 5H); 7.4 (sr 5H).

Example 14 N-1-S-Carbethoxy-3-phenyl-propyl) -S- alanyl-2S, 3aR, 8aR) decahydrocyclohepta [b] pyrrole-2-carboxylic acid benzyl ester (= diastereomer A 14).

H-NMR data: 1.2 (d + t, 6H); 1.3-2.4 (m, 14H); 2.3-3.4 (m, 6H); 4.2 (q, 2H); 4.6 (m. 1H); 5.2 (s, 2Hj; 7.25 (s, 5H); 7.4 (s, 5H).

Example 15 N- (l-S-Carbethoxy-3-phenyl-propyl) -S- alanyl-2S, 3aR, 6aR-octahydrocyclopenta / b-7pyrrole-2-carboxylic acid tert-butyl ester (= diastereomer A 15).

H-NMR data: 1.1 (d, 3H); 1.3 (t, 3H); 1-, 3 - 2.4 (m, 10H) 1.4 (s, 9H); 2.3-3.4 (m, 6H); 4.2 (q, 2H); 4.6 (m. 1H); 7.2 (s, 5H).

Example 16 N- (1-S-Carbethoxy-3-phenyl-propyl) -S- alanyl-2S, 3aR, 8aR-decahydrocyclohepta [b] pyrrole-2-carboxylic acid tert-butyl ester (= diastereomer A 16).

1 H-NMR data: 1.1 (d, 3H); 1.3 (t, 3H); 1.4 (s, 9H); 1.4 - -2.5 (m, 14H); 2.3-3.4 (m, 6H); 4.1 (q, 2H); 4.7 (m. 1H); 7.3 (s, 5Hj.

Example 17 N- (1-S-Carbethoxy-3-phenyl-propyl) -S- alanyl-2S, 3aR, 7aR-octahydroindole-2-carboxylic acid hydrochloride Method A: 0.7 g of diastereomer A 11 from Example 11 are in 25 ml of ethanol with 100 ml of palladium animal charcoal (10 t) Hydrogenated from 20 to 250C under normal pressure. After separating the catalyst, the Solution mixed with 0.5 N ethanolic hydrogen chloride until an acidic reaction.

The solution is concentrated in vacuo and the residue with diisopropyl ether rubbed in. 400 mg of the title compound with a melting point of 198 ° to 2000 ° C. are obtained.

1 H-NMR data of the free base: 1.0-3.0 (m, 19H); 3.0-3.3 (t, 1H); 3.3-3.9 (m, 3H); 3.9-4.4 (q, 2H); 4.4-4.7 (broad s, 4H); 7.2 (s, 5H) method B: A solution of 0.8 diastereomer A 12 from Example 12 in 5 ml of methylene chloride is saturated with dry hydrogen chloride gas and 16 hours at 20 to 25 ° C ditched. The solution is concentrated in vacuo; the residue is made with diisopropyl ether rubbed and sucked off.

Yield: 550 mg.

Example 18 N- (l-S-Carbethoxy-3-phenyl-propyl) -S- alanyl-2S, 3aR, 6aR-octahydrocyclopenta (b] pyrrole-2-carboxylic acid hydrochloride This compound is from the diastereomer A 13 of example 13 in a to method.A of the example 17 obtained analogous procedure.

1 H-NMR data: 1.2 (d, 3H); 1.3 (t, 3H); 1.2-3.8 (m, 16H); 4.15 (q, 2H); 4.2-4.6 (m, 4H); 7.2 (s, 5H) Example 19 N- (l-S-Carhethoxy-3-phenyl-propyl) -S- alanyl-2S, 3aR, 8aR-decahydrccyclohepta [b] pyrrole-2-carboxylic acid hydrochloride This compound is prepared from the diastereomer A 14 of Example 14 analogously to that in Method A described in Example 17 prepared.

H-NMR data: 1.2 (d, 3H); 1.3 (t, 3H); 1.2-3.8 (m, 2011); 4.2 (q, 2H); 4.0-4.7- (m, 4H); 7.2 (s, 5H) The compounds of Examples 18 and 19 can even from the diastereomers A 15 and A 16 according to the example Method B described in 17.

Example 20 N- (1-S-Carboxy-3-phenyl-propyl) -S-alanyl-2S, 3aR, 7aR-octahydroindole-2-carboxylic acid A solution of 1 g of N- (1-S-carbethoxy-3-phenyl-propyl) -S- alanyl-2S, 3aR, 7aR-octahydroindole-2-carboxylic acid hydrochloride in 10 ml of water is mixed with two equivalents of potassium hydroxide and a 10% excess 4N potassium hydroxide added. After stirring for hours at 20 to 25 ° C, the reaction solution is adjusted to pH 4.0 with 2N hydrochloric acid and concentrated in vacuo. Of the The residue is taken up in ethyl acetate; the deposited salt is filtered off. The ethyl acetate solution is concentrated and the residue is triturated with diisopropyl ether and sucked off.

Yield: 0.6 g 1H-NMR data: 1.2 (d, 3H); 1.2-3.8 (m, 18H); 4.0 - 4.6 (m, 4H); 7.2 (s, 5H).

Example 21 N- (1-S-Carhoxy-3-phenyl-propyl) -S- alanyl-2S, 3aR,, 6aR-octahydrocyclopenta / b ~ / pyrrole-2-carboxylic acid This compound is made from the compound of Example 18 prepared analogously to the process described in Example 20.

H-NMR data: 1.2 (d, 3H); 1.2-3.8 (m, 16H); 4.05-4.7 (m, 4H); 7.2 (s, 5H) Example 22 N- (1-S-Carboxy-3-phenyl-propyl) -S- alanyl-2S, 3aR, 8aR-decahydrocyclohepta / b / pyrrole-2-carboxylic acid This compound is obtained from the compound of Example 19 prepared analogously to the process described in Example 20.

H-NMR data: 1.2 (d, 3H); 1.3-3.9 (m, 20H); 4.0-4.7 (m, 4H); 7.2 (s, 5H).

Example 23 N- (1-S-Carbethoxy-3-phenyl-3-oxo-propyl) -5-alanyl-2β, 3ass, 7ass-octahydroindole-2-carboxylic acid tert-butyl ester 2.5 g N - (- Carbethoxy-3-phenyl-3-oxo-propyl) -5-allanine together with 1.2 g of 1-hydroxybenzotriazole, 2.5 g of 2B, 3ass, 7ass-octahydroindole-2-carboxylic acid tert-butyl ester hydrochloride (d, l), 1.25 ml of N-ethylmorpholine and 2 g of dicyclohexylcarbodiimide in 20 ml of dimethylformamide given. The mixture is stirred at OOC for 1 hour and then at 20 to 25 ° C. for 12 hours.

The reaction solution is diluted with 25 ml of ethyl acetate; more secluded Urea is sucked off. After concentration in vacuo, the residue obtained is taken up in ether, the ethereal solution with saturated aqueous Sodium bicarbonate and washed with water, dried and evaporated. You get 3 g of the title compound as a mixture of diastereomers.

1 H NMR data: 1.2 (s, 9H); 0.9 - 2.6 (m, 18H); 3.5-5.1 (m, 6H); 7.2 - 8.2 (m, 5H).

The mixture of diastereomers can be obtained via silica gel with cyclohexane-ethyl acetate Eluent can be separated into the optically pure compounds.

Examples 24 to 28 The following compounds of Examples 24 to 28 can be used in a procedure analogous to Example 23 using the corresponding bicyclic carboxylic acid ester compounds.

Example 24 N- (1-S-Carbethoxy-3-phenyl-3-oxo-propyl) -S- alanyl-2B, 3aß, 6aB-octahydrocyclopenta / b ~ 7pyrrole-2-carboxylic acid-tert. butyl ester K-NMR data: 1.2 (s, 9H); 0.9-2.5 (m, 16H); 3.5-5.1 (m, 6H); 7.2 - 8.2 (m, 5H).

Example 25 N- (1- S-Carbethoxy- 3-phenyl-3-oxo-propyl) -S- alanyl-2S, 3aR, 8aR-decahydrocyclohepta / b ~ 7pyrrole-2-carboxylic acid tert-butyl ester 1H-NMR data: 1.4 (s, 9H); 1.0-2.8 (m, 20H); 3.4-5.1 (m, 6H); 7.2 - 8.2 (m, 5H).

Example 26 N- (1-Carbethoxy-3-phenyl-3-oxy-propyl) -5- alanyl-2B, 3ass, 7ass-octahydroindole-2-carboxylic acid benzyl ester H-NMR data: 1.2 (d, 3H); 1.3 (t, 3H); 1.4-2.4 (m, 10H); 2.4-3.9 (m, 6H); 4.2 (q, 2H); 4.3-4.8 (m, 1H); 5.2 (s, 2H); 7.2 (s, 5H); 7.4 - 8.0 (m, 5H).

Example 27 N- (1-S-Carbethoxy-3-phenyl-3-oxo-propyl) alanyl-2B, 3ass, 6ass-octahydrocyclopenta / b ~ 7pyrrole-2-carboxylic acid benzyl ester H-NMR data: 1.25 (d + t, 6H); 1.4-2.4 (m, 8H); 2.4-3.8 (m, 6H); 4.2 (q, 2H); 4.3-4.8 (m, 1H); 5.2 (s, 2H); 7.2 (s, 5H); 7.4 - 8.0 (m, 5H).

Example 28 N- (1-S -Carbethoxy-3-phenyl-3-oxo-propy1) -S- alanyl-2β, 3ass, 8ass-octahydrocyclohepta / b ~ 7pyrrole-2-carboxylic acid benzyl ester 1H-NMR data: 1.2 (d. 3H); 1.3 (t, 3H); 1.4-2.5 (m, 12H); 2.4-3.8 (m, 6H); 4.2 (q, 2H); 4.3 - 4.8 (m, 1H); 5.2 (s, 2H); 7.2 (s, 5H); 7.4 - 8.0 (m, 5H).

Example 29 N- (1-s-Carbethoxy-3-phenyl-3-oxo-propyl) -S- alanyl-2 [beta], 3ass, 7ass-octahydroindole-2-carboxylic acid trifluoroacetate 2.6 g of the mixture of diastereomers of Example 23 are stirred in 15 ml of trifluoroacetic acid at 20 to 25 ° C. for 2 hours. The solution is concentrated in vacuo, the residue is triturated with diisopropyl ether and sucks.

Yield: 0.8 g 1 H-NMR data: 1.2 (d + t, 6H); 1.3-3.6 (m, 16H); 4.2 (q, 2H); 4.1-4.6 (m, 4H); 7.3 - 8.1 (m, 5H).

Example 30 N-0-S-Carbethoxy-3-phenyl-3-oxo-propyl) -S-alanyl-2B, 3ass, Gass octahydrocyclopenta / -b / pyrrole-2-carboxylic acid trifluoroacetate This compound is prepared analogously to the procedure described in Example 29.

H-NMR data: 1.2 (d + t, 6H); 1.3-3.6 (m, 14H); 4.15 (q, 2H); 4.0.- 4.6 (m, 4H); 7.3 - 8.0 (m, 5H).

Example 31 N-t s-Carbethoxy-3-phenyl-3-oxo-propyl) -S-alanyl-2B, 3ass, 8ass-decahydrocyclohepta b 7pyrrole-2-carboxylic acid 1 g N- (1-S-carbethoxy-3-phenyl-3-oxo-propyl) -5-alanyl-213,3ass, 8ass-decahydrocyclohepta [b] pyrrole-2-carboxylic acid tert-butyl ester are dissolved in 10 ml of methylene chloride, saturated with hydrogen chloride gas and 16 Left to stand at 20 to 250C for hours. It is concentrated in a vacuum and rubbed in Residue with diisopropyl ether and sucks off. Yield: 0.4 g. K-NMR data: 1.3 (i.e. + t, 6H); 1.3-3.8 (m, 18H) 4.2 4.2 (q, 2H); 4.0-4.7 (m, 4H); - 7.2 - 8.1 (m, 5H).

The carboxylic acids described in Examples 29 to 31 above can also be made from the corresponding benzyl esters by catalytic hydrogenolysis (10% palladium on carbon, ethanol, 20 to 25 ° C).

Example 32 N- (1-S-Carboxy-3-phenyl-3-oxo-propyl) -5- alanyl-2B, 3ass, 7ass-octahydroindole-2 = carboxylic acid To prepare this compound, 1 g of N- (1-S-carbethoxy-3-phenyl-3-oxo-propyl) -S-alanyl-2B, 3ass, 7assoctahydroindole-2-carboxylic acid reacted analogously to the procedure described in Example 19 with potassium hydroxide.

H-NMR data: 1.2 (d, 3H); 1.3-3.6 (m, 16H); 4.1-4.7 (m, 4H); 7.2 - 8.1 (m, 5H).

Example 33 N- (I-S-Carbethoxy- 3 phenyl- 3-hydroxy-propyl) -S- alanyl-2B, 3ass, 7ass-octahydroindole-2-carboxylic acid 1 g N- (1-S-carbethoxy-3-phenyl-3-oxo-propyl) -5- alanyl-2B, 3aß, 7aß - octahydroindole-2-carboxylic acid are anhydrous in 50 ml Dissolved ethanol and with 50 mg palladium / carbon at 20 to 25 ° C under normal pressure hydrogenated with 1 mol equivalent of hydrogen. After filtering off the catalyst the solution evaporated, the residue triturated with diisopropyl ether and filtered off with suction.

Yield: 0.7 g.

H-NMR data: 1.2 (d, 3H); 1.3 (t, 3K); 1.3-3.8 (m, 16H); 4.2 (q, 2H); 4.1-4.6 (m, 4H); 4.7 (d. 1H); 7.1 - 7.4 (m, 5H).

Example 34 N- (1-S-Carbethoxy-3-phenyl-3-hydroxy-propyl) -S- alanyl-2β, 3ass, 6aB-octahydrocyclopenta / b ~ 7pyrrole-2-carboxylic acid This compound is made from the compound described in Example 29 according to that described in Example 33 Procedure produced.

1 H-NMR data: 1.2 (d, 3H); 1.3 (t, 3H); 1.4-3.9 (m, 14H); , 4.2 (q, 2H); 4.1-4.7 (m, 4H); 4.7 (d. 1H); 7.0 - 7.4 (m, 5H).

Example 35 N- (1-Carbethoxy-3-phenyl-3-hydroxypropyl) -S- a lanyl-2B, 3aß, 8aß-decahydrocyclohepta / b ~ 7pyrrole-2-carboxylic acid This compound is made from the Compound described in Example 31 following the procedure described in Example 33 manufactured.

H-NMR data: 1.25 (d + t, 6H); 1.3-4.0 (m, 18H); 4.2 (q, 2H); 4.1 - 4.6 (m, 4H); 4.8 (d. 1H); /, 0 - 7.5 (m, 5H).

Example 36 S-21anyl-25, 3aR, 7aR-octahydroindole-2-carboxylic acid benzyl ester a) N-tert-butoxycarbonyl-S-alanyl-2S, 3aR, 7aR-octahydroindole-2-carboxylic acid benzyl ester To a solution of 19 g of Boc-Ala-OH in 100 ml of DMF, 13 ml of N-ethylmorpholine, 13.5 g of 1-hydroxy-benzotriazole and 29.6 g of 2B, 3ass, 7ass-octahydroindole-2-carboxylic acid benzyl ester hydrochloride given. The mixture is cooled in an ice bath and added with 21 g of dicyclohexylcarbodiimide offset. The mixture is stirred for 15 hours at 20 to 25 ° C. The urea which has precipitated out is suctioned off, the filtrate concentrated in vacuo and taken up in ethyl acetate. The organic Phase is each 3 times with aqueous potassium hydrogen sulfate, and potassium hydrogen carbonate Sodium chloride extracted, dried and evaporated. The residue is on silica gel chromatographed with ethyl acetate / cyclohexane (1: 3). The first fraction contains the desired product. Yield: 21 g. H-NMR data: 1.3 (d, 3H); 1.45 (s, 9H); 1.1 - 2.4 (m, 12K); 3.2-3.9 (m, 2H); 5.3 (s, 2H); 7.4 (s, 5H).

b) S-Alanyl-2S, 3aR, 7aR-octahydroindole-2-carboxylic acid benzyl ester 20.5 g of N-tert. Butoxycarbonyl-5-alanyl-25, 3 aR, 7aR, octahydroindole-2-carboxylic acid-ben zyl esters are dissolved in 50 ml of trifluoroacetic acid. After a reaction time of The solution is concentrated in vacuo for 10 minutes and the residue is digested several times Diisopropyl ether and dry it in vacuo.

Yield: 14 g.

Examples 37 and 38 These compounds are made analogously to the example 36 procedures described under a) and b).

Example 37 S-Alanyl-2S, 3aR, 6aR-octahydrocyclopenta / b ~ 7pyrrole-2-carboxylic acid benzyl ester H-NMR data: 1.3 (d, 3H); 1.1 - 2.4 (m, 10H); 3.2-3.9 (m, 2H); 5.2 (s, 2H); 7.4 (s, 5H).

Example 38 S-Alanyl-2S, 3aR, 8aR-decahydrocyclohepta / -b 7pyrrole Benzyl 2-carboxylate H NMR data 1,3 (d, 3H); 1.1 - 2.4 (m, 14H); 3.2-3.9 (m, 2H); 5.2 (s, 2H); 7.4 (s, 5K).

Example 39 N- (1S-Carbethoxy-3-phenyl-propyl) -5- alanyl-2S, 3aR, 7aR-octahydroindole-2-carboxylic acid a) N- (I-SCarbethoxy-3-phenyl-propyl) -S- alanyl-2S, 3aR, 7aR-octahydroindole-2-carboxylic acid benzyl ester 10 m mol 5-alanyl-25, 3aR, 7aR-octahydroindole-2-carboxylic acid benzyl ester are dissolved in 30 ml of anhydrous ethanol solved. The solution is adjusted to a pH value using ethanolic potassium hydroxide of 7.0 and gives 1 g of powdered molecular sieve (4 Å) and then 10 mmol Add 2-keto-4-phenyl-butyric acid ethyl ester. It becomes a solution of 1 g of sodium cyanoborohydride slowly added dropwise in 10 ml of anhydrous ethanol. After a reaction time of 20 Hours at 20 to 250C, the reaction solution is filtered and the solvent distilled off. The residue is taken up in ethyl acetate / water.

After the ethyl acetate phase has been evaporated, the residue is deposited on silica gel chromatographed with ethyl acetate / cyclohexane (1: 4). The 1H-NMR data agree the data of the compound from Example 11 match.

b) The compound obtained above is as in Example 17, method A described further implemented to the desired compound.

Example 40 N- (1-S-Carbethoxy-3-oxo-3-phenyl-propyl) -S- alanyl-2B, 3ass, 6aB-octahydrocyclopenta / b ~ 7pyrrole-2-carboxylic acid benzyl ester 10 mmol S-alanyl-2S, 3aR, 6aR-octahydrocyclopenta [b] Pyrrole-2-carboxylic acid benzyl ester together with 10 mmol of 3-benzoyl-acrylic acid ethyl ester and 10 mmol of triethylamine dissolved in 100 ml of anhydrous ethanol and the mixture 24 Stirred at 20 to 250C for hours. It is neutralized with 1N hydrochloric acid and evaporated to Dry and the residue is taken up with ethyl acetate / water.

The ethyl acetate phase is dried, evaporated and on silica gel chromatographed.

Example 41 N- (1-S-Carbethoxy-3-oxo-3-phenyl-propyl) -S- alanyl-2 [beta], 3aß, 8aß-decyhydrocyclopenta / -b b ~ 7pyrrole-2-carboxylic acid benzyl ester 10 mmol acetophenone, 10 mmoles of ethyl glyoxylate and 10 mmoles of S-alanyl-2S, 3aR, 8aR-decahydrocyclohepta- / b ~ 7-pyrrole-2-carboxylic acid benzyl ester are heated to 45 ° C. in 30 ml of glacial acetic acid for 36 hours heated. After concentration in vacuo, it is made alkaline with aqueous sodium bicarbonate and extracted with ethyl acetate. The ethyl acetate phase is concentrated and on silica gel chromatographed.

Example 42 N- (l-SCarbethoxy-3-phenyl-propyl) -S- alanyl-25, 3aR, 7aS-octahydroindole-2-carboxylic acid a) DL-2β, 3ass, 7aα-octahydroindole-2-carboxylic acid benzyl ester hydrochloride A solution made at -5 to OOC of 1.4 ml of thionyl chloride in 14 ml of benzyl alcohol at -100 to 0 ° C. 1.4 g of DL-2β, 3ass, 7aα-octahydroindole-2-carboxylic acid given. The mixture is stirred for 1 hour at 0 ° C. and left to stand at 20 ° to 250 ° C. overnight. The benzyl alcohol is distilled off in a high vacuum at 50 ° C. and the residue with Diisopropyl ether digested. 2.5 g of colorless crystals with a melting point of 154 ° C. are obtained.

b) N- (1-S-carbethoxy-3-phenyl-propyl) -S-alanyl-2β, 3ass, 7aα octahydroindole-2-carboxylic acid benzyl ester To a suspension of 2.16 g of N- (1-S-carbethoxy-3-phenyl-propyl) -S- alanine in 8.6 ml of anhydrous dimethylformamide are 1.06 g of 1-hydroxy-benzotriazole, 2.2 g of DL-2β, 3ass, 7aα-octahydroindole-2-carboxylic acid benzyl ester hydrochloride and 1.08 ml of N-ethylmorpholine and 1.7 g of dicyclohexylcarbodiimide at OOC.

After 3.5 hours of stirring at 20 to 25 ° C, the reaction mixture is diluted with 20 mol of ethyl acetate and the deposited dicyclohexylurea filtered off.

After concentration in vacuo, the residue is taken up in ether, washed twice with saturated aqueous sodium bicarbonate, over sodium sulfate dried and evaporated. After chromatography on silica gel with ethyl acetate-cyclohexane The solvent obtained is 2 pale yellow oils in a ratio of 1: 1, each one isomer the desired connection.

H-NMR data of the isomer with 2R, 3aR, 7aS configuration: 7.35 (s, 5H); 7.2 (s, 5H); 5.18 (s, 2H); 4.55 (d, iH); 4.1 (q, 2H); 3.4-2.3 (m, 6H); 2.4-1.3 (m, 12H); 1.3 (t, 3H); 1.1 (d, 3H).

1H-NMR data of the isomer with 2S, 3aS, 7aP configuration: 7.35 (s, 5); 7.2 (s, 5H); 5.16 (s, 2H); 4.9-4.2 (m, 1H); 4.2 (q, 2H); 3.9 - 2.4 (m, 6H); 2.4-1.4 (m, 12H); 1.25 (d + t, 6H).

c) N- (1-5-carbethoxy-3-phenyl-propyl) -5-alanyl-25, 3aR, 7aS-octahydroindole-2-carboxylic acid 1.7 g of the isomer with 2S, 3aS, 7aR configuration obtained under b) are converted into 60 ml of anhydrous ethanol with the addition of 200 mg of palladium-carbon (10%) at 20 to Hydrogenated at 250C under normal pressure for 2 hours. The catalyst is filtered off and the filtrate was concentrated.

The title compound is obtained as a colorless foam.

H-NMR data: 7.2 (s, 5H); 4.4 (m, 4H); 4.2 (q, 2K); 3.6 - 1.3 (m, 18H); 1.28 (d + t, 6H).

The hydrochloride of the above compound appears as colorless amorphous powder obtained.

Examples 43 to 47 The compounds mentioned in these examples are prepared analogously to the procedures described in Example 42.

Example 43 N- (1-S-Carbethoxy-3-phenyl-propyl) -S- alanyl-2S, 3aS, 7aR-octahydroindole- 2-carboxylic acid 1 H NMR data: 7.2 (s, 5H); 4.0-4.6 (m, 4H); 4.15 (q, 2H); 3.8-1.2 (m, 18H); 1.3 (t, 3H); 1.2 (d, 3H).

The hydrochloride is obtained as a colorless, amorphous powder.

Example 44 N-C1-S-Carbethoxy-3-phenyl-propyl) -S- alanyl-2S, 3aR, 6aS-octahydrocyclopenta / b ~ 7pyrrole-2-carboxylic acid 1H-NMR data: 7.25 (s, 5H); 4.35 (m, 4K); 4.2 (q, 2K); 3.9-1.4 (m, 16H); 1.35 (t, 3K); 1.15 (d, 3H).

The hydrochloride is obtained as a colorless, amorphous powder.

Example 45 N- (1-S-Carbethoxy-3-phenyl-propyl) -S-alanyl-25, 3a5 3aR-octahydrocyclopenta [b] pyrrole-2-carboxylic acid H-NMR data: 7.3 (s, 5K); 4.3 (m, 4H); 4.2 (q, 2H); 3.8-1.3 (m, 16H); 1.3 (t + d, 6H).

The hydrochloride is obtained as a colorless, amorphous powder.

Example 46 N- (1-S-Carbethoxy-3-phenyl-propyl) -S- alanyl-2S, 3aR, 8aS-decahydrocyclohepta [b] pyrrole-2-carboxylic acid H-NMR data: 7.15 (s, 5H); 4.4 (m, 4H); 4.2 (q, 2H); 3.8-1.3 (m, 20H); 1.3 (t + d, 6H).

Example 47 N- (1-S-Carbethoxy-3-phenyl-propyl) -S- alanyl-25, 3aS, 8aR-decahydrocyclohepta [b] pyrrole-2-carboxylic acid H-NMR data: 7.2 (s, 5H); 4.4 (m, 4H); 4.25 (q, 2H); 3.8-1.2 (m, 20H); 1.3 (t, 3H); 1.15 (d, 3H).

Example 48 2ß, 3aß, 7aα-octahydroindole-carboxylic acid a) 3-chloro-N-acetyl- Ganine methyl ester 181 g of 3-chloroalanine methyl ester hydrochloride with 163.9 g of acetyl chloride in 1.5 l of anhydrous toluene heated under reflux for about 5 hours, until a clear solution is obtained. It is concentrated to dryness and crystallized the residue Ethyl acetate / petroleum ether. There are 170 g of product obtained from m.p. 1040C.

b) 3- (2-Oxo-cyclohexyl) -N-acetyl-alanine methyl ester Dissolve 160 g of 3-chloro-N-acetyl-alanine methyl ester and 171.9 g of 1-pyrrolidino-cyclohexene in 1,2 1 absolute DMF and let the mixture stand for 3 days at 20 to 25 ° C.

The solution is concentrated in a high vacuum, the residue obtained in. 600 ml of water and added with conc. Hydrochloric acid to a pH of 2.0 posed.

The aqueous solution is extracted using ethyl acetate and dried organic phase over sodium sulfate and concentrated. The product appears as a yellow oil obtain.

c) 3, 3a, 4,5,6, 7-2H-hexahydroindole-2-carboxylic acid hydrochloride 220 g of the compound obtained under b) is refluxed with 1 1 2N hydrochloric acid for 2 hours heated to boiling.

The reaction mixture is extracted with ethyl acetate and the concentrated aqueous phase. Residual amounts of water are removed by three evaporation in a vacuum removed with the addition of toluene. 210 g of the product are obtained as a yellow oil, which crystallizes when left to stand.

d) 213, 3aß, 7a-octahydroindole-2-carboxylic acid 128 g of 3, 3a, 4,5,6,7-2H-hexahydroindole-2-carboxylic acid hydrochloride are in 700 ml of glacial acetic acid with the addition of 4 g of platinum / carbon (10%) under normal pressure hydrogenated at room temperature.

The catalyst is filtered off and the filtrate is evaporated to dryness a. The residue is dissolved in 500 ml of hot ethanol and cooled to -20 ° C. Here the 2β, 3aß, 7ass-isomer of the title compound precipitates. From the solution one obtains the product by concentration and adding isopropanol in the form of colorless crystals from Fp 2800C.

Example 49 2β, 3aß, 8aα-decahydro-cyclohepta [b] pyrrole-2-carboxylic acid Starting from pyrrolidino-cycloheptene, this compound is prepared analogously to the procedures b) to d) of Example 48 prepared.

Example 50 2β, 3aß, 6aα-Octahydro-cyclopenta [b] pyrrole-2-carboxylic acid This compound is starting from pyrrolidino-cyclopentene analogous to the procedures b) to d) of Example 48 prepared.

Example 51 20P3aL, 7ass-octahydroindole-2-carboxylic acid a) 3,4,5,6,7,8-octahydro-1H1-quinolin-2-one 392 g of cyclohexanone and 212 g of acrylonitrile are used together with 20 g of cyclohexylamine and 4 g of glacial acetic acid and 0.4 g of hydroquinone 4 hours to a final temperature of Heated under reflux at 2000C. After distillation at 100 to 1500C / 0.5 mm Hg The resulting distillate is heated to 2000C with 10 ml of 50% acetic acid for 2 days. After cooling, the reaction mixture is recrystallized from methanol / water. Together with the The distillation residue obtained above that from n-hexane is uncrystallized, 460 g of the product of melting point 143 to 1440 ° C. are obtained.

b) trans-Octahydro-1H-quinoline-2On A mixture of 25 g of the under a) product obtained and 70 g of sodium formate in 120 ml of formic acid is 18 hours heated to boiling under reflux. The reaction solution is made with 20% aqueous sodium hydroxide made alkaline and extracted with ethyl acetate.

The organic phase is dried over sodium sulfate and evaporated. The residue is recrystallized from cyclohexane, the product having a melting point of 1520C is obtained.

c) 3,3-dichloro-trans-octahydro-1H-quinoline-2On To a solution of 19.4 g of the compound obtained under b) and 24.3 g of phosphorus pentachloride in 300 ml of anhydrous chloroform is a solution of 36.4 g of sulfuryl chloride in 40 ml Chloroform was added dropwise at 20 to 300C over 30 minutes. The mixture is 6 hours Heated to the boil and left to stand at 20 to 25 "C overnight.

Neutralize with ice-cold saturated aqueous potassium carbonate, the mixture is extracted with methylene chloride and the organic phase is dried over sodium sulfate and narrow it. After recrystallization of the residue from ethanol with addition 25 g of the product with a melting point of 195 ° to 1980 ° C. are obtained from activated charcoal.

d) 3-chloro-trans-octahydro-1H-quinoline-2On 15; 6 g of the obtained under c) Connection will be in 1 1 of ethanol and 9.7 ml of triethylamine under Addition of Raney nickel at 20 to 250C under normal pressure until 1 is absorbed Molar equivalent of hydrogen hydrogenated.

After filtering off the catalyst, the filtrate becomes dry concentrated and the residue taken up in ethyl acetate. The organic phase will washed twice with water, dried over sodium sulfate and concentrated. The residue is rubbed with diisopropyl ether, filtered off with suction and dried. The product is obtained in the form of pale yellow crystals of m.p. 115-1200C.

e) 2ß, 3aß, 7adv octahydroindole-2-carboxylic acid 3.75 g of the under d) obtained compound become a boiling solution of 6.63 g of barium hydroxide octahydrate given in 120 ml of water. After 4 hours of refluxing, 0.9 ml conc. Sulfuric acid added, refluxed for an additional hour, the Filtered off the reaction solution and the filtrate using 1N sodium hydroxide on a Set pH value of 6.5. After evaporating the solution, the residue is dissolved in ethanol heated, filtered off again and the filtrate concentrated to a small volume.

On cooling, the desired product becomes crystalline with a melting point. 275 to 2760C obtained.

, Example 52 2st3aBt6a * £ ctahydrocyclopenta / b ~ 7pyrrole-2-carboxylic acid a) 1, 2,3,4,6,7-hexahydro-5H-1-pyrind-2-one A mixture of 1 mole of cyclopentanone, one mole of acrylonitrile, 0.05 mole of ammonium acetate and 3 ml of 30% ammonia is in a pressure vessel at 22uOC for 3 hours It is then filtered Mixture over silica gel with ethyl acetate / cyclohexane (1: 1) and the crystallized Evaporation of the filtrate obtained residue from cyclohexane. The product melts at 118 to 120 ° C.

H-NMR data: 9.4 (broad s, 1H); 3.2-2.0 (m, 12H).

b) Octahydro-trans-5H-1-pyrind-2-one This connection is analogous the procedure described in Example 51 under b).

1 H-NMR data: 7.8 (broad s, 1H); 2.9 (broad s, 1H); 2.6 - 2.2 (m, 2H); 2.1-1.0 (m, 8H).

c) 3,3-dichloro-octahydro-trans-5H-1-pyrind-2-one This compound is prepared analogously to the procedure described in Example 51 under c).

1 H-NMR data: 7.9 (broad s, 1H); 3.8 (broad s, 1H); 3.2 - 2.0 (m, 2H); 2.1-1.0 (m, 6H).

d) 3-chloro-octahydro-trans-511-1 -pyrind-2-one This compound is prepared analogously to the procedure described in Example 51 under d).

H-NMR data: 7.8 (broad s, 1H); 4.6-4.3 (m, 1H); 3.3 - 3.0 (m, -111)) 2.1 (d, J = 6 Hz, 2); 1.8-1.1 (m, 6H).

e) 2ß, 3aß, 6a-octahydrocyc lopenta [b] pyrrole-2-carboxylic acid These Connection is analogous to the procedure described in Example 51 under e) manufactured.

H-NMR data: 4.7-4.4 (m, -1H); 3.0-0.9 (, 10H-).

Example 53 2β, 3aß, 8aα-decahydrocyclohepta [b] pyrrole-2-carboxylic acid a) 1,2,3,4,5,6,7,8-Octahydrocyclohepta [b] pyrid-2-one This compound is analogous the procedure described in Example 51 under a) starting from cycloheptanone manufactured.

1 H-NMR data: 9.4 (broad s, 1K); 3.2-2.0 (m, 14H).

b) trans-Decahydrocyclohepta [b] pyrid-2-one This compound is analogous the procedure described in Example 51 under b) starting from the under a) the aforementioned connection established.

H-NMR data: 7.9 (broad s, 1H); 2.9 (broad s, 1H); 2.6 - 2.2 (m, 2H); 2.1-1.0 (m, 12H).

c) 3,3-dichloro-trans-decahydrocyclohepta [b] pyrid-2-one This compound is prepared analogously to the procedure described in Example 51 under c).

1 H-NMR data: 7r9 (broad s, 1H); 3.8 (broad s, 1H); 3.2 - 2.0 (m, 2H); 2.1-1.0 (m, 10H).

d) 3-chloro-trans-decahydro-cyclohepta [b] pyrid-2-one This compound was prepared analogously to the procedure described in Example 51 under d).

1 H-NMR data: 7.8 (broad s, 1H); 4.6-4.3 (m, 1E); 3.3 - 3.0 (m, 1H); 2.1 (d, J = 6Hz, 2H); 1.8-1.1 (m, 10H).

e) 2ß, 3aß, 8a -Decahydrocyclohepta [b] pyrrole-2-carboxylic acid This compound was prepared analogously to the procedure described in Example 51 under e).

1H-NjMR data: 4.7-4.4 (m, 1H); 3.2-1.1 (m, 1H).

Example 54 2β, 3aα, 7ass-Octahydroindole-2-carboxylic acid tert-butyl ester hydrochloride This compound was analogous from 2β, 3aα, 7ass-octahydroindole-2-carboxylic acid the procedure described in Example 8 prepared.

1 H NMR data: 4.7-4.4 (m, 1H); 3.2-1.1 (m, 12H); 1.2 (s, 9H).

The compounds of Examples 55 to 59 below were prepared analogously to Procedure described in Example 8 prepared.

Example 55 2β, 3aß, 7aα-octahydroindole-2-carboxylic acid-tert. butyl ester hydrochloride 111 NMR data: 4.7-4.3 (m, -111); 3.4-1.1 (m, 12H); 1.2 (s, 9H).

Example 56 23, 3a, 6ass-Octahydrocyclopenta [b] pyrrole-2-carboxylic acid tert. butyl ester hydrochloride 1 H NMR data: 4.8-4.4 (m, 1H); 3.4-1.2 (m, 10H); 1.2 (s, 9H) Example 57 2β, 3ass, 6aα-Octahydrocyclopenta [b] pyrrole-2-carboxylic acid tert-butyl ester hydrochloride 111 NMR data: 4.8-4.4 (m, 1H); 3.5-1.2 (m, 10H); 1.2 (s, 9H).

Example 58 2β, 3aα, 8ass-Decahydrocyclohepta [b] pyrrole-2-carboxylic acid tert-butyl ester hydrochloride 1 H NMR data: 4.7-4.4 (m, 1H); 3.3-1.0 (m, 14H); 1.2 (s, 9H).

Example 59 2β, 3aα, 8aα-Decahydrocyclohepta [b] pyrrole-2-carboxylic acid tert-butyl ester hydrochloride 1 H NMR data: 4.7-4.3 (m, 1H); 3.2-0.8 (m, 14H); 1.2 (s, 9H).

Example 60 N- (S-Alanyl) -2S, 3aR, 7aS-octahydroindole-2-carboxylic acid tert-butyl ester hydrochloride a) N- (N'-Benzyloxycarbonyl-S-alanyl) -2S-3aR, 7aS-octahydroindole-2-carboxylic acid tert-butyl ester This compound was produced using Z-alanine analogously to that described in Example 36 under a) Procedure produced.

separated from its isomers as described there.

1 H-NMR data: 7.4 (s, 5H); 5.3-4.8 (m, 1H); 4.2-3.7 (m, 2H); 3.1 - 1.4 (m, 11H); 1.3 (d, J = 7 Hz, 3H); 1.2 (s, 9H).

b) The aforementioned compound obtained under a) is treated with palladium / barium sulfate hydrogenated in in ethanolic hydrogen chloride to give the desired title compound is obtained.

1 H-NMR data: 5.2-4.8 (m 1H); 4.2-3.7 (m, 2H); 3.1-1.4 (m, 11H); 1.3 (d, J = 7 Hz, 3H); 1.2 (s, 9K).

The compounds of Examples 61 to 65 below are analogous the procedures described under a) and b) in Example 60 prepared.

Example 61 N- (S-Alanyl) -2S, 3aS, 7aR-octahydroindole-2-carboxylic acid tert-butyl ester hydrochloride H-NMR data: 5.2-4.7 (m, 1K); 4.4-3.8 (m, 2H); 3.1-1.4 (m, 11H); 1.25 (d, J = 7Hz, 3H); 1.2 (s, 9H).

Example 62 N- (S-Alanyl) -2S, 3aR, 6aS-octahydrocyclope [b] pyrrole-2-carboxylic acid tert-butyl ester hydrochloride H-NMR data: 5.3-4.7 (m, 1H); 4.4 -. 3.8 (m. 2H); 3.1-1.4 (m, 9H); 1.3 (d, J = 7 Hz, 3H); 1.2 (s, 9H).

Example 63 N- (S-Alanyl) -2S, 3aS, 6aR-octahydrocyclope [b] pyrrole-2-carboxylic acid tert-butyl ester hydrochloride H-NMR data: 5.3-4.7 (m, 1H); 4.4 - 3.8 (m, 29); 3.1-1.4 (m, 9H); 1.3 (d, J = 7 Hz, 3H); 1.2 (s, 9H).

Example 64 N- (S-Alanyl) -2S, 3aR, 8aS-decahyddrocyclohepta [b] pyrrole-2-carboxylic acid tert-butyl ester hydrochloride 1 H NMR Spectrum: 5.1-4.6 (m, 1H); 4.5-3.7 (m, 2H); 3.1-1.4 (m, 13H); 1.3 (d, J = 7 Hz, 3H); 1.2 (s, 9H).

Example 65 N- (S-Alanyl) -2S, 3aS, 8aR-decahydrocyclohepta [b] pyrrole-2-carboxylic acid tert-butyl ester hydrochloride H-NMR data: 5.1-4.6 (m, 1H); 4.5-3.7 (m, 2H); 3.1-1.4 (m, 13H); 1.3 (d, J = 7Hz, 3H); 1.2 (s, 9H).

Example 66 N- (1S-Carbethoxy-3-phenyl-propyl) -S-alanyl-2S, 3aR, 7aS-octahydroindole-2-carboxylic acid This compound is analogous to the procedure described in Example 39 under a) starting from N- (S-alanyl) -2S, 3aR, 7aS-octahydroindole-2-carboxylic acid tert-butyl ester manufactured. The tert-butyl group is split off with trifluoroacetic acid.

Example 67 N- (1 S-Carbethoxy-3-keto-3-phenyl-propyl) -S-ala'nyl-octahydroindole-2-carboxylic acid This compound is proceeded analogously to the procedure described in Example 40 of N- (S-Alanyl) -2S, 3aR, 7aS-octahydroindole-2-carboxylic acid tert-butyl ester. The tert-butyl group is split off with trifluoroacetic acid.

H-NMR data: 1.2 (d + t, 6H); 1.3-3.6 (m, 16H); 4-, 2 (q, 2H); 4.1 - 4.6 (m, 4H); 7.3 - 8.1 (m, 511).

Example 68 N- (1S-Carbethoxy-3-keto-3-phenyl-propyl) -S-alanyl-2S, 3aS, 7aR-octahydroindole-2-carboxylic acid This connection becomes' analog the procedure described in Example 40 starting from N- (S-alanyl) -2S, 3aS, 7aR-octahydroindole-2-carboxylic acid tert-butyl ester manufactured. The tert-butyl group is split off with trifluoroacetic acid.

H-NMR data: 1.2 (d + t, 6H); 1.3-3.6 (m, 16H); 4.2 (q, 2H); 4.1 - 4.6 (m, 4H); 7.3 - 8.1 (m, 5H3. -Example 69 N- (1S-Carbethoxy-3-keto-3-phenyl-propyl) -S-alanyl-2S, 3aR, 6aS-octahydrocyclopenta / b / pyrrole-2-carboxylic acid This compound is analogous the procedure described in Example 40, starting from N- (S-alanyl) -2S, 3aR, 6aS-octahydrocyclopenta [b] pyrrole-2-carboxylic acid tert-butyl ester prepared; the splitting off of the tert.

Butyl group is made with trifluoroacetic acid.

1 H-NMR data: 1.1 (d, 3H); 1.35 (t, 3H); 1.0-3.7 (m, 14H); 4.2 (q, 2H); 4.0-4.7 (m, 4H); 7.3 - 8.0 (m, 5H).

Example 70 N- (1S-Carbethoxy-3-keto-3-phenyl-propyl) -S-alanyl-2S, 3aS, 6aR-octahydrocyclopenta [b] pyrrole-2-carboxylic acid This compound is analogous the procedure described in Example 41, followed by an elimination of 0.

the tert-butyl group with trifluoroacetic acid.

1 H-NMR data: 1.1 (d, 3H); 1.35 (t, 3H); 1.0-3.8 (m, 14H); 4.2 (q, 2H); 4.0-4.7 (m, 4H); 7.2 - 8.1 (m, 5H).

Example 71 N- (1S-Carbethoxy-3-keto-3-phenyl-propyl) -S-alanyl-2S, 3aR, 8aS-decahydrocyclohepta [b] pyrrole-2-carboxylic acid This compound is followed analogously to the reaction procedure described in Example 41 from the cleavage of the tertiary butyl group with trifluoroacetic acid.

H-NMR data: 1.2 (d, 3H); 1.4 (t, 3H); 1.2-3.8 (m, 18H); 4.1 (q, 2H); 4.0-4.6 (m, 4H); 7.2- 8.2 (m, 5H).

Example 72 N- (1S-Carbethoxy-3-keto-3-phenyl-propyl) -S-alanyl-2S, 3aS, 8aR-decahydrocyclohepta [b] pyrrole-2-carboxylic acid This compound is followed analogously to the procedure described in Example 41 from the splitting off of the tert. Butyl group with trifluoroacetic acid.

H-NMR data: 1.2 (d + t, 6H); 1.2-3.8 (m, 18H); 4.2 (q, 2H) i 4.0 - 4.6 (m, 4H); 7.1 - 8.1 (m, 5).

Example 73 N- (1S-Carbethoxy-3-hydroxy-3-phenyl-propyl) -S-alanyl-2S, 3aR, 7aS-octahydroindole-2-carboxylic acid This compound is prepared analogously to the procedure described in Example 33.

H-NMR data: 1.2 (d, 3H); 1.3 (t, 3H); 1.3-3.8 (m, 16H); 4.2 (q, 2H); 4.0-4.6 (m, 4H); 4.7 (d. 1H); 7.1 - 7.4 (m, 5H).

Example 74 N- (1S-Carbethoxy-3-hydroxy-3-phenyl-propyl) -S-alanyl-2S, 3aS, 6aR-octahydrocyclopenta [b] pyrrole-2-carboxylic acid This compound is analogous the procedure described in Example 33 prepared.

H-NMR data: 1.2 (d + t, 3H); 1.1 - 3.9 (m, 14K); 4.2 (q, 2H); 4.0 - 4.7 (m, 4H); 4.8 (d. 1H); 7.1 - 7.4 (m, 5H).

Examples 75 to 80: The compounds mentioned in these examples are prepared analogously to the procedure described in Example 20.

Example 75 N- (1S-Carboxy-3-phenyl-propyl) -S-alanyl-2S, 3aR, 7aS-octahydroindole- 2-carboxylic acid H-NMR data: 1.2 (d, 3H); 1.2-3.8 (m, 18H); 4.0-4.6 (m, 4H); 7.2 (s, 5H).

Example 76 N- (1S-Carboxy-3-phenyl-propyl) -S-alanyl-2S, 3aS, 7aR-octahydro indole-2-carboxylic acid H-NMR spectrum: 1.2 (d, 3H); 1.2-3.8 (m, 18H); 4.0-4.6 (m, 4H); 7.2 (s, 5H).

Example 77 N- (1S-Carboxy-3-phenyl-propyl) -S-alanyl-2S, 3aR, 6aSZ octahydrocyclopenta [b] pyrrole- 2-carboxylic acid H NMR data 1,2 (d, 3H); 1.1-3.7 (m, 16H); 4.0-4.6 (m, 4H) ;.

7.2 (s, 5H).

Example 78 N- (1S-Carboxy-3-phenyl-propyl) -S-alanyl-2S, 3aS, 6aR-octahydro-cyclopenta [b] pyrrole-2-carboxylic acid 1 H NMR Spectrum: 1.2 (d, 3H); 1.1 - 3.8 (m, 16H); 4.0-4.6 (m, 4K); 7.2 (s, 5H).

Example 79 N- (1S-Carboxy-3-phenyl-propyl) -S-alanyl-2S, 3aR, 6aS-decahydrocyclohepta / b ~ / pyrrole-2-carboxylic acid 1H-NMR data: 1,2 (d, 3H); 0.9-3.6 (m, 20H); 4.0-4.6 (m, 4H); 7.2 (s, 5K).

Example 80 N- (1S-Carboxy-3-phenyl-propyl) -S-alanyl-2S, 3aS r 8aR-decahydrocyclohepta [b] pyrrole-2-carboxylic acid H-NMR data: 1,2 (d, 3H); 0.8-3.6 (m, 20H); 4.0 - 4.6 (m, 4H); 7.2 (s, 5H).

Example 81 N- (1S-Carboxy-3-keto-3-phenyl-propyl) -S-alanyl-2S, 3aR, 7aS-octahydroindole-2-carboxylic acid 1H-NMR data: 1.2 (d, 3K); 0.9-3.6 (m, 16H); 3.9-4.7 (m, 4H); 7.1 - 8.2 (m, 5H).

Example 82 N- (1S-Carboxy-3-keto-3-phenyl-propyl) -S-alanyl-2S, 3aS, 7aR-octahydroindole- 2-carboxylic acid 1H-NMR data: 1.2 (d, 3H); 0.9-3.6 (m, 16H); 3.9-4.7 (m, 4H); 7.2 - 8.1 (m, 5).

Example 83 N- (1S-Carboxy-3-keto-3-phenyl-propyl) -S-alanyl-2S, 3aR, 6aS-octahydrocyclopenta [b] pyrrole-2-carboxylic acid 1H-NMR data: 1,2 (d, 3H); 1.1 - 3.7 (m, 14H); 3.9-4.6 (m, 4H); 7.2 - 8.1 (m, 5H).

Example 84 M- (1S-Carboxy-3-keto-3-phenyl-propyl) -S-alanyl-2S, 3aS, 6aR-octahydrocyclopenta / b ~ 7pyrrole-2-carboxylic acid H-NMR data: 1,2 (d, 3H); 1.1 - 3.7 (m, 14H); 3.9-4.6 (m, 4H); 7.2 - 8.1 (m, 5H).

Example 85 N- (1S-Carboxy-3-keto-3-phenyl-propyl) -S-alanyl-2S, 3aR, 8aS-decahydrocyclohepta / b ~ 7pyrrole-2-carboxylic acid 1H-NMR data: 1.2 (d. 3H); 1.1-3.7 (m, 18H); 3.9-4.6 (m, 4H); 7.3 - 8.2 (m, 5H).

Example 86 N- (1S-Carboxy-3-keto-3-phenyl) -alanyl-2S, 3aS, 8aR-decahydrocyclohepta / -b 7-pyrrole-2-carboxylic acid 1H-NMR data: 1.2 (d, 3H); 1.1-3.7 (m, 18H); 3.9 - 4.6 (m, 4H); 7.3 - 8.2 (m, 5H).

Example 87 N- (1S-Carboxy-3-hydroxy-3-phenyl-propyl) -S-alanyl-2S, 3aR, 7aS-octahydroindole-2-carboxylic acid 1H-NMR spectrum: 1.2 (d, 3H); 1.1-3.7 (m, 16H); 3.8-4.6 (m, 4H); 4.7 (m. 1H); 7.1 - 7.4 (m, 5H).

Example 88 N- (1S-Carboxy-3-hydroxy-3-phenyl-propyl) -5-alanyl-2S, 3aS, 6aR-octahydrocyclopenta [b] pyrrole-2-carboxylic acid 1 H-NMR data: 1.2 (d, 3H); 1.1-3.7 (m, 14H); 3.9-4.5 (m, 4H); 4.7 (d. 1H); 7.1 - 7.4 (m, 5H).

Claims (13)

Claims: 1. Compounds of the formula I, in which the hydrogen atoms on the bridgehead carbon atoms 3 a and (6 + n) a are cis or trans configured to one another, in the case of the cis configuration the carboxy group on carbon atom 2 is oriented exo to the bicyclic ring system and where n = 0,1 or 2, R1 = hydrogen, (C1-C6) -alkyl, which may optionally be substituted by amino, (C1-C4) -acylamino or benzoylamino, (C2-C6) -alkenyl, (C5- C9) -cycloalkyl, (C5-C9) -cycloalkenyl, (C5-C7) -cycloalkyl- (C1-C4) -alkyl, aryl or partially hydrogenated aryl, each represented by (C1-C4) -alkyl, (C1-C2) -Alkoxy or halogen can be substituted, aryl (C1-C4) -alkyl, which can be substituted in the aryl radical as defined above, a mono- or bicyclic heterocyclic radical having 5 to 7 or 8 to 10 ring atoms, of which 1 to 2 ring atoms sulfur or oxygen atoms and / or of which 1 to 4 ring atoms represent nitrogen atoms, or a side chain of a naturally occurring amino acid, R2 = hydrogen, (C1-C6) -alkyl, (C2-C6J-alkenyl or aryl- (C1-C4) - alkyl, Y = hydrogen or hydroxy, Z = hydrogen or Y and Z = zusalmlesL oxygen, X = (C1-C6) -alkyl, (C2-C6) -alkenyl, (C5- Cg) -cycloalkyl, aryl substituted by (C1-C4) -alkyl, (C1-C4) -alkoxy, hydroxy, halogen, nitro, amino, (C1-C4) -alkylamino, di- (C1-C4) alkyl- amino or methylenedioxi can be mono, di- or trisubstituted, mean indole bonded via carbon atom 3, as well as their physiologically harmless salts. 2. Compounds of the formula I according to claim 1, characterized in that that the carbon atom in position 2 of the bicyclic ring system and that with an asterisk labeled C atoms of the side chain have S configuration. 3. Compounds of formula I according to claims i and 2, characterized in that that R1 = hydrogen, (C1-C3) -alkyl, (C2-C3) -alkenyl, benzyl, 4-amino-butyl, R2 = Hydrogen, (C1-C4) -alkyl, benzyl, X phenyl, which is replaced by (C1-C2) -alkyl, (C1-C2) -alkoxy, Hydroxy, fluorine, chlorine, bromine, amino, (C1- (C1-C4) -alkylamino, di- (C1-C4) alkyl-amino, Nitro or methylenedioxy mono- or disubstituted or, in the case of methoxy, trisubstituted can be mean. 4. Compounds of formula I according to claims 1 to 3, characterized characterized in that R1 = methyl and X = phenyl. 5. Compounds of the formula I according to Claims 1 to 4, characterized in that that 'R2 =' denotes hydrogen or ethyl. 6. Process for the preparation of the compounds of the formula I according to Claims 1 and 3 to 5, characterized in that a) that a compound of the formula II, wherein R1, R2, X, Y and Z have the meanings as in formula I, with a compound of formula III, in which the H atoms on the carbon atoms 3 a and (6 + n) a are cis or trans configured to one another, in the case of the cis configuration the -CO2W group is oriented exo to the bicyclic ring system, and in which n = 0, 1 or 2 and W = 'denote a radical which can be split off by hydrogenolysis or acid, and then the radical W and optionally the radical R2 are split off with formation of the free carboxy groups, or b) to prepare the compounds of the formula I, in whichY and Z together denote oxygen, b1) a compound of the formula IV in which the H atoms on the carbon atoms 3 a and (6 + n) a to one another - are cis or trans configured, in the case of the cis configuration the group -CO2W being oriented exo to the bicyclic ring system, and in which n and R1 have the meanings as in formula I and W have the meanings as in formula III , with a compound of the formula V, R2O2C-CH = CH-CO-X V in which R2 and X have the meanings as in formula I, and then splits off the radical W and optionally also the radical R2 to form the free carboxy groups, or b2) a compound of the formula IV mentioned under b1) with a compound of the general formula VI, in which R2 has the meaning as in formula I, and with a compound of the general formula VII> OHC-CO 2R2 X-CO-CH3 VI VII in which X has the same meaning as in formula I, and then the radical W and optionally the radical R2 are split off with formation of the free carboxy groups, or c) that for the preparation of compounds of the formula I in which Y and Z are each hydrogen, c1 ) a ver binding of the formula IV mentioned under b1) with a compound of the formula VIIII wherein R2 and X have the meanings as in formula I, the Schiff bases are reduced and then the radical W and optionally the radical R2 splitting off with formation of the free carboxy groups, or c2) a compound of the formula I in which y and Z together denote oxygen, catalytically reduced with hydrogen, or d) that for the preparation of compounds of the formula I in which Y = hydroxy and Z = hydrogen, a compound of the formula I in which Y and Z together denote oxygen, catalytically reduced using hydrogen or a reducing agent such as sodium borohydride. 7. Use of a compound according to claims 1 to 5 as a medicament. 8. Agent containing a compound according to Claims 1 to 5. 9. Compounds of the formula III ', in which the H atoms on the carbon atoms 3 a and (6 + n) a are configured cis or trans to each other, in the case of the cis configuration the group -CO2W on carbon atom 2 exo to the bicyclic Ring system is oriented and where n = 0, 1 or 2 W1 = 'hydrogen or a hydrogenolytically or acidic residue. 10. Verfanren for the preparation of the compounds of the formula III according to claim i, characterized in that a) that a compound of the formula IX, in which the H atoms on the carbon atoms 3 a and (6 + n) a are cis or trans configured to one another and where n is the number 0.1 or 2 is acylated, then with an alcohol in the presence of a conductive salt to form a Compound of formula X, where n has the meaning given above and R3 = (C1-C4) -alkyl, anodically oxidized, this with trimethylsilyl cyanide in the presence of a Lewis acid to form a compound of the formula XI, wherein the'H atoms on the carbon atoms 3 a and (6 + n) a are configured cis or trans to one another, wherein in the case of the cis configuration the group -CN is oriented exo to the bicyclic ring system and in which n has the abovementioned meaning, and this is hydrolyzed by the action of acids or bases to form a compound of the formula III with = = hydrogen and the latter is optionally esterified, or b) that a compound of the formula XII, wherein the H atoms on the carbon atoms 3 a and (6 + n) a are cis or trans configured and n has the meaning given above in a Beckmann rearrangement to give a compound of the formula XIII wherein n has the abovementioned meaning, converts this to a compound of the formula XIV, in which n has the abovementioned meaning and Hal is a halogen atom, halogenated, this to a compound of the formula XV, in which n and Hal have the meanings given above, reduced, and these are then reacted under the action of a base to form a compound of the formula III 'with W =' hydrogen and this is optionally esterified, or c) that a compound of the formula IIIi, wherein the H atoms on the carbon atoms 3 a and (6 + n) a are cis-configured, a compound of the formula XVI, wherein n has the abovementioned meaning under metal catalysis in a protic medium to a compound of the formula XIII mentioned under b), and this, as described under b), is further reacted, or d) that one for the preparation of a compound of the formula III, wherein the H atoms on the carbon atoms 3 a and (6 + n) a have a trans configuration, d1) a compound of the formula XVI mentioned under c) is reduced with sodium formate and formic acid to a compound of the formula XIII mentioned under b), and this, as described under b), further converts, or d2) a compound of the formula XVII, in which Hal is a halogen atom and R4 = (C1-C4) -alkyl, or a compound of the formula XVIII, wherein R4 has the meaning given above, with a compound of the formula XIX, in which n has the meaning given above and A is a chemical bond, a methylene group or an oxygen atom, to a compound of the formula XX, in which n and R4 have the meanings given above, converts them with a maleic acid to give a compound of the formula XXI, in which n has the meaning given above, cyclized and this reduced to a compound of the formula III 'with w = hydrogen and this optionally esterified. 11. Use of a compound according to Claim 9 for the preparation of a Connection according to claims 1 to 5. 12. Use of a compound according to claims 1 to 5 in combination using a diuretic as a remedy. 13. Composition containing a compound according to claims 1 to 5 in Combination with a diuretic.