1232280
- 2 -
This application is a Divisional of Canadian Patent
Application Serial Number 441,040, filed November 14, 1983.
The invention relates to new derivatives of tri-
cyclic aminoacids, of the formula I
~ H
~6
~l 4 O F.
(I)
C
i
p~ 'CH - ?dF: -- CII - (CIi? ) n - C - X
CO R1
in which
n denotes 0 or 1,
A denotes -CIi = CIi- or -CH2 - CH2-,
R denotes hydrogen, (Cl to CE_)-alkyl or aralkyl with 7 to 9
carbon atoms,
Rl denotes hydrogen, or (Cl to C6)-alkyl, which can be opt-
Tonally substituted by amino, (C1 to C4)-acylamino, in part-
icular (C1 to C4)-alkanoyl amino, or benzoylamino, or (C2 to
C6)-alkenyl, (C~ to C9)-cycloalkyl, (C5 to C9)-cycloalkenyl,
(CS to C~)-cycloalkyl-(Cl to C4)-alkyl, (C6 to C1~)-aryl or
partially hydrogenated (C6 to C1.2)-aryl, each of which can be
substituted by (Cl to C4)-alkyl, (Cl or C2)-alkoxy or halo-
gen, or (C6 to C12}-aryl-(Cl to C4)-alkyl or (C~ to C13)-ar-
oyl-(Cl to C4)-alkyl, both of which can be substituted in the
aryl radical as defined above, or a monocyclic or bicyclic
heterocyclene radical with 5 to 7 or 8 to 10 ring atoms, 1 or
2 ring atoms of which are sulfur or oxygen atoms
1232280
- 3 -
and/or 1 to 4 ring atoms of which are nitrogen atoms, or a
side chain of a naturally occurring aminoacid, which may be
protected,
R2 denotes hydrogen, (Cl to C6)-alkyl, (C2 to C6)-alkenyl or
(C6 to C12)-aryl-(Cl to C4)-alkyl,
Y denotes hydrogen or hydroxyl and
Z denotes hydrogen, or
Y and Z together denote oxygen, and
X denotes (Cl to C6)-alkyl, (C2 to C6)-alkenyl, (CS to C9)
cycloalkyl, (C6 to C12)-aryl, which can be mono-, d:i- or tri
substituted by (C~_ to C4)-alkyd, (Cl to C4)-alkoxy, hydroxyl,
halogen, nitro, amino, (Cl to C4)-alkylamino, di-(C'.l to C4)
alkylamino and/ar methylenedioxy, or 3-indolyl, arid physio
logically acceptable salts thereof.
ls, If R1 represents a side chain of a protected natur-
ally occurring a-aminoacid, such as, for example, protected
Ser, Thr, Asp, Asn, Glu, Gln, Arg, Lys, Hyl, Cys, Orn, Cit,
Tyr, Trp, His or Hyp, preferred protective groups are the
conventional groups of peptide chemistry (cf. Houben-Weyl,
Volume XV/1 and XV/2). If Rl denotes the protected Lysine
side chain, the known amino-protective groups, especially
(Cl-C6)-alkanoyl, are preferred. Preferred O-protective
groups for tyrosine are methyl and ethyl.
Possible salts are, in particular, alkali metal and
alkaline earth metal salts, salts with physiologically ac-
ceptable amines and salts with inorganic or organic acids,
such as, for example, HC1, HBr, HZS04 malefic acid and fumaric
123220
- 4 -
acid.
Here and in the following text, aryl is to be un-
derstood as meaning preferab.Ly optionally substituted phenyl
or naphthyl. This applies analogously to aroyl residues.
Alkyl can be straight-chain or branched.
The configuration of the H atoms on C-2 and C-6 of
the tricyclene is the cis configuration. There are also two
other possible configurations of the H atoms on C-2 and C-6
of the tricyclic radical, i.e. the exoposition of t=he H atoms
in respect of the bicyclic [2.2.1] part of the ring (radical
Ia) and correspondingly the endo-position (radical Ib).
6
~'w CO2R
~ ~% N
(Ia) ~~ ' (Ib)
1 ~~ ~
C02R
The carboxyl group on C-4 both in radical Ia and in
radical Ib can be orientated in the trans-position (radicals
Ic + If) or in the cis-position (radicals Id + Ie) relative
to the hydrogen on C-2. This invention relates to all the
abovementioned configuration isomers and the mirror image
isomers of the formulae Ic to If.
m r. v
(I~)
6 ~f O.,R G
H
n j;~ N ' FI
1 H
(ZC) ' ~II
I1 ~ G FI ~y 4
~ iV (, O l .. ~ 'r-~.
A __ ; 'iI COII; I1 ~ t ~I
-~ ' 2 / ~ C02 R
(zo,'~ ~N
;1232~c;80
- 5 -
Compounds of the formula I have chiral carbon atoms
in positions C-1, C-2, C-4, C-6 and C-7 and. at the carbon
atoms labeled with an asterisk in the side chain. The invent-
ion relates both to the R-configurations and to they S-config-
urations at all the centers. The compounds of the formula I
can therefore be in the form of optical isomers, diastereom-
ers, racemates or mixtures thereof. However, preferred comp-
ounds of the formula I are those in which C-4 in the tricyc-
lic ring system and the carbon atoms labeled with an asterisk
(*) in the side chain have the S-configuration, with the ex-
ception of (-CO-*C'.HR1-NH-) - Cys, where the R-configuration
is preferred.
Particularly preferred compounds of the formula I
are those in which
1~, n denotes 1,
A denotes CH=CH or CHI-CH2,
R denotes hydrogen or alkyl with 1 to 4 carbon atoms,
R1 denotes hydrogen, (C1 to C3)-alkyl, (C2 or C,3)-alkenyl,
benzyl, 4-alkoxybenzyl, phenethyl, 4-amino-butyl or benzoyl-
methyl,
R2 denotes hydrogen, (CL to C4)-alkyl or benzyl and
X denotes phenyl, which can be mono- or di-substituted by (Cl
or C2)-alkyl, (Cl or C2)-alkoxy, hydroxyl, fluorine, chlor-
ine, bromine, amino, (Cl to (;4)-alkylamino, di-(C1 to C4)-al-
kylamino, nitro and/or methylenedioxy or trisubstituted by
methoxy, and in particular those compounds of the formula I
in which n denotes l, A denotes CH2-CH2, R denotes hydrogen,
1232280
6 -
R1 denotes methy:L or the radical of an optionally protected
naturally occurring aminoacid, X denotes phenyl, R2 denotes
hydrogen or ethyl, the hydrogen atoms on C-2 and C-6 have the
cis-configuration and the exo- or endo-configuration in res-
pect of the bicyclic [2.2.1] skeleton, the carboxyl group on
C-4 is orientated in the cis- or traps-position relative to
the hydrogen on C-2, and the chiral carbon atoms labeled with
an asterisk (*) and C-4 have the S-configuration.
Very particularly preferred compounds are endo-exo:
N-(1-S-carbethoxy-3-phenylpropyl)-S-alanyl-1R, 2R, 4S, 6S,7S-
tricyclo [5.2.1.02'6]-3-aza-decane-4-carboxylic acid, N-(1-S-
carboxy-3-phenylpropyl)-S-alanyl-1R, 2R, 4S, 6S, 7S-tricyclo
[5.2.1.02'6]-3-aza-decane-4-carboxylic acid, Na-(1-S-carbeth-
oxy-3-phenylpropyl)-S-lysyl-l..R, 2R, 4S, 6S, '7S-tricyclo
1~~ [5.2.1.02'6]-3-aza-decane-4-carboxylic acid and
Na-(1-S-carboxy-3--phenylpropyl)-S-lysy:l-1R, 2R, 4S, 6S, 7S-
tricyclo [5.2.1.02'6]-3-aza-decane-4-carboxylic acid, endo-
endo
N-(1-S-carbethoxy-3-phenylpropyl)-S-alanyl- 1S, 2S, 4S, 6R,
2C) 7R-tricyclo [5.2.1.02'6]-3-aza-decane-4-carboxylic: acid, N-
(1-S-carboxy-3-phenylpropyl)-3-alanyl-1S, 2S, 4S, 6R, 7R-tri-
cyclo (5.2.1.02'6]-3-aza-decane-4-carboxylic acid., Na-(1-S-
carbethoxy-3-phenylpropyl)-S-lysyl-1S, 2S, 4S, 6R, 7R-tricyc-
to C5.2.1.02'6]-3-aza-decane-4-carboxylic acid and Na-(1-S-
25 carboxy-3-phenylpropyl)-S-lysyl-1S, 2S, 4S, 6R, 7R-tricyclo
[5.2.1.02'6]-3-aza-decane-4-carboxylic acid, and exo-endo
12322~U
N-(1-S-carbethoxy-3-phenyl.propyl)-S-alanyl-1R, 2S, 4S, 6R,
7S-tricyclo [5.2.1.02'6]-3-aza-decane-4-carboxylic acid,
N-(1-S-carboxy-3-phenylpropyl)-S-alanyl-1R, 2S, 4S, 6R, 7S-
tricyclo [5.2.1.02'6)-3-aza-decane-4-carboxylic acid, Na-(1-
S-carbethoxy-3-phenylpropyl)-S-lysyl-1R, 2S, 4S, 6R, 7S-tri-
cyclo [5.2.1.02'6]-3-aza-decane-4-carboxylic acid and
Na-(1-S-carboxy-3-phenylpropyl)-S-lysyl (1R, 2S, 4S, 6R, 7S-
tricyclo [5.2.1.02'6]-3-aza-decane-4-carboxylic acid, and
exo-exo
N-(1-S-carbethoxy-3-phenylpropyl)-S-alanyl-1S, 2R, 4S, 6S,
7R-tricyclo [5.2.1.02'6]-3-aza-decane-4-carboxylic acid,
N-(1-S-carboxy-3-phenylpropyl)-S-analyl-1S, 2R, 4S, 6S, 7R-
tricyclo [5.2.1.0,2'6]-3-aza-decane-4-carboxylic acid, Na-(1-
S-carbethoxy-3-phenylpropyl)-S-lysyl-1S, 2R, 4S, 6S, 7R-tri-
cyclo [5.2.1.02'6]-3-aza-decane-4-carboxylic acid and
Na-(1-S-carboxy-3-phenylpropyl)-S-lysyl-1S, 2R, 4S, 6S, 7R-
tricyclo [5.2.1.02'6]-3-aza-decane-4-carboxylic acid.
The invention furthermore relates to processes for
the preparation of the compounds of the formula I. One pro-
2p cess variant comprises reacting a compound of the formula II
HOC-Cad-.~'H-CIi- ( C312 ) n- ~ -X ( I I )
F;~ CO?R2 ?.
1232280
_8_
in which n, R1, R2, X, Y and Z have the meanings as in
formula I, ~-:ith a compound of the formula III
H
s
7
t
C02it ( I I I )
H H
in which
A has the meaning as in formula T and
4J denotes hydrogen or a radical which can be split off
under acidic, basic or hydrogenolytic conditions, in
particular a tert.-butyl or benzyl radical,
by known amide formation methods of peptide chemist:ry,.
and; where relevant, subsequently splitting off thE: radi-
cal lJ by treatrnent G~ith an acid or base or hydrogenolysis,
and, where relevant, also splitting oif the radical R2
by additional treatment with acid or base, the free: car-
boxylic acids in each case being obtained.
Further synthesis processes for the preparation
of compounds of the formula I ire ~;~hich Y and Z together
denote oxygen comprise reacting a compound of the formula
IV
ii
(IV)
' C O S~l
2
ii
CO--CI-I-hH?
R~
in ~-:iiiel~ Rt ano A hUve tfie meaning as in formula I and
11 inns the meaning as in formula I1L; ~:~ith a conpound of
tfie formula V
. 12322$0
_ g _
R202C--C H=C H-C 0-X (V)
in which Rz and >; have the meanings as in formula 7:, in a
h?ichael reaction in a known manner (Organikum, 6th edi-
tion, page 492, 1967), and, where relevant, splitting off
S the radical tJ and/or the radical R2 as described above,
or reacting a compound of the abovementioned formui.a IV
with a compound of the general formula VI, in which R2
has the meaning as in formula I, and with a compound of
the general formula VII
OHC-C02R2 X-CO-°CH3
(V l) (VII)
in v,~hich Y, has the nean-ing as in formula I, -in a (~?annich
reaction in a known manner <Sutl. Soc. Chim. Franca 1973,
page 625), and, where relevant, subsequently splitting
1 S o f f the radi ca l 41 and/or the radi ca l R2 os descri bed
above to form free carbonyl groups.
Compounds of the formula I in which Y and ~~ each
denote hydrogen can also be prepared by reacting a corn--
pound of the abovementioned formula IV with a compound o.
the formula VIII
~02R2
O - C~ (VII:I)
~I12__~F3?-x
-in which R2 and i; !oave tire meaning, as in formula i, by
the procedure described in J. Arner. Cher>>. 'Soc. 93, 297
(i97i), reducing the resulting Schiff's baSES and, where
2S relevant,. sub;equ~ntly splitting of. t!~~ r~dicaL 4d and/or
thc: radical. ~~ as described above to form the free
1232280
- 10 -
carboxyl groups. The reduction of the Schiff's bases can
be carried out catalytically, electrolytically or with
reducing agents, such as, for example, complex boranates,
preferably sodium borohydride or sodium cyanoborohydride.
S Compounds of the formula I in which Y denotes
hydroxyl and Z denotes hydrogen can also be obtained, for
example, by reduction of a compound I in which Y and Z
together denote oxygen obtained by the above procedures.
This reduction can be carried out catal.ytically with hydro-
gen or ~.rith another reducing agent, such as sodium boro-
hydride and other complex boranates or, for example,
borane-amine conpl.exes.
Compounds of the formula I in which R represents
ii j'ur vycn Cari, i i Gc5 i r i:ij, be COnvei'it=U ~tlip l(?211' t'Siers
1S ef the formula I in which R denotes (C1 to C6>-alk;,~l or
tC7-C~>-Gralkyl by methods which are knoh~n per se.
The invention also relates to compounds of the
formula III in suhich the H atoms on C--2 and C-6 are in
the cis-configuraoion relative to one another, the pyrro-
lidine ring is orientated in the er~do-- or exo-position
re lat ive to the bi cyc l i c ri ng syster~;, the group --C02;:? on
C-~o is in the cis- or t:rar~s-position relative to the
hydrogen on C-2, 4; denotes hydrogen or a radical w!wich
can be split off under acid, basic or hydrogenolyt=ic con-
2> ditions and ~~ denotes a CH=CH or CF!2--CHZ group.
These compounds are used according to the iinven-
lion us st2rting substances in the synthesis of cor;pounds
or the formula T, and ran be prepareJ,, according to the
invention, l:y the follos;ing pr~ocerJuro:
1232280
- 11.-
In one synthesis variant, a compound of the formula
IX or X
~ H
2
1~
(L1~)
o r o
(Xa) 1; (71~) H
in which the hydrogen atoms on C-2 and C-6 are in the cis-
configuration relative to one another and the cyclopentanone
ring is oriented either in the endo-position (formulae IX a
and b) or in the exo-position (formulae X a and b) relative
to the bicyclic ring system, is used as the starting sub-
stance.
The compounds of the formulae IX a and X a are
known from R. R. Sauer, J. Org. Chem. 39, 1850 (:1974), and
the compounds of the formulae IX b and X b are described in
J. Org. Chem. 32, 3120 (1967).
The ketones IX and X are converted by known methods
into the oximes or oxime derivat=ives of the formula XI
123220
- lz -
(XI)
A
H
N.~OR3
in which the H atoms on C-2 and C-6 are in the cis-configura-
tion relative to one another, the cyclopentane ring is orien-
tated in the endo- or exo-position relative to the bicyclic
ring system, A denotes a CH=CH or CH2-CH2 group and R3 de-
notes hydrogen, alkyl, aryl, aralkyl, -S03H, arylsulfonyl or
another group suitable for Beckmann rearrangement. R3 is pre-
ferably hydrogen; (Cl to C6)-alkyl, (C6 to C9)-aryl, (C~ to
C10)-aralkyl, S03H, benzenesulfonyl or p-toluenesulfonyl. The
compounds of the formula XI are converted into a compound of
the formula XII }j
1 ~~
<Y,II)
}3 i O
li
in which the H atoms on C-2 and C-7 are in the cis-configura-
tion relative to one another, the lactam ring is orientated
in the endo- or exo-position relative to the bicyclic ring
system and A has the abovementioned meaning, in <~ Beckmann
rearrangement, cf. Organic Reactions 11 (1960) 1-1!~6, by re-
action with a mineral acid, such as, for example, sulfuric
acid or polyphosphoric acid, or, if R3 denotes H, with ben-
zenesulfonyl chloride or p-tol.uenesulfonyl chloride and a
base, such as tri-
- ~.~~~r~r~0
13 -
ethylamine, or with an organic acid, such as, for
example, formic acid. The regio-isomers which arise
after the E3eckmann rearrangement can easily be removed
by recrystallization or by column chromatography over
silica gel. The compounds of the formula XII are halo-
genated to give a compound of the formula XIII
Y FIal
via 1
CXTII)
FI
in which A has the abovementioned rneaning and Nal denotes
a halonen atom, pr~wierably chlorine or bromine. Examples
of suitable halogernating agents are inorganic acid
halides, such as ~C15, S02C1?, POCl3, SGCl2 and
PBr3, and halogens, such as bromine. It is advantageous
to_use PClS or POCl3 in combination with S02C12.
An imide halide is first formed as an intermediate,, and
then reacts further with the halogenating agents men-
tinned and ~y subs~que~~t hydrolysis under basic co~ndi-
Lions, preferably with aqueous alkali metal carbonate,
~o give a compound of the formula XIII.
The compounds of the formula XIII are subsequently
catalyt~ically reduced 'in a polar protic solvent, such as,
for example, Gn alcohol, prcferall~~ ethanol, or a carboxy-
lic acid; such as, for example, acetic acid, Y;ith addi-
tion of an acid acceptor, sucf~ as, for exampla, sodiu~~
acetate or tnictHy~~mir~ef to give a cor-pound of tfie
i!5 formula XIV
1,~ - 123280
H
ial tXIV)
' IW
H Ii
in ~rhich A and Hal have the abovementioned meanings.
Examples of suitable catalysts are Raney nickel and
palladium- or platinum-on-animal charcoal.
'> If A denotes CH=CH, it is necessary to protect
the C-C double bonds via a cyclopentadienyl-iron dicarbonyl
complex of the formula XV. The iron complex is removed
again with ~1a in acetone after the hydrogenation,. as des-
cribed in J. Amer. Chem. Soc. 97, 3254 01975) K.M.
.0 t~iicholas.
CO 1' ijal
f
C C C, ..t
~, ~ )
CO I~ ti
BFI
Compounds of the formula XIIr can also be prepared
directly by halo~~enation of the compounds of the formula
XII usincJ srnaller amounts of the abcvementioned halogem t-
15 ing agents.
Compounds of the formula XIV are con~,~erted into
a compound of the formula III in ~;hicin r! de°~otes hydrogen
by tl~e knovan Favorskii reaction in the presence of a
base, una', v.~here relevar;t, the product is esterified.
20 1'he abovernentioncd Favorskii reaction i_ car.ied out in
an alcoholic solver~i-, ~uc'~ as merhancl, ethanol or 2ert.-
b!Wanol, or in winter or mir,tur~:s thereof at tci:y,nratures
12322$0
- 15 -
in the range from 20°C to 140°C, preferably between 60°C
and
100°C. Alkali metal or alkaline earth metal hydroxides, such
as sodium hydroxide, potassium hydroxide or barium hydroxide,
or alkali metal alcoholates, such as, for example, sodium
methylate or potassium tert.-butylate, are advantageously
used as bases.
The compounds of the formula III in which W denotes
hydrogen which are obtained by the Favorskii reaction are
racemates, and can be obtained i.n the form of a di~astereomer
mixture. Thus, starting from the ketones of the formula IX,
the aminoacids of the formulae IIIa and IIIb together with
the mirror image isomers are obtained, and starting from the
ketone of the formula X, the aminoacids of the formulae IIIc
and IIId and the associated mirror image isomers are ob-
tained, W denoting hydrogen and A having the above meaning.
n C02~:
i=
A ~ FjN H
~J
J
'' H
H
t~ ~.~ 2~~~ n ~02w
(IIIa) (IIIb) (IITc)
2 5 ''-~5 4,~~ ~ I ,
I~I CO ld
2.
'' f 1
Ii
(zm)
12u z,2$0
- 16 -
The hydrogen atoms on C-2 and C-6 are in the cis-
configuration relative to one another in all four compounds
of the formulae IIIa-IIId; in compounds of the formulae IIia
and IIIb, the pyrrolidine ring is orientated in the endo-pos-
ition relative to the bicyclic ring system and in the form-
ulae IIIc and IIId, the pyrrolidine ring is orientated in the
exo-position, the -C02W groups on C-4 in the compounds of the
formulae IIIa and IIId are orientated in the cis-position re-
lative to the hydrogen atom on C-2, and in the compounds of
the formulae IIIb and IIIc these groups are correspondingly
in the transposition. In the following reactions, the corres-
ponding racemates or diastereomer mixtures can be used. The
racemates can also first be separated into the optical anti-
podes by known methods of peptide chemistry, and they diaster-
eomer mixtures can be separated into the diastereomers by
fractional crystallization, or by column chromatography over
silica gel as diastereomers or after formation of suitable
derivatives.
If desired, the aminoacids can be esterified. The
preferred tert.-butyl esters and benzyl esters of the amino
acids of the formula I:II (W denotes tert.-butyl or benzyl)
are obtained by the conventional methods of peptide chemist
ry, such as, for example, in the case of the tert.-butyl es
ter, by reaction of the acids with isobutylene in an inert
organic solvent (for example dioxane) in the presence of
acids (such as, for example, sulfuric acid). If A denotes
CH=CH, the following process has proved to be particularly
advantageous: the corresponding aminoacid is acylated on the
nitrogen with a group
1232280
_ 17 _
which can be split off under basic canditions, such as,
for example, the methytsulfonylethoxycarbonyl group
(= P~1SC), Tesser, Balvert-Geers, Int. J. Pept. Protein
Res. 7, 295 (1975).
The carboxylic acid is reacted with tert.-butanol
in the neutral to weakly basic pH range in an organic
solvent, such as, for example, pyridine, in the presence
of propylphosphonic acid anhydride to give the corres-
ponding tert.-butyl ester. The tert.-butyl ester of the
formula III C4! denotes tert.-butyl) is obtained by
splitting off the h?SC protective group with an alkali in
the strongly alkaline pH rance irr an aaueaus solvent.
The benzyL esters of the formula II (IJ denotes
vcnej-'v) arc Gbtaiii'cv uj" tile vGriVcrW iGrioi net ivu lritil
benzyl alcohal and thianyl chloride.
The compounds of the formula II in wrhich n cenotes
1, Y and Z denote hydrogen, R1 denates methyl, R2 denotes
methyl or ethyl and ;; denotes phenyl which are used ss
starting substances for the preparation of compounds of
the farmula I are kno;.rn (European t'atent application t~EO.
~7,2Ji>. The compounds of the formula ZI cUn be pre;~ared
bj~ various pr~oced~nes. In one synthesis ~!ar iant, a
ketone of the abovementioned formula VII is used as the
starting substance, and is reacted with a compound of the
abovementioned formula VI together faith arninoacid esters
of the formula Y,VI
fI2N - Cfi - C02i"I' Z~,"O?C-C'E~--NEi-CEI-CFI?-CO--X
l
(~;VZ) (;vVl.I)
12322$0
- 18 -
in which Rl has the abovementioned meaning and W' denotes a
radical which can be eliminated by hydrogenolysis or under
acidic conditions, in particular a benzyl or a tert.-butyl
radical, by known procedures in a Mannich reaction to give a
compound of the formula XVII in which Rl, R2, X and W' have
the abovementioned meanings, with the restriction that if W'
denotes a radical which can be split off hydrogenolytically,
in particular benzyl, R2 may not have the meaning of W' . If
the radical W' is split off hydrogenolytically with the aid
of, for example, palladium, compounds of the formula II in
which Y and Z denote hydrogen are obtained with a hydrogen
uptake of 3 molar equivalents. If the uptake of hydrogen is
stopped at 1 molar equivalent, compounds of the formula II in
which n denotes 1 and Y and ;~ together denote oxygen are ob-
tained, these compounds also being obtained if the radical W'
of the formula XVII is split off with acids, such as, for ex-
ample, trifluoroacetic acid or hydrochloric acid, in an inert
organic solvent, such as, for example, dioxane.
Compounds of the formula XVII are also accessible
by Michael additions of a compound of the abovement:ioned for-
mula V to a compound of the abovementioned formula XVI by
known procedures. This process is preferably suitable for the
preparation of these compounds of the formula XVII in which
R1 denotes methyl, R2 denotes ethyl and X denotes aryl.
The compounds of the formula XVII are obtained as
diastereomer mixtures. Preferred diastereomers of t:he formula
XVII are those :ire which the chiral carbon atoms labeled with
an asterisk each have the S-configuration,
- 19 - X232280
These can be separated off by, for example, crystalliza-
tion or chromatography, for example on silica gel. The
configurations of the chiral carbon atoms are retained
during subsequent splitting off of the radical W'.
The compounds of the abovementioned formula IV
used as starting substances for the preparation of the
compounds of the farmula I are obtained from the com-
pounds of the abovementioned formula III by reaction vrith
an N-protected 2-aminocarboxylic acid of the formula XVTII
(XVI:II)
V - HI\ - CIA - C02H
in Hhicf~ V denotes> a protective group and R1 has the
abovementioned meaning, by known procedures. Examples of
suitable protective groups V h~hich are split off again
when the reaction has ended are tort.-butoxycarbonyl and
benzyloxycarbonyl.
The reaction of a compound of the forrnula II 4aith
a compound of the formula III for the preparation of a
compound of the formula T is carried out as a condensa-
tion reaction known in peptide chemistry, in which,. fcr
example, dicyclohexylcarbodiir~ide and~i-hydroxy-benzo-
triazole are added as con<i~nsinr_, agents. Trifluoroacet-ic
acid or hydrochloric acid is preferably used as the acid
in the subsequent splitting off of the radical 4~t under
acid conditions. The t~enz~~l group (tv denotes benzyl) is
preferable split ofi by Irydroger~olysis on ,palladiur~°on-
charc.o~~. in alcohol.
The conviruraticn_> of the inter7ediates on toe
- 2 0 - 1232280
bridge head C-2 and C-6 are in each case retained in the
reactions described above for the preparation of the com-
pounds of the formulae III, IV and I.
The compor.m ds of the formula III obtained accord-
S ing to the procedure described above are obtained as a
mixture and can be separated from one another by, for
example, recrystall.ization or chromatography.
The compounds of the formula III are obtained as
racemic mixtures, and can be used as such in the other
syntheses described above. However, lifter separation of
the racemates into the optical antipodes by conventional
methods, for example by s2lt formation ~~ith optically
active bases or acic!s, they can also be used as pure
enantiomers. The pure enantiomers can also be ohtained_
If the compounds of the formula T are obtained as
racemates, these can also be split into their enantiomers
by the convent i ona 1. methods, such as, for exarno le, by
salt formation with optically active bases or acids, or
they can be separated by chromatography.
The compc:unds of the formula I according to the
invention arc in the form of inner saW s if R is f.ydrogen.
As amphoteric compounds, they can form salts with acids
or bases. These salts are prepared in a conventional
manner b)~ reaction ~;ith one equivalent of acid or base.
The compoun~s of the formula I and their salts
have a lon5-LGsting, intensive hypotensive action. They
are you~erful inhibitors of the anc3iotensin-coyerting
enzyme CA!'~ inhihit~rs). They can t;e used for comba~in~
high blcocs pressure cf various origins. It is also pos°
X232280
- 21 -
sible to combine them with other hypotensive, vasodilating or
diuretic compounds. Typical representatives of these classes
of active compounds are describedin, for example, Erhardt-
Ruschig, Arzneimittel (Drugs), 2nd edition, Weinheim 1972.
They can be used intravenously, subcutaneously or perorally.
The dosage for oral administration is 1-100 mg,
preferably 1-40 mg, per individual dose for adult patients of
normal weight, which correspands to about 0.013-1.3 mg/kg/day
preferably 0.013 t:o 0.53 mg/kg/day. In severe cases, it can
also be increased, since no toxic properties have as yet been
observed. It is also possible to reduce the dose, and this is
especially appropriate if diuretics are simultaneously
administered.
The compounds according to the invention can be ad-
ministered orally or parenterally in an appropriate pharma-
ceutical formulation. For an oral use form, the active comp-
ounds are mixed with the conventional additives for this,
such as excipients, stabilizers or inert diluents, and are
brought into suitable administration forms, such as tablets,
dragees, push-f.it~ capsules, aqueous, alcoholic or oily sus-
pensions or aqueous, alcoholic or oily solutions, by convent-
Tonal methods. Examples of inert carriers which can be used
are gum arabic, magnesium carbonate, potassium phosphate,
lactose, glucose and starch, especially maize st=arch. The
formulation can be carried out either with dry granules or
moist granules. Examples of suitable oily excipients or sol-
vents are vegetable and animal oils, such as sunflower oil
and cod-liver oil.
lz3zz~o
_ 22 _
For subcutaneous or intravenous administration,
the active compounds or physiologically acceptable salts
thereofi are dissolved, suspended or emulsified, if
desired with the substances conventional for this, such
as solubilizing agents, emulsifiers or other auxiliaries.
Examples of suitable solvents for the new active com-
pounds and the corresponding physiologically acceptable
salts are: water, physiological saline solutions or
alcohols, for example ethanol, propanediol and glycerol,
and in addition also sugar solutions, such as glucose
solutions or mannitol solutions, or a mixture, of the
various :;olven~s n;entioned.
The a>:at°~ples which iollo~.~ serve to illustrate
the inventions t,rit:hout restriction it to the compounds
i5 mentioned as representatives.
Unless indicated otherwise, the 1N-r7 i~1 F; data given
in the examples vi~ich follow were determined by measure-
ment in CDCl3 ancf are given in ~~ (ppm).
Example 1
hl-(i-S-Carbetho>:y-~-phenylpropyl)-S-alanyl-iR,2R,4S,bS,
?S-tricycloC5.2.1.02'~J-3--aza-decane°4-carl;oxylic acid
hydroci~lo~~ide
a) Ci~) Cndo-tricy~loC6°2.'1.02'7J-3-aza-j~-oxo-undec;sne
7.8 g of (+,7 endo~-tricycloC:.2.1.0'°6J-3-oxo-dacane
2S (Journ. Org. Chern. ~2, 3120, 196-l) ire dissolved in 52 ml
of 95% strength ropwmic acid. 9.1 g of hy~roxylamirie-0-
sulfionic acid, dissolved i~~ 2h ml of 95i> strength formic
aciu; ire added dropwise thereto in the course of 10
minutes. The my~;v:ure is then bpi led under rcflox for 2
sz3zzso
_ 23 _
hours. After cooling, ice is added, and the mixture is
neutralized with concentrated sodium hydroxide solution,
with ice-cooling. The mixture is extracted with methyl-
ene chloride and the extract is washed with Hater, dried
S and concentrated on a rotary evaporator. Crude yield:
7.4 g of mixture. The mixture, which is composed of
endo-tricycloC6.2.1.02-77-3-aza-4-oxo-undecane and endo-
tricycloC~.2.1.02'77-4-aza-3-oxo-undecane is separated
into its components over silica gel w ith methylene chlor-
ide/methanol 95:5.
Yield: 4.S g; melting point: 170°-17?_°C
b) C+) Endo-tricycLoC6.2.i.0~'7~-3-aza-4-oxo-5,5-di-
chloro~undecane
4.S g of the lactar,7 frorn Example 1a are dissolved
1S in 70 ml of anhydrous chloroform, and S.b g of phosphorus
pentachloride are lidded at room temperature, v:~hile stirr-
ing. 7.8 g of sulfuryl chloride in 8 ml of chloroform
are added dropwise to this mixture in the course of 30
minutes, and the rr~iature is then refluxed for 3 hours.
Thereafter, it is rencered neutral Hith saturated potas-
siurn carbonate solutiUrl, while cooling. After the
chloroform pl~a~.:e his l:~cen seraarated o'f, the ac~uoous
phase is er.tracted vi th meti~ylene chloride and thc~
organic pl~asea arc combined, Hashed with water, dried and
concentna~ed in vacuo. The crude product -is -filtered
over si lica gel with metl~ylene chloricJe/methanol 95:5.
Yield: ~.7 g; rnel-t ing paint: 199-200°C
_ 2 4 _ 1232230
c) (+) Endo-tricycloCb.2.1.02-77-3-aza-4-oxo-5-chloro-
undecane
2.9 g of the dichlorolactam from Example 1b and
1.7 ml of triethylamine are dissolved in i70 ml of
ethanol. About 0.7 g of Raney nickel is added thereto
and hydrogenation is carried out. P,fter 1 equivalent of
hydrogen has been taken up, the hydrogenation is inter-
rupted, the catalyst is filtered off 4rith suction and the
ethanol solution is concentrated in vacuo. The residue
is taken up in ethyl acetate and the mixture is crashed
with ~dater, dried and evaporated. The residue is separa-
ted into its components over silica gel t-pith mechylene
chloride/methanol 95:5.
Yield: 1.7 g; melting point: 179-1E1"C
d) 1:1 mixture cf 1R,2R,4S,6S,7S--tricycloC5.2.1.02'b7-3-
aza-decane-4-carboxylic acio' and 1S,2S,4R,bR,7R-t~i-
cycloC5.2.1.02-r'W3-aza-decane-4-carbo;;ytic acid
1.3 g of the monochlorolactam from Example 1c are
added to a boiling solution of 2.2 g of bariurn hydroxide
?0 oc tahydrate i n 39 ml of Ovate r. The rsi xture i s ref luxed
for 4 hours and then adjusted to pH (>.5 reith concentrated
sulfuric acid and refluxed for 1 hour. After cooling,
the precipitUt~ is filtered off s,~ith suction. The mother
liquor is concentrated to dryness and the residue is
crystallized from ethyl acetate.
field: 1.1 g,-. R~_: 0.b1 (SiU2; CH2Cl2 / CHSOH /
Ci;3C02ti / H2C 20:15:2:4)
According vo the 1H-f~i~~R (270 i'fl;z), a small. amouou
of 1S,2S,4S,bf;,-~I;-tric:ycloC5.2, i.OZ-57-3-~aaa-decaoe-Ir--
_ lz;~zzso
- 25 -
carboxylic Gcid and 1R,2R,4R,6S,7S-tricycloC5.2.1.02~67-3-
aza-decane-4-carboxylic acid, which can be separated off,
are formed.
e> 1 :1 mi xture of benzyl 1 R,2R,<<S,6S,7S-t ri cyc lo-CS.2.1 .
S 02~67-3-aza-decane-4-carboxylate hydrochloride and
benzyl 1S,2S,4R,6R,7R-r_r-icycloCS.2.1.02~67-3-aza-decane-
4-carboxylate hydrochloride
ml of benzyl alcof~ol are cooled to -SoC and
i.7 g of thionyl chloride are' added dropwise. 1.1 g of
10 the racemic aminoacid from Example 1d are added to this
solution. The mixture is allowed to corne to 0oC and is
stirred at 5°C for 17 hou r. ~ihe benzyl alcohol is
distilled off in vacuo and the residue is triturated with
ui isop; Opyl etiner-.
Yield: 1.1 g
1H-PJf-;R (Dt'SO-db) : 1 .0-3.0 (n, 51~),. 3.2--4.3 Cm 3H)
5.2 (s, 2H), 7.4 (broad s 5!~) and 9.2--10.5 (broad,. 2H)
f) Eenzyl tJ-(1-S-carbethoxy-3-phenylprohyl)-S-alanyl°
11:,2R,4S,bS,7S-tricycloC5.2.1.02'67-'-aza-decar~e-4-
carboxylate
0.96 ~ of N~-(1-S--carbWhcxy-~-phenylpropyl.)-S-
alun;ine, 0.46 g of hydro;:ybenzotriazole, i g of tfoe
benzyl ester from Cxarnple 1e, 0.7 g o~f dicyclohexy lcarbo-
diirnide and 0.4 g o. I;--ethylmorphol-ine are added succes-
sivel~ to 10 ml of anf~ydrous dimethyl~ormamide,. with ice-
cooling, and the mixture is stirred at room temperature
for 17 hours. It is then diluted with i2 rsl of ethyl
acetate and the urea which ha.s precipitated is filtered
oi' uith suction. ~-Hr~> solvent i; d-istilled off in vacuo.
123220
-- 2 b -
The residue is taken up in ether and the mixture is.
washed with saturated sodium carbonate soLuticn and Hater,
dried and concentrated. The 'i.7 g of residue is separated
into the pure diastereomers over silica gel with cyclohexan~/
ethyl acetate 8:2.
The fractian Hhich runs through rapidly contains
benzyl N-(9-S-carbethoxy-3-pf~enylpropyl)-S-alanyl-9S,2S,
4R,bR,7R-tricy~clo-C5.2.1.02-67-3-aza-decane-4-carooxylate.
900 mg; m/e: 532;. Rf - 0.52 (S-i02; cyclohexene/ethyl
acetate 1:1).
The fraction which runs through slowly contains
400 mg of benzyl hd-(1-S-carbethoxy-3-phcnylpropyl)--S-
alanyl-1R,2R,4S,6S,7S-tricyctoC5.2.1.C2'67-3-aza-decane-
4-car'~o ~lat~.
y
mle: 532; Rf - 0.43 (Si02; cyclohexane/ethyl
acetate 1:1)
g) i~-(1-S-Carbethoxy-3-phenylpropyl)-5-alanyl-9R,2R,4S,
6S,7S-tricycloC5.2.1.02°GJ-3--aza-decane-4-carboxylic
acid hydrochloride
350 mg of l>enzyl W-(1-S-carbevhuxy-3-phenyl-
propyl)-S-alanyl°1R,2R,4S,bS,7S-tricycloC5.2.i.C2WJ--3-
aza-decane-4-carbo>:ylate from Example 1f are dissolved in
10 ml of ethanol, 3C ng of 10'/., strengtSs palladium-on-
charcoal are added anti hydrogenation is carried Olll Gt
room temperature. After the catalyst has bean filtered
off trith sucvion, t:he solution is concentrated in v~cuo,
the residue is dis~;olved in ethyl aceta~e end the solu-
tion is render ed ac id with eti~~~r~olic hydrogen chloride
and canc~ntrated on ~ rotary ev;~t~orut:or. The residue is
lz3zz~o
- 27 -
triturated with di.isopropyl ether.
Yield: 270 mg; melting point: 162-165°C (decomposii~ion); Rf -
0.42 (Si02; methyl.ene chloride/methanol 8:2)
Example 2
N-(1-S-Carbethoxy-3-phenylpropyl)-S-alanyl-1S,2S,4S,6R,7R-tri-
cyclo[5.2.1.02'6]-3-aza-decane-4-carboxylic acid hydrochlor-
ide
N-(1-S-Carbethoxy-3-phenylpropyl)-S-alanyl-1S,2S,4S,
6R,7R-tricyclo[5.2.1.02'6]-3-aza-decane-4-carboxylic acid hy-
drochloride is obtained in an analogous manner by the process
described in Example le to lg using 1S,2S,4S,6R,7R-tricyclo-
[5.2.1.02'6]-3-aza-decane-4-carboxylic acid as the starting
substance.
Example 3
N-(1-S-Carbethoxy-3-phenylpropyl)-S-alanyl-1S,2R,4S,6S,7R-tri-
cyclo[5.2.1.02'6]-3-aza-decane-4-carboxylic acid
a) (+) Exo-tricyclo[6.2.1.02'7]-3-aza-4-oxo-undecane
The compound is prepared by the process described
in Example la), starting from (+) exo-tricyclo[5.2.1.02'6]-3-
oxo-decane (Journ. Org. Chem. 32, 3120 (1967)). The lactam
mixture is separated into its components over silica gel us-
ing methylene chloride/methanol. 9:1. Rf = 0.49 (Si02; CH2C12/
CH30H 9:1); melting point: 178-180°C
b) (+) Exo-tricyclo[6.2.1.02'~]-3-aza-4-oxo-5,5-dichloro-un-
decane
The compound is prepared by the process described
in Example lb, starting from the lactam of Example 3a.
Melting point: 240°C; Rf: 0.49 (Si02; CH2C12/
D
12322$0
_ 2g _
CH30H 95:5)
c) C1) Exo-tricycloC6.2.1.02~77-3-aza-4-oxo-5-chloro-
undecane.
The compound is prepared by the process described
in Example 1c, starting from the dichlorolactam of
Example 3b.
Rf - 0.26 <Si02; CH2Cl2 / CH30F1 95:5)
d> 1:1 mixture of iS,2R,4S,6S,7R-tricycloC5.2.1.02°67-3
aza-decane-4-carboxylic acid and mirror image isomers
and 1R,2S,4S,bR,7S-tricycloC5.2.1.02~G7-3-aza-decane
4-carboxylic acid and mirror image isorners
-the compounds are prepared by the process des-
cribed in Example 1d, starting from the monochlorolGctam
oT ~xanple ~c.
Ri - 0.54 CSi02; CH2Cl2/CH30H/Cl?3C02H/H20
20:15:2:4)
Nf-1R (D20) . 0.°-1.6 (m 8H); 2.1-2.5 (m 3H); and 3.~'+-4.0
(m, 2H)
e) 1:1 mixture o. benzyl 1S,2R,4S,GS,7R-tricyclo-
C5.2.1 .02.G~._~_a,a-dec::ne-4-carboxyl a to and ~ri r rcr
image i some r s ~: nd benzy L 1 R,.2S,4SF6R,.-lS-t ri cyc lo-
C5.2.1 .02'~'~--3-aza--decane-4-carhoxylate and mirror
image isomers
The compo~.rnds are prepay ~d by tl~~ process des-
crib~d in Example 1e, starting rom the aminoacid mixture
of Example 3d.
Rf - U.?1, diastereomer I (SiOZ; CH?Clr/CH~01-i 95:5)
R.~ - 0.26 diastercomer II.
The mixi:ur~, can be separated preparatiuely into
- 2 9 _ ~i~ra.~. 2~r8~
the tuo racemic diastereomers chromatographically over
silica gel avter t:-acylation.
f) Mixture of benzyl N-(1-S-carbe-thoxy--3-phenylpropyl)-S-
alanyl-1S,2R,4S,6S,7R-tricycloC5.2.1.02-67-3-aza-~ecane-
4-carboxylate, benzyl N-(1-S-carbethoxyw3-phen)-lpropyl)-
S-alanyl-1R,2S,4R,6R,7S-tricycloC5.2.1.02-67-3-aza-
decane-4-carboxylate, benzyl N-Ci-S-carbethoxy-:3-
phenylpropyl)-S-alanyl-1R,2S,4S,6R,7S-tricyclo-
C5.2.1.02'67-3-aza-decane-4-carboxylate and benzyl
td-(1S-carbethoxy-3-phenylpropyl)-S-alanyl-1S,2R,4R,
6S,7R-tricycloC5.2.1.02'67-3-aza-decane-4-carboxylate
The compounds are prepared by the process aes-
cribed in Example 1 f, starting from the benzyl ester
mixture of Example 3e. The diastereon~er mixture is
i5 separated into its components over silica gel using
raethylene chloride/ethyl acetate 9y:i to ~:2.
Diastereomer A
f; f - 0.134 (Si02; .methylene c:hloride/ett;yl acetate
95:5)
m/e - 532
Diassereomer B
Rf - 0.126 CSiU2; rr~ethylen~ chloride/ethyl acetate
95:5)
m/e - 53
C-i~5stereomer C
Rf - 0.105 CSiU~; methylene chlo~ide/eth~l acetate
95:5)
mie - 532
- 3 0 - 12~22~'30
Diastereomer D
Rf - 0.074 (Si02; methylene chloride/ethyl acetate
95:5)
m/e - S32
S g) td-(1-S-Carbethoxy-3-phenylpropyl)-S-alanyl-1S,2R,4S,
6S,7R-tricycloC5.2.1.02'67-3-aza-decane-4-carbo;~cylic
acid hydrochloride, N-C1-S-carbetl~oxy-3-phenylpropyl)-
S-alanyl-1R,2S,~:R,6R,7S-tricycloC5.2.1.02'67-3-aza-
decane-~r-carboxylic acid hydrochloride, N-(1-S-carb-
ethoxy-3-phenylpropyl>-S-alanyl-iR,2S,4S,6R,7S-tri-
cycloC5.2.i.02'G7-3-aza-docane-4-carbor.ylic acid
hydrochloride and hJ-(i-S-carbetho>:y-3-phenylpropyl)-S-
alanyl-1S,2F,41~,bS,7R-tricycloC5.2.1.02'67-3-aza-dec~ne-
.. _ : .~ v . ,~ ~. I ,. '
Y V U r V V /v r l 1 V Q t. I U I l ~' V I ~ 1i I 1 l V 1 I ~ C '
are formed .!hen the diastereomers A, B, C and D of Example
3g are each react~ci by the process described in Ex.ampt.e
1g.
Diastereomer A'
Rf ~- 0.191 (Si02; methylene chloride/methanol 9:i)
mie . 514 as the trimethylsilyl derivative
Diastereor.~er B'
R~ - 0.231 (Si02; methylene chloride/methanol 9:1)
m/e . 514 as the t~~imethyls-ilyl derivative
Diastereomer C'
R.~ 0.301 (Si02; methylene chloride/methanol 9:i)
-
m/e . 514 as the trimetlnylsilyl derivative
Diastereomer
D'
Rf - 0.35 (Si02; ~I~ot'n~~lene ci~lorideimethanol
9:1)
rn/~ . 514 as the trimetlnylsi lyl. derivative
- 31 - li~a~~r~r~0
Example 4
N-(1-S-Carboxy-3-phenyLpropyl)-S-aLanyl-1R,2R,4S,6:>,7S-
tricycloC5.2.1.02'67-3-aza-decane-4-carboxylic acid
1 g of the ester from Example 1g is dissolved in
S 20 ml of dimethoxyethane. One drop of a dilute indicator
solution, for example bromothymol blue, is added, <snd an
equivalent amount of 4 N aqueous potassium hydroxide
solution is added in the course of S minutes, ~rith vigor-
ous stirring, so that the indicator shovels a pH value of
S-10 at the end of the reaction. The mixture is then
adjusted to pli 4 ~.rith hydrochloric acid and concentrated
to drynoss in vacuo, the residue is taken up in ethyl
acetate and the mixture is filtered. Rfter the ethyl
acetate solution tia~, been concentrated, 0.~5 g of a solid
residue is obtained.
m/e . 414
Example 5
N-(1-S-Carboxy-3-phenylpropyl)-S-alonyt-1S,2R,4S,
6S,7R-tricycLoCS.%_'.1.02'67-3-aza-dec~ne'4-carboxylic acid,
N-(1-S-car boxy--3-,~i~enylprcpyl)-S-alany.l-1F:,2S,.4R,6R,7S°
tricycloC5.2.1.02'E'~-3-aza-decane-4-caraoxylic acid;
N-C1-S-carbor.y-3-pl~enyLpropyl )-S-4lanyL-1R,2S,.4S,6F;; 7S-
tricycloCS.2.1.02'6~-3-aza-decane--4-carboxylic acid and
N-(1-S-carboxy-~3-ptreny lprcpyl)-S-alanylw1S,2R,~t",bS,7R-
tricycLcCS.2.1.02"67-3-aza-decane-4-carboxylic acid arz
formed from the dia.stereomers A', B', C' and D' of
~xample 3g after hydrolysis, 2s described in Ex«mpLe t;,
- 3 2 - 1232280
Example 6
N-(1-S-Carbethoxy-3-oxo-3-phenylpropyl)-S-alanine benzyl
ester
65.7 g of ethyl 4-phenyl-4-oxo-butene-2-carboxyl-
S ate (ethyl benzoylacrylate) are dissolved in 225 ml of
ethanol, and 1 ml of triethylamine is added. A solution
of 70 g of S-alanine benzyl ester in 90 ml of ethanol is
rapidly added dropwise to this solution at room tempera-
tore. The mixture is stirred at room temperature for 2
hours and the solution is then cooled. The S,S-isomer
crystallizes out.
Yield: 94.3 g; melting point: 73-74°C
C~72p - + 17.f3° Cc - 1, CH30~~)
Example 7
iv-(1-~S-Carbethoxy-3-oxo-3-phcnylpropyl)-S-alanine
0.5 g of the compound from Example G are dissolved
in 40 ml of ethanol, 0.1 g of 10~ strength Pd!C is added
and hydrogenation is carried out at room temperature and
under normal pressure.
Yieid: 300 mg; pelting point: 210-220°C
1H-f~';~1P CD~~SO-d6): 1.0-1.<< Ct:, 6li>; 3.2-S.0 (m; Fiii);
7.2-F~.1 Cm, 51-I>
Example 8
Benzyl ~!-('i-S-carbethoxy-3°o>:o-3-p~ienypropyl)wS--alanyl-
1R,2R,4S,6S,7S-tric;cloC5.2.1.02'67--3-aza-decane-4-
car boxyl_ate
The compound is prepa:re~i analogously to the pro-
cess described iv ~r,ample 1v from We bF:~zyl ester mix-
W re cf Exar~pl4 1a and !~l-C1--;Wcarbeti~or,~~--3-oxo-v--pheny-
1232280
- 33 -
propyl-S-alanine from Example 7. The diastereomers are
separated over silica gel.
Example 9
Pl-(1-S-Carbethoxy-3-oxo-3-phenylpr~pyl)-S-alanyl-1R,2R,
4S,6S,7S-tricycloCS.2.1.02-6J--3-aza-decane-4-carboxylic
acid
1 g of the benzyl ester fram Example ~ is dis-
solved in 30 ml of ethanol and hydrogenation is carried
out ~iith 100 mg of Pd/C (10% strength) at room ternpera-
ture and under normal pressure. After one molar equiva-
lent of hydrogen has been taken up, the hydrogenation is
interrupted. The catalyst is filtered off with suction
and the solution is concentrated.
i~ i a l v : 7 i 0 ~~~ ~ a f a ; c i l
The following coropounds are prepared analogously
by the processes d~°scribed in Examples 8 and 9, starting
from, the a~rinoacic: benzyl esters of Example 3e: Pd-(1-S-
carbethoxy-3-oxo-~-phenylpropyl>-S-alanyl-iS,2R,4S,6S,7R-
tricycloC5.2.1.02'~J-3--aza-decane-4-carboxylic acid,
(~!-(1-S-carbethoxy-'-oxo-3-phenylpropyl)-S-alanyl-1R,2S,
4R,6R,~S-tricycloC5.2.i.02'67_3-aza-decane-4--carboxylic
acid, (~I-(1-S-carbethar,y-3-o>:o-3-phenylpropyl)-S-al anyl-
1R,2S,4S,6R,7S-trio:yclaC5.2.1.02'67-3-aza-decane-4-
carboxylic acid and t~J-(1-S-Garb°tho;;y-~-oxo-phenylprapyl)-
2> S-alanyl-1S,?R,~+R,6S,7(t-tricycloC5.2.1.G'"67-3-aza-decane-
4-carboxylic acid.
- 3 ~ . - lz3~z~o
Example 10
N~ (1-S-Carbethoxy-3-ahenylpropyl)-S-lysyl-1R,2R,4S,6S,
7S-tricycloCS.2.1.02~6~-3-aza-decane-4-carboxylic acid
dihydrochloride
S a) tJ~-C1-S-Carbethoxy-3-oxo-3-phenylpropyl)-fd~-benzyloxy-
carbonyl-S-lysine benzyl ester
g of ethyl 4-phenyl-4-oxo-butene--2-carboxylate
are dissolved in 100 ml of ethanol. 19.1 g of N~-benzyl-
oxycarbonyl-S-lysine benzyl ester and 0.2 g of triethyL-
10 amine are added thereto. The solution is stirred at room
temperature for 5 hours and is then concentrated in vacuo.
The oily residue (31 g) is dissolves in isopropanol/
diisopropyl ether and the solution is cooled. 13 g of
f,l~-(1-C-r~arh~rhpvv--~-nY.O' .... .. . . .. .~-Yhnn,'lr~~pr~ 1 )-~I~-F~~.,~y
l,~y~-
carbonyl-S-lysine benzyl ester crystallize.
p0 - 3.5° (c - 1, CH~OH)
1H-fdPiR (CDCL~): i.0-1.4 (tr. 3H); 1.0-2.0 Crn, 9H);
2.0-2.6 (broad s, 1H); 2.9--3.9 (n,
6H); 3.9-~t.4- (q, 2H); ~r.b-4.9 (broad
s, 1ti); 5.0-5.2 (double s, 4H) 7.1
E3.1 Cm, i 5H)
b) fd~ <1-S-Carbethoxy-3-phenylpropyl)--N~-ben: yloxy-
carbonyl--~-lysine
~>.C g of the lysine benzyl ester derivative pre°
2S pared in E:xar~ple i0a are dissolved i!~ SO ml of glacial
acct i c ac i d, ano' 0.6 g of Pd; C (1 0°e s t rength) and 0.5 g
of concent:r~ted sulfuric acid are added thereto, tiydro-
genation is carried out at roc.n~ temperature an:.' und~:r
nora~a 1. pressure ~ ~r .6 hour. The cata Lyst i s t hen f i L-
123220
- 35 -
tered off with suction and the ethanolic solution is
stirred with 1.4 g of solid sodium bicarbonate. The
solution is concentrated on a rotary evaporator and the
residue is dissolved in water. The aqueous phase is
extracted with ethyl acetate and methylene chloride. The
organic phases are discarded and the aqueous phase is
evaporated to dryness in vacuo. The residue 'is extracted
by stirring with methanol. lifter the methanol has been
evaporated off, an oily residue remains, which solidifies
when treated with diisopropyl ether. Yield of t~l~-C1-S-
carbethoxy-3-phenylpropyl)-S-lysine: 2.0 g
1H-tl~'R CD20): 1.0-1.4 Ctr, 3t~>; 1.0--2.5 Cm, 9lI>,
2.5-4.4 C.m, 9H); 3.9-4.<< Cq, 2!i),
~:.5-5.0 (:~, 1!-'); ?. 1--?.G ;T, 51;;
m/e: 336
3.4 g of Pd~,~ C1-S-carbethoxy-3-phenylpropyl )-S-
lysine art dissolv~~.~d in 30 ml of methylene chloride and
the solution is cooled to 0°~. Sdith ice-cooling, 2.1 g
of triethylarnine are added thereto, and 1 .9 g of benzyl
chlor°formaie are then added dropurise. TE,e mixture is
stirred at 0°C for 1 hour and then brought to room tem-
perature. The rnetl~yle~e chloride solution is then
extracteu by sl~~l;ing s:~ith v;ai:er, sodium carbonGte solu-
t icn and ~nacer. fi.ft~r dry ing,, the solution is concentr~-
tPd and the oily residue is chromatographed over silica
gel using meti~ylene chloride/methanol. 2.0 g of N~-C1-S°
carbet~-~oxy--3~-pl~er-~yLpropyl)-t~! -benzyloxycarbon~~l-S-lysine
C..
are o~tairvcd.
1N-(vflR CD~g): 1.0--1..4 (t_r, ~11>; 1.0-2.5 Cm,9H) ;
1232280
- 36 -
2.S--4.4 (m, 9H>; 3.9-4.4 (q, 2H);
4.S-S.0 (m, 1H); 5.1 Cs, 2H);
7.1--7.5 <m, 10H>
c) Benzyl N~--(1-S-carbethoxy-3-phenylpropyl)-P;~-benzyl-
oxycarbonyl-S-lysyl-1R,2R,4S,6S,7S-tricycloC5.2.1.02'67-
3-aza-decane-4-carboxylate
S00 mg of the benzyl ester hydrochloride prepared
in Example 1e are reacted with 900 mg of N,~°(1wS-carb
ethoxy°3-phenylpropyl)-N~-benzyloxycarbonyl-S-Lysine,
prepared according to Example 10 b, analogously to
Example 1f. Rfter working up, 1.5 g of an oil which is
a mixture of two diastereomeric compounds are obtained.
The diastereoroeric mixture is separated into the
individual components by cciumn chromatograpPry witn
silica gel, and cyclohexane/cthyl acetate 2:1 as the
eluting agent. The isomer el.~!ted first is the above com-
pound. 0.6 g of oil is obtained.
1H-Ni~iR (CDCI~y, after replacer~ent of ti by U t~ith D20):
0.9-~.1 (m, 1 QE;); 3.2-5. i Cm,. 14H>, 5.1-S.3 (ds, 4H)
7.1-7.6 (m, 15H)
d) ty-C1-S-CarSe~hoxy-3-phenylpropyl)--S-l~~syl-iR,<'_R,,4S,
6S,7S-tricycl_oCS.2.1.02'~l-3-aza-d~ca.ne-4-carboxylic
acid dihydrochLoride
500 mg of benzyl i~l~-(1-S-carbethox,~~w3-phenyl-
z5 propyl)-P!~-benzyloxycarbcnyl~-S-lysyl-1R,2R,4S,6S,7S-tri-
cycloC5.2.1.02'~'7-~--aza--decane-4--carbor.ylic acid ben~yl
ester from Erampte 10c: are dissolved in ?0 ml of ethanol
and hydrogenoly~~ic def~enzylation i~ carried our under
normal pressure, with addition of 0.1 n of 10;! stren~tt~
123220
- 37 -
Pd/C. 4!hen the uptake of hydrogen has ended, the cata-
lyst is filtered off, ethanolic hydrogen chloride solu-
tion is added to the e2hanolic solution until the pH
reaches 1, and the ethanol is evaporated off in vac:uo.
Diisopropyl ether is added to the residue, ~-rhereupon the
product solidifies. 200 mg are obtained.
tlhtR (D20) : 1 .0-3.1 Cm, 18H); 3.1-5.2 (m, 14h) 7.2 Cs,
Std)
Example 11
1'he follot~ring compounds are obtained analogously
by the process described in Example 10c, by reacting the
aminoacid benzyl ester of E>;ample 3e pith t.~,~°Ci-S-carb-
ethoxy-3-phenylpropyl)-td-benzyloxycarbonyl-S-lysine, des-
cr-iueu ire cxaraple i0t~: oeyu i~i~-ii-S-carbethoxy-3-
- 1S phenylpropyl)-td~-benzyloxycarbonyl-S-lysyl--1S,2R,4S,6S,
7F-tricycloC5.2.1.02'6J-3-aza-deca.ne--4-carboxylate
(Diastereomer E>, benzyl to"~-(1-S-carbethoxy-3-pi~enyl-
propyl)-tybenzylor,,ycarbonyl-S-l;~syl-iR,2S,4R,6R,7S--tri-
cyclol:5.2.1.02'67-3-azo-decane-4-carboxylate CDiastereo-
mor F), benzyl tJ.~-C1-S-carbethoxy-3-phenylpropy! )°fJ~-
benzyloxycarbonyl-S°-lysyl-1R,2S,4S,6R,7S-tricyclc-
CS.2.1.02'6J-3-aza--decane-4-carboxylate CDiasW r~erner
G) a~~d benzyl t!,1--C1-S-ca~~betlno;y-3--phenylpropyl)-I~t~~-
benzyloxycarbonyl~-S--ly~yl~1S,2R,.4R,,6S,.7R-tricyclo--
ZS CS.2.1.02'67-3--aza-decane--4-carboxylar_e CDi~:stereomer t;).
If the ber~zyl 1S,2S,.~.S,5R,7R-tricycloCS.2.'1.02'f~Jw
s-aza.-°decane-4-cark~c>:ylato is used, benzyl t~l"~-C1-S-carb-
ethoxy-3-p!~enylpropyL)-i~E-k~enzy~,or.ycarbonyl-S-lysyl-1S,2S~,
~,S,.6r,7R-tr~i cyc LoCS.'2.1 .0 '_ ' f~_;;._azu-d~~~ane--~:-carbor.y late
1232280
- 38 -
(Diastereoruer K) is obtained analogously.
Example 12
If the diastereomers E, F, G, H and K are hydro-
genated by the process described in Example 10d, diastereo-
mer E gives Pd~-(1-S-carbethoxy-J-phenylpropyl)-S-lysyl-
1S,2R,4S,6S,7~-tricycloCS.2.1.Oz-6J-3-aza-decane-4-
carboxylic acid dihydrochloride (Diastereomer E')
1 H--t,lt~R (D20) : 0.9-3.0 (m, 1 8H) , 3 .0-4.9 (m, 1 4H),
7.2 (s, 51-1),
IO diastereomer F gives t~~-(1-S-carbethoxy-3-phenylpropyl)-
S-lysyl-1R,2S,4R,5R,7S-tricycloC5.2.1.02'6)-3-aza-decane-
4-carboxylic acid dihydrochloride (diastereomer F')
1H-t~hiR (D20) : 1 .0-3.2 Cm 18H); 3.2-S.1 (m, 141i);
7.i (s, 5H),
diastereomer G gives t~;,~,-(1-S-carbetf~exy-3--phenylpropyl)-
S-lysyl-1R,2S,4S,5R,7S-tricycloC5.2.1.02'6)-3-aza-d~cane-
4-carboxylic acid dihydrochloric~e (diastereoner G')
1H-hlt~iR (D20): 1.0-3.3 (m, 20H); 3.~+-S.0 (m, 12H);
7.2 (s, 51i),
diastereomer H gives r!~-(i-S-carbethoxy-3-phenylpropyl)-
S-lysyl-1 S,2R,4,°,; 55,71?-t ~,i cyc IoCS .2.1 .02'6)-3-aza-decan~ -
4-carboxylic acid dihydrochloride (diastereomer la')
1 H_.Iit,~R (p20) : 0.9-;~ .0 (m, 1 ~.t;>; 3.0-4.° (m, 1 4H);
7.2 (s; SH)
and diastereomer f~ gives t~~-(1--S-c4rbethoxy-3-phenyl.-
propyl)-S-lysyl-1S,2S,irS,6R,alt--~ricycloCS.2.1.02-6)-3--
aza-decane--~+--carbo;:ylic acid d-ihydrochloride <diastereo-
mer t:')
1H.-;;t~F; (D20) : 1 .0--:~.1 Cm, 18f~); 3.0-4.F (m, .14H);
- 39 - 123220
7.2 Cs, 5H).
Example 13
h:~-(1-S-Carboxy-3-phony lpropyl)-S-lysyl--1 R,2R,4S,6;5,7S-
tricycloC5.2.1.02~6J-3-oza--decane--4-carboxylic acid
S hydrochloride
0.5 g of the ethyl ester dihydrochloride from
Example 10d are suspended in 20 ml of dimethoxyethane.
Aqueous 4 ~t KOH is added unti t the pH rea;.hes 9-10.
The mixture is stirred for half an hour. Jt is tt~~n
adjusted to pt~ 4 with hydrochloric acid and concentrated
to dryness in vacuo, the residue is taken up in ethyl
acetate and the mixture is filtered. 'Ft~e ethyl acetate
solution is concentrateG and the residue is tritur.ated
4!liiW iISONfOp;'~_ oiler', HiWieU~70r1 it SOi'luli'iES.
Yield: 30U mg
1H-tJ'rlR CD2U) : 0.9--2.S' Cm, 15H); 3.0-4.~ Cm, 12H>;
7.2 (s, 5!i)
Example i4
The following dicarboxylic acids are prepared
analogously k>y the process described in Exa;nnl~ 1S,
starting from the diastereomers E', F', G', H' and
t~-C1-S-carbox.y-3wN!-~enylpr opyl)-S°lysyl-1S,2R,4S,6S,7F;-
tricycloCS.?_.1.G~'f'~-~3--aza-decane-4-carboxylic acid
hydrochloride
2S ItH-~.1;-sR (D20>: 1.0-3.0 Cm, i5H)r j.0-5.C Cm, 12F!>;.
7.2 Cs, 51~)
i~i~-(1-S-curboxy-3-phenylpropy l)-S-lysyl~-li~,CS,~rf?,GR,7S-
tricycloC5.2.i.02-~~--3-azawuecan;w'~-carboxylic aciG
hydrochloride
123220
- 40 -
tJ~-(1-S-carboxy-3-phenylpropyl)-S-lysyl-1R,2S,4S,6R,7S-
tricycloC5.2.1.02W~-3-aza-decane-4-carboxylic acid
hydrochloride
1H-tJt~iR (D20) : 1 .0-3.3 (m, 16H>, 3.3-5.0 (m, 11H),
7.2 (s, 5H)
r~-(1-S-carboxy-3-phenylpropyl>-S-lysyl-1S,2R,4R,6S,7R-
tricycloCS.2.1.02'61-3-aza-decane-4-carboxylic acid
hydrochloride, N~-C1-S-carboxy-3-phenylpropyl)-S-lysyl-
1S,2S,4S,6R,7R-trirycloC5.2.1.02'6-3-aza-decane--4-
carboxylic acid hydrochloride
1 H-t;MF (D20) : i .0--3.1 (m, 1 5H); 3.1-4.9 Cm, 12H);
7.2 <s, 5H>
Example 15
to t . uii ty t .i"a ~8ii;y ~ W ,Gm,wJ,vJ, 1 "°e i i Ly C ~iW a . L. t
.v J
3-aza-decane-4-carboxylate
a> 1:1 mi>;ture of 1R,2R,4S,6S,7S-tricycloC5.2.1.02'67
3-aza-decane-4-carboxylate and the corresponding
mirror image isomer
2.S g of the aminoacid from Example 1d are reac-
ted e~ith 30 ml of isobutylene and 2.5 rnl of concentrated
sulfuric acid in 30 ml of dio}:ane. After the mi;:tur~
has been I:ept at rook: temperGture .or i4 hours, it is
rends. red alkaline with sodiur~ I~ydroxide solut ion and con-
centrated in v4cuo, 20 ml of ~uater are added to the resi-
due and the ester is extracted by s!~aking with rnethylene
chloride. After the methyleni chloride has been evapora-
ted ov'r,. 2.0 a o'r a colorless ci l ar a obtained.
~H--f;P1R: 0.9 -- 3.0 (n, Gi-I'; 1 .4 (s, SH); 3. i-4.9 (~n,7H)
Cafter replacemcr~t of f~ by t~)
123220
- 41 -
b) tert.-E3utyl N-benzyloxycarbonyl-S-alanyl-1R,2R,4S,6S,
7S-tricycloC5.2.1.02-53-3-aza-decane-4-carboxylate
0.67 g of 1-hydroxy-benzotriazole and 1.47 g of
the tert.-butyt ester prepared in Example 15a are added
S to a solution of 1 g of Z-Ala-Ofl in 10 nO of dimethyl
forrnamidz. The pit value is adjusted to 8.0 with N-
ethylmorpholine. Tine mixture is cooled ir; an ice-bath,
and 1.05 g of dicyclohexylcarbodiimide are added. The
mixture is stirred at 20 - 25°C for 15 hours. The urea
which has precipitated is filtered off with suction, the
filtrate is concentrated in vacuo and the residue is
taken up in ethyl acetate. the organic phase is washed
successively :pith potassium bisulfate solution, potassium
bicarbonate solution and sodium chloride solution, dried
and evaporated. The residue is chromatographed on silica
gel using ethyl aceta~e/cyclof~er,an~ 1:1 in order to
separate the diastereomers.
field: 0.7 g of tert.-butyl D;-benzyloxycarbonyl-S-aLanyl-
i R,.22,4-S,6S,7S-t ri cyc to C5 .2 .1 .02' ~'7-3-aza-decane-4-
c~rbor,ylate.
c) tert.-E3utyl S-at.anyl-1 R,2f:,~øS,6S,7S-tricycloC5~2.1.02°6~-
3-aza-decane-4-car i>oxyl-ate
1.2 g of the tert.-butyl ester from Exarn~le 15b
are dissolved in 2~ ml of ethanol and hydrogenation is
carried out with 100 rig of Pd/C t10% strength) at room
temperature and under normal pressure. The catalyst is
filtered off with suction anci tl~e residue is concentrated
'1 n V a r l' U .
Yiold: 0.8 g of colorless oil
_ 123224
- 42 -
1H-I~t-iR (after replacement of H by D): 0.9-3.1 Cm, 6H>;
1.2 Cd, 3H); 1 .4 Cs, 9H); 3.1-5.0 Cm, 8H)
Example 16
tert.-Butyl N-(1-S,R-carbethoxy-3-oxo-3-phenylpropyl)-S
S alanyl-1R,2R,4S,6S,7S-tricycloC5.2.1.02'67-3-az4-decane
4-carboxylate
This compound is prepared from the compound of
Example 15b using ethyl benzoylacrylate, analogously to
the process described in Example 10a.
Example 17
N-C1-S,R-Carbe thoxy-3-o;;o-3-pheny lpropyl)-S-a lany l-1 R,2F;,
4S,bS,7S-tricycl.oCS.2,1.02'6-3-aza-decane-4-carboxylic
acid trifluoroacetate.
0.5 g of the tort.-butyl ester prepared in
Example 1b are dissolved in 5 ml of trifluoroacetic acid
and t~~e solution is stirred at room ter~perature for 30
minutes. The trifluoroacetic: acid is then stripped off
in vacuo and the residue is triturated t~~ith dii~opropyl
ethe r,
Yield: 0.25 g of solid residue
rH-I~:f~lR Cafter replacement of H b~ C>: 1.0-3.2 Cm, 1?I~>,
3.3-4.9 (m, 13H); 7.2-3.2 Cm, 5H).
Example 1Q
tert.-E3utyl P~--t1-S,R--car bethoxy-3-oxo-3-phenylpropyl)-S
Glanyl-iR,2R,~S,bS;7S-tricycloC5.2.1.02'~'~-3-azu-decGne
4-carboxylate
5 mmoles of ucetoohenone, S mmoles of eth;~l gly
oxylate and 5 mrncles of the tE:rt.-butyl ester e~' E:r"mple
0
14 c> in 15 cO of ~~l.a~wiat acf~tic acid ar a h;.ated t:o 45 C
12:~22~30
- 43 -
for 3G hours. ;after the mixture h4s been concentrated
in vacuo, the residue is rendered neutral trith sodium
bicarbonate solution and extracted with ethyl acetate.
The ethyl acetate phase is concentrated and the residue
S is chromatographed an silica gel using ethyl acetate/
cyclchexane 1:1 as the eluting agent.
Example 19
tert.-Butyl N-(1-S-carbethoxy-3-phenylpropyl)-S-al~anyl-
1R,2R,.4S,6S,?S-tricycloC5.2.1.OW 6~-~-aza-decane-4--
cGrbox~~late
S mmoles of the tert.-butyl ester of Example 15c
are dissoled in i~ ml of anhydrous ethanol. The solution
is adjusted to p1i ?.0 with ethanolic potassium hydroxide
and u.? g of a po~.~~dored molecular sieve i~~R) and then 5
mmoles of ethyl 2--keto-4--phenyl-butyrate are added thereto.
A solution of 0.6 g of sodium cyanoborohydride in ~5 ml of
anhydrcus ethanol is slo~.~ly added drop~.~ise. After a
reaction time of ?0 hours at 20 to 2~°C, the solution
is filtered and the solvent is distilled off. The residue
?-0 is taken up in ethyl acetate/a~ater. After the ethyl
acetate phases have been evaporated, t11residue is
chromategr~phed on silica gel using ethyl acetate/cyclo-
hexane 1:4.
1H--P!t~~: i.0-3.0 tm, 1oii); 1.4 (s, 9H); 3.0-S.0 (m,
11 I!); 7.2 (s, 5H) (after replaceroent of H by U)
Example 20
N- (1 °~-Ca rbethc.>;y--3-piner~y lpropy 1_) -S--a lany l-1
R,2R,4S,.6S;
?S--tr ~i~yclofSo2.1..C2'E'7-:5-aza°decanc-~+-ca:rboxylic acid
Inydrochloride
123224
- 44 -
0.4 g of the tert.-butyl ester prepared in
Example 1Q iu dissolved in 5 ml of trifluoroacetic acid
and the solution is stirred at room temperature for 30
minutes. The trifluoroacetic acid is then stripped off
S in vacuo. The residue is dissolved in ~~ater/~~etfiar~ol and
the solution is digested with acetate-charged ion exchan-
ger until the pH is about 5. The ion exchanger is fil-
tered off and the solution is brought to pH 1 with
efihanolic hydrochloric acid. The solvent is stripped off
i0 in vacuo and the residue is triturated with ether.
Yield: 0.25 g
Rf: C.42 (SiC2; methylene cl~loride/methaool 8:2)
Example 21
ter'~.-r;ietyi u-ei:iryi-S-r:yrUS inyl-iR,W<,.~;;,oS,7S-zriC:yclo-
15 C5.2.1.02'~J-3-aza-decane-4-c<arbexylate
a) tert.-E'utyl ll°i~enzyl.oxycarbenyl-G-ethyl-S-t~~rosinyl-
1R,2R,4S,6S,.7S-tric;ctoC5.2.1.02'6J°3-aza-decane-4-
carboxylate
The compound is prepared from 0-ethyl-Z-tyrosine-
20 OH and the tert.-butyl ester described in Example 15a
analogously to the process described in Er.ample 15b. The
diastereomers are separated over silica gel using c;yclo-
hexane/etl~yl acetate.
1Ef-tJivlR Cafter replacement of ii b;~ D): 0.9 - 3.0 :m,
25 1 iH>; i.4 Cs, 9H>; s.0--!~~9 (rn, 12H); b.6-7.0 Cm, 4 H);
7.2 Cs, 5H)
b) tert.-Hutyl 0-ethyl-S-tyrosinyl-1R,?_R,4S,GS,~S-t_ri-
cycloi5.2.1.02'f'7--3-aza-cic>cane-+--carboxylate Cdiastereo--
mer 1).
~23228U
- 45 -
The compound is prepared by hydrogenation of the
tert.-butyl ester of Example 21a analogously to Example
15c.
1H--~~9R (after replacement of H by D): 1.0-3.1 (m, 11H>;
1.3 (s, 9H>; 3.1-4.9 (m, 10H>; 6.6-7.0 Cm, 4!i)
The following compounds are obtained from the
corresponding starting materials analogously to the pro-
cess described in Example 21: tert.-butyl 0-ethyl-S-
tyrosinyl-1S,2S,4S,6f;,7R-tricycloC5.2.1.02'67-3-aza-
1D decline-4-carbox~~lato (diastereomer 2), 0-ethyl-S-tyrosin
yl-1R,2S;4S,ELF,7S-tricyctoC5.2.1.02'G7-3-aza-decane-4
carboxylate (diastereomer ~) and D-ethyl-S-tyrosinyl°1S,
2R,4S,GS,7R-aricyctoC5.2.1.02"67-3-aza-dQcane-4-carboxy-
iaie (di asiereor~er 4) .
Example 22
terv.-Butyl ~a-(1--S--carbethoxy-3-oxo-3-pher~ylpropyl)-CO-
ethyl-S-t~~rosinyl7-1R,2R,4S,6S,7S-tricycloC5.2.1.02'G7-.s-
aza-decane-4.-carboxylate (diastereomer i').
This compound is obtained from the diastereoner
1 from Example 21 b and ethyl benzoylacrylate analeg~~usly
to the process described in Exarnple 10a.
'tl~e follou!ing compounds are prepared iro~~ tire
diastereomers 2, 3 and 4 analonously to this process:
tern.-bu~yl IJ-(1--S-carbethoxy-3-oxo-3-phenylprcpyl)-CO-
ethyl-S-tyrosi nyl7-1 S,2S,~;S; C~P,7t;-tri cyc LoC5.2. ; .02'G7-3-
aza-decane°4-carboxylate (diastereomer 2'), tert.-butyl
:-(1-S-carb2thox;~-3-or,o-3-pi~enylpropyl)-CO-ethyl-S-tyro-
s i ny l7-1 R; 2S; 4S, f~R,7S-t ri cyc loCS .2: i .02 'G7-.5-aza-deca.ne-4-
curboxylate (diast;:reoe~ei, 3'> and tert.wbutyl (~d-(1-~S-
12;3220
- 4b -
carbethoxy-3-oxo-3-phenylpropyl)-CO-ethyl-S-tyrosinylJ-
1S,2R,4S,6S,7F;-tricycloC5.2.1.02-67-3-aza-decane-4-
carboxylate (diastereomer 4')
Example 23
P!-C1-S-Carbethoxy-3-oxo-3-phenylpropyl)-CO-ethyl-S-tyro-
sinyl7-1R,2R,4S,bS,7S-tricycloC5.2.1.02-6J-3-aza-decane-
4-carboxylic acid trifluoroacetate
Diastereomer 1' of Example 22 is reacted by the
process described in Example 17.
1H-Mh~R Cafter replacement of H by D): 1.0-3.1 Cm, 1bH);
3.1-4.9 (m, 13H); b.6-7.0 <m, 4H); 7.2 <s, SH)
The follo~.~in~ compounds are obtained from the
diastereomers 2', 3' and 4' analogously to this process:
t..'-('1-S--carbethoxy-3-oxo-5°phenyl.prcp~~l)-CO-etf~yl-SWyro-
1a sinyl7-1S,2S,4S,6R,7R-tricycloC5.2.1.02'6J-3-aza-dE:cane-
4-carboxylic acid trifluoroacetate, t.-Ci--S-carbethox,y-3-
or.o-3-phenylpropyl)-CO-ethyl-S-tyrosinylJ-1R,2S,4S,.bR,7S-
tricycloC5.2.1.02'"J-3-~zr.-decane-4-carboxylic arid
trifluoroacetate and P:-(1-S-carbethoxy-3-oxo-3-phenyl-
propyl)-CC-ethyl-S-tyros-ir~yl7°-lS,2t;,4S,6S,7f;--tricyclo-
C~.2.1..OW67-~-aza-decane-4-c~rlJoxyl~ic acid trifluoro-
acetate.
Examr~le 24
tert.-~'utyl h~-C1-S-~carhethoxy-~--phenylpropyl)~-CO--et:hyl-S-
r
2S tyrosinylJ-1R,2R,~rS,6S,7S-tricycloCS.2.'1.02'''J-3-aaa-
decane-~:-carboxylate (diastereomer 1)
Th i s cur~pCm_anc~ i s ob to i ned f ram t he compound of
F:~ar~.ple 21 b and ethyl 2-heto-4-phenyl-t,ut)~rate analog-
ously to the process described in E:x;~:~;sl.e 19.
12322$4
- 47 -
1H-NhiR (after replacement of ~I by D) : 1 .0-3.0 (m, '18H);
1.4 (s, 9H), 3.1-5.0 (m, 13H), 6.6-7.0 (m, 4H); 7..? (s,
SH).
The following compounds are obtained from the
diastereomers 2, 3 and 4 of Example 21 and ethyl 2-keto-
4-phenyl-butyrate analogously to this process: tert.-
butyl N-(1-S-carbethoxy-3--phenylpropyl)-CO-ethyl-S~-
tyrosinyl7-1S,2S,4S,6R,7R-tricycloC5.2.1.02'6J-3-ava-
decane-4-carboxylate (diastereomer 2); 1H-tJtylR (after
replacement of H by D): 1.0-3.0 (m, 18H); 1.4 (s, ~H);
3.0-4~9 Cm, 13H); b.b-7.0 (m, 41;); 7.2 (s, SH), tert.-
butyl N-C1-S-carbethoxy-3-phenylpnopyl)-CO-eth)~l-S-
tyrosinyl7-1R,2S,4S;6R,7S-tricycloC5.2.1.0?°~'7-3-aza-
decane-4-carboxylate (diastereorner 3); 1H-t,!NiR (after
replacemem of H by D) : 1 .0-:5.0 (m, l z~H>; 1 .4 Cs, '~F~>;
3.0--5.0 <m, l3ii>; b.6--7.0 (m, 4t;); 7.2 (s, 51;) and tert.--
butyl tJ-(i-S--carbethoxy-3-phenylpropyl)-CO-ethyl-S-
tyrosinyt7-1S,2F;,~rS,6S,7R-tricyr.loC5.2.i.02'67-3-aza-
decane--4-carboxylate Cdiastereorner ~;); 11i-h;t~1(~ Cafter
replacement of !; by D): 0.9-3.1 (m, 18H>;. 1.4 (s, '~H);
3.2-4.9 Cc~, 'I~'1-1>; f~.6-7.0 (m, 41;); ?.2 (s, St;>.
Example 25
tJ-C1-S-Carbethu>:y-3--phenylpropy~)~CO--~tl~~~l-S°tyrosinyl J-
i F,2f;,~::~,6S,?S--t r~i cyc to C5 ~.2.1 . C' ' ~:l-~-aza-decane-4--
carboxylic acid hydrochloride
The carboxylic acid is obtained by reacting the
tert.-butyl ester of Example 2~: ~.~ith trifluoroacetic acid
a;~alogous!y to the process desc~ira~d in E;;anple 20.
1
H-t!f~lR (a~ ter replacement ~i If "~y D): l.Ci-3.1 (m, 1F?h);
_ 48 - sz3zz~o
3.1-S.0 (m, 13H); b.b-7.0 (m, 4Ff>; 7.2 .(s, 5H).
The Following compounds are obtained analogously
from the diastereomers 2, 3 and 4 of Exarr,ple 24: hd-(1-S-
carbethoxy-3-phenylpropyl)--CO-ethyl-S-tyrosinyl7-1S,2S,
S 4S,bR,7R-tricycloC5.2.1.02-67-3-aza-decane-4-carboxylic
hydrochloride; 1H-~f~~F; (after replacement of H by D):
0.9-3.0 (m, 1~H), 3.0-4.9 (m, 13H); b.6-7.0 (m, 4H); 7.2
(s, SI~), fJ-(1-S-carbethoxy-3-phenylpropyl)--CO-ethyl-S-
tyrosinyl7-1R,2S,4S,6R,7S-tricycloC5.2.1.02'6J-3-aza-
decane-4-carboxylic acid hydrochloride; 1H-tdNER (after
replacement of N by D) : 1 .0-2.9 (r~~, i 8H); 3 '0-~; .9 Cra, 13H);
b.b-7.0 (m, 4H); 7.2 (s, 5H> and N-(1-S-carbethoxy-3-
phenylpropyl)-CO-ethyl-S-tyrosinyl~-1S;2R,4~,bS,7Rwtri-
cycloC ~.2. i .:u'~'~-3-aza--Cecane-~+-carboxylic ac id hydro-
chlor ide; 1H--PJF',R Cafter replacemen~ of H by D): 1.0-3.1
(m, 1~1-I); 3.1-5.U (m, 13H>; 5.6-7.0 Cm, 4H>; 7.2 (s, 5H).
