Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
i7~
2 -
KOE ~3/F 119
This is a Divisional of Canadian Patent Application Serial
Number 458,205 filed July 5, 1984.
I ~
The invention relates to der;vat;ves of 2-aza~
bicyclo~3.1.0~hexane-3-carboxylic acid of the formula I
02R ~I)
I .~ ' * Y
Co-C~3-~H-~H-/CH27n-¢-~t
R 1 C2n Z
in which the hydrogen atoms at the br;dgehead carbon atoms
have the c;s conf;~uration with respect to one ano~her,
and the COOR group on carbon atom 3 ;s oriented exo or
endo to the bicyclic ring system, and in which
n denotes O or 1,
R denotes hydrogen, ~C1-C6) alkyl, ~C2-C6)-aLkenyl or
~C6~C12)~arYi-(c1-c4)-a~ky~
R~ denotes hydrogen or ~C~ ~o C6)-alkyl, uhich can
optionally be subst~tuted bY am;no tC~ to C6)-
acylam;no or benzoylamino, ~C2 to C6~-alkenyl,
~C5 to C9)-cycloalkyl, ~C5 to C9)-cycloalkenyl,
~C5 to C7)-cycloalkyl-~C1 to C4)-alkyl, ~C6 to
C12)-aryL or partially hydrogenated ~C6-C12)~
aryl, each of ~Ihich can be substituted by ~C1 to
C4~-alkyl~ (C1 or C2)-alkXY or halogen,
~ 7~
- 3 -
(C6-c1Z)-aryl-(c1 to C4)-3lkyl or (C7-C13)-
aroyl-(Cl-C2)~alkYl~ both of ~h;ch can be substi-
tuted in the aryl radical as defined above~ a
monocyclic or bicycLic heterocyclic radical
having 5 to ~ or 8 to 10 ring atoms respectively,
1 or 2 of these ring atoms being sulfur or oxy-
gen atoms and/or 1 to 4 of these ring atoms
being nitrogen a~oms, or an optionally protected
side chain of a naturally occurring ~-aminoac;d
Rt-CH(NH2)-COOH,
R2 denotes hydrogen, (C1-C6)-alkyl~ ~C2-C6)~alkenyl
or tC6-C12)-arYl-(~1-c4)-alkyl~ ~
denotes hydrogen or hydroxyl,
Z denotes hydrogen, or
Y and Z together denote oxygen, and
X denotes tC1-C6)-alkyl, (C2-C6) alkenyl~ ~Cs 9
cycloalkyl, (C6-C1z)-aryl, preferably phenyl~
~h;ch can be monosubstituted, disubstituted or
trisubstituted by ~C1-C4)-alkyl, (C1-C4)-alkoxy~
hydroxyl, halogen, nitro, amino, acyl ~ no,~C1-C4)-aLkyl-
amir~o, di- (C1-C4-alkylamino and~or met}~.ylene~
dioxy, or 3-indolyl,
and their physiologically acceptable salts.
Those compounds of the formula I in which
n is 1,
R~ denotes hydrogen, allyl, vinyl or an optionally pro-
tected side chain of a naturally occurring ~-
aminoacid, and
R, RZ, Y, Z and X have the prev;ous mean~ngs, are preferred9
- 4 -
in part;cular those compounds of the formula I ;n wh;ch
n denotes 1,
R denotes hydrogen,
R1 deno~es me~hyl~ ~he optionally acylated side chain of
lysine or the 0-(C1-C6)-alkyLated side cha;n
of tyrosine,
R2 denotes hydrogen, methyl, ethyl, benzyl or tert.-butyl,
X denotes phenyl or phenyl ~hich is monosubstituted or d;sub-
stituted by fluorine and/or chlor;ne,
Y denotes hydrogen or hydroxyl,
Z denotes hydrogen, or
Y and Z together denote oxygen.
Particularly preferred compounds which may be mentioned
are:
N-tl-S-carboethoxy-3-phenylpropyl)-S-alanyl-cis-2-aza-
bicycloC3.1.0~hexane-endo-3-S-carboxyl;c acid,
N-t1-S-carboxy-3-phenylpropyl)-S-alanyl-c;s-2-azobicyclo-
C3.1.0]hexane-endo-3-S-carboxylic ac;d~
N-(1-S-carboethoxy-3-phenylpropyl)-S-lysyl-cis-2-azabi-
cycloC3.1.~hexane-endo-3-S-carboxYlic acid,
N-t1-S-carboxy-3-phenylpropyl)-S-lysyl-cis-2 azabicyclo-
~3.1.0~hexane-endo-3-S-carboxylic acid,
N-t1-S-carboethoxy-3-phenylpropyl)-0-ethyl-S-tyrosyl-cis-
~2-azabicycloC3.1.0~hexane-endo-3-S-carboxylic acid,
N-t1-S-carboethoxy-3-phenylpropyl)-0-methyl-S-tyrosYl-
cis-2-azabicycloC3.1.0~hexane-endo-3-S-carboxylic ac;d~
N-t1-S-carboethoxy-3-phenylpropyl)-S-alanyl-cis-2-azab;-
cycloC3.1.0~hexane-exo-3-S-carboxylic acid,
N-tl-S-carboxy-3-phenylpropyl)-S-alanyl-cis-2-azabicyclo-
32
-- 5 --C3~1.0~hexane-exo~3-S-carboxylic acid,
N-(1-S-carboethoxy-3-phenylpropyl)-S lysyl-cis-2-azabi-
cycloC3.1.0~hexane-exo-3-S-carboxylic acid,
N-~1-S-carboxy-3-phenylpropyl)-S lysyl-c;s-2-azab;cYclo-
~3.1.0~he~ane-exo-3-S-carboxylic acid,
N-(1-S-carboethoxy-3-phenylpropyl)-0-ethyl-S-tyrosyl-cis~
2-azabicyclo;3.1AO~hexane-exo-3~S-carboxylic acid and
N-(1-S-carboethoxy-3-phenylpropyl)-0-methyl-S-tyrosyl-c;s~
2-azabicyclo~3.1.0~hexane-exo-3-S-carboxyl;c acid.
Particularly su;table salts are alkali metal and
alkaline earth metal salts, salts with physiolo~ically
tolerated amines, and salts w;th ;norganic or organ;c
ac;ds, such as, for example, HCl, ~IBr, H2S04, maleic acid,
fumaric ac;d or tartar;c acid.
In th;s context as in the following, aryl is to be
understood to be opt;onally substituted phenyl, naphthyl
or b;phenylyl, but particularly phenyl. Alkyl can be
straight-chain or branched.Acyl~no is to be ~nderstQod to be in par-
ticular (Cl-C6)-a~noyl~no,Bcc-aNno or benzcyl~no.
A monocyclic or bicyclic heterocyclic radical hav-
ing S to 7 or 8 to 10 ring atoms respectively, 1 or 2 of
these r;ng atoms being sulfur or oxygen atoms and/or 1 ~o 4
of these r;ng atoms being nitrogen atoms, ;s understood to
include, for example~ thienyl, benzo~b~thienyl, furyl,
pyranyl, benzofuryl, pyrrolyl, imidazolyl, pyrazolyl,
pyr;dyl, pyrimidinyl, pyridazinyl~ indazolyl, isoindolyl,
indolyl, purinyl, quinol;z;nyl, isoquinolinyl~ phthala-
zinyl, naphthyridinyl, quinoxalinyl, quinazolyl, cinnolinyl,
pteridinyl, oxazolyl, isoxazolyl, thiazolyl or isothiazolyl.
These radical3 can also be partially or completed hydrogenated.
.
z
Naturally occurring ~-aminoac;ds are described in,
for example, Houben-~eyl, Volumes XV/1 and XY/2.
. If R1 represents a protected side chain of a
naturally occurring ~-aminoac;d, such as, for example, pro-
tected Ser, Thr, Asp, Asn~ Glu, Gln, Arg, Lys, Hyl, Cys,
Orn, C;t, Tyr, Trp, His or ~yp, ~he preferred pro~ec~ive
groups are those customary in peptide chemistry ~cf.
Houben-Weyl, Volumes XV/1 and XV/2~. In the case where R1
denotes the protected side chain of lysine, the known amino
protect;ve groups, but particularly ~C1-C6)-alkanoyl, are
preferredn In the case where R1 denotes the protected
s;de cha;n of tyros;ne, the ether protective group on ~he
oxygen, ;n particular ~C1-C6)-alkyl, is preferred; par-
t;cularly preferred protect;ve groups are methyl and ethyl.
Compounds of the formula I have ch;ral carbon
atoms. The invention relates to both the R and the S con-
f;gurations at all centers of asymmetry. Thus the -corn-
pounds of the formula I can exist as optical isomers, as
diastereomers, as racemates or as mixtures of these. How-
ever, those compounds of the formula I ;n wh;ch the carbon
atom 3 in the b;cyclic ring system as well as the carbon
atoms ;n the side chain labelled with an asterisk t*) have
the S configuration are preferred, ~ith the exception tha~
the R configuration of this center is preferred when
tNH-GHR~ CO) = Cys.
In addition, the invent;on relates to a process for
the preparation of the compounds of the formula I which
comprises reacting, by methods of am;de formation known in
peptide chemistryO a compound of the formula II, in which
`` ~L2~i79@~2
n, R1, R2, X, Y and Z have the previously mentioned meanings,
wi~h the exception of that of R2 = hydrogen, with a compound
of the-formulae IIIa or IIIb, or the m;rror ;mage or the
racemate~ ;r, wh;ch W denotes a group ester;fy;ng carboxyl,
suc.h as (C1 C6) alkyl or tC7-C8)-aralkyl, preferably
tert.-butyL or benzyl, and subsequently l;beratin~ the com-
pounds of type I w;th R = hydrogen by hydrogenation or
treatment with ac;d and/or base.
D;astereomers of the formula I can be separated
~rom one another by, for example, crys~allization or chro-
matography.
Z R
X~C-~CH2;7n-CH-N~H-CH_Co2H (II)
Y C02R
~N ~ ~IIIa) and m;rror ;mage
~ '
H:
- ~IIIb) and m;rror .mage
~02C ~1 .
Further synthet;c processes for the preparation of
the compounds of the formula I in which Y and Z together
denote oxygen entail reacting, in a known manner ;n a
~;chael reaction (Organikum, 6th Edit;on, page 492, 1967~,
a compound of the formula IV
~d902
-- 8 --
CO
~\~ 2 (IV~
, CO-C~ TH2
R1
in ~h;ch R1 has the meaning as in formula I, and ~ has the
meaning as in formulae IIIa and b, with a compound of the
formula V
R202C-CH=CH-Co-x ~V)
in which R2 and X have the meanings as in formula Io and,
where appropriate, splitting off the radical W and/or the
radical R2 as described above, or reacting, in a known
manner in a Mannich reaction ~Bull. Soc. Chim. France
10 1973, page 625), a compound of the abovementioned formula
IV uith a compound of the general formula VT, in which R2
has the meaning as in formula I, and with a compound of the
general formula VII
OHC-C02R2 ~YI) X-C0-CH3 (VII~
in which X has the meaning as in formula I, and then, where
appropriate, splitting off the radical ~ and/or the radical
R2 as described above with formation of the free carboxyl
groups.
In addition, it ;s also poss;ble to prepare com-
pounds of the formula I w;th Y and Z each being hydrogen
in a manner such that the compound of the abovementioned
formula IY is reacted, in accordance w;th the procedure
described ;n J. Amer. Chem. Soc. 93, 2897 t1971), with a
compound of the formula VIII
3%
2 ~VIII)
2R
' O = C\
2 CH2 X
;n which R2 and X have the meanings as ;n formula I,
reducing the resulting Sch;ff's bases and then, where
appropriate, splitting off the rad;cal W andtor the
radical R2 as described above with formation of the free
carboxyl groups. The reduction of the Sch;ff's bases can
be carried out electrolytically or us;ng reducing agents
such as, for example, sodium borohydride or sodium cyano-
borohydride.
Compounds of the formula I with Y being hydroxyl
and Z be;ng hydrogen can also be obtained by, for example,
reducing a compound I, by Y and Z together being oxygen,
uhich is obtained w;th the above procedures. This reduc-
t;on can be carried out w;th a reducing agent, such as
sod;um borohydr;de and other complex boronates or~ for
example, borane-am;ne complexes.
Compounds of the formula I in which R represents
hydrogen can, where appropriate, be converted by methods
known per se into their esters of the formula I in which R
denotes (C1 to C6)-alkyl or (C7 to C9~-aralkyl.
The react;on of a compound of the formula II with
a compound of ~he formula $II to prepare a compound of the
formula I is carried out ;n accordance w;th a condensation
reactinn known in peptide chemistry, the condensing agents
added being~ for example, d;cyclohexylcarbod;;mide and 1-
~ 10 -
hydroxybenzo~r;azole. When subsequently spl;tting off the
radical ~ with acid, the acids ~hich are preferably
employed are trifluoroacetic acid or hydrogen chloride.
Compounds of the formula II have already been pro-
posed. Those w;th X be;ng phenyl, Y be;ng H, Z be;ng H,
R1 be;ng CH3 and R2 be;ng CH3 or CzH5 are known tfor
example from European Patent 0,037,231) and are accessible
by various routes. The benzyl esters tR2 = benzyl) can be
preparcd analogously~
The Mannich reaction of acetophenones of the for-
mula IXa, in wh;ch X represents aryl ~h;ch is opt;onally
subst;tuted as previously, with gLyoxylic esters and ~-
aminoscid esters leads to compounds of the formula II in
~hich n denotes 1 and Y and Z together denote oxygen (for-
mula IX). In formula IX, W' denotes a radical which can be
split off by hydrogenolysis, or by base or acid, preferably
benzyl or tert.-butyl, and X, ~here appropriate, represents
the meanings defined previously.
However, in the case of the benzyl ester (W' = ben~
zyl), R2 may not be benzyl. On hydrogenolysis of these
compounds with Pd, compounds of the formula II in which Y
and Z are hydrogen are produced.
R~
-CO-CH3 + SHO ~ H2N-CH-C02W' C02R2 R1
C02R2 - ~ X-CO-CH2-CH-NH-C~-CO W '
(IXa) (IX) 2
Compounds of the formula II in ~ilich Y and Z to-
gether denote oxygen can likewise be obta;ned in high
~ ~ . .
.. .. .
y;elds by M;chael add;~ion of appropr;a~e acylacryl;c
esters and ~-aminoac;d esters. Ester cleavage leads to
the same products as does the Mann;ch react;onl
~1 (IX)
- X-C-C.~-CX-C02~2 ~ NH2-CH-COzW~ ~
The amount of the d;astereomers hav;n~ the pre-
ferred S,S conf;gura~;on produced on using es~ers of L-
aminoac;ds predominates, and they can be obtained by crystal-
~izat;on or chromatographic separation of the esters on
silica gel.
The compounds of the abovementioned formula IV used
as starting materials for the preparation of the compounds
of the formula I are obta;ned from the compounds of the
abovementioned ~ormulae IIIa or b or the mirror images by
reaction, by kno~n procedures, ~ith an N-protected 2-amino-
carboxylic acid of thc formula X
~X)
Y - HN - C~ - C02H
in ~hich V is a protective group and R~ has the abovemen-
tioned meaning. An example of a suitable protec~ive group
~V, which is spli~ off again after reaction is Gomplete, is
tert.-butoxycarbonyl~
The invent;on also relates to compounds of the
formulae IlIa and IIIb and their m;rror imagcs in ~hich W
denotes hydrogen or a group esterifying carboxyl, preferably
(C1 to C6)-alkyl or ~C7 or C3)-aralkyl, and to a process
'' -: ,.
- 1Z -
for their preparation which comprises rearranging compounds
of the formula XI
Hal
(XI)
O
H
;n which Hal represents halogen, preferably chlorine or
bromine, in the presence of a base~ and, where appropriate,
converting~ in a manner known per se, the result-ing com-
pounds of the formulae IIIa or IIIb (W = hydrogen) and/or
their m;rror images into the abovementioned esters.
Compounds of the general formula XI can be prepared
by converting a compound of the formula XII (Limasset et
al., 8ull. Soc. Chimn France 1969, 3981)
(XII)
O,
into its oxime, reacting the latter in a aeckmann rearrange-
ment, for example ;n analogy to Helv. Ch;m. Acta 46, 1190
~1963) to give a compound of the formula XIII
<~ ~XIII)
H
halogenating the latter to give a compound of the formula
XIV
67~32
- 13 -
Hal
- ~Hal ~XIV)
N~ o
in which Hal denotes a halogen atom, preferably chlorine
or bromine, and catalytically reducing the latter to give
compounds of the formula XI.
S The conversion of the ketone XII ;nto the corres-
pond;ng oxime ;s usually carr;ed out ;n an aqueous-alcoholic
med;um w;th excess hydroxylamine hydrochloride, the free
acid being neutralized with sodium carbonate or sodium
acetate. In place of hydroxylamine, ;t is also possible
to use sod;um hydroxyla~ine-N,N-disulfonate ~Org. Synth.
3 C1923] 61) or the sod;um salt of hydroxylam;ne-N-mono-
sulfonic acid (J. Amer. Chem. Soc~ 46 ~1924~ 12~0).
Reaction of the ketone XII with hydroxylamine-O-
sulfonic ac;d ;n a concentrated organ;c ac;dr preferabLy
formic acid, has proved to be particularly advantageous,
the oxime be;ng formed ;n s;tu and rearranged, without
isolation, into the compound XIII~ wh;ch ;s produced to-
gether w~th ;ts ;somer of the formula XIIla.
~XIIIa3
~lH
o
Examples of suitable halogenating agents are inor-
ganic ac;d haLides, such as PCls~ S02Clz, POCl3, SOCl2 or
P~r3~ or halo9ens, such as bromine or chlor;ne. It ;s adv2n-
tageous to use PCls or POCl3 combined with S02Cl2 in an
~.~67~
- 14 -
organic solvent. An imide halide is initially formed as
an ;ntermed;ate and reacts w;th the halogena~ing agents
mentioned and then reacts ~urther by hydrolysis under basic
cond;tions, preferably with aqueous alkali metal carbonate,
to give a compound of the formula XIV.
The compounds of the formula XIV are subsequently
catalyticalLy reduced in a polar protic solvent, such as,
for example, an alcohol, preferabty ethanol, or a car-
boxylic acid, such as, for example, acet;c acid, ~ith the
1û addition of an acid acceptor, such as, for example, sodium
acetate or triethylamine, to give a compound of the for- -
mula XI in which Hal has the abovementioned meaningO
ExampLes of suitable catalysts are Raney nickel, or palla-
dium or platinum on animal charcoal Compounds of the
formuLa XI can also be prepared directly or as mixtures
with compounds of the formula XIV by halogenation of the
compounds of the formula XIII using smaller amounts of the
abovementioned halogenat;ng agents.
Compounds of .he formula XI are reacted in accord-
ance with the known Favorskii react;on in the presPnce ofa base to give the compounds of the formulae IIIa or b with
W being hydrogen, and the latter are esterified where
appropriate~ The abovementioned Favorskii reaction is
carried out in an alcoholic solvent such as methanol,
ethanol or tert.-butanol or in water or ;n mixtures of
these, at temperatures in the range from 20 to 140C,
preferably between 60 and 100C~ The bases which are
advantageously employed are alkali metal or alkaLine earth
metal hydroxides, such as sodium, potassium or barium
~2~
- - 15 -
hydroxide or alkal; metal alcoholates, such as, for exam-
ple, sodium methylate or potassium tert.-butanolate.
The compounds of the formula IIIa and IlIb or
their mirror ;mages ~hich are obtained in accordance with
the procedure descr;bed above result as mixtures of stereo-
isomers, and these can be separa~ed from one another by, for
example, recrys~allization or chromatography. It may be
necessary, where appropriate, for the mixtures to bc appro-
priately derivatized in order for the stereoisomers then
to be separated froln one another by recrystalli~ation or
chromatography.
Racemic mixtures of compounds of the formulae IIIa
and IIIb can be employed as such in the further syntheses
described above. However, if desired, they can also be
separated into the enantiomers before further reactions by
the known methods of racemate resolution (cf. for example,
Quart. Rev. 25 ~1971) 323 ff.).
If the compounds of the formula I result as race-
mates, these can also be resolved into their enantiomers
or separated by chromatography by the customary methods~
such as, for example, via salt formation with optically
active bases or acids.
When R is hydrogen, the compounds of the formula I
according to the invention exist as internal salts. S;nce
they are amphoteric compounds, they can form salts wi~h
acids or bases. These salts are prepared in a customary
manner by reaction with one equivalent of acid or base.
The compounds of the formula I and their salts
have a long-lasting and strong hypotensive effect. They
~ i7~
~ 16 -
are potent inhibitors of ang;otensin convert;ng enzyme
tACE inh;bitors~ and can be employed to control hyperten-
sion of a variety of etiologies~ It is also possible to
combine them with other compounds having hypotensive, vaso-
dilator or d;uretic activity. Typical representatives ofthese classes of active compounds are described in, for
example, ~rhardt-Ruschig, Arzneimittel (Drugs), 2nd Edition,
Weinhe;m, -1972. They can be administered intravenously,
subcutaneously or orally. The dosage on oral adm;r;stra-
tion is 1 - 100 mg, preferably 1 - 50, in part;cular
1 - 30 mg, per single dose for an adult of normal weightO
This corresponds to about 13 - 1,300 ~g/kg/day, preferably
13 - 650 ~gJkg/day, in particular 13 - 400 ~g/k/dayO The
dose can also be increased in severe cases~ since toxic
properties have not hitherto been observed. It ;s also
possible to reduce the dose, and this is particularly appro-
priate when diuretics are administered concurrently.
The compounds according to the invention can be
administered orally or parenterally in appropriate pharma-
ceutical formulations. For a form for oral use, the activecompounds are mixed with the addi~ives customary for this
purpos~, such as vehicles, stabilizers or inert diluents,
and converted by customary methods into suitable forms for
àdministration, such as tablets, coated tablets, hard gela-
tin capsules, aqueous, alcoholic or oily suspensions oraqueous, alcoholic or oily solutions. Examples o~ ;nert
vehicles ~hich can be used are gum arabic, magnesium car-
bonate, potassium phosphate, lactose, glucose or starch,
in particular corn starch. For this purpose, the preparation
` - ~2~
- 17 -
can be carried out either as dry or as moist granules.
Examples-o-f suitab~e oily vehicles or solvents are vege-
table and animal oils, such as sunflower oil or fish liver
o; ~.
For subcutaneous or ;ntravenous adm;nistrat;or,, the
ac~;ve compounds or t~e;r phys;olog;cally tolerated salts
are converted into solutions, suspensions or emulsions
~ith, if desired, the substances customary for th;s pur-
pose, such as solub;lizers, emulsif;ers or other auxil;ar;es.
Examples of suitable solvents for the new ac~ive compounds
and the corresponding physiologically tolerated salts are:
~ater, physiological sal;nes or alcohols~ for example
ethanol, propaned;ol or glycerol, but also sugar solutions,
such as glucose or mann;tol solutions~ or a mixture of the
various solvents ment;oned.
The examples wh;ch follow are intended to ilLus-
trate the procedures according to the invention without
restrict;ng the invention to the substances mentioned here
as representatives.
The lH NMR data are S vaLues.
Example I
N~ S-carboethoxy-3-phenylpropyl)-S-alanyl-cis-2-az~bi-
cyclo~3.1.03hexane-~-carboxylic acid hydrochloride
~1~ Cis-2-azabicycloC4.1.0]-3-oxoheptane
1 9 of cis-bicycloC3.1.0~-2-oxohexane are dissolved
in 10 ml of 97% strength formic acid. While cooling in
ice, 1.8 9 of hydroxylamine-0-sulfol1ic acid in 5 ml of 97X
strength form;c ac;d are added, and the mixture is then
brought to reflux temperature for 45 minutes. After
;26~ 2
- 18 -
~ . ~
cooling, the m;xture is poured on to ice, neutralized with
sol;d NaHC03 and extracted with ethyl acetate. After
drying and evaporating, a residue of 1 9 of oil remains.
~2) Cis-2-azabicycloC4.1.0]-3-oxo-4-dichloroheptane
11 9 of ~he crude product obtained accord;ng to
Example I (1) are dissolved in 250 ml of d;chLoroethane.
h'hile cooling in ice~ Z0.8 9 of phosphorus pentachloride
are introduced. The mixture ;s st;rred at room temperature
for 30 minutes. Then, while cooling ;n ice, 17 ml of
sulfuryl chloride are added dropwise, and the mixture is
stirred under nitrogen at room temperature for 1 hour and
at 60C (bat'h temperature) for 5 hours. After cooling,
2ûO g of ;ce are added, and the mixture ;s neutralized with
solid sodium carbonate, the dichloroethane phase is separa-
ted off, and the aqueous phase is extracted with methylenechloride. The organic phases are dried, evaporated, and
the residue (20 9) is chromatographed on silica gel u'sing
methylene chlor;de/ethyL acetate 19:1 as eluting agentO
iield: 4.2 9 Melting po;nt: 174 - 175C
(3) C;s-2-azab;cycloC4.1.0~-3-oxo-4-chloroheptane
3.0 9 of I(2) are dissolved in ethanol, 2.8 ml of
tr;ethylam;ne and 2.5 9 of Raney nickel are added and the
mixture is hydrogenated for 2û min. The catalys~ is
removed by f;ltrat;on with suct;on, the f;ltrate is eva-
porated and the res;due ;s chromatographed on s;lica gelus;ng methylene chloride and ethyl acetate 19:1 as the
elut;ng agent.
Yield: 1.8 g
~2~i7~32
- 19 -
Analys;s: C8H~NOCl: calculated 49.5 5.5 9.6 24~3
found 49.8 5.Z 9.3 23.9
~4a) Cis-2-azabicycloC3.1.0]hexane-3-carboxylic acid
1~6 9 of I(3) are suspended in 55 ml of water, and
4.0 9 of ~a(OH)2.8H20 are added. After refluxing for 1 hour,
the pH is adjusted to 2.5 ~ith 2 N sulfuric acid, the pre-
cip;tate is f;ltered off with suction, and the aqueous solu-
tion is adjusted to pH 6~ evaporated to dryness, ethanol
and methylene chloride are added, and the precipitate is
f;ltered off with suction, the solutivn is concentrated and
ethyL acetate is added to the residue. YieLd 1.5 9 of
colorless soLid product.
H NMR/60 MHz, D20: 0.4 - 1.2 (m, 2 H);
105 - Z.9 (m, 3 H);
3.1 - 4.4 (m, 2 H~
~4b) Cis-2-azab;cycLo~3.1.0~hexane-endo/exo-3-carboxyl;c
acid
The product obtained ;n Example I(4a) compr;ses a
mixture of cis-endo and cis-exo. After derivatizat;on to
giYe the benzyl ester followed by N-acylation wi~h benzyl
chloroformate, this product can be separated into the cis-
endo and the cis-exo derivat;ves by silica gel chroma-
tography. The racem;c cis-endo and c;s-exo aminoacids are
~obtained by subsequent hydrogenat;on w;th Pd/C (10X) as the
catalyst.
1H NMR of the c;s-exo-2-azabicycloC3~1.0]hexane-3-
.
carboxylic acid
~270 MHz, D20~: 0.8 - 0.93 ~m, 2 H);
1.8 - 1.92 (m, 1 H);
~2~
- 20 -
2 1 - Z.24 tm, 1 H3;
2.45- 2.55 (qu, 1 H);
3029- 3.37 tm, 1 H);
3.78~ 3088 (dd, 1 H)
5 1H NMR of the c;s-exo-2-azabicycloC3.1_0]hexane~3-
carboxyl;c ac;d
(270 MHz, D20): 0.56 - 0.66 (m, 1 H);
- 1.87 - 0.99 (spl;t qu, 1 H)
- 1079 - 1.9 (m, 1 H);
2.32 - 2.41 (m, 1 H);
2.48 - 2~62 (m, 1 H);
3.30 - 3.39 (m, 1 H)
4.26 - 4.35 ~split d, 1 H)
The d;astereomerically pure products or the mixture
can be employed in the subsequPnt reactions.
(5a) Ben~yl cis-2-azab;cycloC3.1O0~hexane endo/exo-3-carboxylat~
1.22 ml of th;onyl chloride are added dropwise, at
-15C, to 30 ml of benzyl alcohol. Then, at -10C, 1.5 9 of
the cis-endo/exo-am;noacid mixture prepared in Example
I~4a) are introduced. After a reaction time of 24 hours
at room temperature, the mixture ;s diluted with e~her ~nd
extracted by stirring with wa~er, cooling in ice. The
aqueous solution is neutralized with NaHC03 and extracted w;th
ether/methylene chloride which, after drying, is evaporated
Residue 2.2 9 of oil~
Rf: 0.65 ~silica gel, methylene chlorid0, methanol,
~lacial acetic acid, water Z0:10:2:2, ninhydrin
stain)
.2~i7~3~2
- 21 -
(Sb) ~enzyl cis-2--azabicycloC3~1.0]hexane-exo-3-carboxylate
Th;s compound is obtained by reacting the cis-exo-
am;noac;d prepared in Example I(4b) w;th benzyl alcohol and
th;onyl chlor;de by the process ind;cated ;n Example I~5a).
Rf 0.62 (sil;ca gel, m~thylene chloride, methanol,
glacial acetic acid, water 20:10:2:2, ninhydr;n
sta;n)
sc? Benzyl c;s-2-azab;cycloC3D1 O~hexane-endo-3-carboxylate
This compound is obtained by reacting the cis-endo-
aminoacid prepared ;n Example I~4b) with benzyl alcohol and
th;onyl chloride by the process ind;cated ;n Example I(5a~.
R 0.69 (sil;ca gel, methylene chloride, methanol,
glacial acetic acid, ~ater 20:10:2:2, ninhydr;n
stain)
(6) ~enzyl N-~1-S-carboxoethoxy-3-phenylpropyl)-S-alanyl-
cis-2-azab;cycloC3.1_.03hexane-exo/endo-3-carboxylate
2.0 9 of the benzyl ester prepared accordin~ to
Example I(Sa) are brought to react;on w;th 1.4 g of hy-
droxybenzotriazole (HOBt), 1.76 9 of dicyclohexylcarbo-
diimide and 2.2 9 of N-(1-S-carboethoxy-3-phenylpropy~)-S-
alanine in 28 ml of d;methylformam;de. After st;rring at
room temperature for 10 hours, the precipitated dicyclo-
hexylurea ;s f;ltered off ~I;th suction, the filtrate ;s
concentrated, the res;due ;s taken up ;n methylene chlor;de
and th;s solut;on ;5 extracted 2 x with saturated NaHCO~
solut;on. The organic phase is dr;ed, concentrated and 5.4 g
of the mixture of c;s-exo and-cis-endo diastereomers are
ob~a;ned.
- 22 -
~7) 3enzyl N-t1-S-carboethoxy-3-phenylpropyl)-S-alanyl-
cis-2-azabicycloC3~1.0]hexane-endo-3-S-carboxylate
t;somer 1)
The crude product obtained in Example I~6) ;s chro-
matographed on silica gel using cyclohexane/ethyl acetatein the ra~io 1.5:1. The isomer which is eluted first is
the S,SOS-cis-endo compound.
Rf: 0.24 ~silica gel, cyclohexane/e~hyl acetate 1:1)
1H NMR (CDCl3): 0.6 - 3.0 (m 13 H);
ln 3.2 - 3.9 (m 4 H~;
3.95 - 4~4 (q, 4 H);
4.8 - 5.0 ~doublet of doublets, 1 H)
5.15 (s, 2 H);
7.25 (s, 5 H);
7.35 (s, S H)
t8) ~enzyl N~ S-carboethoxy-3-phenylpropyl)-S-alanyl
c;s-azab;cyclo~3.1.0~hexane-endo-3-R carboxyLate
~isomer 2)
The crude product obtained in Example It6) ;s chro-
matographed on a column of silica gel using cyclohexane
ethyl acetate in a ratio 1.5:1. The isomer which is
eluted fourth is the cis-endo-S,S,R compound.
Rf: 0.09 ~silica gel, cyclohexane/ethyl acetate 1-1)
~ ~9) Benzyl N-(1-S-carboethoxy-3-phenylpropyl)-S-alanyl-
25` c;s-2-azab;cyclo~3.1~û]hexane-exo-3-S-carboxylate
~;somer 3) _ _
The crudc product obtained in ExampLe 1(6) is
chro~atographed on a sil;ca gel column using cyclohexane/
ethyl acetate ;n the rat;o 1.5:1. The ; omer wh;ch is
~.2~
- 23 -
eluted second is the cis-exo-S~S S compound.
R~ 0.20 (silica gel~ cyclohexane/ethyl acetate 1:1)
t1Q) Benzyl N-(1-S-carboethoxy-3-phenylpropyl)-S-alanyl-
cis-2-azabicyclo[3~1.0]-hexane-exo-3 R-carboxylate
S (;somer 4)
~ The crude product obtained in Example 1~6) is
chromatographed on a silica gel column using cyclohexane/
ethyl acetate in the ratio 1.5:1. The ;somer which is
eluted third ;s the cis-exo S S R compound.
R~ : 0.14 (silica gel cycLohexane/ethyL acetate 1:1)
~11) N-(1-S-Carboethoxy-3-pheny~propy~)-S-a~anyl-cis 2-
azab;cyclo~3.1.0~hexane-3-carboxylic acid hydro~
chloride
1.0 9 of the benzyl ester prepared in Example I(6)
is dissolved as the mixture of d;astereomPrs in 50 ml of
ethanol. 100 mg of palladium on charcoal t10%) is added
to this and hydrogenation is carried out at room temp-era-
ture under atmospheric pressure. After filtering off the
catalyst by suct;on the ethanolic solution is evaporated
ethanolic hydrochloric acid is added to the remaining oil
and the solvent is evaporated off. The residue is vigorously
stirred u;th ethyl acetate whereupon a colorless solid
mixture of the diastereomeric exo/endo carboxylic acids
Chydrochlorides) remains.
Y;eld: 0.7 9
Fxample I~
N-(1-S-Carboethoxy 3-phenylpropyl)-S-alanyl-cis-2-a~ab;-
cyclo~3.1.0~hexane-endo-3-S-carboxylic acid hydrochloride
(isomer I)
~2~
- 2~ -
0.2 9 of ~he benzyl ester prepared in Example I~7)
is subjected to catalytic removal of the benzyl group in
analogy to Example I(11), and the product ;s converted into
the hydrochlorideO
Yield: 0~125 9
H NMR (DMS0-d6): 0.6 - 5.0 (m, 21 H);
7.3 ts, 5 H);
9.~ (very broad s)
Example III
N-~1-S-Carboethoxy-3-phenylpropyl)-S-alanyl-cis-2-azabi-
cycloC3.1.0]hexane-endo-3-R-carboxylic acid hydrochloride
(isomer 2) _
0.22 g of the benzyl ester prepared in Example I(8)
is subjected to catalytic removal of the benzyl group in
analogy to Example 1(11), and the product is converted ;nto
the hydrochlor;de.
Yield: 0.13 9
H NMR (DMS0-d63: 0.5 - 5.1 tm, 21 H);
7.2 (s, 5 H);
10.1 (very broad s)
Example IV
N-(1-S-Carboethoxy-3-phenylpropyl)-S-alanyl-cis-2-azab;-
cycloC3.1.0~hexane-exo-3-S-carboxylic acid hydrochloride
~isomer 3~
0.27 9 of the benzyl ester prepared in Example I~9)
is subjected to cata~yt;c removal of the benzyl group in
ana~ogy to Example I(11), and the product is converted
into the hydrochloride.
Yield. 0.23 9
- 25 -
1H NMR ~DMS0-d63: 0.5 - 4u7 ~m 21 H);
7~3 ~s 5 ~);
10.0 (very broad s)
Example V
N~ S-Carboethoxy-3-phenylpropyl)-S-alanyl-cis-2-azabi-
cyclo~3.1.0~hexane-exo-3-R-carboxylic asid hydrochloride
~;somer 4)
,
0.3 9 of the benzyl ester prepared in ~xample I~10)
;s subjected to catalytic removal of the benzyl group in
analogy to Example It11)~ and the product is converted
into the hydrochloride.
Yield: 0.26 g
H NMR tDMS0-d6): D.4 - 4.8 ~m 21 H~;
7.3 ~s 5 H);
9.8 ~very broad s)
Example VI
N-~1-S-Carboxy-3-phenylpropyl)-S-alanyl-cis-2-a~abicyclo-
~3.1.0~hexane-endo-3-S-carboxylic acid (isomer 1) _
0.2 9 of the ethyl ester from Example II is dis-
solved ;n 5 mL of ~ater~ The solution is basified w;th a4 N aqueou~ solution of potassium hydrox;de. It is left
to stand at 0C overn;ght. After react;on has ended~
the pH ;s adjusted to 5 with concentrated hydrochloric
acid. The solution ;s appl;ed to 20 ml of strongly acid
;on exchanger ~IR 120~ H~ form)~ wh;ch ;s developed with
water and eluted w;th water rontaining 2X of hydrin The
fractions containing the above compound are evaporated.
The res;due is treated 2 x ~ith toluene and the toluene is
removed under reduced pressure. Ether ;s added to ~he
` - ~L2~9~3Z
- 26 -
resi due.
Yield: 0.13 9
lH NMR (D20) 0.6 - 5.1 ~m, 15 H)
7.3 (s, 5 H)
5 Example VII
N-t1-S-Carboxy-3-phenylpropyl)-S-alanyL-cis-2-azabicyclo-
C3.1 0]hexane-exo-3-S-carboxylic acid (isomer 3)
0.2 9 of the ethyl ester from Example IV is hydro-
lyzed and ~orked up in anaLogy to Example VI..
1û Yield: 0~12 9
H NMR ~D20): 0.4 - 4.8 (m, 16 H);
7.2 ts, 5 H)
