NZ206980A

NZ206980A - Resolving racemic mixtures of bicyclic imino-alpha-carboxylic esters

Info

Publication number: NZ206980A
Application number: NZ206980A
Authority: NZ
Inventors: R Geiger; V Teetz; D Langner; H Urbach; R Henning
Original assignee: Hoechst Ag
Priority date: 1983-01-31
Filing date: 1984-01-30
Publication date: 1988-05-30
Also published as: IE56654B1; NO840350L; GR82650B; ES8500228A1; JPH0788358B2; AU566589B2; ES8501759A1; IL70830A; CA1317067C; FI88153C; DK41584D0; HUT34159A; DK174386B1; EP0115345A1; ES531284A0; NO166641C; IE840210L; CA1283249C; FI840350A0; EP0115345B1

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £06980 206980 Priority Date(s): Complete Specificati Class: . on Filed: SP.7l. f. 7/oO Publication Date: .. J 0 MAY 1988 1 P.O. Jr. aerial. No: . . /3o£ 5 NO DRAWINGS NEW ZEALAND Patents Act, 1953 COMPLETE SPECIFICATION "A PROCESS FOR THE RESOLUTION OF RACEMATES OF OPTICALLY ACTIVE BICYCLIC IMINO-& -CARBOXYLIC ESTERS, AND THE USE OF THE COMPOUNDS THUS OBTAINABLE FOR THE SYNTHESIS OF CARBOXYALKYLDIPEPTIDES. 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 heareby 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: - 20698 0 - 2 - laas-ai*.. nilL^r- The resolution of racemates of aminoacids via crystallization of diastereoneric salts is a widely used process (Review: Boyle, Quart. Rev. 25_ (1971 ) 323). Usually, N-acylated aminoacids are employed, the salts 5 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. 71_ (1949) 2541, 3251). It is also possible to carry out the converse process and to 10 crystallize ami noacid esters or amides with optically active acids (Chem. Ber. 86^ (1953) 1524). Optically active compounds, such as 10-camphoi— sulfonic acid, abietic acid or tartaric acid or their 0-derivatives, for example, are used for this purpose. This 15 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 forma-20 tion with optically active bases, split off the acyl radical and then esterify the free arninoacid. A process suitable for bicyclic i m i n o-oc~ ca r bo xy I i c esters has not hitherto been described. It emerged from experimental tests that all customary acids are unsuitable 20698.0 3 for resolution of the racemates. A process is known, from European Patent A 37,231, for octahydroindoLe-2-carboxyLic acid, using which the N-benzoyl compound of the racemate can be resolved via the salt with optically active a~ 5 phenyIethy I amine. However, for the reasons mentioned, \ this process is uneconomic when the esters are required as intermediates for further syntheses. 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 i m i no-oc- c a rb oxy I i c esters. This is because the (S,S)- or (R,R)-salts usually precipitate spontaneously from suitable solvents, while (S,R)-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 recrysta I I ization 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 racernic mixtures of bicyclic imi no-a-ca rboxy lie esters into the components of the formulae la and lb It has now been found, surprisingly, that N-acyl B 2 C C B I / H H (la) (lb) 20S980 - 4 - 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 denote hydrogen, and 2 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 -CCp~CH=CH-CCH23with (p+q) 10 being 1,2, 3 or 4, b) C and B^ denote hydrogen, and A A and B together form a chain of the formula with n being 3, 4, 5 or 6, or a chain of the formula -CCH2^p~CH=CH-CCH23q-/ with B^ and B^ together form a chain of the formula —CCH23nt—^ with m being 4, 5, 6 or 7, by crystallization of di astereomeri c salts, which process 20 comprises preparing the salts of the racemic esters with optically active N-acylated R- or S-aminocarboxyIic acids which contain a phenyl nucleus, recrystallizing them from an aprotic organic solvent or an alcohol having up to 6 carbon atoms, decomposing the precipitated, optically 25 homogeneous diastereomeri c salts in a manner known per se, and isolating the enantiomers of the formulae la and lb and, where appropriate, converting the latter into the free acids by hydrolysis or hydrogenolysis in a manner known per se. o 5 Resolution of racemates of compounds of the foi— inula la and lb in which a) A and denote hydrogen, and 2 B1- and C together form a chain of the formula 5 with 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 10 b) C and B^ denote hydrogen, and A and B^ together form one of the chains defined above under a) i s 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 figuration and the C00R group is oriented endo with respect to the bicyclic ring system. are esters with aliphatic, a I icyclic or araliphatic alco-20 hols,which can be cleaved by hydrogenolysis or hydrolysis, as are described in, for example, Houben-Weyl, Methoden der organi schen Chemie (Methods of Organic Chemistry), Volume XV/1, Stuttgart 1974, on pages 314-427, or "Peptide Synthesis", by Bodanszky et al., 2nd edition (1976), John 25 Wiley 8 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 N(>2, are preferred, in particular alkyl esters having up to 4 alkyl 15 which the two bridgehead hydrogen atoms have the cis con- Particularly suitable imino-crcarboxylic esters carbon atoms and aralkyl esters, such as benzyl, nitro-benzyl or benzhydryl esters. Examples of suitable N-acylated aminocarboxyIic acids containing a phenyl nucleus are derivatives of R- or 5 S-phenyI alanine, -C-phenylglycine, -p-pheny l-a-aminobutyric acid, -3 ,4-di h'ydroxypheny la lani ne , -(3-phenylserine and -tyrosine. N-Acyl derivatives of R- or S-phenyla lanine, -C-phenylglycine and -tyrosine are preferred. The N-acyl protective groups which can be used are 10 the customary NH;> protective groups described in, for example, Houben-Weyl, Volume XV/1, pages 46-305 or Bodanszky et al., "Peptide Synthesis", 2nd edition (1976), John Wiley & Sons. Alkanoyl having 1 to 6 carbon atoms, in particular formyl, tert.-butoxycarbonyI, and benzyloxy-15 carbonyl are preferred. Any free OH groups present can, where appropriate, be 0-alkylated by alkyl having 1 to 6 carbon atoms, in particular methyl, ethyl or tert.-butyl, by benzyl or by other OH protective groups customary in peptide chemistry (cf. for example Houben-Weyl, Volume XV/1 20 or Bodanszky et al., "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. Oct ahydroindo le-2-carboxyIic acid is known from { N.2.. Sptc'.-fVcttftbA ^ C^U.S. Patent 4,350,704. Cc pmo n Patent Application P "^apa,37S 26—768 i1 relates to 2-azabieye loC3.3.03octane-3-carbox- -Xo^>,fe'2>S y-licacid, and Gorman- Patent Aixplicr.tion P 32—1-0—496 . J <0 & relates to 2,3,3a,4 ,5,7a-hexahydroE1HDindole-2-carboxyIic (sj. z. speci-ficofioA <2o3,*7 acid. Cormon Patent Application P 32—W—67 6 »4 relates to octahydroisoindoIe-1-carboxyIic acid and 3-aEabieyelo- [3 .3 .ODoctane-4-carboxyIic acid. Racemic bicyclic ci s, endo-imino-orcarboxylic acids _of the formulae la + lb/ in' which C and denote hydrogen, and A and together denote the abovementioned chain, can be prepared from, for example, enamines of a eyeloaIkanone and N-acylated p-ha logeno-a-ami-noea rboxy I i c esters of the formula IV, in which X' represents a nucleo-fugic group, preferably chlorine or bromine, Y 1 represents alkanoyl having 1 to 5 carbon atoms, aroyl having 7 to 9 carbon atoms or other protective groups which are customary in peptide chemistry and which can be split off with acid, and R^ represents alkyl having 1 to 5 carbon atoms or aralkyl having.7 to 9 carbon atoms, X1 \:h. (IV) CH y-HN COOR4 or with acrylic esters of the formula V, in which Y' and R^ have the abovementioned meaning. 206980 - 8 - by reacting the Latter to give compounds of the formula VI in which A, , R^ and Y" have the abovementioned meaning, CH2 = c. •COOR' iNH-Y' (VI) cyclizing the Latter using strong acids, with cleavage of the acrylamide and ester, to give compounds of the formula Vila or b. B V A- N COOH (Vila) (VITb) 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 which R has the meaning defined above. Racemic bicyclic imi no-orcarboxyIic acids of the formulae la and lb, in which A and denote hydrogen and - 9 - and C together denote the chain pared from, for example, compounds 2069f«9,, mentioned, can be pre of the formula VIII (VIII) in which 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 4J[, 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 are 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. Chem. 197 8, 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 + 4 0 ° C , with the 20 formation of a compound of the formula IX in which B^ and C have the abovementioned meaning and = C-j-C^-a Iky I. - 10 - 20698$) (IX) The resulting compound of the general formula IX is reacted with trimethy I si ly I 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 j^0°C, in the presence of a Lewis acid, such as, for example, ZnC^r SnCl2/ SnCl^, T i C 14 or BFj-etherate, preferably BFj-etherate, and the resulting compound of 10 the formula X CN (x) in which the bridgehead hydrogen atoms are cis or trans with respect to one another, the CN group being located cis with respect to the bridgehead hydrogen atom on carbon 15 atom (4-in), and in which n, Bc and C have the abovementioned meanings, is, after purification and resolution of the mixture of diastereomers 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 R = hydrogen, and the latter is esterified. 206980 - 11 - HCl or HBr, 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 which 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 NO^, and A, , B^ and C are defined as above, and to those compounds 15 of the formulae la or lb in which R denotes hydrogen and a) A and B*' denote hydrogen, and B^ and C together form a chain of the formula -CCHpUn-/ with n being 3, 4, 5 or, 6/(.Nor a chain of the formula 20 -CCH2Dp-CH = CH-[:CH2lIq"r with (p + q) being 1, 2, 3 or 4, or b) C and 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-carboxylic ester of the formula la or lb, in which A, B^, B^, C and R have the meanings defined above as being preferred., and an optically 206980 - 12 - active N-acylated R- or S-aminocarboxylic acid which contains a phenyl nucleus and which 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 ? B B C CO OH 0 = c - if CH I - NH R 1 * 1 CH - ZCH - C ! I co2ir z - x (Ha) 1 2 BBC C00H 0 = C - CH Ji NI-I * ! CH - £c- C I p I C02?/ z - X (lib) 10 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 denote hydrogen, and and C together form a chain of the formula ~CCH2Hn-, 15 n being 3, 4, 5 or 6, or a chain of the formula -CCI^Dp-C^CH-CCHgHq- , 2 0 £ 9 8 0 - 13 - (p+q) being 1, 2, 3 or 4, b) C and denote hydrogen, and A and B^ together form a chain of the formula with n being 3, 4, 5 or 6, or a chain of the 5 formula -CCH23p-CH = CH-[:CH23q-/ with (p + q) being 1, 2, 3 or 4, or c) A and C denote hydrogen, and B^ and B^ together form a chain of the formula -ECH23m-, with m being 4, 5, 6 or 7, 10 r denotes 0 or 1, 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 15 radical having 4 to 11 carbon atoms, an optionally substituted aromatic radical having 6 to 12 carbon atoms, which can also be partially hydrogenated, an optionally substituted araliphatic radical having 7 to 15 carbon atoms, an optionally substituted aroyl-20 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 25 being nitrogen atoms, or a side chain of a naturally occurring aminoacid which is optionally protected, denotes hydrogen, an optionally substituted aliphatic radical having 1 to 6 carbon atoms, or an optionally substituted araliphatic radical having 7 to 15 carbon - ^ - t!. L' u v> u U atoms, Y 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 to 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, B^, 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, with optically pure compounds of the formula III 20 r | (III) H00C - CH - NH - CH - [CH„ I _ r - Y Ij. I 2 ' R co2r z in which the two carbon atoms labeled with an asterisk (*) have the (S,R), (R,S), (R,R) or, preferably, (S,S) configuration, and " - -> R ' R ' x' Y ancl z have the abovementioned meanings, 25 <*\ splitting off the radical R by hydrogeno lys i s or hydroly- "u e~t\ sis, and, where appropriate, converting the optically I 'i 206980 - 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 which r denotes 0 or 1, R denotes hydrogen, (C-j to C6)-alkyl or aralkyl having 7 to 9 carbon atoms, R1 denotes hydrogen or (C-j to C^J-alkyl, which can 10 optionally be substituted by amino, (C-] to C^'acyl- amino or benzoy lamino, (C2 to C6)-alkenyl, (C5 to C9)-cycloalkyl, (C5 to C^J-cyc loa Ikeny I, (C5 to C7)-cyclo-alkyl-(C^ to C/f)-alkyl, aryl or partially hydrogenated aryl having 6 to 12 carbon atoms, each of which can be 15 substituted by (C^ to C^J-alkyl, (C-j or C2)~alkoxy or halogen, (C$ t 0 C-j 2 ) ~a py *■"" (C1 " C4 )-a I ky I or (C7-c<j3)-a roy I-(C-| - C2)-a Iky I, both of which can be substituted in the aryl radical as defined above, a monocyclic or bicyclic heterocyclic radical having 5 20 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 R2 denotes hydrogen, (C-j to C6)-alkyl, (C2 to C6)-alkenyl or (C^ to C-| 2)-a ry I - ( C<| to C^)-alkyl, Y denotes hydrogen or hydroxyl, Z denotes hydrogen, or Y and Z together denote oxygen, and 20698. - 16 - X denotes CC-j to C^i-alkyl, <C2 to. C^'alkenyl, (Cc; to C^-cyc loa Iky I, (C^ to Ci2)-aryl, which can be monosubstituted, disubstituted or trisubstituted by (C-j to C^-alkyl, (C-j to C^J-alkoxy, hydroxyl, halogen, nitro, amino, (C-j to C^J-a Iky I ami no, di-CC-j to C^.)- \ alky-lamino and/or methylenedioxy, or 3-indolyl. The preparation of the S,S,S-compounds of the formula Ila is preferred. In this context as in the following, aryl is to 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, in which the ring atons have the abovementioned meanings, include thienyl, benzoCbDthieny I, furyl, pyranyl, benzo-furyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimi-dinyl, pyridazinyl, indazolyl, isoindolyl, indolyl, purinyl qui no I iziny I, isoquino liny I, phtha lazinyI, naphthyridinyI, quinoxalinyl, quinazolyl, cinnolinyl, pteridinyl, oxa-zolyl, isoxazolyl, thiazolyl or isothiazolyl. It is also possible for these radicals to be partially or completely hydrogenated. Where R ^ represents a side chain of a protected naturally occurring a-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 206980 - 17 - and XV/2). In the case where denotes a protected side chain of a lysine, the known amino protective groups, but in particular ( C-j - C$ )-a Ikan oy 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 with 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 a(3, 7 a(3) ~o c t a hy d r o-C1 HI] - i ndo I e-2-carboxylate followed by elimination of a tert.-butylester, whereupon a corresponding octahydroindole 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 B2 each being H and A + being (^2)4, and w ij O - 18 - 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 5 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 formulae 10 Ila and lib by separating conventional diastereomeric salts with 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 be prepared directly in an optically pure form by A/.z. specifica-hon straightforward routes from Gorman Patent -Application P .»oa 32 26 7 68 .1-. However, in this reference, it was 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 20'. - 19 - of stereoisomers, some of which 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-Weyl, Volume XV, or in "The Peptides - Analysis, Synthesis, Biology, Vol.1 Major 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 must be temporarily protected by the known methods of peptide chemistry (for example Houben-Weyl, Volume XV, or Bodanszky et al. 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, R2, 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 20690 - 20 - activity. Typical representatives of these classes of active compounds are described in, for example, Erhardt-Ruschig, Arzneimittel (Drugs), 2nd edition, Weinhein, 1972. They can be administered intravenously, subcutaneous ly or 5 orally. c The dosage on oral administration is generally 1-5 00 mg, preferably 1-100 rag, per single dose for an adult patient of normal weight. 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 when 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 with 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 which 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 206980 - 21 - salts are converted into a solution, suspension or emulsion, where appropriate with the substances customary for this purpose, such as so lubi 1 izers, 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 which 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-carboxyI ate hydrochloride (abbreviated to (S)-Aoc-OBzl-HCI) (A) Methyl 2-acetylamino~3-(2-oxocyclopentyl)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. 1H-NMR : 2.0 2 (s,3H); 3.74 (s,3H>; 4.4-4.8 (m,lH), (CDC 13) - 22 - Analysis: C H N calculated 58.1 7.5 4 6.16 found 58.5 7.2 6.5 (B) cis,endc-2-AzabicycloC3.3.0!3octane-3-carboxylic acid 5 hydroch lori de \ 270 g of the acetylami no derivative prepared under (A) in 1.5 liters of 2 N hydrochloric acid are boiled under reflux for 45 minutes. The mixture is evaporated in vacuo, and the residue is taken up in glacial acetic acid, 5 g 10 of Pt/C (10% Pt) are added and hydrogenation is carried under 5 bar. After filtration, the filtrate is evaporated and the residue is crystallized from chloroform/diisopropyl ether. Melting point: 205-209°C, 15 Yield: 150 g (C) Racemic Aoc-OBzl.HCl 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 dropwise, 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 206980 - 23 - vacuo. A further precipitate separates out of the combined diisopropyl ether solutions overnight. Yield: 168.5 g (90.6%) (D) (S)-Aoc-OBzl.Z-Phe-OH 166.0 g (0.589 mol) of racemic Aoc-OBzl.HCl are suspended in 500 ml of methylene chloride and thoroughly shaken with 25 g (0.625 mol) of NaOH in 250 ml of water. A solution is produced. After a short time, the initially formed emulsion has separated. The methylene chloride phase is separated off, washed with 100 ml of 0.1 N NaOH and twice with 50 ml of water each time and the combined aqueous phases are extracted twice with 100 ml of methylene chloride each time. The combined methylene chloride phases are dried over sodium sulfate and evaporated under mild conditions with 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 loxycarbony I-S-phenylalanine (Z-Phe-OH) in 200 ml of ethyl acetate is added. The flask is rinsed with 100 ml of ethyl acetate. 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 250 ml of ethyl acetate/cyclohexane (1+4) and dried. Yield: 133.6 g of (S)-Aoc-OBz I.Z-Phe-0H (50.9%, corresponding to 102% of theory), melting point 101-103°C; Ca3^: -5.3° (c = 1, methanol). After recrysta 11 ization from ethyl acetate/cyc lo- 2 0 6 9 H 0 - 24 - hexane (1:1), the following data are found for the Z-Phe-OH salt: melting point: 103-104°C/ Ca3^: -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 with 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 with 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 (81.3%) Melting point: 185-186°C CaD^0: -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 from the methylene chloride mother liquor from Example 1(D) in the manner described. Table 1 Diastereoisomeric Salts Exam- Imino- • Ester Acid ' Solvent " m"p* (c=T,MeOH) pie carboxylic R acid 2' XIII Methyl Z-Phe-OH Diethyl 11&-1160C + 5.3° ether 3 XIII Benzyl Z-Phe-OH Ethyl acetate/ 104-l05°C + 6,2° | cyclohexane ■ 4 XIII Benzyl Z-Phs-OH Isopropanol 103-104°c - 6.0° 5 XIII Benzyl Z-R-Phe-0HEthyL acetate/ 102-104° C + 4.4° cyclohexane - 6 XIII Benzyl Z-Pgl-OH Ethyl acetate 128-130°C + 32.1° 7 XIII 'Benzyl Z-Tyr-OH Ethyl acetate/ '25-126°C -0,4° cyclohexane 8 XIII Benzyl Z-Tyr Ethyl acetate/ 104-105° C - 3.4° (But)-OH cyclohexane 9 XIII Benzyl For-?h«-0H Isopropanol 107-109° C + 1-7° 10 XIII Nitro- Z-Phe-OH Ethyl acetate ' 122-124° C - 1,3° benzyl * 0 0-- 11 XI Benzyl Z-Phe-OH Ethyl acetate/ 106-107 c -13-5. cyclohexane 12 Methyl Z-Phe-Oh Ethyl acetate/ 107-108° c. + 47. 1° a * cyclohexane <$ * - $ o ° tti ,,1QJ Final product S-Fonn R-Form Ac<id • 'm.p. c=1,Hf» m.p. . A*.^c=1,H20) conponerit TosOH 191-192°c - 12.9° 190-192°C 4 12,6° HCl 184-186°C - 41.2° '183-185°C +42.5° HCl .182-185°C -39,9° HCl 185-186°C +41.9° HCl 184-185°c - 40,9° ^ HCl 184~185°C - 41.6° HCl 178-181°c - 39.1° TosOH - 29.8° TosOH 152-153°C - 36.2° HCl +68.4° r\j HCl 181-183°C -,40.0° ro o Ov vO OO o n 1 26 The Heis,endo3-imino-a-carboxyIic esters in Table 1 are prepared and subjected to racemate resolution in an analogous manner. This Table details their optically active crystallization partners, and the solvents, yields 5 and properties of the salts and the final products in the form of the ester hydrochlorides or ester tosylates. Explanations of Table 1 CXI) and mirror image H H (XII) H and mirror image H H 10 (XIII) H and mirror image The free iminocarboxylic acids can be prepared from the esters by hydrolysis or hydrogenolysis. Example 13 N-(1S-Carboethoxy-5-phenylpropyl)-S-aLanyl-2-cis,endo- 15 azabi eye I oC3.3.03octane-3S-carboxyli c acid 206980 - 27 - (A) Benzyl N-(2S-carboethoxy-3-phenylpropyl)-S-alanyl-cis,endo-2-a?-abicycloE3..3.0]octane-3S-carboxylate 14 g of the benzyl ester hydrochloride prepared according to Example 1 E are converted into the free ester 5 by extracting by shaking the alkaline aqueous solution with 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-phenylpropyl)-S-alanine and 10.2 g of dicyclo-hexylcarbodiimide in 200 ml of dimethylformamide. After 10 stirring at room temperature for 3 hours, the precipitated dicyclohexylurea 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 with 3 x 500 rn I of 5 per cent NaHCOg solution. The organic 15 phase is evaporated. 22.4 g (90%) of product are obtained as an oil. ^ H NMR 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,5 H), 7.32 (s,5H) (cdci3) 20 Ana lysis: C H N ^30^38^2^5 calculated 71.1 7.56 5.53 found 70.8 7.8 5.7 (B) N - (1S-Carboethoxy-3-phenylpropyl)-S-alanyl-ci s,endo-2-azabicyclo[3.3.0!]octane-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 hydrogeno lysis under atmospheric pressure with the addition of 0.5 g of 10% Pd/C. This reaction can also be carried out under elevated pressure which involves 0 o cj 0 - 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 zwitterion 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 Ana lysis: C H N C23H32N2®5 calculated 66.3 7.7 6.73 found 66.1 7.8 6.6 The NMR and mass spectra which are obtained are consistent with the structure indicated. 15 toQjj = +15.6° (c = 1, methanol). Example 14 N-(lS-Carboethoxy-2-benzoylethyl)-0-ethyl-S-tyrosyl- cis,endo-2-azabicycloC3.3.03octane-3S-carboxylic acid a.— b€.o2.oyl«.+^yl (A) N-(1 S-Carboethoxy-3 phc ny Ip po|»y-t) - O-ethyl-S- 20 tyrosine benzyl ester 24 g of ethyl benzoyI acryI ate in 100 ml of ethanol are reacted with 30 g'of 0-ethy l-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 cTra"£tereome rs by chromatography on silica gel using the »I i .system ethyl acetate/cyclohexane (1:3). ^ ; cVie Id: 17 g of the S,S compound. _ 2 9 - 0 w o O D A— btrtroy^yl (B) N-(lS-Carboethoxy-3-phenylprop;rt)-0-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-tate/cyclohexane (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 a-benxoylemyl (C) N-(1.S-Carboethoxy-3-phcnylpropyl)-0-ethyl-S-tyrosyl-cis/endo-2-a2abicycloC3.3.03octane-3S-carboxylic acid In analogy to Example 13 A, 8 g of the free benzyl ester obtained in accordance with Example 1 E and extracted from alkaline solution by shaking with diethyl ether are reacted with 8 g of the compound obtained in accordance with Example 14 B using 4.4 g of dicyclohexylcarbodiimide in the presence of 2.7 g of 1-hydroxybenzotriazole, and 14.3 g of oily benzyl ester are obtained as an intermediate. The 1H NMR and mass spectra are consistent with the structure indicated. The benzyl ester in 50 ml of ethanol is cataly-tically 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 Examp le 15 N- (1S-Ca rboet hoxy-3-ph eny Lpropyl)-0-methyL-S-tyrosyl-cis,endo-2-azabicycloC3.3.0I]octane-3S-carboxylic acid The procedure is carried out as described in 5 Example 14, but in the stage analogous to (A) O-methyl-S-tyrosine benzyl ester is used and the title compound is obtained, the ^H NMR spectrum of which is consistent with the structure indicated. 1H NMR (CDCl3): 1.2-3.0 (m,15H); 1.27 (t,3H); 1.4 <t,3H); 10 3.0-4.3 (m,4H>; 3.8-4.2 (m,4H); 6.5-7.1 <2d,4H>; 7.3 (s,5H) Examp le 16 N-(1S-Carboethoxy-3-phenylpropyl)-S-aLanyL-2-azaspiro-C4.53decane-3S-carboxyLic acid 15 (A) 1-(DiethoxyethyL)cycLohexanecarbonitri le 51.7 ml (0.5 mol) of anhydrous diethylamine are added dropwise, under protective gas at -10°C, to 312.5 ml (0.5 mol) of a 15% strength solution of n-butyllithium in hexane. The mixture is stirred for 20 minutes and then 20 cooled to -70°C. 54.6 g of cyc lohexanecarbonitri le are added dropwise over the course of 30 minutes and, after a further 30 minutes, 98.5 g of bromoacetaLdehyde diethyl acetal are added within 1 hour and the mixture is left at low temperature for 24 hours. It is then warmed to room 25 temperature, 100 g of ice are added, and the mixture is extracted twice with 500 ml of ethyl acetate, and the organic phase is dried over sodium sulfate, evaporated in vacuo and the residue is subjected to vacuum distillation. Yield: 90 g (about 80% of theory), boiling point 78-79°C at 206980 - 31 - 8 torr (10.7 mba r) . (B) 1-Aminomethyl-1-(diethyloxyethyl)cyclohexane 90 g of diethyIoxycyc lohexanecarbonitri Ie are dissolved in 1 liter of ethanol, and 60 g of sodium are 5 added. After the metal has dissolved, 100 ml of water are added and the solvent is largely removed in vacuo. 300 ml of water 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 roC4.53decane-3-carbonitrile 80.2 g of aminomethyldiethyloxycyclohexane 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) f°r 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 about 5 hours. 25 Completion of reaction is checked using thin-layer chromatography (system ethyl acetate/petroleum 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 accor- - 32 - dance with Example 16 D or E. (D) 2-Azaspi roC4.5!3decane-3-carboxylic acid 250 ml of 4 N hydrochloric acid are 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(II) salt solution). The solution is neutralized, evaporated to dryness and extracted several times with n-butanol. The residue from evaporation of the organic phase is a) crystallized from chloroform/diisopropyl ether to obtain the hydrochloride and, if necessary, again precipitated from a mixture with ethanol or b) purified in aqueous solution by stirring with an ion exchanger, for example IR 45 (OH form) (Amber I ite^) and, after removing the water, the zwitterion is crystallized from ethanol/ether. Yield from a): 31-32 g (82%) Melting point 205°C (decomposition), hydrochloride (E) Benzyl 2-azaspiroC4.53decane-3-carboxy I ate hydrochloride Half of the aminoacid nitrile obtained in accordance with 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 sodium bicarbonate solution is added until the pH is 8.5 and the benzyl ester is extracted into ethyl acetate. The organic phase is dried, 206980 - 33 - an equivalent amount of ethereal hydrochloric acid is added and the mixture is evaporated. The residue crystallizes from diisopropyl ether and can be recrystallized from methylene chIoride/diisopropyI ether. 5 Yield: 43 g (about 80%) Melting point 145°C (decomposition) (F) Benzyl 2-azaspiroC4.53decane-3S-carboxy I ate 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. (G) Benzyl N-(1S-carboethoxy-3-phenylpropyl)-S-alanyl-2-azaspi roC4.53nonane-3S-carboxylate 15.6 g of benzyl 2-azaspiroC4.53nonane-3S-carboxy-15 late hydrochloride, 6.7 g of 1-hydroxybenzotriazoIe and 13.8 g of (S,S)-N-(1-carboethoxy-3-phenyIpropyI)alanine are dissolved in 200 ml of DMF and reacted overnight with 10.2 g of dicyc lohexy I carbodiimide. Addition of tertiary bases, for example 6.4 ml of N-ethyImorpho Iine, increases 20 the yield only inconsiderably. The precipitated DC- urea 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-(lS-Carboethoxy-3-phenylpropyl)-S-alanyl-2-aza-spi roC 4.5 3nonane-3S-carboxylic acid The benzyl ester obtained in Example 16 G is </div>

Claims

<div class="application article clearfix printTableText" id="claims"> ^ vj o ^ u U - 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 5 foam of the zwitterionic dipeptide derivative can be obtained in vacuo with the addition of pentane. = 38.3° (c = 1, methanol) Example 17 N-(lS-Carboethoxy-3-phenylpropyl)-S-alanyl-cis,endo-10 2,3,3a,4,5,7a-hexahydroC1HHindole-2S-carboxyli c acid (a) Methyl cis-2,3,3a,4,5,7a-hexahydroC1HHindole-2S-carboxylate hydrochloride Racemic methyl cis-2,3,3a,4,5,7a-hexahydroC1HD- indole-2-carboxy late hydrochloride (obtainable in analogy Kl- z. speciF*:<x4ioa 15 to the procedure described in Gorman Patent Application ».o3 ( P- 32—4-0—4-96.0) is subjected to racemate resolution in analogy to Examples 1 D and E. CoG D = +68.4° (c = 1, H20) (B) N- (1S-Carboethoxy-3-phenyIpropyl)-S-alanyl-cis,endo-20 2,3,3a,4,5,7a-hexahydroClH3indoLe-2S-carboxyli c acid hydroch lori de The title compound is obtained by a procedure analogous to that described in Examples 13 A and B. 1h NMR data 0.9-3.0 (m, 17 H); 25 3.4-4.9 (m, 6 H); 5.2-6.0 Cm, 2 H); 7.2 (s, 5 H) WHAT WE CLAIM IS: - 35 - u, Ui/Oo U 1. A process for resolving racemic mixtures of bicyclic imino-a-carboxylic esters into the components of the formulae la and lb COOR RGO (la) (lb) 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^ denote hydrogen, and B2 and C together form a chain of the formula -CCH2Un_, with n being 3, 4, 5 or 6, or a chain of the formula -CCH2:p-CH=CH-CCH23q-, with (p+q) being 1, 2, 3 or 4, b) C and B2 denote hydrogen, and A and B^ together form a chain of the formula -CC^Dp-, with n being 3,'4, 5 or 6, or a chain of the formula -CCH2Dp-CH=CH-CCH23q", with (p+q) being 1, 2, 3 or 4, or A and C denote hydrogen, and ^B^ and B2 together form a chain of the formula -CCH23m~/ ■**•« ',1 '-"/I with in being 4, 5, 6 or 7, i : U w uuU - 36 - by crystallization of diastereomeric salts, which process comprises preparing the salts of the racemic esters with optically active N-acylated R- or S-aminocarboxyIic acids which contain a phenyl nucleus, recrysta11izing 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 enantiomers of the formulae la and lb and, where appropriate, converting the latter into the y Or kiylrcx^twol tjVi *> free acids by hydrolysislin a manner known per se. 2. The process as claimed in claim 1, wherein a) A and denote hydrogen, and B^ and C together form a chain of the formula "CCHgDp-, with n being 3,4, 5 or 6, or a chain of the formula -CCH23p-CH=CH-CCH2Dq- 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) 3. The process as claimed in claim 2, wherein the % salts of racemic esters of the formulae la and lb in which w on-the br't«i^h«<Ki <wbor> ate.ws the two bridgohoad hydrogen atomsi have the cis configuration and the COOR group is oriented endo with respect to the bicyclic ring system are precipitated. 4. The process as claimed in one of claims 1 to 3, "wherein R represents alkyl having 1 to 6 carbon atoms, o\ cycloalkyl having 4 to 8 carbon atoms or aralkyl having 7 % ^ ij uo u U to 13 carbon atoms which can optionally be substituted by N02. 5. The process as claimed in one of claims 1 to 4, wherein the amino group of the N-acylated R- or S-amino-carboxylic acids which are used for salt formation is protected by alkanoyl having 1 to 6 carbon atoms, tert.-butoxycarbony I, benzy loxycarbony I 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 alkyl having 1 to 6 carbon atoms, benzyl or other OH protective groups customary in peptide ch emi s t ry . w at> *)ePinecJ> claiM I 6. A compound of the formula/? la or Iblin which the non bridgehead cavbon atams iave the cis configuration, the COOR group is oriented endo with respect to the bicycli ring system, the carbon atom a to the COOR group has the R or S configuration, and A, , B^ and C have the meanings defined in claim 2, and R has that defined in claim 4, and its salts. • as, cfefi'oe<J *"«"> l 7. A compound of the formula/? Ia or Iblin which the on-toe bri<ij«hedd covbon c*Vorv\S two bpi dgohoad hydrogen atomslhave the cis configuration, the COOR group is oriented endo with respect to the bicycli 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 claim 4, a) A and B^ denote hydrogen, and B^ 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 L •' f , • 'k. ' • ^ JO u U U - 38 - -CcH23p-cH=cH-CcH23q-/ with (p+q) being 1, 2, 3 or 4, or b) C and denote hydrogen,"and A and B^ together form one of the chains defined aboveia), with n being 3, 5 or 6 and (p+q) •being 1, 2, 3 or 4, and its salts. 8. A compound as claimed in -erre—©+ claim^ 6 or 7, wherein the carbon atom a to the COOR group has the S cqnf iguration. 9. A diastereomeric salt of a bicyclic imino-oc-car-boxylic ester of the formula/ la or lb as claimed in -^4 clainyf 6 or 8, in which R has the meanings defined in claim 4, and an N-acylated, optically active R- or S-aminocarboxy I ic acid which contains a phenyl nucleus and is protected as defined in claim 5. 10. cis/endo-2-AzabicycloC3.3.0Doctane-3S-carboxylic acid. 11. A cis,endo-2-azabicycloC3 .3.03octane-3S-carboxyIic ester in which R has the meaning defined in claim 4. 12. Benzyl cis,endo-2-azabieye loC3.3.03octane-3S-car-_ boxylate. 13. A c i s, endo-oct ahyd roC1 H3 i ndo le-2S-ca rboxy I i c es^Vrx in which R has the meaning defined in claim 4. 14. Benzyl cis,endo-octahydroC1H3indo le-2S-carboxy1ate 15. A process for the preparation of optically pure compounds of the general formula^ Ila ©V ^ ** firu iml - 39 - 206980 (Ila) Y 1 C - X t z 1 ? B B C 7^." A % CO OH I . 0 = C - CH - NH i' 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 denote hydrogen, and B2 and C together form a chain of the formula -CCH2Dn~, with n being 3, 4, 5 or 6, or a chain of the formula -tCH2Dp-CH=CH-CCH2Dq~ , with (p+q) being 1, 2 , 3 or 4, b) C and b2 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-CCH23, with (p+q) being 1, 2, 3 or 4, or c) A and C denote hydrogen, and 1 o b and b^ together form a chain of the formula 1 2 BBC 0 = C - CH - NH - CH - £C\]J - I I r 1 2 R. C02 Y * I ch - ZcH„y._- c - x ' 2 C02R^ (lib) 20 *'98 0- - 40 - -CC H23 m", with m being 4, 5, 6 or 7, r denote s 0 or 1, 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 alicyclic-aliphatic radical having 4 to 11 carbon atoms, an optionally substituted aromatic radical having 6 to 12 carbon atoms, which 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 ami noacid whi ch 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, Y denotes hydrogen or hydroxyl, Z denotes hydrogen, or Y and Z together denote oxygen, and X denotes an a I iphatic radica I having 1 to 6 carbon atoms, an alicyclic radical having 5 to 9 carbon atoms, an optionally substituted aromatic radical having 6 to 12 carbon atoms, or indolyl, which process comp rises reacting, in the presence of a condensing agent or, where appropriate, as an active ester, optically pure compounds of the formula^ la or lb, -4-fv de^'VKd ifl C.1 <3iVf\ l ir» Iwhich A, B^, 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 carbon atoms or an optionally substituted araliphatic radical having 7 to 15 carbon atoms, with optically pure compounds of the formula III (III) Y s x i HOOC - CH - NH - CH - jfCH„7 - C - X 'l 1 2 1 k 1 co r z r 1 _ in which X, R1, R^, X, Y and Z have the abovementioned meanings splitting off the radical R by hydrogenolysis or hydrolysis, and, where appropriate, converting the optically pure compounds of the formula^ la or lb into physiologically tolerated salts. 16. The process as claimed in claim 15, wherein are prepared compounds with the formula^ Ila or lib in which r denotes 0 or 1, R denotes hydrogen, (C^ to C^)-alkyl or aralkyl having 7^p*o 9 carbon atoms, 3*1 denotes hydrogen or (C-, to C^-alkyl, which can \ V -'•i '.i . -o // optionally be substituted by amino, (C-j to C^-acyl-amino or benzoyI amino, (C2 to C^-alkenyl, (c5 to c9)- 0 O iy O Li - 42 - cycloalkyl, (C5 to C9)-cycLoa IkenyI, (C5 to C7>-cyclo-alkyl-CC-j to C^-alkyl, aryl or partially hydrogenated aryl having 6 to 12 carbon atoms, each of which can be substituted by (C-j to C^J-alkyl, (C-j or C2)~alkoxy or halogen, <C6 to C-j 2)-a ry I-( C-| - C4)-a Iky I or ( Cy-C-j 3 >-a r oy I-(C-j-C2 >~a Iky I, both of which can be substituted in the aryl radical ae 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, R2 denotes hydrogen, <C-j to C$)-alkyl, (C2 to C^)-alkenyl or (C$ to C-j 2)-a ry I-(C-j to C^J-alkyl, Y denotes hydrogen or hydroxyl, Z denotes hydrogen, or Y and Z together denote oxygen, and X denotes (C<| to C^J-alkyl, (C2 to C^J'alkenyl, (C 5 to C9>-cycloalkyl, (C ^ to C<j2)-aryl, which can be monosubstituted, disubstituted or trisubstituted by CC1 to C4>-alkyl, CC-| to C^J-alkoxy, hydroxyl, halogen, nitro, amino, (C-j to C^)-a Ikylamino, d i — (C -j to C^)-alkylamino and/or methyIenedioxy, or 3-indolyl. 17. The process as claimed in ent of claim^ 15 or 16, wherein are prepared compounds of the formula Ila or lib ':i in which +-'\ jaj) A and denote hydrogen, and ^ ^ B2 and C together form one of the chains defined in m 206980 - 43 - claim 15 (under a) or b) C and B2 denote hydrogen, and A and together form one of the chains defined in claim 15 (under b). 18. The process as claimed in one of claims 15-17, wherein the (S,S,S) compound is prepared. 19. The process as claimed in claim 17, wherein a cis,endo compound is prepared. 20. The process as claimed in one of claims 1-5, wherein the resulting compounds of the formula la or lb are further reacted by a process according to claims 15-19. 21. A process according to claim 1 substantially as herein described or exemplified. 22. A compound of formula la or lb as described in claim

1 -when resolved by a process according to any one of claims 1 to 5. HOECHST AKTIENGESELLSCHAFT By Their Attorneys HENRY HUGHES LIMITED By= Q&jC' ■ J; </div>