NZ214877A - Cepyrrol-2-ylcarboxylic acid derivatives - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £14877 <> Pn Ck-VTiG< •-' Ghcs: .. 214877 Under the provisions of RcjJtin iation 23 (I) ths j Co */7M£— *"* -• llrtW Specification has been ante-datet *3 ~jto _ 9f ...„ 19J&?: ZM,& ^ ' - initials XL, • VS2, '; ,-c.c:; .'.t-oi 1*2.-62 Pubbcation Djio: .., "'® JAN 1988 Journal, i\c: , .

NEW ZEALAND Patents Act 1953 N.2. No.

COMPLETE SPECIFICATION "Compounds" We, HOECHST AKTIENGESELLSCHAFT, a corporation organized under the laws of the Federal Republic of Germany,of D-6230 Frankfurt/Main 80, Federal Republic of Germany, do hereby declare the invention, for which we pray that a Patent may be granted to us, and the method by which it is to be performed,to be particularly described in and by the following statement:— - 1A - 2J.4877 The invention relates to compounds of the formula III", in which n represents a whole number from 0 15 to 10, represents hydrogen, alkyl having 1 to 18 C atoms or aralkyl having 7 to 10 C atoms and Rj, R^ and/or R^ ■cocw' III" 1*3 represent hydrogen, or Rj and R^ or R^ and R^ together each denote a.chemical bond.

Preferred compounds of the formula III" are com pounds of the formula III1 H 'n 3a (6+n)f I II >aL -^^CX)2WI .III* >1 2 wherein C-2, C-3a and C-(6+n)a have the same configuuS^ip^ as in formula III, n denotes 0, 1 or 2 and W* has the meaning of W in formula III and also denotes hydrogen. According to the invention, these compounds serve as starting materials for the synthesis of compounds of the formula I and can be prepared according to the invention by 'the following procedures.

The compounds of formula I are described and claimed in Patent Specification No 202903. The compounds I have the formula in which the hydrogen atoms on the bridgehead C atoms 35a and (6 + n)a have the cis or trans configuration relative to one another, wherein, in the case of the cis configuration,the carboxyl group on C atom 2 is oriented exo to the bicyclic ring system and wherein n denotes 0,1 or 2, R^ denotes hydrogen, (Cj-Cg)-alkyl which can optionally be mono-substituted by amino, (C^-C^-acylamino or benzoylaroino, (C2-C^)-alkenyl, (C^-Cg)-cycloalkyl, (C^-Cg)-cycloalkenyl, (C^-Cy)-cyclo-alkyl-(C1 I R, C02T*2 2 radical of which can be substituted es defined previously^ a monocyclic or bicyclic heterocyclic radical having 5 to 7 or 8 to 10 ring atoms respectively, 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 aminoacid which side chain differs from the radicals defined in the aforegoing, R2 denotes hydrogen, (ci~cg)~ alkyl, ^-Cg)-alkenyl or aryl-(C^-C^)-alkyl, W* denotes hydrogen, alkyl having up to 18 carbon atoms or aralkyl having 7-10 carbon atoms , Y denotes hydro- and gen or hydroxyl denotes hydrogen or Y and 2 together denote and oxygen,/OC denotes (Cj-Cg)-alkyl, (C2-C6)-alkenyl, (C5_CV eycloalkyi or aryl which can be mono-, d.l- or tri-substituted by (C^-C^)-alkyl, (C^-C^)-alkoxy, hydroxyl, halogen, nitro, amino, (C^-C^)-alkylamino, di- (C^-C^)-alkylamino or methylenedioxy, or indol-3-yl, and their physiologically acceptable salts. One variant starts with a compound of the formula IX H H 11 wherein the H atoms on the C atoms 3a and (6+n)a have the cis or trans configuration relative to one another and wherein n denotes the number 0, 1 or 2.

Compounds of the formula IX with n being 0 are known from Booth et al., J. Chem. Soc. 1939. page 1050, those with n being 1 are known from King et al., J. Chem. • -4- Soc. 1953. pages 250 and 253 and those with n being 2 are known from Ayerst et al., J. Chem. Soc. 1960. page 3445.

These compounds of the fonnula IX are acylated in 20 a known manner, an aliphatic or aromatic acyl radical, preferably an acetyl or benzoyl radical, being bonded to the nitrogen atom, and the N-acylated compounds obtained are anodically oxidized (in analogy with Liebigs Ann. Chem. 1978 page 1719) in an aliphatic alcohol, preferably an alkanol having 1 to 4 C atoms, in particular methanol, - *t- ?*7ZJW%/ il in the presence of a conducting salt, preferably at temperatures in the range from 0 to +40°C with formation of a compound of the formula X, wherein n denotes 0, 1 or 2 and Rj denotes fc.pC^-alkyl.

The compound of the general formula X obtained is reacted with trimethylsilyl cyanide in accordance with Tetrahedron Letters 1981 page 141 in an aprotic organic 10 solvent, such as, for example, in a hydrocarbon, halogen-atcd hydrocarbon, 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 Lev/is acid, such as, for example, ZnCl2, SnCl2, SnCl^, TiCl^ or BF^ etherate, preferably 15 BFj etherate, and the compound of the formula XI obtained 3a oT]2 XI j CN H Acyl wherein the H atoms on the C atoms 3a and (6+n)a have the cis or trans configuration relative to one another, wherein in the case of the cis configuration, the group -CN is 20 oriented exo to the bicyclic ring system and wherein n has the abovementioned meaning, after purification and separa- ^ \ r tion from by-products by means of recrystallization or - 4JUNl987nvj , h/S. .v ' ^ ' column chromatography, is hydrolyzed by the action of acid or bases in 'a known manner to give a compound of the formula III having W' o hydrogen, and the latter is esteri-fied if appropriate. In particular, in the acid 5 hydrolysis of the nitrile group, HC1 or HBr is used as the acid. In this instance as in the following, the esteri-fication is carried out by the procedures usual in amino-acid chemistry.

Compounds of the general formula Iir can also be 10 prepared by converting, in a Beckmarm rearrangement analogous to Helv. Chim. Acta £6, 1190 (1963), a compound of the formula XII II ■»i J xii H NCti wherein the H atoms on the C atoms 3a and (6+n)a have the 15 cis or trans configuration and n has the abovementioned meaning, into a compound of the fonnula XIII, wherein n has the abovementioned meaning, xiii and the latter is halogenated to give a compound of the 20 formula XIV 13 4 J U 1987 r> ' 1 1 • i <7 r> r k(ai2H Ci XIV I H \ u wherein n has the abovementioned meaning and Hal denotes a halogen atom, preferably chlorine or bromine. Examples of suitable halogenating agents are halides of inorganic acids, such as PCl^t SO2CI2, POClj, SOCI2, PBr^ or halogens, such as bromine. It is advantageous to use PCl^ or POClj combined with SO2CI2. The intermediate initially formed is an imide halide, which, with the halogenating agent mentioned and subsequent hydrolysis under basic conditions, preferably with aqueous alkali metal carbonate, reacts further to give a compound of the fonnula XIV.

The compounds of the formula XIV are subsequently reduced catalytically in a polar protic solvent, such as, for example, an alcohol, preferably ethanol, or a carboxy-lic acid, such as, for example, acetic acid, with the addition of an acid acceptor, such as, for example, sodium acetate or tri ethyl amine, to give a compound of the formula XV Hal XV wherein n and Hal have the abovementioned meanings. Examples of suitable catalysts are Raney nickel or platinum on animal charcoal. Compounds of the formula XV can also be prepared directly by halogenation of the compounds of the formula XIII by using smaller amounts of the abovementioned halogenating agent.

Compounds of the formula XV are converted,in accordance with the known Favorskii reaction in the presence of a base,- into c compound of the formula III' with V/' being hydrogen, and the latter is esterified if appropriate. The abovementioned Favorskii reaction is carried 10 out in an alcoholic eolvent, 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 60° and 100°C. Bases which are advantageously employed are alkali metal or alkaline earth metal hydrox-15 ides, such as sodium, potassium or barium hydroxide or alkali metal alcoholates, such as, for example, sodium methylate or potassium tert.-butanolate, Furthermore, the compounds of the fonnula III', wherein the H atoms on the C atoms 5a and (6+n)a have the 20 cis configuration, can be prepared from the compound of the formula XVI, wherein n denotes 0, 1 or 2, by reducing the latter by means of platinum oxide/acetic acid in accordance with Ann. Chim. 62, 200 (1972) to give 25 a compound of the abovementioned formula XIII and reacting the latter in accordance with the procedures described 7" r* 9 1 < 8 ^ -» above. Compounds of the fonnula XVI are known from J. Org. Chem. 2£, 2780 (1964).

Compounds of the formula III', in which the H atoms on the C atoms 3a and (6+n)a have the trans config-5 uration, can also be prepared from a compound of the abovementioned formula XVI by reducing the latter with sodium formate/formic acid in accordance with Bull. Soc.

Chim. BeDg. 8£ 11 (1976) to give a compound of the formula XIII and reacting the latter further in accordance with the procedures described above.

•-Trans-configurated I 2-Azabicycloalkane-3-carboxylic acids of the formula III1, in which n denotes a whole number from 0 to 10 and V represents hydrogen, and their alkyl and aralkyl esters can be prepared from enamines .of the formula XVII 15 in which n has the previous meaning and X represents dialkylamino having 2 to 10 C atoms or a radical of the formula XVIIa, wherein m and o denote a whole number from 1 to 3, (m + o) ^ 3 and A denotes CH2, NH, 0 or S (Chem.Ber. 92 . (1960) 909), 1 XVII XVIIa together with N-acylated 0-halogeno-a-aminopropionates of the formula XVIII (for the free amino compound, cf. Helv. Chim. Acta 40, 1541 (1957)), in which X^ represents halogen, preferably chlorine or bromine, Y1 represents alkanoyl having 1 to 5 C atoms, aroyl having 7 to 9 C atoms or other protective groups which are customary in peptide chemistry and which can be split off by acid, and 5 R^1 represents alkyl having 1 to 5 C atoms or aralkyl having 7 to 9 C atoms, ' x2 ch2 XVIII cu yn-1.n< "coor4 or together with acrylates of the formula XIX (Chem. "Ber. 91 2427 (1958)), in which Y^ and R^1 have the previous 10 meaning ^ coor41 . ch0 * c ci * 1 XIX 1 to give compounds of the formula XX, in which R^' and Y have the previous meaning, ^coov xx the latter are cyclized, with acylamide and ester cleavage, by means of strong acids to give compounds of the formula XXIa, which can also be in the tautomeric form of the formula XXIb, and in which n has the previous meaning 4JUNI987 XXIa <\ / A O 11 and the compounds of the formula XXIa or b, if appropriate after conversion into their C^-C^g-alkyl or Cy-C^-aralkyl esters, are converted by catalytic hvdrogenation in the presence of transition metal catalysts or by reduction itrans-confiqurated with borane-amine complexes or complex borohydriaes, intoi compounds of the formula III' , in which n has the previous meaning and V represents hydrogen, alkyl having 1 to 18 C atoms or aralkyl having 7 to 10 C atoms, end esters of the formula III' are saponified if appropriate, and the latter, if V is hydrogen, esterified, if appropriate, to give compounds of the formula III1 in which n has the previous meaning and V/' represents alkyl having 1 to 18 C atoms or aralkyl having 7 to 10 C atoms.

The reaction of 3-bromopropylamine with an enamine of cyclohexanone is described in J.AiiuSoc. 81. (1956) 2596. It is also stated that a free NH2 group is necessary for successful alkylation. Thus it is extremely surprising that even halogenopropionic acid derivatives having an acylated amino group, as do the compounds of the formula XVIII described previously, can be employed for the alkylation of enamines. Enamines of cyclohexanone or cycloheptanone are preferably employed for this purpose. Examples of suitable amine components are diethyl amine, pyrrolidine, piperidine or morpboline. However, ther secondary amines are also suitable. Pyrrolidinocyclo- : * : 'V o ^ - 12 - ■ 'V;fp - alkylenes are preferred.

Particularly suitable groups Y1 in the p-bromo~ or chloro-a-aminocarboxylates of the formula XVIII are formyl, acetyl, propionyl or benzoyl, or other protective 5 groups which can be split off with acid, such as, for example, tert.-butyloxycarbonyl. The C^-Cj-Qlkyl or the benzyl esters are preferably employed.

" The acrylic acid derivatives of the formula XIX, which are produced as intermediates from the 0-halogeno-10 a-amin©propionates under the basic conditions of the experi-—- ment, are also suitable as the starting compounds. They are prepared, for example, by treatment of the halogeno-aminopropionic acid derivatives or the analogous o-tosyl-serine derivatives with bases. Tertiary organic bases, 15 such as, for example, triethylamin are preferably used.

It is advantageous to carry out the reaction with the addition of small amounts of polymerization inhibitors, such as, for example, hydroquinone in organic solvents. The acrylic acid derivatives of the formula XIX can be 20 employed instead of the halogenopropionic acid derivatives under identical reactions conditions.

Suitable solvents for the enaraine synthesis are organic solvents which.cannot be alkylated, such as, for example, dimethylacetamide, DMSO, THF or toluene. Dimethyl-25 formamide is particularly suitable.

It is advisable to employ the enamines of the formula XVII in excess in order to avoid impurities of v fJ-acylacrylates in the final product. i The hydrolysis of the N-acyl group necessary for !v - 4JUK1987 ■ j cyclization is generally brought about at the same time as cleavage of the ester function by strong aqueous mineral acids, such as sulfuric acid or, preferably, hydrochloric acid. In the case of the N-tert.-butyloxycar-5 bonyl derivatives of the formula XVII, it is possible, for ' example, on using dioxane/HCl or anhydrous trifluoroacetic acid to retain the ester functionality and to isolate the esters of the dehydrocarboxylic acids XXIa or XXIb. The latter can be converted by hydrogenation in the presence of metal catalysts or reaction with borane-amine complexes or complex borohydrides into the trans-configurated 2-azabicyclocarboxylates of the formula III'.

Noble metal or nickel catalysts are suitable for catalytic hydrogenation. The isomeric ratio occurring on catalytic hydrogenation depends on the reaction conditions and the type of catalyst used.

It is possible to shorten the reaction time by increasing the ■pressure of hydrogen, but the temperature should be kept near room xemperature. Examples of suitable solvents for the catalytic hydrogenation are ethanol, methanol, ethyl acetate, diox- .ane, glacial acetic acid or mixtures of these solvents.

Jb Compounds of the formula IIIl, in which n represents a whole number from 0 to 10 and W represents hydrogen, I ' ■ Ill'b COOH I II -^;an, also be obtained by reduction of compounds of the ..formulae XXIa or b, in which n has the previous meaning, with borane-amine complexes or complex borohydrides in lower alcohols having up to 6 carbon atoms. The preferred reducing agent is sodium borohydride in alcohols, in particular in metha-... nol, ethanol or isopropanol. Amine-borane complexes in glacial acetic acid can equally be used.

Isolation of the pure trans compounds of the formula Ill'b can, for example, be carried out by chromatographic processes or crystallization processes. f. n r ■ ^ 4JUNI98/ ! S - as - " 1 The Jpure trans compound of the formula Ill'b is advantageously separated out of the mixture of diastereo-mers from the amine-borane-complex or boronate reduction 5 by fractional crystallization.

The compounds of the formulae III' can, if appropriate, be converted into the C^-C^g-alkyl pr C^-C^q-aralkyl esters by methods which are described, for example, in Houben-Weyl, volume VIII (1952). 10 The compounds of the formula II with Y and Z being hydrogen, R^ being methyl and R2 being methyl or ethyl and X being phenyl which are used as starting materials for the preparation of the compounds of the formula I are known (European Patent Application No. 37,231). The com-15 pounds of the fonnula II can be prepared by various procedures. One sythetic variant starts from a ketone of the abovementioned formula VII, which is reacted by known procedures in a Mannich reaction with a compound of the abovementioned formula VI together with aminoacid esters 20 of the fonnula XXII H_N - CH - CO.." \fO~C-CH-KH-CH-CIl~-CO-X o\\ ' I ' 2 | l i , -» *1 ■ C02R2 -4JUNI987£| /J X^j**2^ XXII XXIII wherein R^ and V have the abovementioned meanings, to give a compound of the formulaXXIII, wherein R^, R2, X and W have the abovementioned meanings, with the proviso that in 25 the case where V denotes a radical which can be split off by ^ 7 - - 16 - r ' •' --1P hydrogenolysis, in particular benzyl, R2 may not have the meaning of W. If the radlc&l W is split off by hydrogen-olysis using, for example, palladium, compounds of the formula II with Y and Z being hydrogen are obtained. If 5 the radical V is split off with acids, such as, for example, trifluoroacetic acid or hydrochloric acid in an inert organic solvent, such as, for example, dioxane, compounds of the formula II with Y and Z together being oxygen are " obtained.

Compounds of the formula XXIII can also be obtained by Michael addition of a compound of the above-mentioned formula V with a compound of the abovementioned formula XXII by known procedures.Preferentially, this process is suitable for the preparation of those compounds of 15 the formula XXIII in which denotes methyl, R^ denotes ethyl and X denotes aryl.

The compounds of the formula XXIII are obtained as mixtures of diastereomers. Preferred diastereomers of the formula XXIII are those in which the chiral C atoms 20 labeled with an asterisk are each in the S configuration. These can be separated out by recrystallization or by chromatography, for example on silica gel. The configurations of the chiral C atoms are maintained during the subsequent splitting off of the radical W. 25 The compounds of the abovementioned formula IV used as starting materials for the preparation of the compounds of the formula I are obtained by known procedures from compounds of the abovementioned formula III by reaction with an N-protected 2-aminocarboxylic acid of the formula XXIV • ^ v - im - ch - co2h * 1 xxiv R1 wherein V is a protective group and R1 has the above-mentioned meaning. Examples of suitable protective 5 groups V, which are split off again after completion of the reaction, are the groups benzyloxycarbonyl or tert.-butoxycarbonyl.

The reaction of a compound of the formula II with a compound of the formula III to^prepare a compound of 10 the formula I is carried out by a condensation reaction known in peptide chemistry, the condensing agent added being, for example, dicyclohexylcarbodiimide and 1-hydroxy-benzotriazole. In the subsequent removal of the radical V by hydrogenolysis, the catalyst used is preferably 15 palladium, while the acids employed for the acid removal of the radical V are preferably trifluoroacetic acid or hydrogen chloride.

In the reactions described above for the preparation of the compounds of the formulae III', IV and I, the . 20 configurations at the bridgehead C atoms 3a and (6+n)a in the intermediate products are retained in each case. In the case of the trans configuration of the H atoms on the C atoms 3a and (6+n)a, the relevant compounds are obtained, in some cases, as pure diastereomers, and in 25 other cases, as mixtures of diastereomers, which have the 20, 3acc, (6+n)a0 or the 20, 3ap, (6+n)aa configuration as indicated above. These isomers can easily be separated / - i* - ^' - '<9 ~ by recrystallization or chromatography. If, for the preparation of the compounds of the formulae III', IV or I, corresponding starting materials having the cis configuration of the H atoms on C-3a and C-(6+n)a are 5 employed, the exo (or 0) isomers are obtained almost exclusively, and small proportions of the other isomers can be removed by recrystallization or by chromatography.

The compounds of the formula III* obtained according to the procedures described above are produced as 10 racemic mixtures and can be employed as such in the further syntheses described above. However, they can also be employed as the pure enantiomers after separation of the racemates into the optical antipodes by customary methods, for example, via salt formation with optically 15 active bases or acids.

If the compounds of the formula I are produced as racemates, these can also be resolved into their enantiomers by customary methods, such as, for example, via salt formation with optically active bases or acids, 20 The compounds of the formula I according to the invention are in the form of internal salts. Since they are amphoteric compounds, they can form salts v/ith acids or bases. These salts are prepared in a customary manner by reaction with one molar equivalent of acid or base. 25 The compounds of the formula I and their salts have long-lasting and powerful hypotensive activities.

They are strong inhibitors of the angiotensin converting ' c> enzyme (ACE inhibitors). They can be employed to control ligh blood pressure of various etiologies. It is also -4JUN1987Zj f* -Im possible to combine them with other compounds having hypotensive,' vasodilator or diuretic activity. Typical representatives of these classes of active compounds are described, for example, in "Physicians" Desk Reference, 35th edition, Oradell N.Y., 1981. They can be used intravenously, subcutaneously or perorally.

The dosage on oral administration is 1-100 mg, preferably 1-40 mg, for a single dose for en adult patient of normal weight. This can also be increased in severe 10 cases, since no toxic properties have been observed ^ . hitherto. A decrease in the dose is also possible and is particularly appropriate when diurotics are administered concurrently.

The compounds according to the invention can be 15 administered orally or parenterally in an appropriate pharmaceutical formulation. For a form for oral use, the active compounds are mixed with the additives customary for this purpose, such as vehicles, stabilizers or inert diluents and converted by customary methods into suitable 20 forms for administration, such as tablets, coated tablets, hard capsules, aqueous, alcoholic or oily suspensions or aqueous, alcoholic or oily solutions. Inert vehicles which can be used are, for example, gum arabic, magnesium carbonate, potassium phosphate, lactose, glucose or starch, 25 particularly corn starch. In this context, the formulation can either be as dry or as moist granules. Examples of suitable oily vehicles or solvents are plant and ' > animal oils, such as sunflower oil or cod-liver oil. v * - For subcutaneous or intravenous administration. -4JUNI987 ~>1 - 20 - ' the active compounds or their physiologically tolerated « * • salts are converted into solutions, suspensions or emulsions, if desired together with the substances customary for this purpose such as solubilizers, emulsifiers or 5 ottier auxiliaries. Examples of suitable solvents for the new activc compounds and the corresponding physio- « logically tolerated salts are: water, physiological saline or alcohols, for example ethanol,propane-1,2-diol or glycerol, additionally also sugar solutions, such as glucose or 10 mannitol solutions, or also a mixture of the various solvents mentioned.

The extremely high activity of the compounds according to formula I is demonstrated by the pharmacological data in the following tables: ^5 Intraduodenal administration to the anesthetized rat, .. 50 # inhibition of the pressor reaction induced by 310 ng of angiotensin I 30 min. after administration in the dose.... = Table I .01 atoms on C-3a and C-(6+n)a in formula I have the cis configuration and the C02H g'roup is exo configurated) .

II X y .2 R2 R1 ED50 ° H H C2"5 CH3 O H H H CH- 700 'HQ '3 1 II H C2I15 CH3 50 S) "O VH "A 7 11 H II CH, 600 3 - Z1 - 2 Us- * / n X Y Z R g Rn ED50 (tig/Kg) -o H H C2I)5 CH3 230 2 " H M CH3 840 -Q - O - C?I15 C»3 390 The symbols n, X, Y, Z, R,j end R2 relate to the compound of the formula I.

Table II H atoms on C-3a and C-(6+n)a have the trans configuration} X ■: phenyl, « methyl n y Z *2 Configuration of the bicycte ED50 0 li H 11 2S, 3sP.i 6aS 700 0 it H C2"5 , 3aR, 6aS i 40 1 ii H 11 , 3aR, 7cS COO • 1 ii H " C2ri5 2S, 3aR, 7aS 55 1 H 11 11 2S, 3aS, 7aR 850 1 H H C2H5 , 3aS, 7aR G5 2 11 H JI 2S/ 3clTt j Cc3S 1080 2 1 H - O H C2»5 c2ii5 2S, 2S, 3aK, 3uR, 8a S 7aS iio 180 The symbols n, X, Yt Zf and R2 relate to the compounds of the formula I.

The following examples serve to illustrate the invention but do not restrict it to the compounds men- tioned as representatives: f. < ; • J11f • v r\ -22- •?/ tetramethylammonium tetrafluoborate, according to the details in Liebigs Ann. Chem. 1978, page 1790. The . " 4JUNl987£ji solvent was distilled off and the residue was filtered through 500 g of silica gel by means of ethyl acetate. 53.6 g of the abovementioned product were obtained from the ethyl acetate solution after evaporation. value 5 (thin-layer chromatogram): 0.33 (silica gel, ethyl acetate) c) N-Acetvl-20. 3n8 .7afi-octahydro-lH-indole-2-carbonitrile 1 25 g of trimethylsilyl cyanide in 50 ml of methy lene chloride were added dropwise to a solution of 49.8 g of N-acetyl-2-methoxy-3ap,7ap-octahydro-lH-indole in 250 ml 10 of methylene chloride at -40°C. Subsequently, 35.9 g of boron trifluoride etherate vere added dropwicc so that the temperatvre of the reaction mixture did not exceed -20°C. After 2 hours of reaction at -20°C, the temperature was slowly raised to 0°C, the mixture was stirred 15 overnight at 0°C and then for one hour at PO to 25°C.

Water was added to the mixture and this was stirred 10 min. The aqueous phase was extracted three times with methylene chloride. The combined organic extracts were dried, concentrated and the residue was triturated with diisopropyl ether.

Yield: 47 g; m.p. 128° to 130°C. d) 20. 3a6.7ag-Octahydro-lH-indole-2-carboxylic acid 10 g of N-acetyl-2p,3ap,7ap~octahydro-lH-indole-2- carbonitrile in 30 ml of concentrated hydrogen bromide were heated to boiling for 2 hours. After distilling off the hydrogen bromide, the residue was stirred with a little acetone and filtered off with suction.

An aqueous solution of the product was adjusted m'jbo a pH of 6.0 with a weakly basic ion exchanger. After rs filtration, the solution vas evaporated and the residue was filtered" through 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 was concentrated and 5 the residue was triturated with diisopropyl ether.

Yield: 7.6 g 1H NMR spectrum*: 1.0-2.5 (m, 11H); 3.4-3.9 (m, 1H); procedures described under Example 1, the compounds mentioned under Example 2 and Example 3 in the following text were obtained: Example 2 2B.3a8.6aS-0ctahvdrocvcIopentafb1pvrrole- 2-carboxylic acid a) N-Acetyl-cis-octahydrocyclopenta[b]pyrrole 1H NMR data: 1.0 to 2.3 (m 9H); b) Acetyl-2-methoxy-cis-octahydrocyclopenta[b]pyrrole 4.0-4.5 (m, 1H); 7.5-8.3 (broad s, exchangeable with D20) Vhen the process was carried out in analogy to the 2.0 (d, 3H); 3.3 to 4.2 (m, 3H) 1H NMR data: 0.9 to 2.6 (m, 9H); 2.1 (s, 3H); 3.3 (s, 3H); 3.8 - 4.3 (m, 1H); 4.7 - 5.5 (m, 1H).

*Here and in the following text, the NMR data were 4JUN]987rKi obtained in CDCl^ and are reported in ppm. ? 1 * < 148?-? c) N-Acetyl-2-cyano-cis-octahydrocyclopenta[b]pyrrole 1H-NMR data:* 1.0 - 3.0 (m, 9H); 2.1 (d, 3H); 3.5 - A.1 (m, 1H); A.A - A.7 (m, 1H). d) 2p,3a0,6ap-0ctahydrocyclopenta[b]pyrrole-2-carboxylic acid 1H NMR data: 1.0 - 2.3 (m, 9H) 3.5 - 3.9 (m, 1H) A.O - A.6 (m, HI) 7.7 - 8.A (broad s, exchangeable with DgO) Example 3 26.3aB.8a9-Decahvdrocyclohcpta[b1i;vrrole-2-carboxyIic acid a) N-Acetvl-cis-decahydrocycIoheptafblpyrrole 15 1H NMR data: 0.9 - 2.5 (m, 13H); 2.1 (s, 3H); 3.1 - A.1 (m, 3H). b) N-Acetyl-2-raethoxv-cis-decahydrocvcloheptarblpyrrole 1H NMR data: 0.9 - 2.7 (m, 13H); 2.1 (s, 3H) 3.2 (s, 3H); 3.7 - A.2 (m, HI); A.7 - 5.3 (m, 1H) c) N-Acetvl-2-cvano-cis-decahydrocyclo:hepta[bIpyrrole 1H NMR data: 0.9 - 3.1 (m, 13H); 2.1 (s, 3H); * 3.5 - A.1 (m, 1H); 4.3 - A.7 (m, 1H). - 4JUNI987Z i i. < i ^ - 26 - / ., ' * d) 2B.3a 0.8aB-Decah vdroc vcl ohepta Tblpyrrole-2-carboxvllc acid 1H NMR data: 0.8 - 2.4 (m, 13H); 3.5 - 3.9 (m, 1H); 4.1- 4.6 (in, 1H)j ,7.6 - 8.3 (broad e, exchangeable with DgO) Example 4 28. 3a P. 7aP-Octahydro-lH-indole-2-carboxylic acid a) 3.4.5.6.7.8-Kexahvdro-1H-quinolin-2-one 392 g of cyclohexanone and 212 g of acrylonitrile together with 20 g of cyclohexylamine, 4 g of glacial acetic acid end 0.4 g of hydroquinone were heated under reflux for 4 hours up to a final temperature of 200°C.

After distillation at 100 to 150°C/0.5 mm Hg, the residue 15 remaining, which contained the desired product, was recrystallized from n-hexane.

The distillate was heated with 10 ml of 10 % strength acetic acid at 200°C for 2 days. After cooling down, further product was obtained which was crystallized 20 from methanol/water.

A total of 460 g of title compound was obtained, m.p.; 143 - 144°C. b) Cis-octahvdro-1H-quinolin-2«-one One gram of platinum (IV) oxide was added to a 25 solution of 80 g of 3,4,5,6,7,8-hexahydro-1H-quinolin-2-one and this v:as hydrogenated at 20 to 25°C under normal pressure. After filtration of the reaction solution, it was evaporated and the residue was fractionally crystal-m4Ji',\!987 lized from n-hexane. 35 g of cis-octahydro-lH-quinolin- 2-one having a melting point of 123 to 126°C were obtained c) 3.3-Djchloro-cis-octahvdro-lH-qulno]ln-2~one 28.8 g of phosphorus pentachloride were added to a solution of 23 g of cis-octahydro-1H-quinolin-2-one in 350 ml of anhydrous chloroform. To this were added drop-wise 43.1 g of sulfuryl chloride in 45 ml of anhydrous chloroform at 20 to 30°C within 30 rain and the reaction mixture was stirred at the boiling point for 5 hours.

After allowing to stand overnight, the mixture was neutral ized with aqueous potassium carbonate cooled to 0°C. The aqueous phase was extracted twice with methylene chloride. The combined organic phases were dried over sodium sulfate and concentrated. The residue was recrystallized from ethanol with the addition of active charcoal. 32 g of -,5 pale yellow crystals, having a melting point of 176 to 177°C, were obtained. d) 3-Chloro-cis-octahydro-1H-quinolin-2-one .9 g of 3,3-dichloro-cis-octahydro-1H-quinolin-2-one in one liter of ethanol, with the addition of 10 ml of triethylamine and Raney nickel, were hydrogenated at 20 to 25°C under normal pressure until one mole-equivalent had been taken up. After filtration, the solution was evaporated, the residue was taken up in ethyl acetate, the solution was extracted twice with water and dried over 25 sodium sulfate. After removal of the solvent, the produc was triturated with diisopropyl ether and filtered off with suction. Colorless crystals, having a melting point y v .of 185°C, were obtained.

Ci -\ * e) 28. 3a 3.7aB-Octahydro-lH-indole»2-car£oxylic acid £ of 3-chloro-cis-octahydro-1H-quinolin-2-one were added to a boiling solution of 6.63 g of barium hydroxide octehydrate in 120 ml of water. After heating 5 under reflux for 3.5 hours, 0.9 ml of concentrated sulfuric acid was added to the reaction mixture and this was heated j to boiling for a further hour and then allowed to stand overnight.

The precipitate was filtered off with suction and 10 the filtrate was adjusted to a pH of 6.5 with 1N sodium hydroxide and evaporated to dryness. The residue was extracted witi boiling ethanol, concentrated and induced to crystallize.

Yield: 3.1 g The compounds 26-cis-octahvdrocycl openta fb"lpyrr ole- 2-carboxvlic acid (corresponds to the compound from Example 2 d) and 26. 3a8. 8a8-decahyflrocvcloheptafbIpyrrole-2-carboxylic acid (corresponds to the compound in Example 3 d) may be prepared in a manner analogous to that 20 described in Example k.

Example 5 Benzyl 26.3aB.7ap-octahydro-lH~indole-2-carboxylate hydrochloride 3 ml of thionyl chloride vere added dropwise to 25 25 ml of benzyl alcohol. 3 g of 2(5,3a|3,7ap-octahydro-lH-indole-2-carboxylic acid hydrochloride vere added to this mixture. The reaction mixture was allowed to stand at 5°C for 2 days, after which a clear solution had formed. o7 After evaporation, diisopropyl ether was added to the ? 1,1 w - 21 - residue obtained and this was filtered off with suction. 3.8 g of the title compound, having a melting point of 150°C (with decomposition), were obtained.

The following ester compounds in Examples 6 and 7 5 may be prepared in a manner analogous to that described in Example 5i Example 6 Benzyl 2P. 3aB. 6aB-octahvdrocyclopentafblpyrrole-2-car-boxylatc hydrochloride 10 1H NMR data: 1.0 - 2.3 (m, 9H).'r 3.4 - 3.9 (m, 1H); 4.1 - 4.6 (m, 1H); .1 (s, 2H); 7.2 (s, 5H).

Example 7 Benzyl 26. 3a6.8a8-decahydrocvcloheptafb1pyrrole«-2-car- boxylate hydrochloride 1H NMR data: 0.9 - 2.3 (m, 13H); 3.5 - 3.9 (m, 1H); 4.2 - 4.7 (m, 1H); .2 (s, 2H); 7.2 (s, 5H).

Example 8 Tert.-butyl 28. 3a(3.7aP-octahydro-IH-indole-2-carboxylate 25 hydrochloride ^=-5. 10 ml of concentrated sulfuric acid and 50 g of o\ isobutylene vere added to a solution of 10 g of 2p,3ap,7a|5 -r\ " +jUKl987^ octahydro-lH-indole-2-carboxylic acid in 100 ml of dioxane > J cooled down to -10°C. The reaction mixture was slowly warmed to 20 to 25°C in an autoclave and stirred at this temperature for 20 hours.

The mixture was added to ice-cold 50 # strength aqueous sodium hydroxide and extracted with methylene 5 chloride. The combined organic phases were washed with water, dried with sodium sulfate and concentrated. The residue was taken up in ether and the pH was adjusted to 2.0 to 3.0 by means of ethereal hydrogen chloride. The mixture was evaporated to dryness and the product was 10 triturated with diisopropyl ether. 7.3 g of the title compound were obtained after filtering off with suction. 1H NMR data: 1.0 - 2.5 (m, 11H); 1.5 (s, 9H); 3.4 - 3.9 (m, 1H); 4.0 - 4.5 (m, 1H).

The following ester compounds of Examples 9 and 10 can be prepared in analogy to the procedure described in Example 8: Example 9 Tert.-butvl 26.3aB.6aB-octahvdrocvclopentarb1pyrrole-2-carboxylate hydrochloride 1H NMR data: 1.0 - 2.7 (m,9H); 1.3 (s,9H); ; 3.4 - 3.9 (m,1H); 4.0 - 4.5 (m,1H).

Example 10 s Tert.-butvl 26.3aB.8aB-decahydrocycloheptarblpyrrole-3- v. carboxylate hydrochloride 37JpH NMR data: 0.8 - 2.9 (m,13H); •' < *U}~- 1.3 (s,9H); ' 3.4 - 3.9 (m,1H); 4.0 - 4.5 (n,1H).

Example 11 Benzvll-tN-dS-carboethoxv-^-rhcnvl-DroDvl )-S-alanvlj-2S. 3aR.7oR-octahydro-lH-indole-2-carboxylate ("diastereomer All) and benzyl 1I>K 1S- c arboethoxy- 3 -phen yip ropvl) - S- al anvlj-2R.3aS.7aS-- octahydro-lH-indole-2-carboxylate (-diastereomer B 11) 2.5 £ of N-(1S-c&rboethoxy-3-pberiylpropyl)-S-alanine, 1.22 g of l-hydroxybenzotriazole, 2.5 g of benzyl (d,l)-20,3aP,7a?-octahydro-lH-iiidole-2-carboxylate hydrochlo-ide, 1.25 ml of N-ethylmorpholine and 2 g of dicyclohexyl-carbodiimide were edded to 20 ml of diffiethylfcrmamide at 0°C.

The mixture was stirred at 0°C for 1 hour, then slowly wanned to room temperature and stirred at 20 to 25°C overnight. ml of ethyl acetate were added to the reaction mixture and precipitated N,N'-dicyclohexylurea was filtered of£wit. suction. After evaporation of the solution, the residue obtained was taken up in 50 ml of ether, the ethereal solution was washed with saturated aqueous sodium bicarbonate and water, dried and concentrated. A mixture of the abovementioned diastereomers A 11 and B 11 was obtained which was separated over silica gel using a mixture of cyclohexane and ethyl acetate (4:1).

Rj. value for diastereomer A 11: 0.36 Rj. value for diastereomer B 11: 0.34 The following compounds in Examples 12 to 16 were obtained, in'a procedure analogous to that described in Example 11.

Example 12 Tert. -butyl ljM-( 1 S-carboethoxy- 3-phenvlpropyl )-S-nlanv^-2S.3aR.7aR- octahydro-lH-indole-2-carboxylate (■diastereomer A 12) 1H NMR data: 1.25 (d+t, 6H); 1.35 (sf9H); 1.3 - 3.6 (m, 18H)? 4.2 (q, 2H); 4.4 (o, 1H); 7.3 (s, 5H).

Example 13 Benzyl lftK'iS-carboethPxy-3-phenvlpropyl )-S-alanvl^-2S. 3aR. 6aR-octahydrocyclopenta[blpyrrole-2-carboxylate (^diastereomer A 1?) 1H 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); .2 (s, 2H); 7.2 (s, 5H); 7.4 (s, 5H).

• V\V , A >987, j r\ Example 14 Benzvll-|hJ-(1S-carbopthoxy- 3-phenvlpropyl )-S-aIanv!^-2S. 3aR.8aR-d Example 15 Tert .-butvll-[N-(1S-carboethoxy-3-phenvlpropyl )-S-alanvl|-15 25.3aR.6aR-octahydrocvclopenterblT)yrrole-2-carboxvlate (edlastereomer A 15) 1H 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)j 4.6 (m, 1H); 7.2 (s, 5H).

\ Example 16 Tert. -butyll|N-(1S-carboethoxy-3-phenylpropyl )-S-alanyjj-2S. 3aR. 8eR-decahydrocyclohepta [b ]pyrrole-2-carboxylate (=diastereoraer A 16) 1li NMR data: 1.1 (d, 3B); '4JUN1987$j 1.3 (t, 3H); - 5-1 - . . ■?/ 1.4 (s, 9H); 1.4 - 2,5 (s>, 14H); 2.3 - 3.4 (mf 6H)j 4.1 (q, 2H); 4.7 (m, 1H); 7.3 (s, 5H).

Example 17 26. 8.7aa-Octahydro-lH-indole carboxylic acid a) Methyl 3-chloro-N-acetylalonine 181 g of methyl 3-chloroalanine hydrochloride were heated under reflux with 163.9 g of acetyl chloride in 1.5 1 of anhydrous toluene for about 5 hours until a clear 20 solution was obtained. This was evaporated to dryness and the residue was crystallized from ethyl acetate/ petroleum ether. 170 g of product of m.p. 104°C were obtained. b) Methyl 3-(2 -oxocyclohexyl)-N-acetylalanine 25 160 g of methyl 3-chloro-N-acetylalanine and 171.9 g of 1-pyrrolidinocyclohexene were dissolved in 1.2 1 of absolute DMF,and the mixture was allov/ed to stand 1 - , at 20 to 25°C for 3 days.

The solution was concentrated under high vacuum, * 4JUNW,:. the residue obtained was taken up in 600 ral of water and the pH was adjusted to 2.0 with concentrated hydrochloric acid. The aqueous solution was extracted with ethyl acetate and the organic phase was dried over sodium sul-5 fate and evaporated. The product was obtained as a yellow oil. c) 3t 3a. U. 5.6.7-2H-Hexahydro-lH-lndole-2-carboxylic acid hydrochloride 220 g of the compound obtained under b) were 10 heated to boiling under reflux with 1 1 of 2N of hydrochloric acid for 2 hours. The reaction mixture was extracted witn ethyl acetate and the aqueous phase was concentrated. Residual amounts of water were removed by evaporation in vacuo with the addition of toluene three 15 times. 210 g of the product were obtained as a yellow oil which crystallized on being left to stand. d) 20.3aB.7ag-Octahydro-lH-indole-2-carboxylie acid 128 g of 3,3a,4,5,6,7-2H-hexahydro-lH-indole-2-car-boxylic acid hydrochloride were hydrogenated under normal 20 pressure in 700 ml of glacial acetic acid with the addition of 4 g of platinum/charcoal (10 %) at room temperatxire. The catalyst vas filtered off and the filtrated was evaporated to dryness. The residue was dissolved in 500 ul of hot ethanol and cooled down to -20°C. Phis caused the 25 2{3,3ap,7aP-isomer of the title compound to precipitate out. The product was obtained fr*ora the solution by concentrating and adding isopropanol, in the form of colorless crystals of in. p. 280°C. 4JUNW7 Example 18 2B.3aB.8flecahvdrocvcloheptafb1pyrrole-2-carboxyllc acid This compound was prepared in analogy to the procedures b) to d) of Example 17 starting from pyrrolidino-5 cycloheptene.

Example 19 2fl.3aP.6anc-Octahydrccvclopentafb"|pvrrole-2-carboxylic acid This compound was prepared in analogy to the procedures b) to d) of Example 17, starting from pyrrol!dino-10 cyclopentene.

Example 20 26.3ag.7afi-Octahydro-lH-lndole-2-carboxylic acid a) 3.4.5.6.7.6-Octahydro-lH-quinolin-2-one 392 g of cyclohexanone and 212 g of acrylonitrile, 15 together with 20 g of cyclohexylaminet A g of glacial acetic acid and 0.4 g of hydroquinone, were heated under reflux for 4 hours up to a final temperature of 200°C. The distillate obtained after distillation at 100 to 150°C/ 0.5 mm Hg was heated with 10 ml of 50 % strength acetic 20 acid at 200°C for 2 days. After cooling down, the reaction mixture was recrystallized from methanol/water. Combined with the residue from distillation, obtained previously, which was recrystallized from n-hexane, 460 g of the product of ra.p. 143 to 144°C were obtained. 25 b) Trans-octahydro-1H-quinolin-2-one A mixture of 25 g of the product obtained under a) and 70 g of sodium formate in 120 ml of formic acid were heated to boiljng under reflux for 18 hours. The reaction o -^solution was made alkaline with 20 % strength aqueous 4JUNI987£j ?f . - 38 - . . ■ ' vf; sodium hydroxide and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated. The residue was recrystallized from cyclohexane and the product was obtained having an m.p. of 152°C. 5 c) 3.3-Dichloro-trans-octahydro-1H-quinolin-2-one A solution of 36.4 g of sulfuryl chloride in 40 ml of chloroform was added dropwise at 20 to 30°C over 30 min-* utes to a solution of 19.4 g of the compound obtained under b) and 24.3 6 of phosphorus pentachloride in 300 ml 10 of anhydrous chloroform. The mixture was heated to boiling for 6 hours and allowed to stand overnight at 20 to 25°C.

The mixture was neutralized with ice-cold saturated aqueous potassium carbonate, extracted with methylene chloride, and the organic phase was dried over sodium sul-15 fate and then concentrated. After recrystallization of the product from ethanol, with the addition of active charcoal, 25 g of the product, of m.p. 195 to 198°C, were obtained. d) 3-Chloro-trans-octahydro-1H-quinolin-2-one 20 15.6 g of the compound obtained under c) were hydrogenated under normal pressure in 1 1 of ethanol and —9.7 ml of triethylaraine, with the addition of Raney nickel, at 20 to 25°C until 1 mole-equivalent of hydrogen had been taken up.

After the catalyst had been filtered off, the fil trate was evaporated to dryness and the residue was taken up in ethyl acetate. The organic phase was washed twice N; with water, dried over sodium sulfate and evaporated. -fche residue was triturated with diisopropyl ether, ' 4JUN1987:l!} _ 39 _ filtered off with suction and dried. The product was obtained in the form of pale yellow crystals of m.p. 115 - 120°C. e) 2B. 3ag.7a6—Octahydro-lH-indole-2-carboxylic acid 3.75 s of the compound obtained under d) were added to a boiling solution of 6.63 g of barium hydroxide octehydrate in 120 ml of water. After heating under reflux for A hours, 0.9 ml of concentrated sulfuric acid were added, heating under reflux vas continued a further hour, the reaction solution v/as filtered and the filtrate was adjusted to a pH of 6.5 with 1N sodium hydroxide.. After evaporation of the solution, the residue was heated in ethanol, again filtered and the filtrate was evaporated to, a small volume. On cooling down, a crystalline 1:1 mixture of the title compound and the compound of Example A8, of m.p. 275-276°C was obtained.

Example 21 . 3a6. 6aoc-Octahydrocyclpenta[b1pvrrole-2-carboxvlic acid a) 1.2. 3. A.6.7-Hexahydro-5H-1-pyrin ! Jo ' i > - 40 ~ b) 0ctahv(iro-trans-5H-1-pyrlnd-2-one This compound was prepared in analogy to the pro-' cedure described in Example 20 under b). 1H NMR data: 7.8 (broad s, 1H) 2.9 (broad s, 1H) 2.6 - 2.2 (m, 2H) 2.1 - 1.0 (in, 8H). c) 3.3-Dichlorooctahydro-trans-5H-1-pvrind-2-one This compound was prepared in analogy to the pro-10 cedure described in Example 10 under c). 1H NMR data: 7.9 (broad s, 1H) 3.8 (broad sf 1H) 3.2 - 2.0 (m, 2H) 2.1 - 1.0 (m, 6H), d) p-Chl oroc?ctahydro-trans-5H-1-pyrind-2-one This compound was prepared in analogy to the procedure described in Example 20 under d).

NKR data: 7.8 (broad s, 1H) 4.'6 - 4. 3 (m, 1H) 3.3 - 3.0 (id, 1H) 2.1 (d, J = 6 Hz, 2H); 1.8 - 1.1 (m, 6H). e) 20,3aPr6a«-0ctahydrocvclopentarb1pvrrole-2-carboxvIic acid This compound vas prepared in analogy to the pro cedure, described in Example 20 under e). 1H NMR data: 4.7 - 4.4 (m, 1H); 3.0 - 0.9 (m, 10H). 4JUM987', , i V - 4i - Example 22 26. 3aB.8aff-flccahydrocyclghepta rblpyrrole-2-carboxvllc acid a) 1.2.3.4.5.6.7.8-0ctahydrocyclohepta[b1pyrid -2-one This compound v/as prepared in analogy to the pro- cedure described in Example 20 under a), starting from cycloheptanone.

NMR data: 9.4 (broad s, 1H); 3.2 - 2.0 (m, 14H). b) Trans-DecahydrocycloheptafbIpyrid -2-one 10 This compound was prepared in analogy to the procedure described in Example 20 under b), starting from the compound previously mentioned under a). 1H NMR data: 7.9 (broad s, 1H); 2.9 (broad s, 1H); . 2.6 - ?..? (id, ?H); 2.1 - 1.0 (m, 12H) c) 3.3-Dlchloro-trans-decahydrocvcloheptarblpyr,i^ -2-one This compound was prepared in analogy to the procedure described in Example 20 under c).

NMR data: 7.9 (broad s, 1H); 3.8 (broad sf 1H); 3.2 - 2.0 (in, 2H); 2.1 - 1.0 (m,' 10H). d) 3-Chloro-trar)S-decahydrocycloheptarb1pyrid -2-one 25 This compound v/as prepared in analogy to the procedure described in Example 20 under d).

NMR data: 7.8 (broad s, 1H); A.6 - A.3 (m, 1H); 4JUN}987?^ 3.3 - 3.0 (in, 1H); rv 2.1 (d, J « 6 Hz, 211); 1 <

Claims (6)

- 44 - 10 Example 29 7aa, 26.' -octahydro-lH-iridole-2-carboxylic acid 290 g of the acetylamino derivative obtained in accordance with Example 1 were heated with 2N hydrochloric acid as indicated in Example 2. The mixture was evapor-15 ated in vacuo, the residue was taken up in 1 1 of iso-propanol and reduced with about 35 g of NaBH^ which was added in portions in the course of 30 minutes. The reaction temperature was kept at 40 - 50°C. The reaction v/as allowed to continue for about 4 hours, then the mixture 20 was evaporated in vacuo, the pH was adjusted to 6.5 with dilute hydrochloric acid, solid sodium chloride was used to saturate, and the aniinoacids were extracted several times with n-butanol. The residue remaining after concentration of the organic phase was fractionally crystallized from- 25 chloroform/diisopropyl ethsr as described in Example 2. r.3aa» ,7aa, Yields: 40 - 60 g of 2p,'-product 20 g of a mixed fraction r 3ag, 7aa- 100 -130 g of 23#l -product. r3aB, 7aa- In the same manner, 2B, -2-azabicyclol5.3.0J- r3a$, 7aa- decane-3-carboxylic acid and 2$,' -2-azabicycloL6.3.0J-undecane-3-carboxylic acid can be prepared. / •v * JUN1987^ \ . J • JHAT WE CLAIM IS: - 45 - n i t Q iv^ ( <

1. A compound of the formula III' III" in which n represents a whole number from 0 to 10, W1 represents hydrogen, alkyl having 1 to 18 C atoms or aralkyl having 7 to 10 C atoms, and R^, R^ and/or represent hydrogen, or R^ and R^ or R^ and R^ together each denote a chemical bond. with the proviso that such compounds of the formula III" are excluded: a) in which R,, R. and R_ each denote hydrogen, n is zero, W* denotes hydrogen, TC,-Cg)-alkyl or (C? or Cg)-aralkyl including nitrobenzyl, R. and R, have the cis configuration relative to one another and COOw' faces the cyclopentane ring, or b) in which R3, and R- and R5 are defined as under (a), n is 1, W' denotes hydrogen or (C^-C^)-alkyl and COOW* faces the cyclohexane ring, or c) in which R, denotes hydrogen and R. and R,. together denote a chemical bond, or R5 denotes hydrogen and R_ and R. together denote a chemical bond, n is zero and W denotes hydrogen. ^

2. A compound of the formula III * as claimed in claim 1, H 3 a n (6+n) a (2 xiV V co W H 2 H in which the H atoms on the C atoms 3a and (6+n)a have the cis or trans configuration relative to one another, wherein, in the case of the cis configuration, the group -CO2V1 on C atom 2 is oriented exo to the bicyclic ring system and wherein n denotes 0t 1 or 2 and V/1 denotes hydrogen or a radical which can be split off by ' hydrogenolysis or acidelysis.

3. A process for the preparation of the compounds of the formula III1 as claimed in claim 2 which comprises a) acylating a compound of the formula IX T L /; 7 ifcv - 47 - '14877 3 a (6+n)a u H IX H wherein the H atoms on the C atoms 3a and (6+n)a have the cis or trans configuration relative to one another and wherein n denotes the number 0, 1 or 2, subsequently anodically oxidizing the compound obtained with an appropriate alcohol in the presence of a conducting salt to give a compound of the formula X .H (CH2)n' b (6+n)a 'OR, Acyl X wherein the H atoms on carbon atoms 3a and (6+n)a have a cis or trans configuration and n has the abovementioned meaning and R^ denotes (Cj-C^)-alkyl, reacting this product with trimethylsilyl cyanide in the presence of a Lewis acid to give a compound of the formula XI H 3a XI (6+n)a £ N^^CN t Acyl wherein the H atoms on the C atoms 3a and (6+n)a have the cis or trans configuration relative 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, and hydrolyz-ing the latter by the action of an acid or base to give a compound ,y \ i ^ ' ©V of the formula III' with W = hydrogen and optionally esteri- CV- % f - 48 - fying appropriately, the letter, or ti) reacting a compound of the formula XII H 3 a 214877 XII vdierein the H atoms on the C atoms 3a and (6+n)a have the cis or trans configuration and n has the abovementioned meaning, in a Beckmann rearrangement to give a compound of the formula XIII XIII wherein the H atoms on carbon atoms 3a and (6+n)a have a cis or trans configuration and n has the t abovementioned meaning.halogenating the latter to give a compound of the formula XIV XIV wherein the H atoms on carbon atoms 3a and (6+n)a have a cis or trans configuration and n has the abovementioned meaning 18 AUG 1987 J/ . '■4 l. it* L 49 - 214877 and Hal denotes a halogen atom, reducing the latter to give a compound of the formula XV XV wherein the H atoms on carbon atoms 3a and (6+n)a have a cis or trans configuration and n and Hal have the abovementioned meanings, and subsequently reacting the latter under the action of a base to give a compound of the formula III' with W' = hydrogen and optionally esterifying appropriately the letter, or c) for the preparation of a compound of the formula III*,* wherein the H atoms on the C atoms 3a and (6+n)a have the cis configuration, reducing, under metal catalysis in a protic medium a compound of the formula XVI XVI viherein n has the abovementioned meaning, to give a compound of the formula XIII mentioned under b), and reacting the latter as described under b). or v* '' '/V O A A o-j '8 AUG 1987,„ i.+. / d) for the preparation of a compound of the formula III', j wherein the H atoms oil the C atoms 3a and (6+n)a have the trans configuration, reducing a compound of the formula v XVI mentioned under c) with sodium formate and formic acid 1 to give a compound of the formula XIII mentioned under b) and further reacting the latter as described under b)# A process w d./for the preparation of compounds of the formula III/T

4. 4 | in which n represents a whole number from 0 to 10 and W1 has the j "i meaning given in claim 1 which comprises reacting an enamine of the formula XVII, "1 I in "which n has the previous meaning and X repres- | ents dialkylamino having 2 to *10 C atoms or a I radical of the formula XVIIa, wherein m and o denote a whole number from 1 to ^ (m + o) ^ 3 and A denotes CHg, MH, 0 or S, together v/ithjN-acylated p-halogeno-a-arainopropionic acid 2 ester of the formula XVIII, in v.'hich X represents chlorine 1 or bromine, Y represents alkanoyl having 1 to 5 C • atoms, aroyl haying 7 to 9 C atoms or g^her protective group Is which are customary in ipeptide chemistry and which can be split off by ae«t, and R^f represents alkyl having 1 to 5 C atoms or aralkyl having 7 to 9 C atoms, •- i '10; C|*2 XVIII 1 Y -HN / C00R4 or together with an acrylate of the formula XIX, in which Y*and R^' have the previous meaning, ^ COOR.' / u CH, — CT . XIX 1 NH - Y 1 to give a compound of the formula XX, in which R^' and Y have the previous meaning. o Vcv„'V - CH2 - CH ^ COOR,' / 4 sNH-Y1 XX cyclizing the latter, with acylamide and ester cleavage, by means of a strong acid, to give a compound of the formula XXIa or b, in which n has the previous meaning. J 4 SEP 1987 u CV^ N ~x COOH XXIa VCH^ \N/\ COOH XXI b converting the latter, optionally after conversion into a Cj-Cjg-alkyl or C^-C^-aralkyl ester, by catalytic hydrogenation in the presence of a transition metal catalyst or by reduction with a borane-amine complex or complex-borohydride, into a compound of the formula Ill'b, in which t - -/ " 52— o a ( f, f-M M'iCiH n has the previous meaning, and V.M represents hydrogen, alkyl having 1 to 18 C atoms or aralkyl having 7 to 10 C atoms, 'saponifying, if appropriate, [l&ter of the rb formula IIJw and, if is hydrogen, optionally esterjTying to give [compound of the formula III1*), in which n has the previous meaning and V/' represents clkyl having 1 to 18 C atoms or aralkyl having 7 to 10 C ot.rwr,.

5. A compound of formula III" according to claim 1 substantially as herein described or exemplified.

6. A process according to claim 3 substantially as herein described or exemplified. HOECHST AKTIENGESELLSCHAFT By Their Attorneys HENRY HUGHES LIMITED '|*28 AUGW87")