IE56477B1 - Derivatives of cis,endo-2-azabicyclo(3.3.0)octane-3-carboxylic acid,a process for their preparation,agents containing these compounds and their use - Google Patents

Description

Derivatives of cis,endo-2-asabicycIo[3.3.03octflne-3^c&rte;sylic acid, procesoSQ for their preparation, agents containing them and their use.

A process for th© preparation of 0-aroyX-©-(&1« succinyl) minopropionic acidfi hy reaction of ^-aroylaryl acids with aspartic acid in the presence of pot&sesiuia hydroxide is known from Cheat· £tetr· 89. [1978] 215 732 p. gp~&~0,0£0,362 relate®, inter alia, to octahydrocyclopeate(e]pyrrol*-l'C ^ovel cis, ©ndo-2asahicyclo[ 3.3.0 ]©ctene«3~ carboxylic acid derivatives have now teen found which strongly inhibit ACB and have & long-lasting, intense hypotensive action.

The invention relates therefor© to derivatives of cis,endo-2-azabicyclo[3.3.0]oct£iine'-3-carbo^rylic acid of the formula I y. r^· φ <» fl w X-G~CH. -CH-I I ' I a co2a2 I 1 ea.co-s-cs- ch. (x> a I & I raiP ra ra* /\/\/ B©oc ra«3 ra* in which th® hydrogen atoms on the bridge-head carbon otoma 1 and 5 are in th© cia«configuration relative to one another and the carte&^l group on carbon atom 3 ii=i orientated in the endo-position relative to th© bicyclic ring systems (i.©0 towards th© cyclopentane ring), and in which n1 denotes hydrogen, allyl, vinyl or a sido-ehain of a naturally occurring acid R*~CEg( 1¾)^ GO052, which may te protected3 El3 denote® hydrogen, Xi^syl, (Gg—Cgl—alhenyl p aryl-(C^^)-alkyl or aitrotenssyl, ij t? Y denotes hydrogen or hydroxyl, ©nd £ denotes hydrogen, or Y and 2 together denote oxygen, xdett^s (Ci-Ca)«alkyl, (C3-Ca)-alkenyl, (C3q,-cycloalkyl, 5 (Ca-CjsJ-a^yl, which can te mono-, di- or trisubstituted by (Ci-CJ -alkyl p (Cj-C$)-alkoxy, hydroxyl, halogen, nitro, amino, (C^fXJ-aXkjXamino, di-(C&-C4)-alkylamino or methylenedioxy, or denotes indol-3-yl, and physiologically acceptable salts thereof, compounds - of the formula X ©nd salts thereof being excluded in which the centers of chirality on the two carbon atoms labeled with a star (*) in the chain and on carbon ©tom 3 of the bicyclic ring system are present in tha 8IS configuration and in which R* denotes methyl, &a denote® hydrogen, methyl, ethyl or tensyl, Y denotes hydrogen, 8 denotes hydrogen and X denotes phenyl.

Compounds of the formula X in which a1 denotes sue thyl, the side-chain of lysine, which may te acylated, or the O-olkylated aide-chain of tyrosine, a3 denotes hydrogen, methyl, ©thyl or teasyi, s denotes phenyl, or phenyl which is mono- or di-substituted by fluorine and/or chlorine, Y denotoe hydrogen or hydroi-ryl ©nd 2 denotes hydrogen, or Y ©nd § together denote oxygen, are preferred* Xf &x represents a side-chain of a protected naturally occurring «-amino acid, such as, for example, protected Ser, Thr, Asp, Is», Glu, Gin, Arg, X/ys, ^yl, Cys, Oct, Cit, Tyr, ®sp or Sie, th© group© customary in 30 peptide chemistry are preferred as protective groups (ef * Houben-tssyl, Voluas 07 X and W/2). In the case where Hx denote® the protected lysine side-chain, the known amisao^ protective groups are preferred, especially (£ι~€^)~ alkmaoylo Preferred ^-protective groups for tyrosine ©re methyl and ethyl» Possible salt® are, in particular, the hydrochlorides, meleatos and tartrates, and the alkali metal, Cs, &£g md Sn salts.

The centers of chirality on the carbon atoms labeled a star (®) In the chain and on carbon atom of the bicyclic ring system can hove either the R·» configuration or the ©-configuration. However, compounds in which these centers are in tho ©“configuration are preferred. Xf represents Cy^ hwm?f the Reconfiguration of thi^; center Is preferred e Th© invention furthermore relates to a process for the preparation of the compounds of th© formula X, which comprises reacting a compound of the formula XX in which X, Y, £ and Rl are as defined above and R* has th© abovementioned meanings, with the exception of hydrogen, with a compound of th© formula XXXa or XXXb, in which &7 denotes a corbo&yl-esterifyiag group, such as (Gi~C$)^ alkyl or (C7-Ca) -aralkyl, preferably tert. -butyl or IS benzyl, by the known ©mid© formation methods of peptide chemistry, and then liberating the compounds of type ϊ by hydrogenation or treatment with an acid or/and base and, if appropriate, converting the compounds obtained into their physiologically tolerated salts. ri g RX x - c - ch9 - ch - m - ra θ co2h I ’ I , y C0aR« (XX) H w2e m (XXX©) (XXXb) Coapounde of the formula XX ia whleh '& is phenyl, Y is Η, Z is H and R is CH^ 0^¾ are known (for exanple from Patent Specification No. 52663) and are accessible in various ways.

$ The benzyl eatera (R3 « bansyl) can be prepared analogously.

Xt hes furthermore been found that the Mannich reaction of acetophenones of the formula XV©, in which X represents aryl which in optionally substituted as described above, with glyosylic acid esters and a® amino acid esters leads to compounds of the formula XX in which 1Γ and g together denote oxygen (formula XU). Hydrogenolysis of these compounds with ?d gives compounds of the formula XX in which Y and $ aro hydrogen.

Compounds of the formula XX in whieh Y and £ together denote ossygen can also be obtained in high yields by Michael addition of corresponding keto-acrylic acid esters with ©-amino acid esters. Ester cleavage leads to the same products as the Mannich reaction.

Th® invention relates therefore also to a process for the preparation of compounds of the formula XX, in which X, Π1 and a3 have the meanings defined above, Y denotes hydrogen or hydro&yl and g denote© hydrogen, which comprises a) if X is aryl, reacting aryl methyl ketones with glyoKylic acid esters CH0-C0aR2 aad ©-amino acid esters Η^-ΌΗ(R*) in which W is a radical which can be split off by basic or acidic hydrogeno25 lyaie, preferably beasyl or tert.-butyl, and Ss does not denote benzyl or nitrobengyl if W* is bensyl, to give compounds of the formula XV.

C0gR2 RX I I ι j·^·» x - co - ch2 - cb - nb - ca - co2w· * in which X, w*, a1 and si have the meanings given above^ or b) reacting k©to-aerylic acid esters X-CXM9S ® C^-CO-rf with ©-amino acid ^stares SH2^-CB(^')-C03^r to give compounds of the formula X^, if appropriate, subjecting these compounds obtained 35 according to a) or b), if w* is a radical which can be split off under acidic or bunic conditions, to acidic or basic ester cleavage, or, if τ$· is bensyl or nitrobensyl (R2 bensyl or aitrotoasyl), converting these compounds into the carboxylic field by hydrogenolysis end hydrogenating the products to give compounds of the formula XI in which X, Rl end R2 have the above meaning, Y denotes hydrogen or hydroxyl and S denotes hydrogen, or the lower alkyl esters thereof, which? if appropriate? can also bs subjected to aeid-catalyeed ontor cleavage.

X « C - CH a CH θ CO2R2 - θ CH - CQ^’ «— When S-alanine esters are used, the diastereomers with the preferred S,S-con£iguration ar© predominantly formed, and can be isolated by crystallisation or by chromatographic separation of the ©stew of XX on silica gel.

The new compounds of the formula X have a longlasting, intense hypotensive action. They are powerful inhibitors of th© angiotensin-converting ongy?na (££B inhibitors) and can be used for controlling high blood pressure of various origins. They can also be combined with other hypotensive, vasodilating or diuretic compounds . Typical representatives of theae elasse^ of active compounds are described in, for example, BrhardtRuschig, ^rsaeimittol (Medicaments), 2nd edition, Woia* helm, 1972. They can be administered intravenously? subcutaneously or perorally.

The dosage for oral administration is 1 - 100 mg per individual dose. Xn sever© cases, it cm also to increased, since no toxic properties have a® yet toon observed* Xt is also possible to reduce the dose, which is appropriate, above all? if diuretic agents are administered at the same time* The compounds according to the invention can to administered orally or parenterally in an appropriate pharmaceutical formulation, j^or an oral use form, tto active compounds are mixed with th© additives customary for this such &0 excipients, stabilisers or inert diluents, end the mixture is converted to suitable administration fossa®, such ©s tablets, coated tablets, push-fit capsules, aqueous, alcoholic or oily suspensions or aqueous, alcoholic or oily solutions, by customary methods. Example® of inert carriers which can be used ar© gum arabic, saagnecsiun carbonate, potassium phosphate, * lactose, glucose and starch, especially com starch. ’She formulation may be prepared in the form of either dry or moist granules. of possible oily excipients or -4 solvents are vegetable and animal oils, such as @nnflo^©r oil or cod-liver oil.

For subcutaneous or intravenous ac^aiais tration, 15 the active compounds or physiologicallx^ acceptable enltu thereof ere dissolved, suspended or emul&liled, if desired with the substances customary for this purpose, such as solubilising agents, emulsifier® or other auxili~ arias, examples oi possible solvents for the novel active compounds and the corresponding physiologically acceptable salts are? water, physiological sodium chloride solution® or alcohols, for example ethanol, propanediol or glycerol, and in addition also sugar solutions, such as glucose or mannitol solution®, or a mixture of the various solvents mentioned.

The exceptionally powerful activity of compounds according to the formula 1 - even when ed« ministered orally - is demonstrated by the following pharmacological data.

Intraduodenal administration to anesthetized rats, 50% inhibition of the pressor reaction induced by 3X0 ng of angiotensin X, 30 minutes after administration of the dose eo.ED^, £ Y £ &1 a» so,, (pe/ke) C6H, O CH, CK, 350 CeK, - 0 CHj c,a3 200 C6Hs 0 CH, & 720 CeHa - 0 CH, CA 250 c6H3 H OH CH, CA 380 P^Cl-CgHi, H H CH, ca 55 p-Cl-CeH0 «a 0 ca, 780 The examples which follow ©re intended to illustrate the procedures according to tto invention, without restricting the invention to the substances mentioned here as representatives.

Reference S&sasspl© - (N- (1 -S-Carbethoxy«3-phenyl-propyI) ~S-©lanyl ] -2-cis, endo^az&bicyclot3.3.0]octane-3®S~carboxyli6 ecid (1) Methyl 2«acetylaxaino-3® (2-oso-cxfClopentyl) propionate?. 26© g of methyl 3«chloro-2“&cetyXssiino-propion&t© and 257 g of cyclopeatenopyrrolidine ia X.5 liters of dimethylformamide are kept at room temperature for 24 hours. The mixture is concentrated in vacuo, the residue is taken up in a little water and the agueous mixture is adjusted to pH 2 with concentrated hydrochloric acid and extracted twice with 4 liter portions of ethyl acetate. On concentration of the oj^gaaie phase, a light yellow oil remains.

Yields 350 g. nms 2.02 (CSCX3) Analysiss C £5 calculated 58.1 7.54 0.1S found 58.5 7.2 i.S . (2) cis, endo-2-toebicyclo( 3.3» 0 ]octaM-3-cestogylle ^cid hydrochloride 270 g of the acetylmino derivative prep$r©d under (1) are boiled under reflux in X«5 liter© of 2 I? hydrochloric acid for 45 minute®· The mixture is concentrated in vacuo, the residue is taken up in glacial acetic acid, 5 g of Ft/C (10% of £t) ar© added and hydrogenation is carried out under 5 bar. After filtra5 tion, th© mixture is concentrated and th© residue is crystallised from chlorofosm/diisopropyl ether.

Melting points 205 - 2O9‘”C, Yields ISO g (3, Benzyl cis ,©ndo-2*ozobicyclo( 3.3. OJoccane-J-e&gbos^10 late hydrochloride g of the c&rbogylic acid prepared under (2) ©re added to an Ice-cold mixture of 390 g oi benzyl alcohol and 55 g of thionyl chloride and the mixture is left to stand at room temperature for 24 hours. After concentration in vacuo, 47 g of th© benzyl ester ar© crystallized from chloroform/Isopropaaol.

Melting points 175®C (hydrochloride) (4) Benzyl 2- ['$- (2 -S-carbethoxy-3-phenyl -propyl) *-8alanyl) -cis, ©ndo-2-azabicyclo [3.3.0]octane-3*S® carboxylate g of the benzyl ester prepared according to (3) are reacted with 6.7 g of SSOBt, 13.0 g of 8®(1~S~ carb©thosy-3-phenyX~propyX)-S-aX&nin© aad 10.2 g of dicyclohexylcarbodiimlde in 200 ml of dimethylformamide.

After the mixture has been stirred for 3 hours at room temperature, th© dicyclohexylurea which has precipitated is filtered off with suction, the filtrate Is concentrated, the residue is taken up in 1 liter of ethyl acetate and the mixture is extracted fry shaking with 3 κ 500 ^1 of 5 per cont strength $u§sCO9 solution. The organic phase is concentrated and the residue is chromatographed over a column of 1 kg of silica gel using ©thyl acetate/petre® leum ether in the ratio 2 ΰ 1. Th© isomer eluted first is th© S,S,S-compound, and concentration of a later eluate gives the s,S,^-compound.

Xn each case 0.0 g of product are obtained as an oil. was of the 3,3,^compounds characteristic signalss 1.20 (d,3H), 1.27 (t,2H), 4.17 (<3,3g3), 5.13 (s,2S3), 7.10 (s,5H) and 7.32 (s,5H) (CDCl,, Analysiss C SS N C„H38M2O, calculated 71.1 7.56 5.53 found 70.Θ 7.Θ 5.7 (5) 2»[Μ-(2-S-Carhethoxy-3-pheayl-propyl) -S-olanyl) ~ cis,endo-2«as&hicyel©[3.3.0 Joctsns-3-g-carboxylic ecid Θ.0 9 of the L,L,L-b®nsiyX ester from (4) are dissolved in 100 ml of ethanol and ere debeatylated hydrogeaolytically under normal pressure, with addition of 0.5 g of X0r3 Pd/C. This reaction can also be carried out under pressure, together with a shortening oi the reaction time. After the calculated amount of hydrogen has been taken up, the catalyst is filtered off and the residue is concentrated in vacuo. The switterioa crystal» Uses from ether, la almost quantitative yields Melting points 110 - 112“C (decomposition) A hydrochloride (decomposition from 120*0) cen be obtained by addition of an equivalent amount of hydro» chloric acid, or a sine complex salt which is particularly stable to heat (decomposition above 160®C) can be obtained by addition of aqueous sine salts to a concentrated saethanolic solution of the title compound. Analysiss C Β H C23H3AO3 calculated 66.3 7.7 6.73 found 66.1 7.0 6.6 The M and mass spectra obtained are in agreement with the given structure.

[B « 15-6® (c 1, methanol)° Example X (1) tert. -Butyl cis ,endo-2-asabicyclo[ 3.3.0 loctan^-^carboxylate g of a£ebicyeio[3.3.0]octane~carbo&yXie odd hydrochloride from the reference example are reacted with 250 ml of isobutylene and 25 ml of concentrated sulfuric ecid in 2S0 ml of dioxane. After 14 hours at roo® ts^eraturs, the mixture is rendered alkaline with sodium hydroxide solution and concentrated in vacuo, 100 sal of water ar© added and the ester ifl extracted with ether. Evaporation of the other gives 15 g oi a colorlesa oil.

Analysiss C C uHsiHOa calculated 63.2 found 67.5 H M .2 6.63 .1 6.3 {2) Ν- (l-S-CarbobentylOKy-3-oiso-3-phenyl-propyl) alanine tert.-butyl ester 12.0 g of acetophenone, 17 g of benzyl glyoxylat© and 31.7 g of alanine tert.-butyl ester tolueaesulfonate are heated to 45 - 50C in 200 ml of glacial acetic acid for 24 to 40 hours o The reaction is monitored by thin layer chromatography and is interrupted at th© optimum reaction point. The mixture is concentrated thoroughly in vacuo, th© residue is rendered basic with aqueous bicarbonate solution and th© mixture is extracted with ethyl acetate. Th© organic phase is concentrated as substantially as possible and the 3,§-isomer is crystallised from cyclohex&ne/petrolenm ether. The a,S-compound remains substantially in solution□ To obtain seed crystals, chromatography of tho crude mixture on silica gel in a 2 § 1 cyclohexane s ethyl acetate system to which 0.1¾ of triethylamine has been added is advisable. The 8,Scompound is eluted as the second of th© two diastereomers and is obtained in the larger amount. 5 g ar© obtained. Analysis s C B H C24H2ftM)3 calculated 70.1 7.1 3.4 found 70.0 6.5 3.5 (3) Bl- (l->S-Carbob©nsyloxy-'3“OMO«3-phQnyl-propyl) -salanine trifluoroacetat© g of th© Mannich condensation product rrom X (2) are dissolved in 25 ml of anhydrous trifluoroacetic acid and the solution is left at room temperature for one hour. The solution i© concentrated in vacuo, diisopropyl eth&r is added and th© oroduct is precipitated ^?ith petroleum ©ther. 7.2 g of obtained.

Analysis s CaaBaaMb&'a calculated found molecular weights 465 an amorphous siubstane© ar© S3 Λ °s °3 · I 4.0 C 56.3 56.0 3.Θ 3.1 XO is (4) tert. -Butyl 2«[^®(l-S-CErbobensylO3sy-3-oxo-3«phenylpropyl)-S-aXaayl l-2-cig,ondO“asafoicyelo[ 3.3.0]oct~ ane-3-carboaylate .5 g oi the ^-substituted alanine from X (3) are reacted with 21.1 g of the tort.«butyl asabicyclo® octane-carboxylate from Example X (1) analogously to th© reference example (4). Chromatography over silica gel gives 20.3 g of th© title compound.

Analysiss C $ C32H40^2Og calculated 70.04 7.35 5.10 found 55.5 7.4 5.3 (5) 2- [M-> {l»s-Carbobdnzyloasy«3«oxo»3»plienyl»propyl) -8® alanyl]-2-cis,endo-asabicyclo[3.3.0)oetaa©-3-car® boirylic acid g of the tert.-butyl ester from X (4) are dissolved in 100 ml of trifluoroacetic acid and the solution is left to stand at room temperature for one hour,, The solution is concentrated in vacuo, the resin which remains is taken up in ethyl acetate and the mixture is neutralised with agueous bicarbonate. 14 g of the title compound are obtained from the ethyl acetate phase.

Analysiss calculated found C 68.27 58.1 S3 6.55 .4 >5 .65 .7 (5) 2- [M® (l<-*S®Carboagy«3«R, 8*->hydxoxy«3->phenyl ®propyl) -8® elanyl ] -cis, ©ndo-asabicyclo[ 3.3.0 ] octane-3-carboxylic acid g of 2-[tf-(l~S-ea?bobensylo2sy-3~cuso-3-pto9)ylpropyl) -S-alanyl )<-’Cis,endo®2-asabicyelo[ 3.3.0 3octane®3“ carboxylic acid are dissolved In 50 ml of ethanol, 150 mg of PdZBaSOs, are added and hydrogenation is carried out under normal pressure. After the calculated amotmt of hydrogen has been taken up, the mixture is filtered, the filtrate Is concentrated and th© residue le chromatographed ow©r silica gel ia th© solvent CQC18ZCS/XRZ(^CQO6 50 s 20 s 5.

Yields 0.5 g (7) 2®[^®(l«8-CarbobensyXoxy-3®R,S®hydroxy®3®pheayl® propyl)-S-&lmayl]~ciQ,en~2<»Asabicyclo[3'3.0 ]“ octene-3-carboxylic acid g of 2-[N-(l-S«carbobensyloxy-3-oxo»3-phenyl~ propyl) -S-alanyl ] -2“Cis, endo-azabicyclo [3.3.0 ) octane- 3carboxylic acid are dissolved in 50 ml of © mixture of acetonitrile and water and are reduced with 150 mg of After 12 hours, the mixture is concentrated to dryness, the residue is rendered neutral with dilute hydrochloric acid and the title compound Is extracted with ethyl acetate. To remov© boric acid and other impurities, the product is chromatographed over silica gel in the solvent CHC13 ,-ch3oh-ch3cg-oh 50 s 10 a 5 - Analysiss c H C2eH3^H2OQ calculated ©7.9© 6.93 5.56 found 67.7 6.6 5.3 General method for the preparation o f compounds of t formula X in which R3 is H by hydrolyls of esters g of the corresponding ethyl or benzyl ester of the formula X are dissolved in 200 ml of dimethossyethane. One drop of a dilute indicator solution, for example bromothymol blue, is added, and an equivalent amount of 4H KOH (aqueous) is added in the course of 5 minutes, while stirring vigorously, so that at the end of th© reaction the indicator Indicates a pH value of B ® . The mixture is then adjusted to pH 4 with hydro25 chloric acid and concentrated to dryness in vacuo, the residue is taken up in 250 ml of ethyl acetate and the mixture Is filtered. On concentration of the ethyl acetate, the dlcarboxyllc acids precipitate as solid, crystalline or amorphous compounds« The yields are between @0 and 95¾.

XX N- (l-S‘-Cerbethojsy-3-oxo-3“phenyl-*propyl) -S-alanine bm&yl ester 65.7 g of ethyl 3-phehyl-3-omo-l-psopeM“l carboxylate (ethyl beasoylac&ylete) are dissolved in 225 ml of ethanol, and 1 ml of triethylamine is added. A solution of 70 g of S-alaain© bsasyl ester in 90 ml of ethanol 1© rapidly added dropwise to this solution at room temperature. The mixture ie stirred at room temperature for 2 hours and the solution is then cooled. The S,S-isomer crystallises out.

Yields 94.3 g Melting points 73 - 74 *C [a]/0 = * 17.8’ {c ® 1, CHjOH, Bxcytnple XXX N- {i-s-’CarbQthoxy«3-'O3£O-3-phenyl-psopyl) “S-alanine 0.5 g ox the compound from Example XX is di#solved in 40 ml of ethanol, 0.1 g of 10% Pd/C is added and hydrogenation io carried out at room temperature end under normal pressure.

Yields 300 mg Melting points 210 - 220‘C lH4W (DMSO-d6) s 1.0-1.4 (t,SH); 3.2-5.0 (SJ,8H); 7.2-8.2 (m,5M) Example XV Benzyl 2-[N-(l-S-carb®thoxy-3-o&O“3-phenyl-propyl) -5alanyl J -cis, endo-2~es$Lhieyclo[ 3.3.0 )octan©-3-S^carbo^ylate The compound is prepared from benzyl cis,endo-220 azabicyclo[ 3.3.0 ]oct&ae-3~S*-carbojsylat© hydrochloride and N« (X-S-cartethory®3’OJiO“3«ph©nyl*i’propyX)-S-alaniae from Example XXX, analogously to the process described in reference example (4) * Ssasple v 2- [M- (I-S-carbethoxy-S-oxo'sJ-’phenyl -propyl) -S-alaayl J cis,endo-2-azebIcycXo[3.3. 0]octane-3-S-carbos^ylie acid g of the bensyl ester from Example iv is dissolved in 30 ml of ethanol and hydrogenated with 100 mg of Pd/C (10%) at roo^ temperature and under normal pressure. After one mole equivalent of hydrogen has been taken up, the hydrogenation is interrupted. Th© catalyst is filtered off with suction and the solution i® concentrated.

Yields 600 mg of an oil. lH~mi (DMSO-dJs 1.0-3.0 3.3-5.0 (m,10^)g 7.2-B.l (m,5&) SxeqpXe vx 2- ί (l-S-Carbethoxy“3‘-phenyl-propyl) «S®lysyl)-cis e endO“2“©sabicyclo( 3.3.0]octane-3-@-casbomylic acid dihydrochloride (1) (l-S-Carbethojjy-3-oxo-3®pheayl -propyl) -Na-ben« syloxy-carbosiyl-S'-lyeinc bensyl ester g of ethyl 3-phenyl-3“Oxo-l-propene-l-carboxy™ lat© ar© dissolved in 100 ml of ethanol. 19.1 g of H, bensyl oxycarbonyl-S-lysine bensyl ester and 0.2 g of triethylamine are added. The solution is stirred at room terapcrcture for 3 hours and is then concentrated in vacuo o Tha oily residue (31 g) is dissolved in iso» propanol/diisopropyl ether and the solution le cooled. 13 g of &V( l-S-cftrbettoKy-S-omo-a-ptonyl-presylJ-Rebensyloxycarbonyl-S-lysino bensyl eetor crystallise. o0w « 3.5“ (c - 1, CHjOH) (CDCl3)s 1.0-1,4 (tr, 3E3); 1.0-2.0 (m,9H); 2.0-2.5 (broad a., 123)? 2.9-3.9 (m,6H)2 3.9-4.4 (quadr., 2H); 4.6-4.9 (broad s., IH); 5.0-5.2 (double &·, 4H); 7.1-0.1 (sn,15R) {2) »e- (X-3-Cartothoxy~3“phenyl~propyX) «-^-beassylosycarbonyl-S-lysine 4.0 g of the lysine bensyl ester derivative prepared in Example VI (1) ar© dissolved in 50 ml of glacial acetic acid, and 0.6 g of ?d/C (10%) and 0.6 g of concentrated sulfuric acid ©re added. hydrogenation is carried out at room temperature and under normal pressure for 6 hours. The catalyst its then filtered off with suction and the ethanolic solution is stirred with 1.4 g of solid sodium bicarbonate. The solution is concentrated on a rotary evaporator and the residue is dissolved in water. The aqueous phase is extracted with ethyl acetate and methylene chloride. The organic phases are discarded and the aqueous phase is evaporated to dryness in vacuo. The residue is extracted by stirring with methanol. After the methanol has been evaporated off, an oily residue remains, which solidifies when treated with diisopropyl ether. Yield of (X-8<^&rteth©xy«3-ph©ayX-prepyI) «Β» Xysi&ea 2.0 g lH-W3a (OgO)s 1.0-1.4 (tr, 3^); 1.0-2.S (a,9H); 2.S-4.4 (m, 9$)*! 3.9-4.4 (q, 222) g $-5-5.0 (m, IH)? 7.1-7-0 (m, SB) m/es 330 3.4 g of Me“(l~S“C&rb©thoxy-3-phenyl-propyl)“S“ lysine are dissolved in 30 ml of methylene chloride end the solution in cooled to 0 C. While cooling with ice, 2.1 g of triethylamine ore added, and 1.9 g oi bensyl chloroformate are then added dropwise. The mixture is stirred at 0 C for 1 hour and is then brought to room temperature · The methylene chloride solution is extracted by shaking successively with water, sodium carbonate solution and water. After the product phase ha® bse^ dried, it is concentrated and the oily residue is chromatographed over silica gel using methylene chloride/methanol. 2.0 g of ^,=-(l-S-carbethoxy-3-pheayl“ propyl j-^-beasyloxycarbonyl-S-lysin© ar© obtained . lH-HMR (DaO)s 1.0-1.$ (tr, 3H)? 1-0-2.5 (m,9B)? 2.5«$.$ (m, 9H)? 3.9-$.$ (g, 2H)? $-5-5.0 (m, 1S2)? 3.1 (a, 2H)? 7.1-7.5 (m, 10B) (3) Bensyl 2-[&V (l«S-casbothoxy*3-phenyl-propyl) bensyloxycarbonyl«S-lysyl ] -eitf, endo-2-asabieyclo [3.3.0]« octane-3-S-cerboxylate a) 560 mg of bensyl 2-©sabicyclo[3.3o0]octan©“3=· carboxylate hydrochloride prepared according to reference example (3) are reacted with 940 mg of ^,-(l-S«carbetho^y« 3-phenyl-propyl) -Jftd~bsasyloxyearbonyl-S~lysi&© prepared according to Example VI (2), analogously to rsf^ronee example (4). z^ftor tta mixture ha® been worked up, 1.5 g of aa oil, which le a mixture of two diastereomoric compounds, ore obtained.

The diastereomer mixture 1® separated into tte individual components bjf column chromatography with silica gel and cyc lohexane/ethyl acetate 2 si a© the ©luting agent. Th© isomers eluted first ar© th© above compound®. 0.0 g of an oil lo obtained.

(C3CX3) (after replacement of H by O with Dg0) a 1.0-2.6 (m, 20H)? 2.6-4,5 (m, 8S2)? 4.6-SoO (ra, 2$)? 5.15.3 (double 8., 48)? 7.1-7.6 (m, 15B) b) Th© later eluate give© 0.4 g of bensyl 2-[SV(l“ S=c©rbethoxy®3-phenyi-propyl) -^-bensylo^ycExbonyl-SlysylJ-cΙα ,endo-2-©aabicyclo[ 3.3.0 ]octane-3-RCarbossylate.

'H-WKR (COC13) (after replacement of H by 0 with 030) s 1.0-2.6 (m, 20B*); 2.6-4.4 (xa, OH); 4.5-5.0 (m, 2H); 5.15.3 (double a., 4&i); 7.1-7.5 (ra, XSH) (4) 2 - [ XV (l»S«Ca?teth0xy-3~pfcesiyl~propyL) -S- lysyl ] cis rendO’2-asabicyclo( 3.3.0 ]octaM'*3-*S«€iorboMylic acid dihydrochloride 500 rag of bensyl 2-[%-( l-S-csrb©thoxy-3-ph©nylPropyl) -N'.-bensylosyc&rbonyl-S-lysyl 3 -cie, ©ado-2-szabi cyclo(3.3.0]octeae*3-S-carboxylet© from Example VX (3©) ©re dissolved ia 20 ral oi ethanol and ©re debensylatod hydrogenolytically under normal pressure, with addition of 0.1 g of 10¾ Pd/C. Whoa the uptake of hydrogen has ended, the catalyst Is filtered off, ethanolic hydrogen chloride solution is added to the ethanolic solution until a pM of 1 is reached, and th© ethanol is evaporated off in vacuo. Dllsopropyl ether is added to the residue, whereupon the product solidifies. 200 rag are obtained. hl-MtB of the betaine (CDClj, after replacement 1.0-2-5 (m, 20H)j 2.6-4.4 (ra, ©S3) g of B by D with D3O) s 4.4-5.1 (ra, 7.2 (s, 5H) 2H)j Example VXX 2-[^-(l-S-C©zbetho^y-3-phenyl=>propyl)-S-lysylJ-cis,endo® 2“ias«iblcyclo(3.3.03octaae^3«R-carbossylIc ©ciddlhydrochlorids 0.3 rag of the corresponding bensyl ester from Example VX (3b) ar© reacted, and the mixture is worked up, analogously to Example vx (4). 110 rag oi th© carboxylic acid are obtained in the form oi the dihydrochlo35 ride.

Wm of the betaine (CDC13, after replacement of H by D with DgO) s 1.0^2.6 (ra, 2022)? 2.6-4.4 (ra, OH); 4.1-5.1 (m,2B); 7.2 (@, SE2) Ex^aXo l“^Carbosy-3-ph©ayi«pro^l)-^-lyBylj-cis,egido-2S8 azabicyclo [3.3. Ojoctene-3-S-carborylic acid hydrochloride 0.5 g of 2*»PV>(I-S-cartethO2 Yield 0.35 g lH-&m (Ds0) S 1.2-2.5 (m, 17H) ? 2.5-4.5 (m, SH)g 4.5-5.0 (m, 2H>? 7.2 (s, 5H) Bsas^le XM 2- [&V (X-S-CarteKy-3-phenyl-propyX) -S«Iyeyl J -cis ,®ndo-2asabicyclo[3.3.0 ]oct&n©-3~R-carboxylie acid hydrochloride 500 mg of 2-[i?V(i-S^eartethoxy-l-phenyl-propyl)20 $-lysyl]-cis,©ndo-2-asabicycl©[3.3.0]octan©-3-B-carborylie acid dlhydrochlorlde from Sample VXX ©re hydrolyzed, and the mixture is worked up, analogously to Example VXXZ.

Yields 0.32 g lH« (0a0)2 1.2-2.5 (a, 178) p 2.5-4.5 (m, 6E)g 4.5-5.0 (a, 28)? 7.2 (s, 5H) Bwasapl© X 2“t^“(l^S-Carb®thosj2f“3'-’phes,syl«“propyX)-0^eth2yl«S-txiro3yl3“ cis,@ado-2*=*©3abieyelo[3.3.0 ]octosKB^3«S<-carboBylic acid (1) S- (1-R, S-Ccrbetho^-3-pteayl-propyl) -O-ethyl-Styrosine beasyl ester g of ethyl benzoyl acrylate in 100 al of ethanol ar© reacted with 30 g of O-othylMS-tyroeine benzyl ester in th© presence of 0.5 ml of triethylaain© analogously to Er.mpXo χχ end 42 es of th© ^,S-componnd are obtained after concentrating the solution sad digesting the residue with diethyl ether /petroleum ether (lsl) and drying in vacuo. (2) &-> (l«n, S-Corbethosy-3-phenyl-propyl) ~O«©thyI~S“ 9 tyrooine g of the compound obtained according to & (1) ere hydrogenated at 100 bar and at room temperature in 800 ml of acetic acid containing 4 g of Pd/C (10%) .

Yield after chromatography on silica gel in the solvent ethyl acetato/cycloh&xan© (1§3) and drying of the evaporation residues 25 g of the title compound which is nearly uniform by thin layer chromatography.

Melting points 205-213°C. i0 C23H30M>3 (399.5) Calc. C 69.15 Ή 7.31 N 3.50 Found C 69.5 % 7.4 K 3.3 (3) 2-(N-( lwS-Carb©thoxy*3-phenyl-propyl)-0-ethyl‘»§tyrosyl ] -cis, endo-2-as&bicyclo[ 3.3.0 ]octane*»3<»S»cer· boxylie acid g of the free benayl eater obtained according to reference example 3 and after extraction from alkaline solution by shaking with diethyl ether is reacted with 8 g of the compound obtained according to $ (2) by m©ans of 4.4 g of dicyclohexylcarbodiimid© in the presence of 2.7 g of l*»hydroxy«bensotrlazole analogously to the reference example (4). After carrying out the chrosiatography described under reference exanple (4), 2.9 g of oily benzyl ester are obtained as aa intermediate* The lB~ NMR spectra end the maos spectra are in agreement with th© structure indicated* The benzyl ester is catalytically hydrogenated under normal pressure on Fd/c in 50 ml of ethanol. After filtering off the catalyst and removing the solvent by distillation, a solid residue remains which is digest30 ed with diethyl ether/petroleum ether and dried.

Yields 2.2 g.

'H-Nm (COCl3)a 1.2-3.0 (m, X32S)s 1.27 (t, 3M); 1.4 (t, 3B>) 3.0-4.3 (m, ffi)? 3.8-4.2 (m, 40); 6.5-7.1 (2d, OJ? 7.3 (s, 5B) Sxesple Χϊ 2- [M- (l-S-Carbethoxy-3-pheayl-propyl) -O-^thyl-S-tyrosyl]-cis ,endo-2-eeablcyclo( 3.3.0 ]octane~3«S-ca«baxyllc acid The procedure is a© described in Example X, but O-Methyl-S-tyrosine benzyl ester Is employed in the step analogous to X (1) and the title compound, the spectrum of which is in agreement with the structure indicated, is obtained. *

Claims (7)

1. Recent Claims

1. A compound of the formula X ϊ a 1 I · I ' X- C - CH- θΟΗ « NH - CK - CO - H - CH - CH 2 I u, * c' 5 1: U 2 /\/\/ SOOC CHg CK 2 in which th© hydrogen etoms on the bridge-head carbon atom© 1 and 5 ar© in the eis«configuratioa relative to one another and the carboxyl group on carbon atom 3 is orientated in the endo-position relative to the bicyclic ring system (i.e. towards the cyclopentane ring), and in which » R 1 denotes hydrogen, allyl, vinyl or a sidechain of a naturally occurring e^aminoacld CH(M 2 )®C00H, which may be protected, R 3 denotes hydrogen, (C 1 -C s ) «alkyl, (Co-C#)altonyl, aryl «(Cp-CJ «©lkyl or nitrobenzyl, Y denotes hydrogen or hydroxyl, and £ denotes hydrogen, or Y and £ together denote oxygen, and X denotes (Cx-C e )-alkyl, (C 2 «C fl )-alkenyl, (C 3 C fl )CyeloaXkyi, (C 0 «C 12 )«-aryl, which cm be mono-, di- or tri®substituted by (€.«04 = alkyl, (Cj-CJ-alkoxy, hydroxyl, halogen, nitro, amino, (C^-CJ«alkylamino, di-(C x -C4~ alicylamiao or saethylenedioxy, or denotes Indol-3-yl, 25 and physiologically acceptable salts thereof, compounds of the formula X being excluded in which the centers of chirality on the two carbon atoms labeled with a star (*) ia the chain aad oa carbon atom 3 of the bicyclic ring system are present ia the S-conflguration ead in which R l R 2 Y z X denotes methyl denotes hydrogen, methyl, ethyl or benzyl, denote® hydrogen, denotes hydrogen and denotes phenyl.

2. A compound of the formula ί as claimed ia claim 1, in which R l denotes methyl, the side-chain of lysine, which may be acylated, or th© 0-alkylated side-chain of tyrosine, R 2 denotes hydrogen, methyl, ethyl or benzyl, X denotes phenyl, or phenyl which is mono*- or di-substituted by fluorine and/or chlorine, Y denotes hydrogen or hydroxyl and Z denotes hydrogen, or Y and £ together denote oxygen.

3. &-<πθ( l-S-Carbethosy“3-phenyl-propyl)-S«lyeyl-cis,endo-2-asabicyclo[ 3.3.0]octano-3-S-carbo^lic acid and physiologically acceptable salts thereof.

4. X-S-Carboxy-3-phenyl-propyl) -S-lysyl-cis ,©ndo~ 3-asabicyclo[3.3.0Joctaae-3-S^carboxylie acid and physiologically acceptable salt® thereof.

5. N-(X-S«Carbethoxy~3-ph©nyl-propyl)-O-ethyl-Styrosyl-cis ,©ndo*-2“asabicyc!o[ 3 □ 3.0]octane«3-8“carboxylic acid and physiologically acceptable salts thereof.

6. ^-(l«S-Carbethoxy«3-phenyl-propyl)-0-methyl-8ty£O8yl~ci8,encto~2'»fi2abicyclo[3o3.01octane-3-Scarbossylic acid and physiologically acceptable salt® thereof.

7. A process for the preparation of a compound as claimed in on® of claims 1-6, which comprises reacting a compound of th® formula XX in which g, γ, 2, R 1 and R a have th® meanings defined in claim X, with th© exception that R 2 cannot bo hydrogen, with a compound of the formula XXXa or