CA1193607A - 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

Abstract

Abstract of the Disclosure Compounds of the formulae IIIa and IIIb

Description

~ ~3~

2 -This application is a divisional of Canadian Patent Application serial number 414,858 filed November 4, 1982.
The ;nvention relates to der;vatives of cis,endo-azab;cyclo-C3~3.0]-octanecarboxylic acid of the formula I

Y R
*
X-f-CE'2-CH ~ NH - C~ - CO ~ N - CH - C~12 ~I3 /\/ \/
I]OOC CH2 CH2 ~n ~hich the hydrogen atoms on the bridge-head carbon atoms 1 and 5 are ;n the c;s-conf;gurat;on relat;Ye to one another and the carboxyl group on carbon atom 3 ~s or~enta-ted in the endo-posit;on relative to the bicyclic r;ng system, and ;n ~h;ch R1 denotes hydrogen, allyl~ vinyl or a side-chain of a naturally occurr;ng ~-am~noac;d R1 CHSNH2)-COOHo wh;ch may be protected, R2 denotes hydrogen, ~C1-C6)-alkyl~ tC2~C6)-alkenyl or aryl-tC1-C4)-alkyl, Y denotes hydrogen or hydroxyl and Z denotes hydrogen, or Y and Z together denote oxygen, and X denotes tC1-C6)-alkyl, ~C2-C6)-alkenyl or (Cs-C9)-cycloalkyl, or tC6-C12)-aryl~ preferably phenyl, ~Ih;ch can be mono-, di- or tr;-substltuted by (C1-C~)~
alkyl, t~ -C~)-alkoxy, hydroxyl, halogen, nitro,

3 -aminn, ~C1-C4)-alkylamino, di-~C~-C4~-alkylamino or methylencd;oxy, or denotes 1ndol-3-yl~
and phys;ologically acceptable salts theresf.
Compounds of the formula I in which R1 denotes methyl, the side-chain of lys~ne, ~h;ch may be acylated, or the O-alkylated side-chain of tyrosine, R2 denotes hydrogen, methyl, ethyl or benzyl, X denotes phenyl, or phenyl wh;ch ;s mono- or di-subst;tuted by fluor;ne and/or chlorine, Y denotes hydrogen or hydroxyl and Z denotes hydrogen, or Y and Z together denote oxygen, are preferred.
If R1 represents a side-chain of a proeected natur-ally occurring ~am;noacid, such as, for example, protected Ser, Thr, Asp, Asn, Glu~ Gln, Arg~ Lys, Hyl, Cys~ Orn, Cit, Tyr, Trp, His or Hyp, the groups customary ;n peptide chemistry are preferred as protective groups tcf. Houben-~eyl~ Yolume XV/1 and ~V~2)). In the case where R1 denotes the protected lysine side-cha;n, the known amino-protective ~roup~ are preferred, espec;ally tC1-C6)-aLkahoy~D Preferred O-protective groups for tyrosine are methyl or ethyl, Poss1ble salts are, in particularO the hydro~
chlorides, maleates and tartrates, and the alkali metal, Ca, Mg and Zn salts.
The ch;ral;ty centers on the carbon atoms labeled with a star t*) in the chain and on carbon atom 3 of the b;cyclic ring system can have e;ther the R-conf;gura~;on or the S-conf;guration~ However, compounds ;n wh;ch these centers are in the S-configuration are preferred~ If 3~

- 4 --NH-*CHRl-C0~ represents Cys, however, the R configuration of this center is preferred.
~he invention furthermore relates to a prooss for the preparatlon of the compounds of the formula I, which compr;ses reacting a compound of the for~ula II in ~h;ch R2 has the abovemen~;oned mean;ngs, w;th the exception o~ hydrogen, w;th a compound of the formula IIIa or IIIb, ;n ~h;ch W denotes a carboxyl-esterifying group, such as ~C1-C6)-a~kyl or (C7-C8)-aralkyl, preferably tert~-butyl or benzyl, by the known am;de formation methods of pept;de chemistry, and then l;berating the compounds of type I by hydrogenat;on or treatment ~;th an ac;d or/and base.

I' I
X C - CH2 - CH -- NH - CH - C02H ( I I ) Y,C02R

H
HN _,p _ , ~O2C ~ ~IIIa) Hl~
wo2c ~J'~,J
(IIIb) Compounds of the formula II in wh;ch X is phenyl, Y is H, Z ;s H and R2 is CH3 or C~H~ are known (for.
example from European Patent 0,037,231), and are access;ble iL~9~1~V7 ln various ways. The benxyl ester ~R2 - benzyl) can be prepared analogously~
It has furthermore been found that the Mannich react;on of acetophenones of the formula IVa~ in ~h;ch X
represents aryl which ;s opt;onally subst;tuted as des-cribed above, w;th glyoxylic acid esters and ~-aminoacid esters leads to compounds of the formula II ;n ~hich Y and Z together denote oxygen (formu(a IV3. In formula IV, W' denotes a rad;cal which can be split off by bas;c or acid;c hydrogenolysis, preferably benzyl or tert~-butyl~
X represents aryl wh;ch ;s optionally substituted as des-cribed above and R1 and R2 have the abovement;oned mean ings. However, ;n the case of the benzyl ester (~' =
benzyl)~ R2 may not be benzyl. Hydrogenolysis of these compounds ~ith Pd gives compounds of the formula II ;n uh;ch Y and Z are hydrogen~

R

X-CO-CH3 ~ CHO H2N-CH-C02W' CO R2 R1 C02R ~ X-CO-C~i2-CH-N}I-C~-C021~ ' IVA IV
Compounds of the formula II ;n which Y and Z
together denote oxygen can also be obtained in h;gh yields by M;chael addition of correspond;ng keto-acryl;c acid esters w;th ~-am;noacid esters. Ester cleavage leads to the same products as the Mann;ch react;on.

~L1936~

Il ~ . I .
X~C-C~l-C~-CO2R ~ ~H2 ~ CH~C02W' ~ V
~ hen L-alan;n~ esters are used, the d;astereomers ~th the preferred S,S configuration are predominantly formed, and can be ;solated by crystall;zation or by S chromatograph;c separat;on of the esters of II on si~lca 9~
It has furthermore been found that cis~ndo-2-aza-b;cyc~o~3.3.0~octane-3-carboxy~;c ac;d esters of the formulae III a and b are access;ble from enam;nes of cyclopentanone of the formula YI, in ~h;ch X1 represents d~alkylamino ~ith 2 to 10 carbon atoms or a radical of the formula VII, in ~h;ch m and o denote ;ntegers from 1 to 3, ~m + o) ~ 3 and A denotes CH2, NH, 0 or S, X1 (Vl) /-- 2--. m -N ~ ~VII) \-and N-acylated ~halogeno-oc-amino-carboxyl;c acid esters of the formula VIII, in which x2 represents a group which can escape nucleofugally, preferably chlorine or bromine, yl represents alkanoyl w;th l to 5 carbon atoms, aro~l with 7 to 9 carbon atoms or other protective groups which are customary in 3;3~ 7 pept;de chem;stry and can be spl;t off under acid cond;-tions, and R2 represents alkyl with 1 to 5 carbon atoms o~
aralkyi w;th 7 to 9 carbon atoms x2 C1~2 ~VIII) C~l y1 HN/ COOR2 or with acryl;c ac;d esters of the formula IX, in ~h;ch y1 and R have the above meanings, COOR2 ' C}12 C t I X ) \ N~

by react;ng these starting materials to give compounds of the formula X, ;n which R2 and y1 have the a~ove mean~ngs~

O ~ CH2 - CH ~X~
~ NH-~ 1 cycl;zing these compounds w;th the a;d of strong aclds, ~;th acylamide and ester cleavage, to g;ve compounds of t~e formula XI a or b 9;~

U~ N1 COOH
tXI) I OOH
H b convert;ng these ;nto compounds of the formula IIIa or b, in which W represents hydrogen, by catalyt;c hydrogenat;on in the presence of transition metal catalysts or by reduc-S tion w;th borane-am;ne complexes or complex borohydrides ;n lower alcohols, and opt;onally esterifying the products to give compounds of the formula III a or b ;n wh;ch ~
represents alkyi with 1 to 6 carbon ato~s or aralky~ ~ith 7 to 8 carbon atoms.
The b;cyclic am;noac;ds o~ the formulae IIIa and b have the cls,endo-conf;guration, i.e. the -C02W group faces the cyclopentane r;ng~ All the other 2-a7abicyclo-C3.3.0~-octane-3-carboxyl;c ac;d der;vatives ment;oned in the present invention are also ;n the cis,endo-confi~ura-15 t;on.
Examples of preferred enamines are pyrrolidino-cyc~opentene and morphol;nocyclopentene. ~ycl;zat;on of the alkylation products of the formula X is preferably carr;ed out with aqueous hydrochloric acid. The compounds of the formula III (in which W is H) can be esterif;ed by the methods customary for am;noac;ds ~cf. for example, Houben-Weyl, Methoden der organischen Chemie ~Methods of Organic Chemistry), Yolume VIII (1952)~, for example with ~936C~7 th;onyl chloride/benzyl alcohol or isobutylene/sulfuric acid. They g;ve, af~er appropriate work;n~ up, compounds of th~ formula III ;n the form of the free base or of a - salt~
The new compounds of the formula I have a long-lasting, intense hypotensive action. They are powerfu~
;nhibitors of the ang;otensin-converting enzyme ~ACE in hibitors) and can be used ~or controll;ng h;gh blood pres-sure of var;ous or;g;ns~ They can also be combined with other hypotensive, vasodilating or d;uretic compounds.
Typical representat;ves of these classes of act;ve com-pounds are described in, for example, Erhardt Ruschig, Arzne;mittel ~Med;caments), 2nd edit;on, Weinheim, 1972.
They can be administered intravenously, subcutaneous(y or perorally. me dosage for oral administration is 1 - 100, preferably 1 - 50, especially 1 - 30 mg per individual dose for an adult o~ normal }~ody weight. In setr3re cases, it can also be ~ncreased, since no toxic properties have as yet been observed. It ;s also possible to reduce th~ dcse, which ~s appropriate, above all, 1f d;uret;c agents are admin~s-tered at the same t~me.
The compounds accord;ng to the ;nvent;on can beadmin;stered orally or parenterally in an appropriate pharmaceutical formulation. For an oral use form, the act;ve compounds are mixed w;th the addit;ves customary for this form, such as excipients, stab;lizers or ;nert diluents, and the m;xture is converted to suitable adminis-trat;on formsf such as tablets, dragees, push-f1t cap-sules, aqueous alcoholic or o;ly suspensions or aqueous alcoholic or oily solutions, by customary methods.

, ~9~o~

,. . .
Examp~es of inert carriers which can be used are gum arab;c, magnes;um stearate, potass;um phosphate, lactose, glucose and starch, espec;ally ma;ze starch. The formula-t;on may be prepared ;n the form of either dry or moist granules~ Examples of possible oily exc;pients or sol-vents are vegetable and an;mal oils, such as sunflower o;L
or cod-liver o;l.
For subcutaneous or ;ntravenous administration, the active compounds or physiologically acceptable salts thereof are dissolved~ suspended or emuls1fied, if des;red ~;th the substances customary for this purpose, such as solubil;zing agents, emulsifiers or other aux;liaries.
Examples of possible solven~s for the new active compounds and thc corresponding physiolog;cally acceptable salts are:
~ater, physiolog;cal sodium chloride solut;ons or alco-hols, for example ethanol~ propanediol or glycerol, and ~n add;tion also sugar solutions, such as glucose or mann;tol solut;ons, or a mixture of the var~ous solvents mentioned.
The except;onally powerful activity of the com-pounds according to the formula I - even when adm;n;stered orally - ;s demonstrated by the follow;ng pharmacological data.
1. Intravenous adm;n;strat;on to anesthetized rats, 50%
;nh;b;t;on of the pressor reaction ;nduced by 310 ng of ang;otens;n I, 30 minutes after adm;n;strat;on of the dose ..~ EDso X y z R'l R2 ED5~ Sllg/k9) - ~6Hs H H C)~3 ~2HS 8,.3 C6H5 H H CH3 H . 2.7 2. Intraduodenal adm;n;strat;on to anesthetized rats

5 X Y Z R1 ~2 ED50 (~g/kg~
~6H5 H H CH3 ~H5 50 C6H5 H H CH3 ~1 60~) e-- ,

6~5 ~ D CH3 CH3 350 C6H5 ~ CH3 CzH5 280 10C6H5 ~ CH3 H 720 ~6Hs H OH CH3 C2H5 380 p-Cl-C6H4 H H c~l3 C2~5 55 , .. . ., . : .
p-Cl C6H4 ~ CH3 H 780 3. On oral admin;stration to consc;ous rats, a dosage of 1 mg/kg of~ for example, the compound of the formula I ;n uh;ch X is phenyl, Y and ~ are each H, R1 ;s CH3 and R2 is ethyl exhib;ts ~0% inhib;tion, last;ng over 6 hours~ of the pressor react;on triggered off by intravenous adm;n;s-tration of angiotens;n I~
The Examples wh;ch follow are intended to ;l~us- -trate the procedures accord;ng to the invention, w;thout restricting the inventlon to the substances mentioned here as representa~;ves.

, l~g3~
~ 12 -~.
N-t1-S-Carbethoxy-3-ehenyl-propyl)-S-alanyl-2-Gis~endo-azab;cyclo-~3~3 OJ-octane-3-S-carbox~_ic acid ~1t Meth~l 2-acetylam;no-3-~?-oxo-cyclopentyl)-propionate:
S 269 9 of methyl 3-chloro-2-acetylamino-prop;onate and 257 g of cycLopentenopyrrolidine ;n 1.5 l;ters of dimethylformam;de ~ere kept at room temperature for 24 hours. The mixture was concentrated in vacuo, the residue was taken up in a little water and the aqueows ~;xture ~as adjusted to pH 2 w;th concentrated hydrochlor;c acid and extracted tw;ce with 4 liter portions of ethyl acetate.
On concentration of the organ;c phase, a light ye(lo~ oil remained.
Y;eLd: 290 9.
NMR: 2.02 ~s,3H); 3.74 (s 3H); ~.4-4.8 ~m,1H) (CDCl3) Analys;s: C H N
calculated 58.1 7.5~t 6.16 found 58~5 7.2 6.5 t2) c;s,endo-2-Azabicyclo-C3.3.0?-octane-3-carboxylic acid hydrochlor;de 270 g of the acetylamino derivative prepared under tl) were boiled under reflux in 1.5 liters of 2 N hydro-chlor;c ac;d for 45 m;nutes. The m;xture was concentrated in vacuo~ the res;due was. taken up ;n glacial acetic acid, 5 9 of Pt/C ~10X of Pt) were added and hydrogenation was carried out under 5 bar. After filtrat;on, the m;xture was concentrated and the res;due was crystallized fro~
chloroform/d;isopropyl ether.
Melt;ng po;nt: 205 - 209~C, ~ 13 Y;eld: 150 9 - ~3) 8enzyl c;s,endo 2-azabicyclo-C3.3.0]-octane-3-carboxyla~e hydrochlor de 40 9 of the carboxylic acid prepared under t2) ~ere added to an ice-cold mixture of 390 9 of benzyl alco-hol and 65 9 of th;onyl chlor;de and the mixture ~s left to stand at room temperature for 24 hours~ After concen tration ;n vacuo, 47 g of the benzyl ester ~ere crystal-- lized from chloroform/;sopropanol.
Melt;ng po;nt: 175C (hydrochlor;de~
~4) Benzyl _- 2-S-carbethoxy-3-phenyl-propyl)-S-alanyL-cis,endo-2-azabicyclo-C3.3.0] octane-3-S-carboxylate 14 g of the benzyl ester prepared according to (3) ~ere reacted w;th 6.7 g of HOBt~ 13.8 g of N-t1-S-carb-ethoxy-3-phenyl-propyl)-S-alanine and 10.2 9 of dicyclo;;
hexylcarbodiim;de in 200 ml of dimethylforma~ide~ After the mixture had been stirred for 3 hours at room tempera-ture~ the dicyclohexylurea which had precipitated was fil-tered off with suction, the filtrate ~as concentrated, the res;due was taken up ;n 1 l;ter of ethyl acetate and the ~;xture was extracted by shaking w;th 3 x SOO ml of S per cent strength NaHC~3 solut;on~ The organic phase was concentrated and the res;due was chromatographed over a column o~ 1 kg of silica gel using ethyl acetate~petroleu~
ether ;n the rat;o 2 : 1. The isomer eluted first was the S,S,S-compound, and concentrat;on of a later eluate gave the S,S,R-compound~
In each case 8.0 9 of product were obtained as an o; l..

1~9;:~6(~7 NMR: of the S,S,S~compound: characteristic s;gnals: 1.20 - (d,3H), 1.27 tt,2H), 4~17 (q,3H), 5.13 ~s,2H~ 7~18 ~s,5H~
and 7732 (s,5H) (CDCL3) Analysis C 5I N
C3~H3gN205 calculated 71~1 7~56 5~53 found 70.8 7~8 5.7 ~5) N~ S-Carbethoxy-3-phenyl-propyl)-S-alanyl-cis,endo-2-azabicyclo-C3 3.0J-oc~ane-3-S-carboxylic_ac;d 8.0 9 of the L~L,L-benzyl ester from t4) ~ere dis-tO solved in 100 ml of ethanol and were debenzyLated hydro-~enolytica~ly under normal pressure, ~;th addition of 0.5 g of 10X Pd/C. This reaction could also have been carr;ed out under pressure~ together ~ith a shortenin~ of the reaction timeO After the calculated amount of hydro-t5 gen had been taken up~ the catalyst was f1ltered off and the res;due was concentrated ;n vacuo. The zwitter ion crystall;zed from ether~ in almost quant;tat;ve yield~
Meltin~ po;nt: 110 - 112C ~decomposition) A hydrochlor;de ~decompos;t;on from 120C) can ~e obta;ned by add;t;on of an equ;valent amount of hydro-chlor;c ac;d, or a z;nc complex salts ~hich is particularly stable to heat ~decompos;t;on above 160C~ can be obtained by add;tion of aqueous z;nc saltsto a concentrated methano-~ic solution of the t;tle compound.
Analys;s ~ H N
C23H3ZN2os calculated 66.3 7.7 6.73 ~ound 66.1 7a8 6~6 The NMR and mass spectra obtained are in agreement with the ~iven structure.

~3~7 ~ 15 -G~JD - + 150b~ tc - 1~ methanol)J
Example II
t1) tert.-~utyl cis~endo-2-azab;cyclo-~3.3.0~-octane-3-carboxylate 25 9 of azab;cyclo-t3.3.0~-octane-carboxyl~c acid hydrochlor;de from Example I (2) ~ere reacted with 250 m~
of isobutylene and 25 ml of concentrated sulfur1c acid in 250 ml of d;oxane. After 14 hours at room temperature, the mixture was rendered aLkal;ne w;th sodium hydrox;de solution and concentrated ;n vacuo, 100 ml of water were added and the ester was extracted with ether. Evaporat;on of the ether gave 15 9 of 3 colorless oil.
Analysis C H N
C12H21N2 calculated 68.2 10~2 6.63 found 67D9 10.1 6.3 ~2) N~ S-Carbobenzyloxy-3-oxo-3-phenyl~e-ro~yl)-s-alanine tert.-butyl ester 12.0 g of acetophenone, 17 9 of benzyl ~lyoxylate and 31.7 g of alan;ne tert. butyl ester toluenesulfonate were heated to 45 - 50C in 200 ml of glac;al acetic acid for 24 to 48 hours. The reaction was monitored by thin layer chromatography and was ;nterrupted at the opt;mum reaction point. The mixture was concentrated thoroughly in vacuo, the res;due ~as rendered basic w;th aqueous bicarbonate solut;on and the mixture was extracted with ethyl acetate The organ;c phase was concentrated as sub-stantially as possible and the S,S-;somer was crystali;zed from cyclohexane/petroleum ether. The R,S-compound re~a;ned substant;ally in solut;on. To obta;n seed crys-33t~

ta~s, chromatography of the crude mixture on silica yel ~n a 2 : 1 cyclohexane : ethyl acetate system to ~hich 001%
of tr;ethy~am;ne had been added was adv;sable. The S,S-compound was elu~ed as the second of the two d;astereomers and was obta;ned ;n the larger amount. 9 9 uere obta~ned.
Analysis C H N
C24H29N05 calculated 70.1 7.1 3.4 found 70.0 6.9 3.5 ~3) N~ S-Carbobenzyloxy-3-oxo-3-phenyl-propyla-S-alanine trifluoroacetate of the Mann;ch condensat;on product from ~2) ~ere d;ssolved ;n 25 ml of anhydrous tr;fluoroacet;c acid and the solution was left at room temperature for one hour.
The solut;on was concentrated in vacuo, di;sopropyl ether 1S was added and the product was prec;p;tated w;th petroleum ether~ 7.2 g of an amorphous substance ~ere obta;ned.
Analysis C H N
C22H22N07F3 calculated 56.3 4.7 3.0 found 56.0 4.8 3.1 Molecular ue;ght: 469 (4) tert.-Butyl N-t1-S-carbobenzyloxy-3-oxo-3-phenyl-propyl)-S-alanyl-2~cis,endo-azab;cyclo-C3.3.0~-octane-3-carboxylate 35.5 g of the N-substituted alan;ne from (3) were reacted with 21.1 9 of the tert.-butyl azabicyclooctane-carboxylate from Example II ~1j analo~ously to Example I
~4). Chromatography over s;liGa gel gave 20.3 g of the title compound.

3~
~ 17 -Analysîs C H N
C32H40N2~6ca~culated 70.04 7.35 5~10 found 69.6 7.4 5.3 ~5) ~
2-cis,endo-a~abicyclo-C3.3.0~-octane~3-carboxylic acid 20 ~ of the tert.-buty~ ester from (4) ~ere dîs-solved in 100 ml of tr;fluoroacetlc acid and the solution was le~t to stand at room temperature for one hour~ The solut;on was concentrated in vacuo~ the res;n wh;ch remained ~as taken up in ethyl acetate and the m~xture was neutral;zed ~ith aqueous bicarbonate. 14 g of the title compound were obta;ned from the ethyl acetate phase.
Analys;s C H N
CZ8H32N2o6 calculated 68.27 6.55 5.69 found 68.1 6.4 5.7 t6) N~ S-Carboxy-3-R,S-hydroxy-3-phenyL propyl)-S-alanyl-c;s,endo-2-azab;cyclo-C3.3.0~-octane-3-carbox~-lic acid 1 g of N-~1-S-carbobenzyloxy-3-oxo-3-phenyL-Z0 propyl)-S-alanyl-c;s,endo-Z-azabicyclo-C3~3~0~-octane-3-carboxylic ac;d ~ere dissolved ;n 5Q ml of ethanol~ 150 mg of Pd/~aS04 were added and hydrogenation was carried out under normal pressureu After the calculated amount of hydrogen had been taken up, the m;xture was f;ltered, the filtrate was concentrated and the residue was chro~ato-graphed over s1lica gel ;n the solvent CHCl3~cH30H/cH3cooH
50 : 20 : 5.
Yield: 0.6 g ~ ~9 C7) N~ S-Carbobe _ yloxy-3-R,S-hydroxy-3-phenyl-pr~yl~
S~alanyl-c;s,endo-2-a~ab1cyclo-~3.3.0~-octane-3-carboxy _;c_acid 1 ~ of N~ S-carbobenzyloxy-3-oxo-3-phenyl-5 propyl~-S-alanyl-Z~c;s,endo-azab;cyclo-~3a3.0J-octane-3-carboxyl;c ac;d were d;ssolved ;n 50 ml of a mixture of acetonitrile and water and ~ere reduced ~ith 150 mg of Na~H4. After 12 hours, the m;xture was concentrated to dryness, the res;due was rendered neutral Hith d;lute hydrochlor;c acid and the title compound was extracted ~ith ethyl acetate. To remove bor;c ac;d and other impuri-t;es, the product was chromatographed over s;l;ca gel ;n the solvent CHCl3/CH30H~CH3COOH 50:10:5.
Analys;s C H N
C23H34N26 calculated 67.99 6.93 5.66 found 67.7 6.6 5.3 Example III
6eneràl method: Hydrolys;s of esters to prepare compounds of the formula I in uhich R2 is H.
10 9 of the correspond;ng ethyl or benzyl ester of the formula I were dissolved ;n 20û ml of dimethoxyethane.
One drop of a d;lute ;nd;cator solut;on, for example bromo thymol blue, ~as added, and an equ;valent amount of 4N KOH
taqueous) was added in the course of 5 m;nutes, while st;rr;ng vigorously~ so that at the end of the reaction the ind;cator ;ndicated a pH value of 9 - ~0. The mixture ~as then ad~usted to pH ~ w;th hydrochlor;c acid and con-centrated to dryness ;n vacuo~ the residue was taken up ~n 250 ml of ethyl acetate and the m;xture was f;ltered. On ~.~93~7 _ ~9 _ concentrat1On of the ethyl acetate, the dicarboxy~c ac;ds prec;p~tated as solidr crystalline or amorphous compounds.
The yields ~ere between 80 and 95X~
ExampLe _III a N~ S-Carboxy-3-phenyL-propyl)-S-alanyL c;s~endo-2-aza b;cyclo-C3.3.0~-octane-3-S-carboxylic acid 1 g of N-~1-S-carbethoxy-3-phenyl-propyl)-S-a~anyl-2-azabicyclo-~3.3.0]-octane~3-S-Garboxylic acid from Example I (5) was hydrolyzed t1 hour) and the mixture was ~orked up, as described under ExampLe III.
Yield: 0.85 g m/e: 388 Example IV
N-t1-S-Carbethoxy-3-oxo-3-phenyl~propyl)-S~alan;ne benzyl ester 65.7 ~ of ethyl 3-phenyl-3 oxo-1~propenr1~ca~boxy1~te tethyl benzoylacrylate) were dissolved ~n 225 mL of ethanoiO
and 1 ml of triethylamine was added. A solut~on of 70 9 of S-alanine benzyl ester in 90 ml of ethanol ~as rap~dly added drop~1se at room temperature. The mixture was stirred at room te~perature for ~ hours and the solut;on ~as then cooLed. The S~S-isomer crystallized out~
Yield: ~4O3 g Melt;ng po;nt: 83 - 74C
G~20 = ~ 17.8 (c = 1, CH30H) ExampLe Y
N~ S-Carbethoxy-3-oxo-3-phenyl-propyL)-S-alanine 0.5 g of the compound from Example IV ~as d;s-solved in 40 ml of ethanol, 0.1 g of 10X PdtC ~as added and hydrogenation was carr;ed out at room temperature and , .

~3~

~ 20 -- under normal pressure.
Yield: 300 mg melting po;nt: 210 ~ 220C
H-NMR ~DMSO-d6): 1,0-1.4 (t,6H); 3.2-5.0 Sm,8H~;

7.2-8.2 ~m~5H) Benzyl N-t1-S-carbe~hoxy~3-o~o-3-phen~ o~yl~-S-alan~l-cis,endo-2-azabicyclo-C3u3.0]-octane~3-S-carbox~late The compound was prepared from benzyl cis~endo-2-azabicyclo-C3.3.0]-octane-3-S~carboxylate hydrochloride and N~ S-carbethoxy-3~oxo-3-phenyl-propyl)-S-alanine from Example V~ analo~ously to the process descr1bed in Example I ~4).~
' ~e~
N-t1-S-carbethoxy-3-oxo-3-phenyl-propyl~-S~alanyl-cis, endo-2-azabicyclo-~3.3.0~-octane-3-S-carboxylic acid 1 ~ of the benzyl ester from Example YI ~as dis-so~ved in 30 ml of ethanol and hydrogenated with 100 mg of Pd~C (lOX) at room temperature and under normal pressure.
After one mole equ;valent of hydrogen had been taken up, the hydrogenation ~las interrupted. The catalyst ~as fil-tered off with suct;on and the sol~t10n was concentrated.
Yield: ~00 ~g of an o;l.
H-NMR ~DMSO-D6): 1.0-3.0 (m,15H); 3.3-5.0 tm~10H);
7.2-8.1 ~m,SH) Example VIII
-~1-S-Carbethoxy-3-phenyl-propy-l-?--s-lysyl-cis~endo-2 azab;cycLo-C3.3.0~-octane-3-S_c_rboxylic~acid d;hydro-chlor;de ~ S~Carbethoxy-3-~ __y~e~ey~ -benzyloxy-carbony~-S~ysine benzyl ester 10 9 of ethyl 3-phenyl-3-oxo-1-propen-1-carboxy~ate ~ere dissolved ;n 100 ml o~ ethanol. 19.1 9 of N~-benzyl-oxycarbony~-S-lys;ne benzyl ester and 0.2 9 of tr-ethyl-amine ~ere added. The solut;on was st;rred at room tem-perature for 3 hours and was then concentrated ;n vatuo.
The oily residue (31 9) was d;ssolYed in isopropanol/di-;sopropyl ether and the solut;on ~as coo~ed. 13 ~ of ~ -~1-S-carbethoxy-3-oxo-3-phenyl-propyl)-N-benzyloxycarbon-yl-S-lysine benzyl ester crystaLlized~
~20 = 3~5 ~c = 1, CH30H) -NMR ~CDCl3) 1.0~ (tr, 3H); 1.0-200 (m,9H);
2.0-2.6 ~broad s~0 1H~; 21~-3.9 ~m~
6H); 3.9-4~4 ~quadr. 2H); 4.6-4~9 ~broad s., 1H); 5.0-5.2 ~double s., 4H) 7.1-8.1 (m,15H) ~2) ~ -~1 S-Carbethoxy-3-phenyl-propyl)-N~-benzyloxy-carbonyl-S-lys;ne 4.0 g of the lysine benzyl ester der;vat;ve pre-pared in Example VIII ~1) were dissolved in 50 ml ofglacial acetic acid, and 0.6 9 of PdfC ~10%) and 0.6 9 of concentrated sulfuric acid were added. Hydrogenat10n was carried out at room temperature and under normal pressure for 6 hours. The catalyst was then f;ltered sff ~ith suc-tion and the ethanolic solution was stirred w;th 1.4 9 ofsolid sodium b;carbonate. The solution was soncentrated on a rotary evaporator and the res;due was d;ssolved in ~ater. The aqueous phase was extracted w;th ethyl acetate and ~ethylene chlor;de. The or~an;c phases were d;scarded ~93~i~7 and the aqueous phase was evaporated to dryness ~n V3CU0.
Ths residue ~as extracted by st;rr;ng with methano~ After the methanol had been evaporated off, an ~ily residue rema;ned, uhich solid;fied when ~reated with di;sopropyl S ether. Y;eld o~ ~ -S1-S-carbethoxy-3-phenyl-propyl)-S
lys;ne: 2.0 ~
~H-NMR (D2o?: 1.0-1.4 Ctr, 3H); 1.0 245 tm, 9H), 2.5-4.4 ~m, 9H); 3.9~4~4 Cq~ 2H);
4.5 S.0 (m, 1H~; 7.1-7~b ~m, 5H) m/e: 336 3.4 ~ of N~-t1-S-carbethoxy-3-phenyl-propyl3-S-lys;ne ~ere dissolved in 30 ml of methylene chloride and the solution was cooled to 0C. While cooling ~ith ice, 201 9 of triethylamine were added, and 1.9 9 of benzyl chloroformate ~ere then added dropwise. The mixtur~ uas stirred at 0C for 1 hour and was then broughS to roo~
témperature~ The methylene chlor;de solut;on was extrac-ted by shak;ng success;vely with ~ater, sodium carbonate solution and water. After the product phase had be~n dr~ed, it was concentrated and the oily residue ~as chromatographed over silica gel using methylene chloride/
methanol. 2 0 9 of N~ S-carbethoxy-3-phenyl-propyl)-H-benzyloxycarbonyl-S-lysine were obta;ned.
1It-NMR tD20): 1.0-1.4 Ctr, 3H~; 1.0-Z.5 (m, 9H~;
2.5~4~4 Cm, 9H); 3.9-4.4 tq, 2H);
4.5-S.0 (m, 1H); 5~1 Cs, 2H); 7.1-7~5 (m, 10H) C3) ~ ~-benzyl-oxycarbonyl-S-lysyl-ci~endo-2-azab~yclo-~3.3~o~octane-,~ .
.

~9361~

- ~3 -~_J~ t a) 560 mg of benzy~ 2~azabicyclo-~3.3.0~ OGtane-3-carboxylate hydrochloride prepared accord~ng to Example I
t3) uere reacted w;th 940 mg of Nd-51-S carbethoxy-3-phenyl-propyl~-Ne-benzyloxycarbonyl-S~lys;ne prepared accord;ng to Examp~e VIII (2), analoyously to Exampl~ I
t4). After the mixture had been worked up, 1~5 g of an o;l, ~h-ch was a m;xture of two d;astereomeric compounds, ~ere obta;ned.
The diastereomer mixture was separated into the ~nd;v;dual components by column chromatography w1th sil;ca gel and cyclohexane/ethyl acetate 2:1 as the elut;ng agent.
The isomer eluted first was the above compound. 0.6 ~ of an o;l was obta;ned.
1H-NMR tCDCl3) tafter replacement of ~I by D ~;th D20):
1.0-2.6 tm, 20H); 2.6-4.5 tm, 8H); 4.6-5~0 ~m, 2H); 5.1-5.3 ~double s~, 4H); 7.1-7.6 tm, 15H) b) The later eluate gave 0.4 g of benzyl Nd~ S-carbethoxy-3-phenyl-propyl)-N~-benzyloxycarbonyL-S-lysyl-;is,endo~2-azab;cyclo-C3.3.0~-octane-3-R-carboxylate.
H-NM~ tCDCl3) tafter replacement of H by D ~;th D20) 1.0-2.6 tm, 20H); 2.6-4.4 tm, 8H~; 4.5-5.0 tm, ZH); 5.1 5.3 Cdouble s~, 4H); 7.1-7.5 tm, 15H) t4) ~ (1-S-Carbethoxy-3-phenyl-propyl)-S-lysyl-cis~endo-Z5 2-azab;cyclo-C3.3.0~-octane-3-S-carboxylic ac;d_dihydro-chlor;de 500 mg of benzyl N~-t1-S-carbethoxy-3-phenyl-propyl)~ -benzyloxycarbonyl-S-lysyl-cis,endo-2-azabi-cyclo-C3.300]~octane-3-S-carboxylate from Example YIII t3a) , l~g~6~7 ~ere d;sso~ved ;n 20 mL of ethanol and were debenzylated hydrogenolyeically under normal pressure, with add;t;on of -0.1 ~ of 10X Pd/C. ~Ihen the uptake of hydrogen had ended, the catalys. ~as f;ltered off, ethanolis hydrogen chloride solut;on uas added to the ethanolic solution unt1l a pH of 1 was réached, and the ethanol was evaporated off ;n vacuo.
D~isopropyl ether was added to the residue, whereupon the product sol;d;fied. Z00 mg were ob~ainedn H-NMR of the beta;ne ~CDCl3, after replacement of H
by D with DzO): 1.0-2.5 (m, 20H~; 2.6-4.4 (m, 8H); 4.4-5.1 (m, 2H); 7.2 ~s~ SH) Examp~e_IX
N -S1-S-Carbethoxy-3-phenyl-propyl)~S-lysyl-cis,endo-2 azabicyclo-~3.3.0~octane-3-R-carboxylic acid dihydro-chlor;de 0~3 mg of the correspond;ng benzyl ester fromExample VIII t3 b) were reacted, and the mixture worked up, analo~ously to Example VIII (4). 110 mg of the car-boxyl;c ac;d were obtained ;n the form of the d;hydro-chlor;de.
H-NMR of the betaine (CDCl3, after replacement of H
by D ~;th D20~o 1.0-2.6 (m, 20H); 2.6-4.4 ~m, 8H);
4.1-5.1 ~m, 2H); 7.2 (s, SH) Example X
N ~ S-Carboxy-3-phenyL-propyl)-S-lysyl-cis~endo-2-aza-bicyclo-~3.3.0]-octane-3-S-carboxyl;c ac;d hydrochloride 0.5 g of N ~ S-carbethoxy-3-phenyl-propyl)~S-lysyl-c;s,endo-2-azab;cyclo-C3.3.0~-octane-3 S-carboxyl;c acid dihydrochlor;de from Example VIII ~4) was suspended .

iL~9 in 20 ml of d;methoxyethane. Aqu~ous 4 N KOH ~as added unti~ a pH of 9-10 ~as reached. The mix~ure w~s st~rr2d for hal~ an hour. It ~as then adjusted to pH 4 ~;th hydrochlor;c acid and concentrated to dryness ;n YaCUO~
the residue was taken up in ethyl acetate and the mixture ~as filtered. The ethyl ac~tate solut;on was concentrated and the residue was tr;turated w;th d;~sopropyl ether, ~hereupon ;t solid~f;ed.
Y;e~d: 0.35 9 1H-t~MR ~D20): 1.2-2.5 ~m, 17H); 2~5-4.5 tmO 6H);
4.5-5.0 ~m, 2H); 7.2 (s, SH) Example XI
~ t1-S-Carboxy 3-~henyl-propyl)-S-lysyl-cis,endo-~ aza-b;cyclo-C3.3.0]-octane-3-R carboxylic ac;~d hydrochloride . 15 500 m0 of N~ S-carbethoxy-3-phenyl-pr~pyl)-S-lysyl-c;s,endo-2-azabicyc~o-C3.3.0~-octane-3-R-carboxyl~c aç;d d~hydrochloride from Exa~p~e IX ~ere hydrolyzed, and the m;xture ~as ~orked up, analogously to Example X.
Yield: 0.32 5 1H-NMR ~D20): 1.2-2.5 ~mO 17H); 2~5-4r5 tm, 6H);
4.5-5.0 (m, 2H); 7.2 ~s, 5H) Example XII
N-tl-S-Carbethoxy-3-phenyl-propyl)-0-ethyl- ~tyrosyl-cis, endo-2-aza bicyclo[3.3.0]-octan-3-S-carboxylic acid .
(l) N-tl-R,S-carbethoxy-3-phenyl-propyl)-O-ethyl-S-tyrosine benzyl ester Analogously to example IV, 24g ethyl benzoyl-acrylate dissolved in lO0 ml ethanol were reacted with 30q O-ethyl-S-tyrosine benzyl ester in the presence of 0.5 ml triethylamine.

3L:19~6137 The solution was concentrated, the resudue was digested with diethyletherlpetroleum ether (1:1) and dried in vacuo. 42g of the RS, S-compound were obtained.
(2) N-(1-R,S-carbethoxy-3-phenyl-propyl)-O-ethyl-S-tyrosine ~ . . _ _ . . ... _ . . _ _ 40g of the product from (1) were dissolved in 800 ml glacial acetic acid and the solution was hydrogenated under 100 bar and room temperature in the presence of 4g Pd/C (10 percent).
After the crude product had been chromatographedover silica gel in the solvent ethyl acetate/cyclohexane 1:3 and the solution had been concentrated to dryness, 25g of the title compound were obtained, which proved to be almost homogen by thin layer chromatography. Melting point: 205-213 C.
Analysis:

23 3~ 5 (399-5~
Calculated: 69.15 C 7.31 H 3.50 N
Found: 69.5 7.4 3.3 (3) N-(l-S-carbethoxy-3-phenyl-propyl)-O-ethyl-S-tyrosyl-cis, endo-2-aza bicyclo[3.3.0]-octan-3-S-carboxylic acid Analogously to example I (4), 5g of the free benzyl ester, obtained from example I (3) by treating with alkali and extracting with diethylether, were reacted with 8g of the compound from example XII (2) and 4.4g dicyclohexyl-carbodiimide in the presence of 2.7g l-hydroxy benzotriazole. After subsequent chromatography as described in example I (4) 2.9g 5 of an oil, which is thP intermediate benzyl ester, were obtained.
lH-HMR- and mass spectra were in accordance with the given structure.

J~3~

The benzyl ester was dissolved in 50 ml ethanol, Pd (C) was added and hydrogenation was carried out under normal pressure.
The mixture was filtered, the filtrate was concentrated, the residue was digested and dried in vacuo. Yield: 2.2g.
lH-NMR (CDCI3): 1.2-3.0 (M, 15H), 1.27 (T, 3H), 1.4 (T,3H), 3.0-4.3 (M, 4H), 3.8-4.2 tM, 4H), 6.5~7.1 (2D, 4H), 7.3 (S, 5H).
Example XIII
N-(1-S-Carbethoxy-3-phenyl-propyl)-0-methyl-S-tyrosyl-cis, endo-2-aza bicyclo [3.3.0]octan,3-S-carboxylic acid The compound was prepared from 0-methyl-S-tyrosine benzyl ester analogously to the process described in example XII. The lH-NMX spectrum is in accordance with the given structure.

Claims (2)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of a compound of the formula IIIa or IIIb IIIa IIIb wherein W denotes hydrogen, alkyl with 1 to 6 carbon atoms or aralkyl with 7 or 8 carbon atoms, or a salt thereof with an acid, or, in the case where W is hydrogen, with a base, in which an enamine of the formula VI

(VI) wherein X1 represents dialkylamino with 2 to 10 carbon atoms or a radical of the formula VII

(VII) wherein m and o denote integers from 1 to 3, (m + o) ? 3 and Z denotes CH2, NH, O or S is reacted with an N-acylated 8-halogeno-.alpha.-amino-carboxylic acid ester of the formula VIII, (VIII) wherein X2 represents a group which can escape nucleofugally, Y1 represents alkanoyl with 1 to 5 carbon atoms, aroyl with 7 to 9 carbon atoms or another protective group which is customary in peptide chemistry and can be split off under acid conditions, and R2 represents alkyl with 1 to 5 carbon or aralkyl with 7 to 9 carbon atoms, or with an acrylic acid ester of the formula (IX) wherein Y1 and R2 have the above meanings to give a compound of the formula X

(X) wherein R2 and Y1 have the above meanings, this compound is cyclized with the aid of a strong acid, with acylamide and ester cleavage, to give a compound of the formula XIa or XIb XIa XIb this compound is converted into a compound of the formula IIIa or IIIb, wherein W represents hydrogen, by catalytic hydro-genation in the presence of a transition metal catalyst or by reduction with a borane-amine comples or a complex boro-hydride in a lower alcohol, and the product may be esterified to give a compound of the formula IIIa or IIIb in which W

represents alkyl with 1 to 6 carbon atoms or aralkyl with 7 to 8 carbon atoms.

2. A compound of the formula IIIa or IIIb as defined in claim 1, whenever obtained according to a process as claimed in claim 1 or by an obvious chemical equivalent thereof.