IE840210L - Resolution of bicyclic amino-ó-carboxylic esters. - Google Patents

Abstract

For the Contracting States BE CH DE FR GB IT LI LU NL SE 1. A process for resolving racemic mixtures of bicyclic imino-alpha-carboxylic esters into the components of the formula Ia and Ib see diagramm : EP0115345,P15,F1 in which R represents an aliphatic radical having 1 to 6 carbon atoms, an alicyclic radical having 4 to 10 carbon atoms, an aromatic radical having 6 to 12 carbon atoms or an araliphatic radical having 7 to 15 carbon atoms, a) A and B**1 denote hydrogen, and B**2 and C together form a chain of the formula -[CH2 ]n -, with n being 3, 4, 5 or 6, or a chain of the formula -[CH2 ]p -CH=CH-[CH2 ]q -, with (p+q) being 1, 2, 3 or 4, b) C and B**2 denote hydrogen, and A and B**1 together form a chain of the formula -[CH2 ]n -, with n bein 3, 4, 5 or 6, or a chain of the formula -[CH2 ]p -CH=CH-[CH2 ]q -, with (p+q) being 1, 2, 3 or 4, or c) A and C denote hydrogen, and B**1 and B**2 together form a chain of the formula -[CH2 ]m -, with m being 4, 5, 6 or 7, by crystallization of diastereomeric salts, which process comprises preparing the salts of the racemic esters with optically active N-acylated R- or S-aminocarboxylic acids which contain a phenyl nucleus, from the series phenylalanine, phenylglycine, beta-phenyl-alpha-aminobutyric acid, 3,4-dihydroxyphenylalalin, beta-phenylserine and tyrosine, recrystallizing them form an aprotic organic solvent or an alcohol having up to 6 carbon atoms, decomposing the precipitated, optically homogenous diastereomeric salts in a manner known per se, and isolating the enantiomers of the formula Ia or Ib, respectively, and where appropriate, converting the latter into the free acids by saponification or hydrogenolysis in a manner known per se. For the Contracting State AT 1. A process for resolving racemic mixtures of bicyclic imino-alpha-carboxylic esters into the components of the formula Ia and Ib see diagramm : EP0115345,P17,F1 in which R represents an aliphatic radical having 1 to 6 carbon atoms, an alicyclic radical having 4 to 10 carbon atoms, an aromatic radical having 6 to 12 carbon atoms or an araliphatic radical having 7 to 15 carbon atoms, a) A and B**1 denote hydrogen, and B**2 and C together form a chain of the formula -[CH2 ]n -, with n being 3, 4, 5 or 6, or a chain of the formula -[CH2 ]p -CH=CH-[CH2 ]q -, with (p+q) being 1, 2, 3 or 4, b) C and B**2 denote hydrogen, and A and B**1 together form a chain of the formula -[CH2 ]n -, with n being 3, 4, 5 or 6, or a chain of the formula -[CH2 ]p -CH=CH-[CH2 ]q -, with (p+q) being 1, 2, 3 or 4, or c) A and C denote hydrogen, and B**1 and B**2 together form a chain of the formula -[CH2 ]m -, with m being 4, 5, 6 or 7, by crystallization of diastereomeric salts, which process comprises preparing the salts of the racemic esters with optically active N-acylated R- or S-aminocarboxylic acids which contain a phenyl nucleus, from the series phenylalanine, phenylglycine, beta-phenyl-alpha-aminobutyric acid, 3,4-dihydroxyphenylalanin, beta-phenylserine and tyrosine, recrystallizing them form an aprotic organic solvent or an alcohol having up to 6 carbon atoms, decomposing the precipitated, optically homogenous diastereomeric salts in a manner known per se, and isolating the enantiomers of the formulae Ia or Ib, respectively, and, where appropriate, converting the latter into the free acids by saponification or hydrogenolysis in a manner known per se. [EP0115345A1]

Description

This invention relates to a process for the resolution of racemates of optically active bicyclic imino-a-carboxylic esters, and the use of the compounds thus obtainable for the synthesis of carboxyalkyldipeptides.

The resolution of racemates of aminoacids via crystallization of diastereomeric salts is a widely used process (Review: Boyle, Quart. Rev. ZS_ (1971) 323). Usually, N-acylated aminoacids are employed/ the salts with alkaloid bases are crystallized, and the homogeneous diastereomeric salts are decomposed by, for example, extraction of the N-acyl-aminoacids from the acidified solution (J. Amer. Chem. Soc. 7J_ (1949) 2541, 3251). It is also possible to carry out the converse process and to crystallize aminoacid esters or amides with optically active acids (Chem. Ber. 86^ (1953) 1524).

Optically active compounds, such as 10-camphor-sulfonic acid, abietic acid or tartaric acid or their 0-derivatives, for example, are used for this purpose. This procedure is particularly appropriate when the intention is to employ optically active aminoacid esters as starting compounds for further syntheses. In this case, it is not advantageous initially to prepare a N-acyl compound and then undertake resolution of the racemate via salt formation with optically active bases, split off the acyl radical and then esterify the free amino&cid.

A process suitable for bicyclic imino-a-carboxylic esters has not hitherto been described. It emerged from experimental tests that all customary acids are unsuitable for resolution of the racemates. A process is known, from European Patent A 37,231, for octahydroindole-2-carboxyIic acid, using which the H-benzoyl compound of the racemate can be resolved via the salt with optically active a~ 5 phenyIethyI amine„ However, for the reasons mentioned, this process is uneconomic ahen the esters are required as a intermediates for further syntheses.

It has now been found, surprisingly, that N-acyl * derivatives of optically active R- or S-aminoacids which 10 contain a phenyl nucleus, such as, for example, S-phenyl-alanine, tyrosine or tyrosine 0-derivatives are suitable as chiral partners for bicyclic imino-a-carboxylic esters. This is because the -15 and (R,S)-salts remain in solution. It is possible, in just a single step, to achieve a greater than 95 per cent enrichment, and a single recrystal lization leads to the optically homogeneous salts in high yield, and these are decomposed in a known manner. 20 Thus the invention relates to a process for resolv ing racemic mixtures Of bicyclic imino-a-carboxylic esters into the components of the formulae la and lb B* C C B2 (la) (it,) In which R represents an aliphatic radical having 1 to 6 carbon atoms, an alicyclic radical having 4 to 10 carbon atoms, an aromatic radical having 6 to 12 carbon atoms or 5 an araliphatic radical having 7 to 15 carbon atoms, a) A and each denote hydrogen, and B^ and C together form a chain of the formula -CCHzln-' with n being 3, 4, 5 or 6, or a chain of the formula -CCH2]p-CH=CH-CCH2]q-/ «ith (p+q> 10 being 1, 2, 3 or 4, b) C and B^ each denote hydrogen, and A and B^ together form a chain of the formula -CCHjJf,-/ with n being 3, 4, 5 or 6, or a chain of the formula -CCHjDp-Cl^CH-CCHjIlq-, taith Resolution of racemates of compounds of the for™ mula la and lb in which a) A and B^ each denote hydrogen, and B^ and C together form a chain of the formula -CCH23n-/ with n being 3, 4 , 5 or 6, or a chain of the formula -CCH2ap-CH=CH-CCH23q" with (p+q) being 1, 2, 3 or 4, or b) C and B^ denote hydrogen, and A and B^ together form one of. the chains defined above under a) is preferred.

A particularly preferred variant of the process comprises precipitating, preferably as crystals, the salts of racemic bicyclic esters of the formulae la and lb in which the two bridgehead hydrogen atoms have the cis configuration and the COOR group is oriented endo with respect to the bicyclic ring systenu Particularly suitable imino-orcarboxylic esters are esters with aliphatic, alicyclic or araliphatic alcohols, which can be cleaved by hydrogenolysis or hydrolysis, as are described in, for example, Houben-Heyl, Methoden der organischen Chemie (Methods of Organic Chemistry), Volume XV/1, Stuttgart 1974, on pages 314-427, or "Peptide Synthesis", by Bodanszky e_t a_l„, 2nd edition (1976), John Wiley & Sons. Esters of the formula la + lb in which R represents alkyl having 1 to 6 carbon atoms, cycloalkyl having 4 to 8 carbon atoms or aralkyl having 7 to 13 carbon atoms, which can optionally be substituted by N02, are preferred, in particular alkyl esters having up to 4 alkyl - 6 - carbon atoms and aralkyl esters, such as benzyl, nitro-benzyl or benzhydryl esters.

Examples of suitable N-acylated aaiinocarboxylic acids containing a phenyl nucleus are derivatives of R- or 5 S-pheny lalanine, -C-pheny Igly cine, -p-pheny l-ac-aminobutyri r. acid, -3,4-dihydroxyphenylalanine1, -0-phenyIserine and -tyrosine. H-flcyl derivatives of R- or S-phenylalanine, -C-phenylglycine and -tyrosine are preferred.

The N-acyl protective groups which can be used are » 10 the customary N H2 protective groups described in, for example, Houben-HeyI, Volume XV/1, pages 46-305 or Bodanszky et al., "Peptide Synthesis", 2nd edition <1976), John Mi ley & Sons. Alkanoyl having 1 to 6 carbon atoms, in particular formyl, tert.-butoxycarbonyI, and benzyloxy-15 earbonyl are preferred. Any free OH groups present can, uhere appropriate, be 0-alkylated by alkyl having 1 to 6 carbon atoms, in particular methyl, ethyl or tert.-butyI, by benzyl or by other OH protective groups customary in peptide chemistry (cf. for example Houben-Weyl, Volume XV/1 20 or Bodanszky e_t _a_l»/ "Peptide Synthesis", 2nd edition <1976), John Wiley & Sons).

Suitable and preferred solvents are aprotic organic solvents, such as, for example, esters, ethyl acetate, cyclohexane and tetrahydrofuran, but it is also possible 25 to use alcohols having up to 6 carbon atoms.

Octahydroindole-2-carboxylic acid is knoun from * U.S. Patent 4,350,704,, German Patent Application DE-A- 3 226 768 relates to 2-azabicycloC3.3.03octane-3-carbox- " ylic acid, and German Patent Application DE-A-3 210 496 - 7 - relates to 2,3,3 a,4,5,7a-hexahydroC1H31ndole-2-carboxyIic acid. German Patent Application de-a-3 211 676 relates to octahydroisoindole-1-carboxylic acid and 3-azabieyelo-CS .3.O]octane-4-carboxyIic acid. 5 Racemic bicyclic cis, endo-i mi no-or-carboxy I i c acids of the formulae la ♦ lb, in uhich C and B^ each denote hydrogen, and A and B^ together denote the abovementioned chain, can be prepared from, for example, enamines of a eyeloa Ikanone and N-acylated p-halogeno-a-aminocarboxyIie 10 esters of the formula IV, in which X' represents a nucleo-fugic group, preferably chlorine or bromine, Y' represents alkanoyl having 1 to 5 carbon atoms, aroyl having 7 to 9 carbon atoms or other protective groups uhich are customary in peptide chemistry and uhich can be split off 15 with ecid, and represents alkyl having 1 to 5 carbon atoms or aralkyl having 7 to 9 carbon atoms.

X' \„ 2 CIV) CIS or with acrylic esters of the formula V, in which Y' and R^ have the abovementioned meaning. coor4 20 (V) ch2 = c; Min-y by reacting the latter to give compounds of the formula VI in which A, D1, R^ and Y' have the abovemcntioncd meaning. b1 ^COOR4 CH„ = C.

MH-Y' (VI) cyclizing the latter using strong acids, with cleavage of the acrylamide and ester, to give compounds of the formula Vila or b, B1 NCOO!l (Vila) (VI)i>) converting the latter, by catalytic hydrogenation in the presence of transition metal catalysts or by reduction with borane-amine complexes or complex borohydrides in lower alcohols, into compounds of the formulae la and lb in which R represents hydrogen, and esterifying the latter to give compounds of the formulae la and lb in uhich R has the meaning defined above.

Racemic bicyclic imino-crcarboxyIic acids of the formulae la and lb, in which A and denote hydrogen and - 9 - and C together denote the chain mentioned, can be prepared from, for example, compounds of the formula VIII I II in uhich the bridgehead hydrogen atoms are oriented cis or 5 trans with respect to one another, and and C have the abovementioned meaning.

Compounds of the formula VIII with n = 1 are known from R. Griot, Helv„ Chim. Acta A2_, 67 (1959), and those with n = 2 are known from C.M. Rice et al°, J. Org. Chem. 10 21_, 1687 (1955).

These compounds of the formula VIII arc acylated in a known manner, an aliphatic or aromatic acyl radical, preferably an acetyl or benzoyl radical, being bonded to the nitrogen atom, and the resulting N-acylated compounds 15 are subjected to anodic oxidation (in analogy to Liebigs Ann. Chen, 1978, page 1719) in an aliphatic alcohol, preferably an alcohol having 1 to 4 carbon atoms, in particular methanol, in the presence of a conducting salt, preferably at temperatures in the range from 0° to +40°C, with the 20 formation of a compound of the formula IX in which and C have the abovementioned meaning and R^ = C^-C^-alkyl. - 10 - Acyl The resulting compound of the general formula IX is reacted with trimethylsilyl cyanide by the method of Tetrahedron Letters 1981, page 141, in a hydrocarbon or 5 halogenated 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 Lewis acid, such as, for example, ZnClj, SnClg, SnCl^, TiCl^ or BFj-ethe rate, preferably BFj-etherate, and the resulting compound of 10 the formula X Acyl in uhich the bridgehead hydrogen atoms are cis or trans uith respect to one another, the CN group being located cis uith rcspect to the bridgehead hydrogen atom on carbon 15 atom (4+n), and in which n> and C have the abovementioned meanings, is, after purification and resolution of the mixture of diastercomers by recrystallization or column chromatography, hydrolyzed in a known manner by the action of acids or bases to give a compound of the formulae la 20 and lb, with n - hydrogen, and the latter is esterified. - 11 - HCl or IIBr, In particular, is used as the acid for the acid hydrolysis of the nitrile group. In this instance and in those which follow, the esterification is carried out by the procedures customary in aminoacid chemistry. 5 The invention also relates to optically homogeneous compounds of the formula la or lb in uhich the two bridgehead hydrogen atoms have the cis configuration, the COOR group is oriented endo with respect to the bicyclic ring system, the carbon atom a to the COOR group has the R or 10 S configuration, R represents alkyl having 1 to 6 carbon atoms, cycloalkyl having 4 to 8 carbon atoms or aralkyl having 7 to 13 carbon atoms, which can optionally be substituted by NOg, and A, , B2 and C are defined as above, and to those compounds 15 of the formulae la or lb in uhich R denotes hydrogen and a) A and b' each denote hydrogen, and B? and C together form a chain of the formula -CCH23n~, n being 3, 4, 5 or 6, or a chain of the formula 20 -CCH23p-CH=CH-CCH23q-, with (p+q) being 1, 2, 3 or 4, or b) C and B2 each denote hydrogen, and A and B^ together form one of the chains defined above a), with n being 3, 5 or 6 and (p+q) 25 being 1, 2, 3 or 4, and their salts.

The invention also relates to diastereomeric salts of a bicyclic cis, endo-imino-a-carboxyIic ester of the formula la or lb, in which A, , B^, c and R have the meanings defined above as being preferred, and an optically - 12 - active N-acylated R- or S-aminocarboxylic acid which contains a phenyl nucleus and uhich is protected as defined above.

The invention also relates to the use of the opti-5 cally pure compounds of the formula la or lb in a process for the preparation of optically pure compounds of the general formulae Ila or lib 1 2 B B C / A>»coon I .

X * I O = C - CH - Mil - CH - LC\\J - C - X (Ila) 'l ' 2 ' )!' C02H Z B1 B2 C CH - !£\\J -I CO^S - i (lib) 10 in which it is possible for the carbon atoms labeled uith an asterisk <*) each, independently of one another, to have the R- or the S-configuration, 4 a) A and B1 each denote hydrogen, and B^ and C together form a chain of the formula 15 n being 3, 4, 5 or 6, or a chain of the fornula -l"CH23p-CH = CH-CCH2Dq- , - 13 - (p+q) being 1, 2, 3 or 4, b) C and B2 each denote hydrogen, and A and B^ together form a chain of the formula -CCH23n-, with n being 3, 4, 5 or 6, or a chain of the formula -CCH23p-CH=CH-CCH23q-, uith (p+q) being 1, 2, 3 or 4, or c) A and C each denote hydrogen, and B^ and B2 together form a chain of the formula -CCH23m-, with m being 4, 5, 6 or 7, r denotes 0 or 1, R1 denotes hydrogen, an optionally substituted aliphatic radical having 1 to 6 carbon atoms, an optionally substituted alicyclic radical having 3 to 9 carbon atoms, an optionally substituted a I icyc I ic-a I iphatic radical having 4 to 11 carbon atoms, an optionally substituted aromatic radical having 6 to 12 carbon atoms, uhich can also be partially hydrogcnated, an optionally substituted araliphatic radical having 7 to 15 carbon atoms, an optionally substituted aroyl-aliphatic radical having 8 to 13 carbon atoms, an optionally substituted monocyclic or bicyclic heterocyclic radical having 5 to 7 or 8 to 10 ring atoms respectively, 1 or 2 of these ring atoms being sulfur or oxygen atoms and/or 1 to 4 of these ring atoms being nitrogen atoms, or a side chain of a naturally occurring aminoacid which is optionally protected, R2 denotes hydrogen, an optionally substituted aliphatic radical having 1 to 6 carbon atoms, or ati optionally substituted araliphatic radical having 7 to 15 carbon - 14 - atoms, V denotes hydrogen or hydroxyl, Z denotes hydrogen, or Y and Z together denote oxygen, and 5 X denotes an aliphatic radicaL having 1 to 6 carbon atoms, an alicyclic radical having 5 t>o 9 carbon atoms, an optionally substituted aromatic radical having 6 to 12 carbon atoms, or indolyl, which process comprises reacting, in the presence of a 10 condensing agent or, where appropriate, as an active ester, optically pure compounds of the formulae la or lb, in which A, B1, B2 and C have the abovementioned meanings, and R represents an optionally substituted aliphatic radical having 1 to 6 carbon atoms, an optionally substituted 15 alicyclic radical having 4 to 10 carbon atoms, an optionally substituted aromatic radical having 6 to 12 carbon atoms or an optionally substituted araliphatic radical having 7 to 15 carbon atoms, uith optically pure compounds of the formula III 20 , I (HI> H00C - CH - NH - CM - [CH„ ] _ c _ v lX I 2 ' r c02r in uhich the two carbon atoms labeled uith an asterisk (*) have the (S,R), (R,S), (R,R) or, preferably, (S,S) configuration, and R, R^, R2, X, Y and Z have the abovementioned meanings, 25 splitting off the radical R by hydrogenolysis or hydrolysis, and, where appropriate, converting the optically - 15 - pure compounds of the formulae Ila or lib into physiologically tolerated salts* A preferred embodiment of the process according to the invention comprises preparing compounds of the for-5 mulae Ila or lib, in uhich r denotes 0 or' 1, R denotes hydrogen, (C-j to C$)-alkyl or aralkyl having 7 to 9 carbon atoms, denotes hydrogen or (C^ to C^^'alkyl, uhich can optionally be substituted by amino, CCf to C$>~acyl~ amino or benzoylamino, (Cj to C$)-alkenyl, (Cj to C9)-cycloalkyl, (C5 to C9)-eyeloaIkenyI, (Cj to C^J-cyclo-alkyl-CC^ to C^-alkyl, aryl or partially hydrogenated aryl having 6 to 12 carbon atoms, each of which can be substituted by (C^ to C^J-alkyl, (C^ or CgJ-alkoxy or halogen, (C$ to C-|2)r/1~*C1~c4^"a 1 kX1 or *c7-Ci3>-aroyl-(Ci-C2>-a Ikyl/ both of which can be substituted in the aryl radical as defined above, a monocyclic or bicyclic heterocyclic radical having 5 to 7 or 8 to 10 ring atoms respectively, 1 or 2 of these ring atoms being sulfur or oxygen atoms and/or 1 to 4 of these ring atoms being nitrogen atoms, or an optionally protected side chain of a naturally occurring aminoacid, 25 R^ denotes hydrogen, (C1 to C^J-alkyl, (C2 to C$)-atfcenyl or (C^ to C-jjJ-aryl~-alkyl, Y denotes hydrogen or hydroxyl, Z denotes hydrogen, or Y and Z together denote oxygen, and 10 15 X denotes (Ci to C$)-alkyl, (C2 to C$)-alkenyl, (C5 to C^J-cycloalkyl, (C$ to Ci2>-aryl, which can be monosubstituted, disubstituted or trisubstituted by -alkylamino and/or methyIenedioxy, or 3-indolyl.

The preparation of the S,S,S-compounds of the formula Ila is preferred.

In this contcxt as in the foil owing, aryl is to 10 be understood preferably to include optionally substituted phenyl or naphthyl, Alkyl can be straight-chain or branched* Examples of a monocyclic or bicyclic heterocyclic radical having 5 to 7 or 8 to 10 ring atoms respectively, 15 in uhich the ring atoms have the abovementioned meanings, include thienyl, bcnzotb]thienyI, furyl, pyranyl, benzo-furyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimi-dinyl, pyridazinyl, indazolyl, isoindolyl, indoLyl, purinyl, qui no lizinyI, isoquino I inyI, phthalazinyI, naphthyridinyI, 20 quinoxa I iny I, quinazolyl, cinnolinyl, pteridinyl, oxa- zolyl, isoxazolyl, thiazolyl or isothiazolyI. It is also possible for these radicals to be partially or completely hyd rogenat ed.

Where R^ represents a side chain of a protected 25 naturally occurring oc-aminoacid, such as, for example, protected or optionally substituted Ser, Thr, Asp, Asn, Glu, Gin, Arg, Lys, Hyl, Cys, Orn, Cit, Tyr, Trp, His or Hyp, the preferred protective groups are those groups customary in peptide chemistry (cf. Houben-Weyl, Vol.XV/1 - 17 - and XV/2)„ In the case where denotes a protected side chain of a lysine, the known amino protective groups, but in particular (Ci-C$)-a Ikanoy I, are preferred. Preferred O-protective groups for tyrosine are methyl or ethyl. 5 In the procedures hitherto known for preparing mixtures of stereoisomers of compounds of the formulae Ila or lib, which started from mixtures of stereoisomers, it was necessary to use elaborate separating procedures to separate the reaction mixture in order to obtain the 10 desired optically pure stereoisomers of the formula Ila or lib. By reacting the optically homogeneous imino-a-car-boxylic esters of the formulae la or lb according to the invention uith optically homogeneous compounds of the formula III, specific synthesis of optically homogeneous com-15 pounds of the formula Ila or lib has become possible. The desired compounds of the formulae Ila or lib are obtained in high yields without using elaborate separating techniques.

Compounds of the formula III are described in the 20 abovementioned documents or are known from European Patent A 46,953. The reaction of a compound of the formula III with tert.-butyl 1 - <2a,3 ap,7a(3)-oct ahydro-C1 H3-indo le-2-carboxylate followed by elimination of a tert.-butyI ester, whereupon a correspondi ng oc t ahyo'roi ndo le derivative of 25 the formula lib results, is known from European Patent A 37,231,, However, it has been necessary to restrict this reaction to reaction of a compound of the formula la or lb with C and B^ each being H and A + B-' being (CH2>^, and it has hitherto only been possible to prepare this in a complicated manner via the N-benzoyl compound, crystallization of the diastereomeric salts with S-a-phenylethyl-amine, liberation of the N-benzoyl compound, elimination S of the benzoyl group and esterification.

It has' not hitherto been possible to transfer this reaction sequence to the intermediates of the formula la and lb according to the invention* Nor has it been possible to resolve racemic mixtures of compounds of the formula 10 Ila and lib by separating conventional diastereomeric salts uith optically active carboxylic or sulfonic acids. The compounds of the formula la and lb have been made accessible for subsequent reactions for the first time by the procedure described above. 15 The process according to the invention is particu larly cost-effective, since compounds of the formula III can bo prepared directly in an opt i cally pure form by straightforward routes from German Patent Application DE-A-3 226 768. However, in this reference, it Mas still 20 necessary for these intermediates to be reacted with a racemic aminoacid and to be converted into an optically pure compound of the general formulae Ila and lib by an additional purification step.

The process according to the invention, which is 25 preferably carried out with S,S compounds of the formula III, thus represents by far the most cost-effective process for the preparation of the compounds covered since, in all the other known procedures, great losses have to be accepted due to the chromatography or crystallization of mixtures - 19 - of stereoisomers, some of uhich are complex.

The condensation step is carried out by one of the conventional processes of peptide synthesis which involve little racemization, such as are described in, for example, 5 Houben-VJey I, Volume XV, or in "The Peptides - Analysis, Synthesis, Biology, Vol.1 ftajor Methods of Peptide Bond Formation, Part A", Gross, Meierhofer, Academic Press N.Y. (1979). The DCC/HOBt method of Chem. Ber» 103 (1979), pages 788-798, is particularly advantageous. In this 10 context, it should be taken into account that reactive functional groups in the radical R^ must be temporarily protected by the known methods of peptide chemistry (for example Houben-Weyl, Volume XV, or Bodanszky e_t a_l. in "Peptide Synthesis", 2nd edition (1976), John Wiley S Sons). 15 The optically homogeneous compounds of the formula Ila or lib are obtained, after eliminating R and, where appropriate, R^, in high yield in a manner known per se without using elaborate separating techniques.

The compounds of the formula Ila and lib and their 20 salts have long-lasting and powerful hypotensive activity. They are potent inhibitors of angiotensin converting enzyme (ACE) and can be employed to control high blood pressure of a variety of etiologies. ACE inhibitors of this type are known from, for example, U.S. Patent 25 4,344,949, European Patent A 49,658, European Patent A 46,953, European Patent A 50,800 and European Patent A 79,022.

It is also possible to combine them with other compounds having hypotensive, vasodilator or diuretic activity. Typical representatives of these classes of active compounds are described in, for example, Erhardt-Ruschig, ArzneimitteI (Drugs), 2nd edition, Meinhein, 1972. They can be administered intravenously, subcutaneously or 5 ora I ly.

The dosage on oral administration is generally 1-500 ng, preferably 1-100 mg, per single dose for an adult patient of normal Height, It is also possible to increase this in severe cases, since no toxic properties 10 have hitherto been observed. It is also possible to reduce the dose and this is particularly appropriate uhen diuretics are administered concurrently.

The compounds according to the invention can be administered orally or parenterally in appropriate pharma-15 ceutical formulations. For a form for oral use, the active compounds are mixed uith the additives customary for this purpose, such as vehicles, stabilizers or inert diluents, and converted by customary methods into suitable forms for administration, such as tablets, coated tablets, hard 20 gelatin capsules, aqueous, alcohol or oily suspensions or aqueous, alcohol or oily solutions. Examples of suitable inert vehicles uhich can be used are gum arabic, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular corn starch.. This can entail formulation 25 either as dry or as moist granules. Examples of suitable oily vehicles or solvents are vegetable or animal oils, such as sunflower oil or fish liver oil.

For subcutaneous or intravenous administration, the active compounds or their physiologically tolerated salts are converted into a solution, suspension or emulsion, where appropriate with the substances customary for this purpose, such as so lubiIizers, emulsifiers or other auxiliaries. Examples of suitable solvents for the new 5 active compounds and the corresponding physiologically tolerated salts are: water, physiological saline or alcohols, for example ethanol, propanediol or glycerol, but also sugar solutions, such as glucose or mannitol solutions, or even a mixture of the various solvents or solutions 10 mentioned.

The Examples uhich follow illustrate the process, but there is no intention to restrict the invention to these specific Examples.

Example 1: 15 Benzyl <1S, 3S, 5S)-2-azabicyc loC3 .3.03octane-3-carboxylate hydrochloride (abbreviated to (S)-Aoc-OBz l-HC I) (A) Wethy I 2-acetylamino-3-(Z-oxocyc I opentyI)propionate: 269 g of methyl 3-chloro-2-acetylaminopropionate and 257 g of cyclopentenopyrrolidine in 1.5 liters of DMF 20 are kept at room temperature for 24 hours. The mixture is evaporated in vacuo, and the residue is taken up in a little water, the pH is adjusted to 2 with concentrated hydrochloric acid and the solution is extracted twice with 4 liters of ethyl acetate each time. A pale yellow oil 25 remains on evaporating the organic phase.

Yield: 290 g.

^H-NHR:2.02 (s,3H); 3.74 Melting point: 205-209°C, 15 Yic-ld: 150 g (C) Racemic Aoc-OBzI.HCI 1.2 liters (11.5 mol) of benzyl alcohoL are cooled 20 to -10°C. 126 ml (1.73 mol) of thionyl chloride are added dropuise, with cooling and stirring, and then 126.5 g (0.66 mole) of crude Aoc.HCl are added at -10°C, with stirring, and the mixture is then stirred at this temperature for 30 minutes,, The temperature is then allowed to 25 rise slowly to 20-25°C with stirring, the product dissolving within 5 hours. After standing overnight, the brown solution is run into 4.0 liters of diisopropyl ether with stirring. After 1 hour, the precipitated crystals are filtered off, washed with diisopropyl ether and dried in - 23 - vacuo. A further precipitate separates out of the combined diisopropyl ether solutions overnight.

Yield: 168.5 g (90.6%) (D) (S)-Aoc-OBzt.Z-Phe-OH 5 166.0 g (0.589 mol) of racemic Aoc-OBzl.HCl are suspended in 500 ml of methylene chloride and thoroughly shaken uith 25 g (0.625 mol) of NaOH in 250 ml of uater. A solution is produced. After a short time, the initially formed emulsion has separated. The methylene chloride 10 phase is separated off, washed with 100 ml of 0.1 N NaCH and twice uith 50 ml of uater each time and the combined aqueous phases are extracted twice uith 100 ml of methylene chloride each time. The combined methylene chloride phases are dried over sodium sulfate and evaporated under mild 15 conditions uith waterpump vacuum. The remaining oil is immediately taken up in 100 ml of ethyl acetate, and a solution of 117.6 g (0.39 mol) of N-benzy loxy c arbony 1--S-phenylalanine (Z-Phe-OH) in 200 ml of ethyl acetate is added. The flask is rinsed with 100 ml of ethyl acetate. 20 1,600 ml of cyclohexane ( = 4 times the amount by volume) are added, with stirring, to the clear solution at room temperature. After scratching, crystallization starts, and this is completed by standing overnight in a cold room. The crystalline precipitate is filtered off, washed with 25 250 ml of ethyl acetate/cyclohexane (1+4) and dried.

Yield: 133.6 g of (S)-Aoc-OBz I.Z-Phe-OH (50.9%, corresponding to 102% of theory), melting point 101-103°C; Ca3^: -5.30 (c = f methanol).

After recrystallization from ethyl acetate/eyelo- - 24 - hexane (1:1), the following data are found for the Z-Phe-OH salt: melting point: 103-104°C, ta.1^: -6.1° (c = 1, in methanol), (E) (S)-Aoc-OBzl„HCl 63„0 g (0.142 mole) of the Z-Phe-OH salt obtained according to (D) are dissolved in 300 ml of methylene chloride and the solution is thoroughly shaken uith 6.0 g (0.15 mole) of NaOH in about 150 ml of water. Phase separation takes some time because of a small amount of insolubles. The methylene chloride phase is separated off, washed with 50 ml of 0.1 N NaOH and twice uith 50 ml of water each time and dried. The solution is evaporated to about 100 ml, diluted with 100 ml of diisopropyl ether and, with stirring, 25 ml of 6 N HCl in ether are added. After 1 hour, the mixture is filtered, and the precipitate is washed with diisopropyl ether and dried.

Yield: 32.5 g (81.3Z) Melting point: 185-186°C [aj30: -42.5° (c = 1, water) Methylene chloride is removed from the basic aqueous phase in vacuo, and it is acidified with concentrated HCl. The precipitated Z-Phe-OH is washed with water and dried.

The R compound and further Z-Phe-OH are obtained fron the methylene chloride mother liquor from Example 1(D) in the manner described.

Table 1 Final prodljct 5 Example Intino- earboxylip acid Ester R Acid Solvent Diastereoisomeric Salts m.p. c=1,XeOH) Acid conpsnent S- 'm.p. C -Form R-Fcrn m.p. - / !»• 1 !"2V/ 2 XI11 Xethyi Z-Fho-CH Diethyl ether 1'5-11S°C + 5.8° TosOil 191-192°C - 12.9° 190-192^ + 12,6° 3 XIII 2erzyi Z-Ptie-CH Ethyl acetate/ cyclohexane "04—105° C f 6.2° HCl 184-186°C - Hi.2° l33-1c5°C + 1*2.5° 10 4 XIII Bonzyl Z-?nc-CH Isopropar.ol 103-10H°c - 6.0° Ha 182-185°C - 39,9° 5 XXII 3er.zyl Z-?.-?he-CH Ethyl acetate/ cyclohexane 102-10^°C + *.K° HCl 1S5-I35°C + *1.9° 6 xm Benzyl Z-?gl-0H Ethyl acetate 128-130°c + 32.1° HCl 181)-185°C - «i0,9° 15 7 x:u 'Benzyl Z-Tyr-OH Ethyl acetate/ cyclohexane '.25-126° C - 0,H° HCl 18U-135°C - 41.6° 8 XIII Benzyl Z-7yr (Bul)-CH Ethyl acetate/ cyclohexane 10!;-105°C - * I;0 *" J** HCl 181-183°C - ifO.O0 9 XIII Benzyl For-?he-CH Isoprcpanel 107-109°C * 1.7° KC1 178-I8l°c - 39.1° 20 10 *1 XIII XI Nitro-benzyl Benzyl Z-Phe-CH Z-Phe-OH Ethyl acetate Ethyl acetate/ cyclohexane 122-'2;l° C 106-107°C - -.3° - 13.5° TosOH TosOH 152-153°C - 29.8° - 36.2° *i 2 XII Xelhyl Z-Fne-0h Ethyl acetate/ cyclohexane 107-103°c + i;7.1° HCl + f,SA° - 26 - The Ccis,endo3-imino-a-carboxylic esters in Table 1 are prepared and subjected to raceiaate resolution in an analogous manner. This Table details their optically active crystallization partners, and the solvents, yields and properties of the salts and the final products in the form of the ester hydrochlorides or ester tosylates. Explanations of Table 1 (XI) n -coor H 11 and mirror image (XII) and mi rror image 10 (XIII) H s COOR H H and mirror image The free i in i noca rboxy li c acids can be prepared from the esters by hydrolysis or hydrogenolysis„ Example 13 N-(1S-Carboethoxy-3-phenylpropyl)-S-alanyl-2-cis,endo-1 5 azabicycloC3."i.0]Qctane-3S-carboxylic acid - 27 - (A) Benzyl N-(2S-carboethoxy-3-phenylpropyl)-S-alanyl- cis,endO"2-azabicycloC3.3.03octane-3S-carboxylate 14 g of the benzyl ester hydrochloride prepared according to Example 1 E arc converted into the free ester 5 by extracting by shaking the alkaline aqueous solution uith diethyl e.ther, and, after distilling out the ether, are reacted with 6.7 g of HOBt, 13.8 g of N-(1S-carbo~ ethoxy-3-phenyIpropyI)-S-alanine and 10.2 g of dicyclo-hexyIcarbodiimide in 200 ml of dimethyIformamide. After 10 stirring at room temperature for 3 hours, the precipitated dieyelohexylurea is filtered off, and the filtrate is evaporated, and the residue is taken up in 1 liter of ethyl acetate and this solution is extracted by shaking uith 3 x 500 ml of 5 per cent NaHCO^ solution. The organic-15 phase is evaporated. 22.4 g (90%) of product are obtained as an oil. ^HNMR of the S,S,S-compound, characteristic signals: 1.20 (d,3H), 1.27 (t,2H), 4.17 (q,3H), 5.13 (s,2H), 7.18 (s,5H), 7.32 (s,5H) (CDCI3) 20 Analysis: C H N c30h38n2°5 calculated 71.1 7.56 5.53 found 70.8 7.8 5.7 (B) H-(1S-Carboethoxy-3-pheny IpropyI)-S-alanyl-ci s,endo-2-azabicycloC3.3.03octane-3S-carboxylic acid 25 8.0 g of the S,S,S-benzyl ester from Example 1 E are dissolved in 100 ml of ethanol, and the benzyl group is removed by hydrogenolysis under atmospheric pressure with the addition of 0.5 g of 10% Pd/C. This reaction can also be carried out under elevated pressure uhich involves - 28 - shortening of the reaction time. After the calculated amount of hydrogen has been taken up, the catalyst is filtered off and the filtrate is evaporated in vacuo. The zaitterion crystallizes from ether in a virtually quanti-5 tative yield: melting point: 110-112°C (decomposition) A hydrochloride (decomposition above 120°C) can be obtained by addition of an equivalent amount of hydrochloric acid. 10 Analysis: C H W c23^32^2^5 calculated 66.3 7.7 6.73 found 66.1 7.8 6.6 The ^H NMR and mass spectra uhich are obtained are consistent with the structure indicated. 15 toQq = +15.6° (c = 1, methanol).

Example 14 M-(1S-Carboethoxy-2-benzoylethyl)-0-ethyl-S-tyrosyl-cis,endo-2-azabi cycloC3.3.03octane-3S-carboxylie acid (A) H-(1S-Carboethoxy-3-phenylpropyl)-0-ethyl-S-20 tyrosine benzyl ester 24 g of ethyl benzoy I aery I ate in 100 ml of ethanol are reacted with 30 g of 0-ethyl-S-tyrosine benzyl ester in the presence of 0.5 ml of triethylamine and, after evaporating the solution and digesting the residue with 25 diethyl ether/petroleum ether (1:1) and drying in vacuo, 42 g of RS,S compound are obtained. Resolution of the diastereomers by chromatography on silica gel using the system ethyl acetate/cyc lohexane (1:3).

Yield: 17 g of the S,S compound. - 29 - ( B ) N- (1 S-Carboet hoxy-3-pheny Ipropy I )-Q-ethyl-S-tyrosine 17 g of the compound obtained according to (A) in 800 ml of acetic acid are hydrogenated with 4 g of Pd/C (10%) under 100 bar and at room temperature. Yield after chromatography on silica gel using the solvent ethyl ace-tat e/eyelohexa-ne (1:3) and drying the residue from evaporation: 12 g of title compound which is virtually homogeneous by thin-layer chromatography.

Melting point 205-213°C Analysis: C23H29NO5 (399.5) calculated C 69.15 H 7.31 N 3.50 found C 69.5 H 7.4 N 3.3 (C) Si-(1S-Carboethoxy-3-phenyI propyl)-0-ethyl-S-tyrosyl-cis,endo-2-azabieyclot3.3.OJoctane-3s-carboxylie acid Sn analogy to Example 13 A, 8 g of the free benzyl ester obtained in accordance uith Example 1 E and extracted from alkaline solution by shaking with diethyl ether are reacted with 8 g of the compound obtained in accordance uith Example 14 B using 4.4 g of dicyclohexyIcarbodiimide in the presence of 2.7 g of 1-hydroxybenzotriazole, and 14.3 g of oily benzyl ester are obtained as an intermediate.

The NMR and mass spectra are consistent with the structure indicated.

The benzyl ester in 50 ml of ethanol is cataly-t i cally hydrogenated on Pd/C under atmospheric pressure. After filtering off the catalyst and distilling off the solvent, there remains a solid residue which is digested with diethyl ether/petroleum ether and is dried.

Yield: 11.2 g - 30 - Example 15 M-(1S-Carbocthoxy-3-phenylpropyl)-0-roethyl.-S-tyrosyl-ci s.endo-2-azabi cycloC3.3.03octane-3S-carboxylic acid The procedure is carried out as described in 5 Example 14, but in the stage analogous to CA) 0-methyl-S-tyrosine benzy.l ester is used and the title compound is obtained, the NMR spectrum of uhich is consistent uith the structure indicated. 1H NMR (CDClj): 1.2-3.0 (m,15H>; 1.27 (t,3H>; 1.4 ; 10 3.0-4.3 (m,4H>; 3.8-4.2 (m,4H); 6.5-7.1 <2d,4H); 7.3 (B) 1-Aroinoroethyl-1-(diethyloxyethyl)cyclohexane 90 g of diethyloxycyclohexanecarbonitrile are dissolved in 1 liter of ethanol, and 60 g of sodium are 5 added. After the metal has dissolved, 100 ml of Hater are added and the solvent is largely removed in vacuo. 300 ml of uatcr are added to the residue and the mixture is extracted 3 x with 200 ml of ether. The ethereal phase is dried over sodium sulfate, evaporated and distilled in 10 vacuo.

Yield: 83 g (about 90% of theory), boiling point 69-72° at 8 torr (10.7 mbar) (C) 2-Azaspi roC4.53 decane-3-earbonitrile 80.2 g of aminomethyIdiethyloxyeyelohexane are 15 stirred in a mixture of 300 ml of ethanol and 300 ml of 1 N hydrochloric acid under a protective gas (Ng or Ar) for about 1 hour.

After the starting product has been completely cleaved, the mixture is cooled to 0°C and the solution is 20 rapidly adjusted to pH 5 by adding 2 N sodium hydroxide solution. 300 ml of glacial acetic acid are immediately added (pH about 3), and the mixture is cooled to -10°C and 17.5 g of sodium cyanide are added. The reaction vessel is closed and left at room temperature for rbout 5 hours. 25 Completion of reaction is checked using thin-layer chromatography (system ethyl acetate/petroleura ether 2:1) (Schiff's base Rf = 0.6-0.7; aminoacid nitrile Rf = 0.28) and the reaction solution is evaporated to dryness. The crude aminoacid nitrile is immediately processed further in accoi— - 32 - dance tilth Example 16 D or E.

(D) 2-Azaspi roC4.53decane-3-carboxy lie acid 250 ml of 4 N hydrochloric acid arc added to one half of the aminoacid nitrile obtained in Example 16 C, and the mixture is heated under reflux for 4 hours. Traces of escaping hydrocyanic acid are made harmless in a suitable manner (freezing out, absorption in basic iron(ll) salt solution). The solution is neutralized, evaporated to dryness and extracted several tines uith n-butanol. The residue from evaporation of the organic phase is a) crystallized from chloroform/diisopropyI ether to obtain the hydrochloride and, if necessary, again precipitated from a mixture uith ethanol or b) purified in aqueous solution by stirring uith an ion exchanger, for example IR 45 (OH form) (Amber I ite) and, after removing the water, the zuitterion is crystallized from ethanol/ether.

Yield from a): 31-32 g (82%) Melting point 205°C (decomposition), hydrochloride (E) Benzyl 2-azaspiroC4.53decane-3-carboxylate hydro-ch lori de Half of the aminoacid nitrile obtained in accordance uith Example 16 C is taken up in 70 ml of benzyl alcohol. A slow stream of HCl gas is passed through the solution at room temperature for 5 minutes, then it is maintained at room temperature for 2-3 hours, evaporated to a small volume in vacuo, and aqueous sodi um bi carbonate so Iut ion is added until the pH is 8.5 and the benzyl ester is extracted into ethyl acetate. The organic phase is dried, - 33 - an equivalent amount of ethereal hydrochloric acid is added and the mixture is evaporated. The residue crystallizes from diisopropyl ether and can be recrysta 11ized 'from methylene ch loride/di isopropyl ether, 5 Yield: 43 g (about 80X) Melting point 145°C (decomposition) (F) Benzyl 2-azaspiroE4.53decane-3S-carboxylate hydrochloride The racemic hydrochloride obtained in accordance 10 with Example 16 E is subjected to racemate resolution in analogy to Examples 1 D and E„ (6) Benzyl N-(1S-carboethoxy-3-phenyIpropyI)-S-aIanyl-2-azaspi roC4.53nonane-3S-ca rboxylate 15.6 g of benzyl 2-azaspiroC4,53nonane-3S-carboxy-15 late hydrochloride, 6,7 g of 1-hydroxybenzotriazole and 13.8 g of (S,S)-N-(1-carboethoxy-3-phenyIpropyDalanine are dissolved in 200 ml of DMF and reacted overnight with 10.2 g of dicyclohexyIcarbodiimide„ Addition of tertiary bases, for example 6.4 ml of N-ethyImorpholine, increases 20 the yield only ineonsiderably. The precipitated DC- urca is filtered off, the filtrate is evaporated in vacuo, the residue is taken up in ethyl acetate, and the solution is extracted by shaking with aqueous sodium bicarbonate solution, and the organic phase is dried over solid sodium 25 sulfate and again evaporated. The NMR spectra (in CDCI3) confirm the structure,, (H) N-(1S-Carbocthoxy-3-phenyIpropyI)-S-aIanyl-2-aza-spiroC4.5]nonane-3S-carboxy lie acid The benzyl ester obtained in Example 16 G is - 34 - taken up in 200 ml of methanol and the benzyl group is removed by hydrogenolysis with 1 g of Pd/C (10% Pd). After uptake of hydrogen is complete, the mixture is filtered and the filtrate is evaporated in vacuo. A solid, hygroscopic S foam of the zwitterionic dipeptide derivative can be obtained in vacuo uith the addition of pentane« ta:g1 = 38.3° (c = 1, methanol) Example 17 H-(1S-Carboethoxy-3-pheny IpropyI)-S-aI any I-ci s,endo-10 2,3,3a,4,5,7a-hexahydroC1H3indole-2S-carboxylic acid (a) Wethy I cis-2#3,3a,4,5,7a-hexahydroC1H3indole-ZS-carboxylate hydrochloride Racemic methyl cis-2,3,3a,4,5,7a-hexahydroE1H3-indole-2-carboxylate hydrochloride (obtainable in analogy 15 to the procedure described in German Patent Application P 32 10 496.0) is subjected to racemate resolution in analogy to Examples 1 D and E.

Ca3D = +68.4° (c = 1, H20) (B) H-(1S-Carboethoxy-3-phenylpropyl)-S-alanyl-cis,endo-20 2,3,3a,4,5,7a-hexahydroC1H3indole-2S-carboxylic acid hydroch lori de The title compound is obtained by a procedure analogous to that described in Examples 13 ft and B.

Iti NMR data 0„9-3.0 (m, 17 H); 25 3 -4-4.9 (m, 6 H); 5.2-6.0 (m, 2 H); 7.2 (s, 5 H) 35 -

Claims (25)

CLAIMS: 1 „ A process for resolving a racemic mixture of bicyclic imino-a-carboxylic esters into the components of the formulae la and lb D2 D / COOR X a a •» \ ii 1:00c.. >— 10 15 20 (la) (lb) in uhich R represents an aliphatic radical having 1 to 6 carbon atoms, an alicyclic radical having 4 to 10 carbon atoms, an aromatic radical having 6 to 12 carbon atoms or an araliphatic radical having 7 to 15 carbon atoms, a) A and each denote hydrogen, and B^ and C together form a chain of the formula -Cd^n"' with n being 3, 4, 5 or 6, or a chain of the formula -CCH23p-CH=CH-CCH23q-, with being 1, 2, 3 or 4, b) C and 8^ each denote hydrogen, and

1. A and B^ together form a chain of the formula "CCHgD,,-, with n being 3, '4, 5 or 6, or a chain of the formula -CCH23p-CH=CH-CCH2]q-, with (p + q> being 1, 2, 3 or 4, or c) A and C each denote hydrogen, and B^ and together form a chain of the formula -CCNg},,,-, uith a being 4, 5, 6 or 7, - 36 - by crystallization of diastereomeric salts, uhich process comprises preparing the salts of the racemic esters uith optically active N-acylated R- or S-aminocarboxyIic acids which contain a phenyl nucleus, selected from phenylalanine, phenylglycine, e-phenyl-a-aminobutyric acid, 3,4-dihydroxy-phenylalanine, B-phenylserine and tyrosine, and whose possibly present free OH-groups are optionally O-alkylated by alkyl having 1 to 6 carbon atoms, benzyl or other OH— protecting group customary in peptide chemistry, recrystal-lizing them from an aprotic organic solvent or an alcohol having up to 6 carbon atoms, decomposing the precipitated, optically homogeneous diastereomeric salts in a manner known per se, and isolating the enant i outers of the formulae la and lb and, where appropriate, converting the latter into the free acids by saponification or hydrolysis in a manner known per se. 2* A process as claimed in claim 1, wherein a) A and B^ each denote hydrogen, and and C together form a chain of the formula "CCHjD,,-, uith n being 3, 4, 5 or 6, or a chain of the formula -CCH23p-CH=CH-CCH23q- with (p+q) being 1, 2, 3 or 4, or b) C and B2 each denote hydrogen, and

2. A and B1 together form one of the chains defined above under a)„

3. = A process as claimed in claim 2, wherein the salts of racemic esters of the formulae la and lb in uhich the two bridgehead hydrogen atoms have the cis configuration and the COOR group is oriented endo with respect to the bicyclic ring system are precipitated.

4. A process as claimed in one of claims 1 to 3, wherein R represents alkyl having 1 to 6 carbon atoms, cycloalkyl having 4 to 8 carbon atoms or aralkyl having 7 - 37 - to 13 carbon atoms uhich can optionally be substituted by N02.

5. A process as claimed in one of claims 1 to 4, wherein the amino group of the N-acylated R- or S-amino-carboxylic acids uhich are used for salt formation is protected by alkanoyl having 1 to 6 carbon atoms, tert.-butoxycarbonyI, benzyloxycarbonyI or another NH2 protective group customary in peptide chemistry, and any free OH groups present in the N-acylated aminoacids are, where appropriate, protected by tlkyl having 1 to 6 carbon atoms, benzyl or other OH protective groups customary in peptide ch emi st ry»

6. A compound of the formula la or lb in uhich the two bridgehead hydrogen atoms have the cis configuration, the COOR group is oriented endo uith respect to the bicyclic ring system, the carbon atom a to the COOR group has the R or S configuration, and A, and C have the meanings defined in claim 2, and R has that defined in claim 4, or a salt thereof.

7. A compound of the formula la or Xb in which the two bridgeheed hydrogen atoms have the cis configuration, the COOR group is oriented endo with respect to the bicyclic ring system, the carbon atom a to the COOR group has the R or S configuration, and R denotes hydrogen or has the meanings defined in cl?in 4, a) A and B^ each denote hydrogen, and and C together form a chain of the formula ~CCH2]n-, with n being 3, 4, 5 or 6, or a chain of the formula - 38 - -CCH23p-CH=CH-CCH23q-# with (p+q) being 1 , 2, 3 or 4, or b) C and B2 each denote hydrogen, and

8. A and B1 together form one of the chains defined above a), with n being 3, 5 or 6 and (p+q) being 1, 2, 3 or 4, or a salt thereof. 8„ A compound as claimed in one of claims 6 or 7, wherein the carbon atom a to the COOR group has the S configuration.

9. A diastereomeric salt of a bicyclic imino-a-carboxylic ester of the formula la or lb as claimed in one of claims 6 or 8, in which R has the meanings defined in claim 4, and an N-acylatcd, optically active R- or S-aminocarboxy I ic acid uhich contains a phenyl nucleus and is protected as defined in claim 5„

10. cis,endo-2-AzabicyctoC3„3„03octane-3S-carboxy lie acid.

11. A cis,endo-2-azabieyeloC3.3.03octane-3S-carboxy11 ester in which R has the meaning defined in claim 4.

12. Benzyl cis,endo-2-azabicycloC3.3.OJoctane-3S-ear- boxylat e.

13. A process as claimed in one of claims 1 to 4 for separating off cis,endo-octahydro[1H]indole-2S-carboxylate.

14. A process as claimed in one of claims 1 to 4 for separating off benzyl cis,endo-octahydro[1H]indole-2S-carboxylate.

15. A process for the preparation of an optically pure compound of the general formula Ila or lib - 39 I)1 B? C (Ila) B1 B2 C COOI! I Y * I O = C - CH - Nil - CH - /CH_7 - C I I ! I - 1 O 4 K1 co2ir z (lib) in which it is possible for the carbon atoms labeled with an asterisk (*) each, independently of one another, to have the R- or the S-configuration, a) A and B^ each denote hydrogen, and B2 and C together form a chain of the formula -CCH23n", with n being 3, 4, 5 or 6, or a chain of the formula -CCH23p-CH=CH-CCH23q~ , uith (p+q) being 1, 2, 3 or 4, b) C and B2 each denote hydrogen, and A and B^ together form.a chain of the formula -CCH23n-, with n being 3, 4, 5 or 6, or a chain of the formula -CCH23p-CH=CH-CCH2aq-, with (p+q) being 1, 2, 3 or 4, or c) A and C each denote hydrogen, and 1 ■> B and Bc together form a chain of the formula - 40 - -CCt^nT' i» being 4, 5, 6 or 7, r denotes 0 or 1, R1 denotes hydrogen, an optionally substituted aliphatic radical having 1 to 6 carbon atoms, an optionally substituted alicyclic radical having 3 to 9 carbon a.toms, an optionally substituted a I i eye 11 c-a I i phat i c radical having 4 to 11 carbon atoms, an optionally substituted aromatic radical having 6 to 12 carbon atoms, uhich can also be partially hydrogenated, an optionally substituted araliphatic radical having 7 to 15 carbon atoms, an optionally substituted aroyl-aliphatic radical having 8 to 13 carbon atoms, an optionally substituted monocyclic or bicyclic heterocyclic radical having 5 to 7 or 8 to 10 ring atoms respectively, 1 or 2 of these ring atoms being sulfur or oxygen atoms and/or 1 to 4 of these ring atoms being nitrogen atoms, or a side chain of a naturally occurring aminoacid uhich is optionally protected, r2 denotes hydrogen, an optionally substituted aliphatic radical having 1 to 6 carbon atoms, or an optionally substituted araliphatic radical having 7 to 15 carbon atoms, V denotes hydrogen or hydroxyl, Z denotes hydrogen, or Y and Z together denote oxygen, and X denotes an aliphatic radical having 1 to 6 carbon atoms, an alicyclic radical having 5 to 9 carbon atoms, an optionally substituted aromatic radical having 6 to 12 - 41 - carbon atoms, or indolyl, uhich process comprises reacting, in the presence of a condensing agent or, where appropriate, as an active ester, ati optically pure compound of the formula la or lb, in 5 which A, , B2 and C have the abovementioned meanings, and R represents an optionally substituted aliphatic radical having 1 to 6 carbon atoms, an optionally substituted alicyclic radical having 4 to 10 carbon atoms, an optionally substituted aromatic radical having 6 to 12 10 carbon atoms or an optionally substituted araliphatic radical having 7 to 15 carbon atoms, with an optically pure compound of the formula III (111) Y * * , J100C - C\\ - KH - CH - fcxj - C - X ■l ' 2 ' K C02R Z in uhich R, R^ , Rz, X, Y and Z have the abovementioned 15 meanings, splitting off the radical R by hydrogenolysis or hydrolysis, and, where appropriate, converting the optically pure compound of the formula Xa or lb into a physiologically tolerated salt.

16. A process as claimed in claim 15, wherein there is 20 prepared a conpound uith the formula Ila or lib in which r denotes 0 or 1, R denotes hydrogen, (C^ to C$)-alkyl or aralfcyl having 7 to 9 carbon atoms, r1 denotes hydrogen or ~acyl~ emino or benzoy lamino, (C2 to C^-alkenyl, (C5 to C9)- 25 - 42 - cycloalkyl, (Cj to C9>-cyc loa IkenyI, CC5 to Cy)~cyclo-alkyl-CC1 to C^J-alkyl, aryl or partially hydrogenated aryl having 6 to 12 carbon atoms, each of Hhicli can be substituted by (Cf to C^)-alkyl, -cycloalkyl, (C$ to C-)2>—aryt., which can be mono-, di- or trisubstitued by (C, to C^J-alkyl, (C-j to C^J-alkoxy, hydroxyl, halogen, nitro, amino, (C^ to C^)-a Ikylami no, d i — C C -j to C^)-alkylamino and/or methyIenedioxy, or 3-indolyl„ 17. A process as claimed in one of claims 15 or 16, wherein there is prepared a compound of the formula XIa or lib in whi ch a) A and 6^ each denote hydrogen, and B2 and C together form one of the chains defined in - 43 -claim 15 (under a) or b) C and B* each denote hydrogen, and

17. A and together form one of the chains defined in claim 15 (under b).

18. A process as claimed in one of claims 15-17, wherein the (S,S,S) compound is prepared.

19. A process as claimed in claim 17, wherein e cis,endo compound is prepared.

20. A process as claimed in one of claims 1-5, wherein the resulting compound of the formula la or lb is further reacted by a process according to any one of claims 15-19.

21. & ps-ocsss to cXelra 1 for resolving a recsoic eiisiture o™ hicyeiAc J.t d.x?,o - a - csj-rfoojty 1 f.c astars into tfe® conpast&s'sft oS tSsts> foxsnslae Xm and lb givsea and deiined in cleies 1, oubss-tiiifitS.Cills' ®s hereiab®£or® dsscH'i.b'Scl and «ases^>X.i£±©d.

22. ^ co!#oimd of tils losianU Se or lb gives* and defied in cleim .t, wfesaewer obtained by a process cJ.aiins.ei ia> tww on® o2 claims 1 to 5 or 2%.

23. M coapourad accosidiiig to cleisa 3, scbsteatielly as heraissbasoire dsscribad and e&eaiplified.

24. a jo:roceaa according to cle^sa 15 for 'She preparation of an opticalX^ &ur@ coajsourad of the general Soraula XXa or lib given and dafiasS in claim 15, substantially as hereinbefore described and fisss^nfied.

25. An optically pure compound of the general formula Ila or lib given and defined in claim 15, whenever prepared by a process claimed in any one of claims 15 to 20 or 24. F.R. KELLY & CO., AGENTS FOR THE APPLICANTS.