Note: Descriptions are shown in the official language in which they were submitted.
~ ~3~
2 -
HOE 82/F 148 J
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
Z C02R2 CH3 CH CH2
/\/ \/
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.
Z R1
I' I
X C - CH2 - CH -- NH - CH - C02H ( I I )
1 2
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~
R1
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)
\-
/CH2-7O
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~
COOR2
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~
- 10 - -
,. . .
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
1 1 -
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,
36V7
~ 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~
- 16 -
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
- 18 -
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-
607
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
- 22 -
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
- 24 -
~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
-- 25
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
- 25 -
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~
- 27 -
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.
