Note: Descriptions are shown in the official language in which they were submitted.
1 341 06 4
Compounds having a cognition adjuvant action, agents
containing them, and the use thereof for the treatment
and prophylaxis of cognitive dysfunctions
The invention relateao to the use of angiotensin converting
enzyme inhibitors (A(:E inhibitors) or their physiologic-
ally tolerated salts as medicaments having a cognition
adjuvant action (improving cognitive function) and to the
use thereof in the preparation of corresponding pharma-
ceutical formulations..
Examples of suitable compounds for this novel use are
those of the formula I
X1 - X2 (I)
in which 8' denotes R300C - CH - N - C - (CHR~), - ,
R,~ IRS I I
0
y'
*
..
~'H2 3 or R3 pOC 0
COOK
X2 denotes
-CH2SH , -CHI-S-C-R6 , -CA2- -R7 or
0 ORB
-y2-(CH2,~P ~H..(CH2)ri R
C00R2
Y1 represents -S- or -CH2-,
Y2 represents -NR9- or -CH2-,
m is 0 or 1,
n is 0, 1 or 2,
p is 0 or 1,
R denotes hydrogen,
an optional~,ly substituted aliphatic radical having
~ 341 06 4
_ 2 _
1-21 carbon atoms,
an option~~lly substituted alicyclic radical having
3-20 carbon atoms,
an optionally substituted aromatic radical having
S~ 6-12 carbon atoms,
an optionally substituted araliphatic radical having
7-32 carbon atoms,
an optionally substituted alicyclic-aliphatic radical
having 4-2:0 carbon atoms,
an optionaU ly substituted heteroaromatic or hetero-
aromatic-(C1-Cg;l-aliphatic radical having 5-l2. ring
atoms, or
a radical ORa or' SRa, in which
Ra represents an optionally substituted aliphatic radical
having 1-4 carbon atoms, an optionally substituted
aromatic radical. having 6-12 carbon atoms, or an
optionally substituted heteroaronratic radical having
5-12 ring atoms,
R1 denotes hydrogen,
an optionally substituted aliphatic radical having
1-21 carbon atoms,
an optionally substituted alicyclic radical having
3-20 carbon atoms,
an optionally substituted alicyclic-aliphatic radical
having 4-20 carbon atoms,
an optionally substituted aromatic radical having
6-12 carbon atoms,
an optionally substituted araliphatic radical having
7-32 carbon atoms,
an optionally substituted heteroaromatic or hetero-
aromatic-(C1-Cg)-aliphatic radical having 5-12
ring atoms, or, if not already covered by the above
definitions, the side-chain, protected where neces-
sary, of a naturally occurring a-amino acid,
R2 and R3 are identical or different and denote hydro-
gen, an optionally substituted aliphatic radical
having 1-21 carbon atoms,
an optionally substituted alicyclic radical having
~ 341 06 4
- 3 -
3-20 carbon atoms,
an optionally substituted aromatic radical having
6-12 carbon atoms,
an optionally substituted araliphatic radical having
7-32 carbon atoms,
R4 represents hydrogen or (C1-C6)-alkyl and
RS represents (C1-(:6)-alkyl, (C3-C6)-cycloalkyl or
or
R4 and RS form, together with the~atoms carrying them,
a mono-, bi- or tricyclic, heterocyclic ring system
having 3 to 15 ring carbon atoms,
R6 denotes hydrogen, amino, (C1-C6)-alkyl, (C6-C12)-
aryl or (C7-C13)-aralkyl,
R7 denotes (C1-C6)-alkyl or (C~-C13)-aralkyl,
preferably -(CHZ,)4-C6H5,
R8 denotes (C1-C6)-alkyl, which is optionally mono-
substituted by (C1-C6)-alkanoyloxy, preferably
2-methyl-1-propionyloxypropyl, and
R9 denotes hydrogen or (C1-C6)-alkyl;
such as compoundls of the formula II,
R300C - CH - N ~- C - CH - NH - ~H - (CH2)n R (II)
~4 ~5 ~ ~1 COOR2
in which
n is 1 or 2,
R denotes hydrogen,
an optionally substituted aliphatic radical having
1-21 carbon atoms,
an optionally substituted alicyclic radical having
3-20 carbon atoms,
an optionally substituted aromatic radical having
6-12 carbon atoms,
an optionally substituted araliphatic radical having
7-32 carbon atoms,
an optionally substituted alicyclic-aliphatic radical
-4- X341064
having 4-2'0 carbon atoms,
an optionally substituted heteroaromatic or hetero-
aromatic-(C1-Cg)-aliphatic radical having 5-12
ring atoms, or
a radical ORa or' SRa, in which
Ra represents an optionally substituted aliphatic radical
having 1-4 carbon atoms, an optionally substituted
aromatic radical having 6-12 carbon atoms, or an
optionally substituted heteroaromatic radical having
5-12 ring atoms,
R1 denotes hydrogen,
an optionally substituted aliphatic radical having
1-21 carbon atoms,
an optionally substituted alicyclic radical having
3-20 carbon atoms,
an optionally substituted alicyclic-aliphatic radical
having 4-20 carbon atoms,
an optionally substituted aromatic radical having
6-12 carbon atoms,
an optionally substituted araliphatic radical having
7-32 carbon atoms,
an optionally substituted heteroaromatic or hetero-
aromatic-CC1-Cg)-aliphatic radical having 5-12
ring atoms, or, if not already covered by the above
definitions, the side-chain, protected where neces
sary, of a naturally occurring a-amino acid,
R2 and R3 are identical or different and denote hydro-
gen, an optionally substituted aliphatic radical
having 1-21 carbon atoms,
an optionally substituted alicyclic radical having
3-20 carbon atoms,
an optionally substituted aromatic radical having
6-12 carbon atoms,
an optionally substituted araliphatic radical having
7-32 carbon atoms, and
R4 and RS form, together with the atoms carrying them,
a mono-, bi- or tricyclic heterocyclic ring system
having 3 to 15 ring carbon atoms.
~ 341 06 4
- 5 -
An optionally substituted aliphatic radical is understood
to be an aliphatic ac;yclic radical, i.e. a radical with an
open, straight or branched carbon chain such as, for example,
alkyl, alkenyl, alkynyl and corresponding multiply unsatu-
rated radicals. It its preferably unsubstituted or, as
described below, for example, for carboxyl, carbamoyl,
aminoalkyl, alkanoylaminoalkyl, alkoxycarbonylaminoalkyl,
arylalkoxycarbonylaminoalkyl, arylalkylaminoalkyl, alkyl-
aminoalkyl, dialkylaminoalkyl, alkylthioalkyl, arylthio-
alkyl, carboxyalkyl, carbamoylalkyl, alkoxycarbonylalkyl,
alkanoyloxyalkyl, alkoxycarbonyloxyaUkyl, aroyloxyalkyl
or aryloxycarbonyloxyalkyl, monosubstituted.
An optionally substituted alicyclic radical, and the corre-
sponding optionally substituted alicyclic-aliphatic radical
which is linked via a~n open carbon chain, is a preferably mono-
to pentacyclic, isocyclic, nonaromatic radical which has
single bonds or asymmetrically distributed double bonds
and can also be branched (i.e. carry open-chain aliphatic
side-chains) and is linked via a ring carbon atom or a
side-chain carbon atom. It is preferably unsubstituted.
When several rings are components of a radical of this type,
they are fused, spiro-linked or isolated. Examples of
radicals of this type are cycloalkyl, cycloalkenyl, cyclo-
alkylalkyl, bicycloalkyl, tricycloalkyl and radicals de-
rived from mono-, bi- or oligocyclic terpenes such as
menthyl, isomenthyl, bornanyl, bornyl, caranyl, epibornyl,
epiisobornyl, isobornyl, menthanyl, neomenthyl, neoiso-
menthyl, pinanyl and thujanyl; they are preferably unsub-
stituted (according to the present definition, aliphatic
side-chains are not substituents).
An optionally substituted aromatic radical is preferably
aryl such as phenyl, biphenylyl or naphthyl, which is op-
tionally mono-, di- or trisubstituted as indicated below
for aryl. Radicals derived from aryl, such as aralkyl,
aryloxy, arylthio or aroyl, preferably benzoyl, can be sub-
stituted as for aryl.
X341064
- 6 -
An optionally substituted heteroaromatic radical is pref-
erably an aromatic mono- or bicyclic heterocyclic radical
having 5 to 7 or 8 to 12, preferably up to 10, ring atoms
respectively, 1 or 2 of these ring atoms representing sul-
fur or oxygen atoms and/or 1 to 4 of these ring atoms repre-
senting nitrogen atoms, and is understood to be, for example,
thienyl, benzoCb7thienyl, furyl, pyranyl, benzofuryl, pyr-
rolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrid-
azinyl, indazolyl, isoindolyl, indolyl, purinyl, quinol-
izinyl, isoquinolinyl, phthalazinyl, naphthyridinyl, quin-
oxalinyl, quinazolyl, cinnolinyl, pteridinyl, oxazolyl,
isoxazolyl, thiazolyl or isothiazolyl. These radicals can
also be partially or completely hydrogenated. A hetero-
aromatic radical and the corresponding heteroaromatic-
aliphatic radical can be substituted as defined below.
An optionally substituted araliphatic radical is under-
stood to be, in particular, aralkyl radicals such as aryl-
alkyl, diarylalkyl, indanyl or fluorenyl, in which aryl is
as defined above and which can be substituted in the manner
indicated there.
R4 and R5 can form, with the atoms carrying them, a mono-,
bi- or tricyclic heterocyclic ring system which has 3 to
15 ring carbon atoms and preferably has up to 2 sulfur
atoms and up to 2 nitrogen atoms in the ring, in particu-
lar up to 1 sulfur atom.
Particularly suitable ring systems of these types are
those of the following group:
Pyrrolidine (0); thiazolidine (R); tetrahydroisoquinoline (A>;
decahydroisoquinoline (8); octahydroindole (C); indoline (Q>;
octahydrocyclopentaCblpyrrole (D); 2-azaspiroC4.57decane CE>;
2-azaspiroC4.47nonane (F); spiroC(bicycloC2.2.17heptane>-
2,3'-pyrrolidineJ (G>; spiroC(bicycloC2.2.2Joctane)-2,3'-
pyrrolidineJ (H); 2-azatricycloC4.3Ø16'9Jdecane (I>;
decahydrocycloheptaCb7pyrrole (J); octahydroisoindole (K);
1 341 06 4
- 7 -
octahydrocyclopentaCc7pyrrole (L>; 2,3,3a,4,5,7a-hexahydro-
indole (M>; 2-azabicycloC3.1.OJhexane (N); 1,2,3,3a,4,6a-
hexahydrocyclopentaCbJpyrrole (P), all of which can option-
ally be substituted. Pyrrolidine (0) and thiazolidine (R);
can be monosubstituted by, for example, (C6-C12)-aryl,
(phenyl, 2-hydroxyphenyl etc.), (C6-C12)-arylmercapto (such
as phenylmercapto) or (C3-C7>-cycloalkyl (such as cyclo-
hexyl). Tetrahydroisoquinoline (A) can carry, for example,
in the aryl moiety, up to 2 (C1-C6)-alkoxy radicals, prefer-
ably methoxy radicals. A corresponding statement applies
to the other ring systems. However,~the unsubstituted
systems are preferred.
With compounds ~of the formula I or II which have several
chiral atoms all possible diastereomers, as racemates or
enantiomers, or mixtures of various diastereomers are
suitable.
The suitable heterocyclic ring systems have the following
structural formulae.
1341064
_8_
/ ' - CooR3 C0op.3
H ,' N' .
)- COORS
' -. C
.. .
. ~COOR3
i ~- CooR3
D ~ ~ ~COOR3
~'1 -. F 1
t:00R3 ~OOR3 COORS
t
G ' ~I I
~..
3 J'-COOR3 3
~- COOK, '~ COOR
1 1 .
J , x i
3
-COORS COOK
H p ._
-. -
3
--COORS COOR
N
O p
I ~- COO;R3 COORS
N
R
1341 U64
9
A preferred embodiment comprises use of compounds of the
formula I, preferably those of the formula II, in which
a> n is 1 or 2;
b) R 1. denotes hydrogen;
2. denotes alkyl having 1-18 carbon atoms;
3. denotes an aliphatic acyclic radical of the for-
mula CaH(2a-~b+1). in which double bonds, if
their number exceeds 1, are not cumulative, a rep-
resents an integer 2 to 18, and b represents an
integer 2 tc~ a;
4. denotes a mono-, di-, tri-, tetra- or pentacyclic,
non-aromatic hydrocarbon radical of the formula
CcH(2c-d-1)~ which is optionally branched, in
which c represents an integer 3 to 20, and d rep-
resents an even number 0 to (c-2);
5. denotes aryl which has 6-12 carbon atoms and can
be mono-, di- or trisubstituted by (C1-Cg)-alkyl,
(C1-C4>-alkoxy, hydroxyl, halogen, vitro, amino,
aminomethyl, (C1-C4)-alkylamino, di-(C1-C4>-
alkylamino, (C1-C4)-alkanoylamino, methylene-
dioxy, carboxyl, cyano and/or sulfamoyl;
6. if n is 2, dlenotes (C6-C12>-aryl-(C1-Cg>-alkyl
or di-(C6-C12)-aryl-(C1-Cg)-alkyl, each of
which can be substituted in the aryl moiety as
described under I.b>5; or
7. alkoxy having 1-4 carbon atoms;
8. aryloxy which has 6-12 carbon atoms and can be
substituted as described under I.b)5;
9. mono- or bicyclic heteroaryloxy or heteroaryl-
(C1-Cg)-alkyl which has 5-7 or 8-10 ring atoms
respectively, up to 9 of these ring atoms repre-
senting carbon and 1 to 2 ring atoms representing
sulfur or oxygen and/or 1 to 4 ring atoms repre-
senting nitrogen, and which can be substituted in
the heteroaryl as described under I.b)5;
10. amino-(C1-C8,)-alkyl;
11. (C1-C4)-alkanoylamino-(C1-C8>-alkyl;
12. (C7-C13)-aroylamino-(C1-Cg)-alkyl;
~3~~ 064
- 10 -
13. (C1-C4>-alkoxycarbonylamino-(C1-Cg)-alkyl;
14. (C6-C12)-aryl-(C1-C4)-alkoxycarbonylamino-
(C1-C8)-alkyl;
15. (C6-C12)-aryl-(C1-C4)-alkylamino-(C1-Cg)-
alkyl;
16. (C1-C4)-alkylamino-(C1-Cg)-alkyl;
17. di-(C1-C4)-ailkylamino-(C1-Cg)-alkyl;
18. guanidino-(C1-Cg)-alkyl,
19. imidazolyl;
20. indolyl;
21. (C1-C4)-alkylthio;
22. if n is 2, (C1-C4>-alkylthio-(C1-Cg>-alkyl;
23. (C6-C12)-arylthio-(C1-C8>-alkyl which can
be substituted in the aryl moiety as described
under I.b>5;
24. (C6-C12)-aryl-(C1-Cg)-alkylthio which can
be substituted in the aryl moiety as described
under I.b)5;
25. if n is 2, carboxy-(C1-C8)-alkyl;
26. carboxyl;
27. carbamoyl;
28. if n is 2, carbamoyl-(C1-Cg)-alkyl;
29. (C1-C4)-alkoxy-carbonyl-(C1-C8)-alkyl;
30. if n is 2, (C6-C12)-aryloxy-(C1-Cg)-alkyl
which can be~ substituted in the aryl moiety as
described under I.b)5; or
31. denotes (C6-~C12)-aryl-(C1-Cg)-alkoxy
which can be~ substituted in the aryl moiety as
described under I.b)5;
c) R1 denotes hydrogen;
1.
2. denotes alkyl having 1-18 carbon atoms;
3. denotes an aliphatic radical of the formula
CaH(2a-b+1) in which double bonds, if their num-
ber exceeds 1, are not cumulative, a represents
an integer f. to 18, and b represents an even
number 2 to a;
4. denotes a mono-, di-, tri-, tetra- or pentacyclic,
non-aromatic hydrocarbon radical of the formula
1 341 06 4
- 11 -
CcH(2c-d-1)~ which is optionally branched and in
which c represents an integer 3 to 20 and d rep-
resents an even number 0 to (c-2);
5. aryl which has 6-12 carbon atoms and can be sub-
s stituted as described under I.b)5;
6. (C6-C12)-aryl-(C1-Cg)-alkyl or (C7-C13)_
aroyl-(C1-C8)-alkyl, both of which can be sub-
stituted as described for aryl under I.b)5;
7. mono- or bicyclic, optionally partially hydrogen-
ated, heteroaryl or heteroaryl-(C1-Cg)-alkyl which
has 5-7 or 8-10 ring atoms respectively, up to
9 of these ring atoms representing carbon and 1
or 2 ring atoms representing sulfur or oxygen and/
or 1 to 4 ring atoms representing nitrogen, and
which can be substituted in the heteroaryl as des-
cribed for aryl under I.b>5; or
8. if not already covered by c) 1. - 8., the option-
ally protected side-chain of a naturally occurring
a-amino acid) of the formula R1-CH(NH2)-COOH;
d) R2 and R3 are identical or different and
1. denote hydra~gen;
2. alkyl havingi 1-18 carbon atoms;
3. denote an aliphatic acyclic radical of the for
mula CaH(2a-b+1). in which double bonds, if
their number exceeds 1, are not cumulative, a
represents a~n integer 2 to 18, and b represents
an even number 2 to a;
4. a mono-, di-~, tri-, tetra- or pentacyclic, non
aromatic hydirocarbon radical of the formula
CcH(2c-d-1). which is optionally branched and
in which c represents an integer 3 to 20 and d
represents a~n even number 0 to (c-2);
5. di-(C1-C4)-a~lkylamino-(C1-Cg>-alkyl;
6. (C1-CS>-alka~noyloxy-(C1-Cg)-alkyl;
7. (C1-C6)-alkoxy-carbonyloxy-(C1-Cg)-alkyl;
8. (C7-C13>-aroyloxy-(C1-Cg>-alkyl;
9. (C6-C12)-aryloxycarbonyloxy-(C1-Cg)-alkyl;
10. aryl having 6-12 carbon atoms; or
1 341 O6 4
- 12 -
11. denote (C7-C20)-aralkyl; it being possible
for thc~ radicals mentioned under d) 8., 9., 10.
and 11.. to be substituted in the aryl moiety as
described under I.b)5;
and
e) R4 and R5 form, together with the atoms carrying them,
a mono--, bi- or tricyclic heterocyclic ring system
having 3 to 15 ring carbon atoms.
A particularly preferred embodiment comprises use of com-
pounds of the formula I, preferably those of the formula
II, in which
n is 1 or 2,
R denotes hydrogen,
alkyl having 1-8 carbon atoms,
alkenyl having 2-6 carbon atoms,
cycloalkyl having 3-9 carbon atoms,
aryl which has 6-12 carbon atoms and can be mono-,
di- or trisubstituted by (C1-C4)-alkyl, (C1-C4)-
alkoxy, hydroxyl, halogen, nitro, amino, aminomethyl,
(C1-C4)-alkylamino, di-(C1-C4)-alkylamino,
(C1-C4)-alkanoylamino, methylenedioxy, carboxyl,
cyano and/or sulfamoyl,
alkoxy having 1-4 carbon atoms,
aryloxy which has 6-12 carbon atoms and can be sub-
stituted as described above for aryl,
mono- or bicyclic heteroaryloxy which has 5-7 or 8-
10 ring atoms respectively, 1 to 2 of these ring atoms
representing sulfur or oxygen atoms, and/or 1 to 4 of
these ring atoms representing nitrogen, and which can
be substituted as described above for aryl, amino-
(C1-C4)-alkyl,
(C1-C4)-alkanoylamino-(C1-C4)alkyl,
(C7-C13)-aroylamino-(C1-C4)-alkyl,
(C1-C4)-alkoxycarbonylamino-(C1-C4>-alkyl,
(C6-C12)-aryl-CC1-C4>-alkoxycarbonylamino-
(C1-C4)-alkyl,
(C6-C12)-aryl-(C1-C4)-alkylamino-(C1-C4)-alkyl,
1341 064
13
(C1-C4)-alkylamino-(C1-C4)-alkyl,
di-(C1-C4)._alkylamino-(C1-C4)-alkyl,
guanidino-(C1-C4)-alkyl,
imidazolyl,, indolyl,
(C1-C4)-alkylthio,
(C1-C4>-alkylthio-(C1-Ct,)-alkyl,
(C6-C12)-airylthio-(C1-C4)-alkyl which can be sub-
stituted in the aryl moiety as described above for
aryl,
(C6-C12>-airyl-(C1-C4)-alkylthio which can be substi-
tuted in the aryl moiety as described above for aryl,
carboxy-(C~-C4)-alkyl,
carboxyl, ~.arbamoyl,
carbamoyl-(C1-C4>-alkyl,
(C1-C4)-alkoxycarbonyl-(C1-C4>-alkyl,
(C6-C12)-airyloxy-(C1-C4)-alkyl which can be sub-
stituted in the aryl moiety as described above for
aryl, or
(C6-C12)-airyl-(C1-C4)-alkoxy which can be sub-
stituted in the aryl moiety as described above for
aryl,
R1 denotes hydrogen,
alkyl having 1-6 carbon atoms,
alkenyl haring 2-6 carbon atoms,
alkynyl haring 2-6 carbon atoms,
cycloalkyl having 3-9 carbon atoms,
cycloalkenyl having 5-9 carbon atoms,
(C3-C9)-cy~~loalkyl-(C1-C4>-alkyl,
(CS-C9)-cycloalkenyl-(C1-C4)-alkyl,
optionally partially hydrogenated aryl which has 6-
12 carbon ~~toms and can be substituted as described
above for li, (C6-C12)-aryl-(C1-C4)-alkyl or (C7-C13)~
aroyl-(C1 or C2)-alkyl, both of which can be substi-
tuted as for the preceding aryl, mono- or bicyclic,
optionally partially hydrogenated heteroaryl which
has 5-7 or 8-10 ring atoms respectively, 1 to 2 of
these ring atoms representing sulfur or oxygen atoms,
1341~~4
- 14 -
and/or 1 to 4 of these ring atoms representing
nitrogen atoms, and which can be substituted as for
the preceding aryl, or
the optionally protected side-chain of a naturally
occurring ~x-amino acid, R1-CH(NH2)-COOH,
R2 and R3 are identical or different and denote hydrogen,
alkyl having 1-6 carbon atoms,
alkenyl having 2-6 carbon atoms,
di-(C1-C4>-alkylamino-(C1-C4)-alkyl,
(C1-CS>-alkanoyloxy-(C1-C4)-alkyl,
(C1-C6>-alkoxycarbonyloxy-(C1-C4>-alkyl,
(C7-C13)-aroyloxy-(C1-C4>-alkyl,
(C6-C12)-aryloxycarbonyloxy-(C1-C4)-alkyl,
aryl having 6-12 carbon atoms,
(C6-C12)-aryl-(C1-C4)-alkyl,
(C3-Cg>-cycloalkyl or
(C3-Cg>-cycloalkyl-CC1-C4)-alkyl, and
R4 and RS have the abovementioned meaning, particularly
such compounds in which
n is 1 or 2,
R denotes (C1-C6)-alkyl, (C2-C6)-alkenyl, (C3-Cg)-
cycloalkyl, amino-(C1-C4)-alkyl, (C2-CS)-acylamino-
(C1-C4>-alkyl, (C7-C13)-aroylamino-(C1-C4>-alkyl,
(C1-C4>-alkoxycarbonylamino-(C1-C4)-alkyl, (C6-C12)-
aryl-(C1-C4)-alkoxycarbonylamino-(C1-C4)-alkyl,
(C6-C12)-aryl which can be mono-, di- or tri-
substituted by (C1-C4)-alkyl, (C1-C4)-alkoxy, hy-
droxyl, halogen, vitro, amino, (C1-C4)-alkylamino,
di-(C~-C4)-alkylamino and/or methylenedioxy, or 3-
indolyl, in particular methyl, ethyl, cyclohexyl,
tert.-butoxycarbonylamino-(C1-C4)-alkyl, benzoyloxy-
carbonylamino-(C1-C4>-alkyl, or phenyl which can
be mono- or disubstituted, or in the case of methoxy
trisubstituted, by phenyl, (C1-C2)-alkyl, (C1 or
C2)-alkoxy, hydroxyl, fluorine, chlorine, bromine,
amino, (C1-C4)-alkylamino, di-(C1-C4)-alkylamino,
- ~ 341 O6 4
nitro and/or methylenedioxy,
R1 denotes hydrogen or (C1-C6)-alkyl which can option-
ally be substituted by amino, (C1-C6)-acylamino or
benzoylamino, or (C2-C6)-alkenyl, (C3-Cg)-cyclo-
alkyl, (C5-Cg)-cycloalkenyl, (C3-C7)-cycloalkyl-
(C1-C4)-alkyl, (Cb-C12)-aryl or partially hydro-
genated aryl, each of which can be substituted by
(C1-C4)-alkyl, (C1 or C2)-alkoxy or halogen, or
(C6-C12>-aryl-(C1 to C4)-alkyl or (C7-C13)-aroyl-
(C1-C2>-alkyl, both of which care be substituted in
the aryl radical as defined previously, a mono- or
bicyclic heterocyclic radical having 5 to 7 or 8 to
10 ring atoms respectively, 1 to 2 of these ring
atoms representing sulfur or oxygen atoms, and/or
1 to 4 of these ring atoms representing nitrogen
atoms, or a side-chain of a naturally occurring,
optionally protected a-amino acid, but in particu-
lar hydrogen, (C1-C3)-alkyl, (C2 or C3>-alkenyl,
the optionally protected side-chain of lysine,
benzyl, 4-methoxybenzyl, 4-ethoxybenzyl, phenethyl,
4-aminobutyl or benzoylmethyl,
R2 and R3 denote identical or different radicals hy-
drogen, (C1-C6)-alkyl, (C2-C6)-alkenyl or (C6-C12)-
aryl-(C1-C4)-alkyl, but in particular hydrogen,
(C1-C4>-alkyl or benzyl, and
R4 and RS have the abovementioned meaning.
If R1 represents a side-chain of a protected naturally
occurring a-amino acid, such as, for example, protected
Ser, Thr, Asp, Asn, Glu, Gln, Arg, Lys, Hyl, Cys, Orn,
Cit, Tyr, Trp or His, preferred protective groups are the
groups customary in peptide chemistry (cf. Houben-Weyl,
vol. XV/1 and XV/2). In the case where R1 denotes the pro-
tected side-chain of lysine, the known amino protective
groups are preferred, but in particular Z, Boc or (C1-C6)-
1 341 06 4
- 16 -
alkanoyl. Suitable and preferred 0-protective groups for
tyrosine are (C1-C6)-alkyl, in particular methyl or
ethyl.
It is possible and particularly advantageous to use the
following compounds according to the invention:
2-CN-(1-S-carbethoxy-3-phenylpropyl)-S-alanyl7-S-1,2,3,4-
tetrahydroisoquinoline-3-carboxylic acid
2-CN-(1-S-carbethoxy-3-cyclohexylpropyl)-S-alanyl7-S-1,2,
3,4-tetrahydroisoquinoline-3-carboxylic acid
2-CN-(1-S-carbethoxy-3-phenylpropyl)-S-lysylJ-S-1,2,3,4-
tetrahydroisoquinoline-3-carboxylic acid
2-CN-(1-S-carbethoxy-3-phenylpropyl)-0-ethyl-S-tyrosyl7-S-
1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid
2-CN-(1-S-carbethoxy-3-phenylpropyl>-S-alanyll-(3S)-deca-
hydroisoquinoline-3-carboxylic acid
1-CN-(1-S-carbethoxy-3-phenylpropyl>-S-alanyl7-(2S,3aS,
7aS)-octahydroindole-2-carboxylic acid
1-CN-(1-S-carbethoxy-3-cyclohexylpropyl)-S-alanylJ-(2S,
3aS,7aS)-octahydroindole-2-carboxylic acid
1-CN-(1-S-carbethoxy-3-phenylpropyl)-S-lysylJ-(2S,3aS,
7aS)-octahydroindole-2-carboxylic acid
1-CN-(1-S-carbethoxy-3-cyclohexylpropyl)-S-lysyl7-(2S,3aS,
7aS)-octahydroindole-2-carboxylic acid
1-CN-(1-S-carbethoxy-3-cyclohexylpropyl>-S-lysyl7-(2s,
3aS,7aS>-octahydroindole-2-carboxylic acid
1-CN-(1-S-carbethoxy-3-phenylpropyl)-0-methyl-S-tyrosylJ-
(2S,3aS,7aS)-octahydroindole-2-carboxylic acid
1-CN-(1-S-carbethoxy-3-phenylpropyl)-0-ethyl-S-tyrosyl7-
(2S,3aS,7aS>-octahydroindole-2-carboxylic acid
1-CN-(1-S-carbethoxy-3-(3,4-dimethylphenylpropyl)-S-ala-
nylJ-(2S,3aS,7aS)-octahydroindole-2-carboxylic acid
1-CN-C1-S-carbethoxy-3-(4-fluorophenyl)-propylJ-S-alanylJ-
(2S,3aS,7aS>-octahydroindole-2-carboxylic acid
1-CN-C1-S-carbethoxy-3-(4-methoxyphenyl)-propyl7-S-alanylJ-
(2S,3aS,7aS)-octahydroindole-2-carboxylic acid
1-CN-C1-S-carbethoxy-3-(3,4-dimethoxyphenyl)-propyl7-S-
1 341 06 4
- 17 -
alanylJ-(2S,3aS,,7aS)-octahydroindole-2-carboxylic acid
1-CN-(1-S-carbe~thoxy-3-cyclopentylpropyl>-S-alanylJ-(2S,
3aS,7aS)-octahydroindole-2-carboxylic acid
1-CN-(1-S-carbe~thoxy-3-phenylpropyl)-S-alanylJ-(2S,3aR,
7aS)-octahydroindole-2-carboxylic acid
1-CN-(1-S-carbe~thoxy-3-cyclohexylpropyl)-S-alanylJ-(2S,
3aR,7aS)-octahydroindole-carboxylic acid
1-CN-(1-S-carbesthoxy-3-phenylpropyl)-S-lysylJ-(2S,3aR,
7aS>-octahydroindole-2-carboxylic acid
1-CN-(1-S-carbeithoxy-3-cyclohexylpropyl)-S-lysylJ-(2S,
3aR,7aS)-octahydroindole-2-carboxylic~acid
1-CN-(1-S-carbethoxy-3-phenylpropyl)-0-ethyl-S-tyrosylJ-
(2S,3aS,7aR)-ocitahydroindole-2-carboxylic acid
1-CN-(1-S-carbe~thoxy-3-phenylpropyl)-S-alanylJ-(2S,3aR,
7aR)-octahydroindole-2-carboxylic acid
1-CN-(1-S-carbethoxy-3-phenylpropyl)-S-lysylJ-(2S,3aR,
7aS>-octahydroindole-2-carboxylic acid
1-CN-(1-S-carbe~thoxy-3-cyclohexylpropyl)-S-alanylJ-(2S,
3aR,7aR)-octahydroindole-2-carboxylic acid
1-CN-(1-S-carbethoxy-3-cyclohexylpropyl)-0-ethyl-S-tyrosylJ-
(2S,3aR,7aR)-octahydroindole-2-carboxylic acid
1-CN-(1-S-carbe~thoxy-3-phenylpropyl)-S-alanylJ-(2S,3aS,
7aR)-octahydroindole-2-carboxylic acid
1-CN-(1-S-carbethoxy-3-phenylpropyl)-0-ethyl-S-tyrosylJ-
(2S,3aS,7aS)-oc~tahydroindole-2-carboxylic acid
1-CN-(1-S-carbevthoxy-3,4-dimethylphenylpropyl>-S-alanylJ-
(2S,3aS,7aS)-oc~tahydroindole-2-carboxylic acid
1-CN-C1-S-carbe~thoxy-3-(4-fluorophenyl)-propylJ-S-alanylJ-
(2S,3aS,7aS)-oc~tahydroindole-2-carboxylic acid
1-CN-C1-S-carbe~thoxy-3-(4-methoxyphenyl)-propylJ-S-alanylJ-
(2S,3aS,7aS)-oc~tahydroindole-2-carboxylic acid
1-CN-C1-S-carbe~thoxy-3-(3,4-dimethoxyphenyl)-propylJ-S-
alanylJ-(2S,3aS,,7aS)-octahydroindole-2-carboxylic acid
1-CN-(1-S-carbe~thoxy-3-cyclopentylpropyl>-S-alanylJ-(2S,
3aS,7aS)-octahydroindole-2-carboxylic acid
2-CN-(1-S-carbe~thoxy-3-phenylpropyl)-S-alanylJ-cis-endo-
2-azabicycloC3.:5.OJoctane-3-S-carboxylic acid
2-CN-(1-S-carbe~thoxy-3-phenylpropyl)-S-lysylJ-cis-endo-
1 341 O6 4
- 18 -
2-azabicycloC3.3.OJoctane-3-S-carboxylic acid
2-CN-(1-S-carbethoxy-3-cyclohexylpropyl)-S-alanylJ-cis-
endo-2-azabicycloC3.3.OJoctane-3-S-carboxylic acid
2-CN-(1-S-carboxy-3-cyclohexylpropyl)-S-alanylJ-cis-endo-
2-azabicycloC3.3.OJoctane-3-S-carboxylic acid
2-CN-(1-S-carbethoxy-butyl)-S-alanylJ-cis-endo-2-aza-
bicycloC3.3.OJoctane-3-S-carboxylic acid
2-CN-(1-S-carbethoxy-3-(3,4-dimethoxyphenylpropyl)-S-ala-
nylJ-cis-endo-2-azabicycloC3.3.OJoctane-3-S-carboxylic acid
2-CN-(1-S-carbethoxy-3-cyclopentylpropyl>-S-alanylJ-cis-
endo-azabicyclo-C3.3.OJoctane-3-S-carboxylic acid
2-CN-(1-S-carbethoxy-3-phenylpropyl>-0-methyl-S-tyrosyll-
cis-endo-2-azabicycloC3.3.OJoctane-3-S-carboxylic acid
2-CN-(1-S-carbethoxy-3-phenylpropyl)-0-ethyl-S-tyrosylJ-
cis-endo-2-azabicycloC3.3.OJoctane-3-S-carboxylic acid
2-CN-(1-S-carbethoxy-3-(4-fluorophenylpropyl)-S-alanylJ-
cis-endo-2-azabicycloC3.3.OJoctane-3-S-carboxylic acid
2-CN-(1-S-carbethoxy-3-(4-methoxyphenylpropyl)-S-alanylJ-
cis-endo-2-azabicycloC3.3.OJoctane-3-S-carboxylic acid
1-CN-(1-S-carbethoxy-3-phenylpropyl)-S-lysylJ-(2S,3aR,
6aS)-octahydrocyclopentaCbJpyrrole-2-carboxylic acid
1-CN-(1-S-carbethoxy-3-cyclohexylpropyl)-lysylJ-(2S,3aR,
6aS)-octahydrocyclopentaCbJpyrrole-2-carboxylic acid
1-CN-(1-S-carbethoxy-3-phenylpropyl)-0-ethyl-S-tyrosylJ-
(2S,3aR,6aS)-octahydrocyclopentaCbJpyrrole-2-carboxylic
acid
1-CN-(1-S-carbethoxy-3-phenylpropyl)-S-alanyll-2-(2S,3aR,
6aS)-octahydrocyclopentaCbJpyrrole-2-carboxylic acid
2-CN-(1-S-carbethoxy-3-phenylpropyl)-S-alanylJ-2-aza-
spiro-C4.SJdecane-3-S-carboxylic acid
2-CN-(1-S-carbethoxy-3-phenylpropyl>-0-ethyl-2-tyrosylJ-
2-azaspiro-C4.5Jdecane-3-S-carboxylic acid
2-CN-(1-S-carbethoxy-3-phenylpropyl)-S-lysyll-2-azaspiro-
C4.5Jdecane-3-S-carboxylic acid
2-CN-(1-S-carbethoxy-3-cyclohexylpropyl)-S-alanyl7-2-aza-
spiroC4.5Jdecane-3-S-carboxylic acid
2-CN-(1-S-carbethoxy-3-cyclohexylpropyl>-S-lysylJ-2-aza-
spiroC4.5Jdecane-3-S-carboxylic acid
2-CN-(1-S-carbethoxy-3-phenylpropyl)-S-alanylJ-2-azaspiro-
C4.47nonane-3-S-carboxylic acid
1 341 06 4
- 19 -
2-CN-(1-S-carbethoxy-:S-phenylpropyl)-0-ethyl-S-tyrosylJ-
2-azaspiroC4.47nonane--3-S-carboxylic acid
2-CN-(1-S-carbethoxy-:S-phenylpropyl>-S-lysyll-2-azaspiro-
C4.4Jnonane-3-S-carboxylic acid
2-CN-(1-S-carbethoxy-:i-cyclohexylpropyl)-S-alanyl7-2-aza-
spiroC4.47nonane-3-S-c;arboxylic acid
2-CN-(1-S-carbethoxy-:S-cyclopentylpropyl)-S-alanylJ-2-aza-
spiroC4.47nonane-3-S-c;arboxylic acid
2-CN-(1-S-carbethoxy-:S-cyclopentylpropyl)-S-lysyl7-2-aza-
spiroC4.47nonane-3-S-c;arboxylic acid
1'-CN-(1-S-carbethoxy--3-phenylpropyl)-S-alanylJ-spiroCbi-
cycloC2.2.17heptane-2,,3'-pyrrolidine7-5'-S-carboxylic acid
1'-CN-(1-S-carbethoxy--3-phenylpropyl)-0-ethyl-S-tyrosyl7-
spiroCbicycloC2.2.1Jheaptane-2,3'-pyrrolidinel-5'-S-car-
boxylic acid
1'-CN-(1-S-carbethoxy-3-phenylpropyl)-S-lysylJ-spiroCbi-
cycloC2.2.17heptane-2,.3'-pyrrolidineJ-5'-S-carboxylic acid
1'-CN-(1-S-carbethoxy--3-cyclohexylpropyl)-S-alanylJ-spiro-
CbicycloC2.2.17heptane~-2,3'-pyrrolidineJS'-S-carboxylic
acid
1'-CN-(1-S-carbethoxy--3-cyclohexylpropyl) -S-lysyl7-spiro
CbicycloC2.2.1Jheptane~-2,3'-pyrrolidinel-5'-S-carboxylic
acid
1'-CN-(1-S-carbethoxy--3-phenylpropyl)-S-alanyll-spiro-
CbicycloC2.2.2.7octane~-2,3'-pyrrolidine7-5'-S-carboxylic
acid
1'-CN-(1-S-carbethoxy--3-phenylpropyl)-0-ethyltyrosylJ-
spiro-CbicycloC2.2.27octane-2,3'-pyrrolidine7-5'-S-car-
boxylic acid
1'-CN-(1-S-carbethoxy--3-phenylpropyl)-S-lysylJ-spiroCbi-
cycloC2.2.27octane-2,'_i'-pyrrolidine7-5'-S-carboxylic acid
1'-CN-(1-S-carbethoxy--3-cyclohexylpropyl)-S-alanylJ-spiro-
CbicycloC2.2.27octane-2,3'-pyrrolidine7-5'-S-carboxylic
acid
2-CN-(1-S-carbethoxy-'_i-phenylpropyl>-S-alanylJ-2-azatri-
cycloC4.3Ø16'97decane-3-S-carboxylic acid
2-CN-(1-S-carbethoxy-'_i-phenylpropyl)-0-ethyl-S-tyrosylJ-
2-azatricycloC4.3Ø1E''9Jdecane-3-S-carboxylic acid
1 341 06 4
- 20 -
2-CN-(1-S-carbethoxy-3-phenylpropyl)-S-LysylJ-2-azatri-
cycloC4.3Ø16'9Jdecane-3-S-carboxylic acid
2-CN-(1-S-carbethoxy-3-cyclohexylpropyl)-S-alanylJ-2-aza-
tricycloC4.3Ø16'9Jdecane-3-S-carboxylic acid
2-CN-(1-S-carbethoxy-3-cyclohexylpropyl)-S-lysylJ-2-aza-
tricycloC4.3Ø16'9Jdecane-3-S-carboxylic acid
1-CN-(1-S-carbethoxy-3-phenylpropyl)-S-alanylJ-decahydro-
cycloheptaCbJpyrrole-2-S-carboxylic acid
1-CN-(1-S-carbethoxy-3-phenylpropyl)-0-ethyl-S-tyrosylJ-
decahydrocycloheptaCbJpyrrole-2-S-carboxylic acid
1-CN-(1-S-carbethoxy-3-phenylpropyl>-S-lysylJ-decahydro-
cycloheptaCbJpyrrole-2-S-carboxylic acid
1-CN-(1-S-carbethoxy-3-cyclohexylpropyl>-S-alanylJ-deca-
hydrocycloheptaCbJpyrrole-2-S-carboxylic acid
1-CN-(1-S-carbethoxy-3-cyclohexylpropyl)-S-lysylJ-deca-
hydrocycloheptaCbJpyrrole-2-S-carboxylic acid
2-CN-(1-S-carbethoxy-3-phenylpropyl)-S-alanylJ-trans-
octahydroisoindole-1-S-carboxylic acid
2-CN-(1-S-carbethoxy-3-phenylpropyl>-S-alanylJ-cis-octa-
hydroisoindole-1-S-carboxylic acid
2-CN-(1-S-carbethoxy-3-cyclohexylpropyl)-S-alanylJ-trans-
octahydroisoindole-1-S-carboxylic acid
2-CN-(1-S-carbethoxy-3-cyclohexylpropyl)-S-alanylJ-cis-
octahydroisoindole-1-S-carboxylic acid
2-CN-(1-S-carbethoxy-3-phenylpropyl>-S-alanylJ-cis-octa-
hydrocyclopentaCcJpyrrole-1-S-carboxylic acid
2-CN-(1-S-carbethoxy-3-cyclohexylpropyl)-S-alanylJ-cis-
octahydrocyclopentaCcJpyrrole-1-S-carboxylic acid benzyl
ester
2-CN-(1-S-carbethoxy-3-cyclohexylpropyl)-S-lysylJ-cis-
octahydrocyclopentaCcJpyrrole-1-S-carboxylic acid
1-CN-(1-S-carbethoxy-3-phenylpropyl>-S-alanylJ-2,3,3a,4,
5,7a-hexahydroindole-cis-endo-2-S-carboxylic acid
1-CN-(1-S-carbethoxy-3-phenylpropyl)-S-lysylJ-2,3,3a,4,
5,7a-hexahydroindole-cis-endo-2-S-carboxylic acid
2-CN-(1-S-carbethoxy-3-cyclohexylpropyl)-S-LysylJ-2-aza-
bicycloC3.1.OJhexane-3-S-carboxylic acid
2-CN-(1-S-carboxy-3-p~henylpropyl>-S-lysylJ-2-azabicyclo-
1341 064
- 21 -
C3.1.OJhexane-cis-endo-3-S-carboxylic acid
2-CN-(1-S-carbethoxy-3-cyclopentylpropyl)-S-alanylJ-2-
azabicycloC3.1.1)Jhexane-3-carboxylic acid
2-CN-(1-S-carbethoxy-3-phenylpropyl)-S-alanylJ-cis-endo-
2-azabicycloC3.l.OJhexane-3-S-carboxylic acid
2-CN-(1-S-carbethoxy-3-cyclohexylpropyl)-S-alanylJ-cis-
endo-2-azabicycloC3.l.OJhexane-3-S-carboxylic acid
1'-CN-(1-S-carb~ethoxy-3-phenylpropyl>-S-alanylJ-(3'S,5'S)-
spiro-bicycloC2.2.2Joctane-2,3'-pyrrolidine-5'-carboxylic
acid '
1'-CN-(1-S-carb~ethoxy-3-phenylpropyl>-S-alanylJ-3'R,5'S>-
spiro-bicycloC2.2.2Joctane-2,3'-pyrrolidine-5'-carboxylic
acid
1'-CN-(1-S-carbethoxy-3-phenylpropyl)-S-alanylJ-(3'S,5'R)-
spiro-bicycloC2.2.2Joctane-2,3'-pyrrolidine-5'-carboxylic
acid
1'-CN-(1-S-carbethoxy-3-phenylpropyl)-S-alanylJ-(3'R,S'R>-
spiro-bicycloC2.2.2Joctane-2,3'-pyrrolidine-S'-carboxylic
acid
1'-CN-(1-R-carbethoxy-3-phenylpropyl)-S-alanylJ-(3'S,5'R)-
spiro-bicycloC2.2.2Joctane-2,3'-pyrrolidine-5'-carboxylic
acid
1'-CN-(1-R-carbethoxy-3-phenylpropyl)-S-alanylJ-(3'S,5'S)-
spiro-bicycloC2.2.2Joctane,2,3'-pyrrolidine-5'-carboxylic
acid
1'-CN-(1-R-carbethoxy-3-phenylpropyl)-S-alanylJ-(3'R,5'S)-
spiro-bicycloC2.2.2Joctane-2,3'-pyrrolidine-5'-carboxylic
acid
1'-CN-(1-R-carbethoxy-3-phenylpropyl>-S-alanylJ-(3'R,5'R)-
spiro-bicycloC2.2.2Joctane-2,3'-pyrrolidine-5'-carboxylic
acid
1'-CN-(1-S-carbethoxy-3-phenylpropyl>-R-alanylJ-(3'S,5'S>-
spiro-bicycloC2.2.2Joctane-2,3'-pyrrolidine-5'-carboxylic
acid
1'-CN-(1-S-carbethoxy-3-phenylpropyl)-R-alanylJ-(3'R,5'S>-
spiro-bicycloC2.2.2Joctane-2,3'-pyrrolidine-5'-carboxylic
acid
~~41 064
- 22 -
1'-CN-(1-S-carbethoxy-3-phenylpropyl)-R-alanyl7-(3'S,5'R)-
spiro-bicycloC2.2.2Joctane-2,3'-pyrrolidine-5'-carboxy-
lic acid
1'-CN-(1-S-carbethoxy-3-phenylpropyl>-R-alanyl7-(3'R,S'R)-
spiro-bicycloC2.2.2Joctane-2,3'-pyrrolidine-5'-carboxy-
lic acid
1'-CN-(1-R-carbethoxy-3-phenylpropyl)-R-alanylJ-(3'S,5'S)-
spiro-bicycloC2.2.2Joctane-2,3'-pyrrolidine-5'-carboxy-
lic acid
1'-CN-(1-R-carbethoxy-3-phenylpropyl)-R-alanyl7-(3'R,5'S)-
spiro-bicycloC2.2.2Joctane-2,3'-pyrrol~idine-5'-carboxy-
lic acid
1'-CN-(1-R-carbethoxy-3-phenylpropyl)-R-alanylJ-(3'S,5'R>-
spiro-bicycloC2.2.2Joctane-2,3'-pyrrolidine-5'-carboxy-
lic acid
1'-CN-(1-R-carbethoxy-3-phenylpropyl)-R-alanylJ-(3'R,5'R)-
spiro-bicycloC2.2.2Joctane-2,3'-pyrrolidine-5'-carboxy-
lic acid
These compounds can be prepared by, for example, the
process described in German Patent Application P 33 33
455.2, in which the tert.-butyl or benzyl derivatives de-
scribed in the application are converted in a known manner,
by acid or alkaline hydrolysis or by hydrogenolysis cata-
lyzed with noble metals, into the monocarboxylic acid
derivatives. The N~-benzyloxycarbonyl protective group
of the lysine derivatives is removed by hydrogenolysis
catalyzed with noble metals. The compounds listed above
can readily be converted with physiologically tolerated
acids or bases (in the case of mono- or dicarboxylic acids)
into the corresponding salts (for example hydrochlorides,
maleates, fumarates etc.>, and be used as salts according
to the invention.
The compounds of the formula I are inhibitors of angio-
tensin converting enzyme (ACE) or are intermediates in
the preparation of such inhibitors, and they can also be
used for controlling high blood pressure of a variety of
1 341 06 4
- 23 -
etiologies. Some of the compounds of the formula I and
processes for their preparation are disclosed in, for
example, US Patent 4,129,571, US Patent 4,374,829, European
Patent A-79522, European Patent A-79022, European Patent
A-49658, European Patent A-51301, US Patent 4,454,292, US
Patent 4,374,847, European Patent A-72352, US Patent
4,350,704, European Patent A-50800, European Patent
A-46953, US Patent 4,344,949, European Patent A-84164, US
Patent 4,470,972, European Patent A-65301 and European
Patent A-52991. New compounds of the formula I are pre-
pared in an analogous. manner.
Orally effective ACE inhibitors (some of the active com-
pounds already mentioned above) are also advantageous,
such as, for example,. ramipril, enalapril(f), captopril(a),
lisinopril(g), cilazapril(o>, RHC 3659, CGS 13945, CGS
13928C(1>, CGS 14824A(h>, CI-906(j), zofenopril(e), foseno-
pril(p), alacepril, (:I-925(k>, pentopril(q), CV 3317(m>,
indolapril(h>, YS 980(b), fentiapril(c), pivopril(d),
perindopril(i), and others. Orally effective ACE inhibi-
tors are described in, for example, 8runner et al.,
J. Cardiovasc. Pharmacol. 7 (Suppl. I) C19857 2-11.
1341 064
- .24 -
. . ~3 /~. 1~'t3
HS-CHZ CH-CO-N HS-CHZ-CH-CO-N
..
r~ ) t,~02H t b ) p02H
._
S : (ate )3-co-s-cH2-t~-oo- ~ ,
ta) Qi2-OOZH
tc)
lN~ ~2H CH CH
~ 00-S-CN -CH-tb-1~1 ~ CH-NH- ~ 2 2~
2
p 1 ~ tf)
t a 1 ~~2H ~3 ~2p2H5 -
N
2H /~2~2 ~ ~ 00 H
~CH-NH -CH . .~
pf 1 1 H ~' 2 Z tJ
(CH2)~-NHZ . GpZH tg) ~i-NH-G' i
p ru m r W
1 341 06 4
- 25 -
n . ~ .
w.
CO H ~~2~2 /
- N 2 CH CH
H ~-~-NH-~i 2 .~~3
1 00 H C2H5
~3 2C2 5 ( i )
X~s H (j)
X' = 3.4 ~CH3 (k)
. . . . / ~ . . . ... . _
t~02H ~~Z~"~2 / ~ ~ ~ ~ .
. . ~'~-~ -'~- ~-NH-CH~~ZCHZ ~
~2C;rH5 ( 1 ) - - p~-pp H I I ~ ~ .
Z , ~ ~2c"ZH5 (m)
~/CN2CH2-~! ~ N .
~N p~
. x,~~ ~~"(Z 2""~
C N
225 . .
QpZH pp2C2H,5 ( o
CHZ-OOZH . (n) .. . .
- OOZH , . .
I) . . .
1~1-00-CH -P-( ) ~ ~ ~ I v
:, Z !i ~ ~~
.tt . '-_ . ~~ .,-~:~2H
. , ~. yC.CH-GI -CH
H3C~ ~~~i-OCO . . . O I . Z I .
~ ' ~H5 ~ ( ) . .~ , r ~ . ~2CZH5
. CH3 ~ . p (q)
~ X41 O6 4
- 26 -
The ACE inhibit~~rs which are disclosed in European Patent
A-79022 and are of the formula III
Coox -
N ~ IS) (SI (III)
- ~H - 1NH - CH - CH2 - CH
O CH3 6008 -
in which
R denotes hydro~~en, methyl, ethyl or benzyl, are pre-
ferred, in particular the compound of the formula III in
which R denotes ethyl (ramipril).
Also preferred .are the ACE inhibitors which are disclosed
in European Patent A-84164 and are of the formula IV
I~
COON (IV)
IS) ~S)
~~'~c=c.H-NH-cH-cHZ-cH2
O C~H3 ~OOA~ '
in which
R4 denotes hydrogen, (C1-C4)-alkyl or benzyl, in par-
ticular the compound of the formula IV in which R4 denotes
ethyl.
Furthermore, preference is given to
1'-CN-(1-S-carboethoxy-3-phenylpropyl)-S-alanylJ-exo- or
endo-spirobicycLoC2.2.2Joctane-2,3'-pyrrolidin-5'-ylcar-
boxylic acid anti isomers, and (S,S,S)-1-methyl-2-(1-car-
bethoxy-3-phenyl.propyl)-2H-undecahydrocyclopentaC4.57-
pyrroloC1,2-a7p;irazin~e-3,8-dione.
The invention also relates to new compounds of the formula
II
~t
R300C - ~ H - N' - ~ -~ CH - NH - CH - ( CH2 ) ri R ( I I )
R4 R5 0 R~ COOR2
a. in which 27 1 3 41 d 6 4 '
I.a) n is 1 or 2;
b) R 1. denotes hydrogen;
2. denotes alw;yl having 1-18 carbon atoms;
3. denotes an aliphatic acyclic radical of the for-
mula CaH(2ai-b+1). in which double bonds, if
their number exceeds 1, are not cumulative, a rep-
resents an integer 2 to 18, and b represents an
integer 2 to a;
4. denotes a mono-, di-, tri-, tetra- or pentacyclic,
non-aromatic hydrocarbon radical of the formula
CcH(2c-d-1). which is optionally branched, in
which c represents an integer 3 to 20, and d rep-
resents an even number 0 to (c-2);
5. denotes aryl which has b-12 carbon atoms and can
be mono-, di- or trisubstituted by (C1-C8)-alkyl,
(C1-C4)-alkoxy, hydroxyl, halogen, vitro, amino,
aminomethyl, (C1-C4)-alkylamino, di-(C1-C4)-
alkytamino, (C1-C4)-alkanoylamino, methylene-
dioxy, carboxyl, cyano and/or sulfamoyl;
6. if n is 2, denotes (C6-C12)-aryl-(C1-Cg)-alkyl
or di~-(C6-C12)-aryl-(C1-C8)-alkyl, each of
which can be substituted in the aryl moiety as
described under I.b)5; or
1. alkox;~ having 1-4 carbon atoms;
g, aryloxy which has 6-12 carbon atoms and can be
substituted as described under I.b>5;
9. mono- or bicyclic heteroaryloxy or heteroaryl-
(C1-Cog)-alkyl which has 5-7 or 8-10 ring atoms
respectively, up to 9 of these ring atoms repre-
senting carbon and 1 to 2 ring atoms representing
sulfur or oxygen and/or 1 to 4 ring atoms repre-
senting nitrogen, and which can be substituted in
the h~~teroaryl as described under I.b)5;
10. amino-(C1-C8)-alkyl;
11. (C1-C,;)-alkanoyl.amino-(C1-Cg)-alkyl;
12. (C7-C~~3)-aroylamino-(C1-Cg)-alkyl;
13. (C1-C,;>-alkoxycarbonylamino-(C1-C8)-alkyl;
1341064
- 28 -
14. (C6-C1;>>-aryl-(C1-C4)-alkoxycarbonylamino-
(C1-Cg)-alkyl;
15. (C6-C1;~)-aryl-(C1-C4)-alkylamino-(C1-C8)-
alkyl;
16. (C1-C4)-alkylamino-(C1-Cg)-alkyl;
17. di-(C1-C4)~alkylamino-(C1-Cg)-alkyl;
18. guanidino-(C1-Cg>-alkyl,
19. imidazolyl;
20. indolyl;
21. (C1-C4)-alkylthio;
22. if n is 2, (C1-C4>-alkylthio-(C1-Cg)-alkyl;
23. (C6-C12)-arylthio-(C1-Cg>-alkyl which can be
substituted in the aryl moiety as described
under I.b)5;
24. (C6-C12)-aryl-(C1-Cg)-alkylthio which can be
substituted in the aryl moiety as described
under I.b)5;
25. if n is 2, carboxy-(C1-Cg)-alkyl;
26. carboxyl;
27. carbamoyl;
28. if n is 2, carbamoyl-(C1-Cg)-alkyl;
29. (C1-C4)-alkoxycarbonyl-(C1-Cg)-alkyl;
30. if n is 2, (C6-C12>-aryloxy-(C1-Cg>-alkyl
which can be substituted in the aryl moiety as
described under I.b)5; or
31. denotes (C~-C12)-aryl-(C1-Cg)-alkoxy which can
be substituted in the aryl moiety as described
under I.b)5;
c) R1 denotes hydrogen;
1.
2. denotes alkyl having 1-18 carbon atoms;
3. denotes an acyclic aliphatic radical of the for-
mula CaH(2a_b+1), in which double bonds, if their
number exceeds 1, are not cumulative, a repre-
sents an integer 2 to 18, and b represents an
even number 2 to a;
4. denotes a mono-, di-, tri-, tetra- or pentacyclic,
non-aromatic hydrocarbon radical of the formula
CcH(2c-d-1). which is optionally branched, in
1 341 06 4
- 29 -
which c represents an integer 3 to 20, and d rep-
resents an even number 0 to (c-2);
5. aryl which has 6-12 carbon atoms and can be sub-
stituted as described under I.b)5;
6. (C6-C1z)-aryl-(C1-Cg)-alkyl or (C7-C13)-aroyl-
(C1-Cg>-alkyl, both of which can be substituted
as for aryl under I.b)5;
7. mono- or bicyclic, optionally partially hydrogen-
ated, heteroaryl or heteroaryl-(C1-Cg)-alkyl which
has 5-7 or 8-10 ring atoms respectively, up to
9 of these ring atoms representing carbon and 1
or 2 ring atoms representing sulfur or oxygen and/
or 1 to 4 ring atoms representing nitrogen, and
which can be substituted in the heteroaryl as des-
cribed for aryl under I.b)5; or
8. if not already covered by c) 1. - 8., the option-
ally protected side-chain of a naturally occurring
a-amino acid of the formula R1-CH(NH2)-COOH;
d) R2 and R3 are identical or different and
1. denote hydrogen;
2. alkyl having 1-18 carbon atoms;
3. denote an aliphatic acyclic radical of the for-
mula CaH(2a_b+1), in which double bonds, if
their number exceeds 1, are not cumulative, a
represents an integer 2 to 18, and b represents
an even number 2 to a;
4. a mono-, di-, tri-, tetra- or pentacyclic, non-
aromatic hydrocarbon radical of the formula
CcH(2c-d-1)~ which is optionally branched and
in which c represents an integer 3 to 20, and d
represents an even number 0 to (c-2);
5. di-(C1-C4)-a-lkylamino-(C1-Cg)-alkyl;
6. (C1-CS)-alkanoyloxy-(C1-C8)-alkyl;
7. (C1-C6>-alko~xycarbonyloxy-(C1-Cg)-alkyl;
8. (C7-C13)-aro~yloxy-(C1-Cg)-alkyl;
9. (C6-C12)-aryloxycarbonyloxy-(C1-Cg>-alkyl;
10. aryl having b-12 carbon atoms; or
11. denote (C7-G20)-aralkyl; it being possible
1341 064
- 30 -
for they radicals mentioned under d) 8., 9., 10.
and 11.. to be substituted in the aryl moiety as
described under I.b)5; and
e) R4 and R5 form, together with the atoms carrying them,
a mono-, bi- or tricyclic heterocyclic ring system
having 3 to 15 ring carbon atoms,
and physiologically acceptable salts thereof.
II. excepting compounds of the formula II and their salts
in which
a) n is 1 or 2,
b) R denotes
1. hydrogen,
2. alkyl. having 1-8 carbon atoms,
3. alkenyl having 2-6 carbon atoms,
4. cycloalkyl having 3-9 carbon atoms,
5. aryl which has 6-12 carbon atoms and can be
mono--, di- or trisubstituted by (C1-C4)-alkyl,
(C1-t:4)-alkoxy, hydroxyl, halogen, vitro, amino,
aminomethyll, (C1-C4)-alkylamino, di-(C1-C4)-
alkyl.amino,, (C1-C4)-alkanoylamino, methylene-
diox~~, carboxyl, cyano and/or sulfamoyl,
6. alkoxy having 1-4 carbon atoms,
7. aryloxy which has 6-12 carbon atoms and can be
substituted as described under II. b) 5;
8. mono-- or bicyclic heteroaryloxy which has 5-7 or
8-10 ring .atoms respectively, 1 to 2 of these
ring atoms representing sulfur or oxygen atoms,
and/or 1 to 4 of these ring atoms representing
nitrogen, and which can be substituted as de-
scribed under II.b)5.;
9. amino-(C1-i~4)-alkyl,
10. (C1-t:4)-alkanoylamino-(C1-C4)alkyl,
11. (C7-t:13)-aroylamino-(C1-C4)-alkyl,
12. (C1-C4)-allkoxycarbonylamino-(C1-C4)-alkyl,
13. (C6-t:12)-aryl-(C1-C4)-alkoxycarbonylamino
(C1-t:4)-allkyl,
14. lC6-t:12)-aryl-(C1-C4)-alkylamino-(C1-C4>-alkyl,
- 31 - 1 341 06 4
15. (C1-C4)-alkylamino-(C1-C4)-alkyl,
16. di-(C1-C4)-alkylamino-(C1-C4)-alkyl,
17. guanidino-'(C1-C4)-alkyl,
18. imidazolyl,
19, indolyl;
20. (C1-C4)-alkylthio,
21. (C1-C4)-alkylthio-(C1-C4)-alkyl,
22. (C6-C12)-arylthio-(C1-C4)-alkyl which
can be sub-
stituted in the aryl moiety as described under
II.b>5;
23. (C6-C12)-aryl-(C1-C4)-alkylthio which be
can
substituted in the aryl moiety as described under
II.b)5;
24. carboxy-(C1-C4)-alkyl,
25. carboxyl,
26. carb~~moyl,
27. carb~~moyl-(C1-C4)-alkyl,
28. (C1-~:4)-alkoxycarbonyl-(C1-C4)-alkyl,
29. (C6-I:12>-aryloxy-(C1-C4)-alkyl which be sub-
can
stituted in the aryl moiety as described under
II.b)5; or
30. (C6-I:12)-aryl-(C1-C4)-alkoxy vhich can sub-
be
stituted in the aryl moiety as described under
II.b)5;
c) R1 denotes
1. hydrogen,
2. alkyl having 1-6 carbon atoms,
3. alkenyl having 2-6 carbon atoms,
4. alkyrnyl having 2-6 carbon atoms,
5. cycla~alkyl having 3-9 carbon atoms,
6. cycla~~alkenyl having 5-9 carbon atoms,
7. (C3-C9)-cyc;loalkyl-(C1-C4)-alkyl,
8. (C5-Cg)-cyc:loalkenyl-(C1-C4)-alkyl,
9. optionally partially hydrogenated aryl which has
b-12 carbon atoms and can be substituted as de-
scribed under II.b)5;
10. (C6-C12)-aryl-(C1-C4)-alkyl or (C7-C13)-aroyl-
~ 341 O6 4
- 32 -
(C1 or C2)-alkyl, both of which can be substi-
tuted in the aryl moiety as described under
II.b)5;
11. mono- or bicyclic, optionally partially hydro-
genated heteroaryl which has 5-7 or 8-10 ring
atoms respectively, 1 to 2 of these ring atoms
representing sulfur or oxygen atoms, and/or 1
to 4 of these ring atoms representing nitrogen
atoms, and which can be substituted as described
under II.b)5; or
12. if not embraced by the above definitions, the
optionally protected side-chain of a naturally
occurring a-amino acid of the formula
R1-CH(NH2)-COOH;
d) R2 and R3 are identical or different and denote
1. hydrogen,
2. alkyl having 1-6 carbon atoms,
3. alkenyl having 2-6 carbon atoms,
4. di-(C1-C4)-alkylamino-(C1-C4)-alkyl,
5. (C1-C5>-alkanoyloxy-(C1-C4)-alkyl,
6. (C1-C6)-alkoxycarbonyloxy-(C1-C4>-alkyl,
7. (C7-C13)-aroyloxy-(C1-C4>-alkyl,
8. (C6-C12)-aryloxycarbonyloxy-(C1-C4)-alkyl,
9. aryl having 6-12 carbon atoms,
10. (C6-C12)-aryl-(C1-C4)-alkyl,
11. (C3-Cg>-cycloalkyl or
12. (C3-Cg)-cycloalkyl-(C1-C4)-alkyl, and
e) R4 and R5 have the meaning defined under I.e),
~8. and compounds of the formula II in which
a) n is 1 or 2;
b) R denotes
1. hydrogen;
2. alkyl having 1-8 carbon atoms;
3. alkenyl having 2-6 carbon atoms;
4. cycloalkyl having 3-9 carbon atoms;
_33_ 1341064 '
5. aryl which has 6-12 carbon atoms and can be mono-,
di- or trisub~stituted by (C1-C4)-alkyl, (C1-C4)-
alkoxy, hydra~xyl, halogen, vitro, amino, amino-
methyl, (C1-C4)-alkylamino, di-(C1-C4)-alkyl-
amino, (C1-C4)-alkanoylamino, methylenedioxy,
carboxyl, cyano and/or sulfamoyl;
6. alkoxy having 1-4 carbon atoms;
7. aryloxy which has 6-12 carbon atoms and can be sub-
stituted as described under e.b)5;
8. mono- or bicyclic heteroaryloxy which has 5-7 or
8-10 ring atoms respectively, up to 9 of these
ring atoms representing carbon and 1 or 2 of
these ring atoms representing sulfur or oxygen
and/or '1 to 4 of these ring atoms representing
nitrogen, and vhich can be substituted as de-
scribed under B.b)5;
9. amino-(l:1-C4)~-alkyl;
10. (C1-C4)--alkanoylamino-(C1-C4)-alkyl;
11. (C7-C13)-aroylamino-(C1-C4)-alkyl;
12. (C1-C4)-~alkox;~carbonylamino-(C1-C4>-alkyl;
13. (C6-C12)~-aryl-(C1-C4)-alkoxycarbonylamino-
( C 1-C4)-.alkyl ,:
14. (C6-C12)-aryl"(C1-C4)-alkylamino-(C1-C4)-alkyl;
15. (C1-C4)-~alkylamina-(C1-C4)-alkyl;
16. di-<C1-C4)-alkylamino-(C1-C4)-alkyl;
17. guanidino-(C1--C4)-alkyl;
18. imidazolyl;
19. indolyl;
20. (C1-C4)-alkylt:hio;
21. if n is 2, lC~~-C4)-alkylthio-(C1-C4)-alkyl;
22. (C6-C12)-arylt:hio-(C1-C4)-alkyl which can be
substituted in the aryl moiety as described under
B.b)5;
23. (Cb-C12)-aryl-U C1-C4)-alkylthio which can be
substituted in the aryl moiety as described under
8.b)5;
24. if n is 2, carboxy-(C1-C4)-alkyl;
25. carboxyl;
1 341 06 4
- 34 -
26. carbamo;~l;
27. if n is 2, carbamoyl-(C1-C4)-alkyl;
28. (C1-C4)~-alkoxycarbonyl-(C1-C4)-alkyl;
29. if n is 2, (C6-C12)-aryloxy-(C1-C4)-alkyl which
S can be ;substituted in the aryl moiety as described
under B.b)5; or
30. (C6-C12)-aryl-(C1-C4)-alkoxy which can be substi-
tuted in the aryl moiety as described under B.b>5;
c) R1 represents the side-chain of valine, leucine,
norvaline, n~~rleucine, methionine, ornithine, cyclo-
hexylalanine, 2-thienylalanine, 3-thienylalanine,
0-(C3-C5)-alkyltyrosine, isoleucine, isovaline or
C-phenylglycine;
d) R2 and R3 are identical or different and denote
1. hydrogen;
2. alkyl having 1-6 carbon atoms;
3. alkenyl having 2-b carbon atoms;
4. di-(C1-C4)-alkylamino-(C1-C4>-alkyl;
5. (C1-C5)-alkanoyloxy-(C1-C4)-alkyl;
6. (C1-C6)-alkoxycarbonyloxy-(C1-C4)-alkyl;
7. (C7-C13)-aroyloxy-(C1-C4)-alkyl;
8. (C6-C1Z)-aryloxycarbonyloxy-(C1-C4)-alkyl;
9. aryl having 6-12 carbon atoms;
10. (C6-C12)-aryl-(C1-C4)-alkyl;
11. (C3-C9)-cycloalkyl; or
12. (C3-C9)-cycloalkyl-(C1-C4)-alkyl, and
e) R4 and RS have the meaning defined under A.I.e), and
their physiologically tolerated salts, or
C. in which
a) n, R, R4 and RS are as defined above under B. and
b) R1 represents the side-chain of alanine, lysine or
e-acyllysine, and
c) R2 and R3 are identical or different and denote
propyl, isopropyl, n-butyl, isobutyl, sec.-butyl,
n-pentyl, sec.-pentyl, iso-pentyl, neopentyl, n-hexyl,
isohexyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclo-
heptyl, cyclooctyl, cyclohexenyl, cycloheptenyl,
1 341 06 4 '
- 35 -
phenyl, a- or S-naphthyl, 2-, 3- or 4-biphenylyl,
phenethyl, 3-phenylpropyl, benzhydryl, a-methyl-
benzyl, a-methylenebenzyl, 2-, 3- or 4-phenylbenzyl,
bibenzyl-a-yl, styryl, 1-indanyl or 9-fluorenyl,
with phenyl, and phenyl as a part-structure of one
of the said radicals, being substituted as defined,
where appropriate, under A.II.b)5,
or one of the radicals R2 and R3 denotes hydrogen,
and the other is as defined above,
or R2 represents benzyl, and R3 represents benzyl,
hydrogen ~or one of the abovementioned definifiions,
and their physiologically tolerated salts.
R4 and R5 form, together with the atoms carrying
them, preferably a mono-, bi- or tricyclic hetero-
cyclic ring system which has 3 to 15 ring carbon atoms
and up to 2, preferably up to 1, ring sulfur atoms)
and up to 1, preferably no, additional ring nitrogen
atom, preferably from the series comprising pyrrol-
idine, thiazolidine, tetrahydroisoquinoline, deca-
hydroisoquinoline, octahydroindole, indoline, octa-
hydrocyclopentaCbJpyrrole, 2-azaspiroC4.5Jdecane,
2-azaspiroC4.4Jnonane, spiroC(bicycloC2.2.1Jheptane)-
2,3'-pyrrolidineJ, spiroC(bicycloC2.2.2Joctane-2,3'-
pyrrolidineJ, 2-azatricycloC4.3Ø16'9Jdecane, deca-
hydrocycloheptaCbJpyrrole, octahydroisoindole, octa-
hydrocyclopentaCcJpyrrole, 2,3,3a,4,5,7a-hexahydro-
indole, 1,2,3,3a,4,5a-hexahydrocyclopentaCbJpyrrole
and 2-azabicycloC3.1.OJhexane.
Suitable salts of the compounds of the formulae I and II
are, depending on the acidic or basic nature of these com-
pounds, alkali metal or alkaline earth metal salts or salts
with physiologically tolerated amines, or salts with inor-
ganic or organic acids such as, for example, HCI, HBr, H2S04,
malefic acid, fumaric acid, tartaric acid and citric acid.
The capillary structure of the blood vessels in the brain
differs from that in other regions of the body. The brain
1 341 06 4
- 36 -
capillaries are surrounded by a layer of endothelial cells
which are partic;ularl;y closely Linked together (by tight
junctions>. In addition, brain capillaries have very many
fewer of the pores through which, in other blood capillaries,
low molecular weight substances can penetrate into or emerge
from the surrounding tissue. In this way, in the brain
capillaries the property of lipid solubility has a very much
greater importance for partition between blood and surround-
ing tissue than is the case for the remainder of the body.
Hence the preferred compounds of the formula II are those
in which at least one of the radicals R, R1, R2 and R3
represents a lipophilic radical, such as a long-chain ali-
phatic, alicyclic-aliphatic, araliphatic or heteroaraliph-
atic radical, a sufficiently large alicyclic radical, or an
appropriately substituted alicyclic, aromatic or hetero-
aromatic radica~'~, or contains a radical of this type as a
part-structure.
In this respect,,
particularly
suitable
compounds
of the
formula II
are those
in which
R denotes (C~~-C1g)-alkyl;
1.
2. (C~l-C1g)-alkenyl;
3. a radical which has 4-18 carbon atoms and is
defined as above under A.I.b)3 and in which
b :, 4;
4. a radical which has 4-20 carbon atoms and is
defined as above under A.l.b>4 and in which
d > 2;
5. is as defined above under A.I.b)5;
6. heteroarylalkyl which is defined as above under
A.I.b)9;
7. amino-(CS-Cg)-alkyl;
8. amino-(C5-Cg>-alkyl;
9. (C1-C4)-alkanoylamino-(CS-Cg)-alkyl;
10. (C7-C13)-aroylamino-(CS-Cg)-alkyl;
11. (C1-C4)-alkoxycarbonylamino-(CS-Cg)-alkyl;
12. (C6-C12>-aryl-(C1-C4)-alkoxycarbonylamino-
(CS-C8)-alkyl;
37 - 1 341 06 4,
13. (C6-C12)-aryl-(C1-C4)-alkylamino-(CS-C8)_
alkyl;
14. (C1-C4)-alkylamino-(CS-C8)-alkyl;
15. di-(C1-C4)-alkylamino-(CS-Cg)-alkyl;
16. guanidino-(CS-C8)-alkyl;
17. if n is 2, (C1-C4)-alkylthio-(CS-Cg)-alkyl;
18. (C6-C12)-arylthio-(CS-C8)-alkyl which can
be substituted in the aryl moiety as de-
s~:ribed above under A.I.b)5;
19. (Cb-C12)-aryl-(CS-Cg)-alkylthio vhich can
bra substituted in the aryl moiety as de-
scribed above under A.I.b)5;
20. i1f n is 2, carboxy-(CS-Cg)-alkyl;
21. i:E n is 2, carbamoyl-(C5-C$)-alkyl;
22. (I:1-C4)-alkoxycarbonyl-(CS-C4)-alkyl;
23, iif n is 2, (C6-C12)-aryloxy-(C5-C8)-alkyl
which can be substituted in the aryl moiety
a:. described above under A.I.b>5; or
24. ((:6-C12)-aryl-(CS-C8)-alkoxy Which can be
substituted in the aryl moiety as described
above under A.I.b)5.
Additional comF~ounds of the formula II which are suitable
are those in which
R1 denotes
1. (C7-Cl~g)-alkyl;
2. (C7-Cl~g>-alkenyl;
3. (C7-C1~;)-alkynyl;
4. ai radical which has 4-18 carbon atoms and is
clefine~i as above under A.I.c)3. and in which
b >~ 2 and only double bonds are present;
5. a~ radical which is as defined above under
A~.I.c)4, excepting cycloalkyl and cyclo-
a~lkenyl~ having up to 9 carbon atoms;
6. optionally substituted (C6-C12)-aryl-
(C5-C8;1-alkyl;
7. optionally substituted (C7-C13)-aroyl-
(C3-Cg;l-alkyl or
1 341 O6 4
- 38 -
8. optionally substituted heteroaryl-(C1-C8)-alkyl,
and those compounds of the formula II in which R1 represents
the side-chain of valine, leucine, norvaline, norleucine,
methionine, ornithine, cyclohexylalanine, 2-thienylalanine,
3-thienylalanine, 0-(C3-C5>-alkyltyrosine, isoleucine,
isovaline or C-phenylglycine.
R2 and R3 are then identical or different and preferably
denote
1. (C7-C1g>--alkyl;
2. (C7-C18)--alkenyl;
3. a radical. which has 4-18 carbon atoms and is defined
as above under A.I.d)3. and in which b > 4;
4. a radical. which is as defined above under A.I.d>4,
excepting (C3-C9)-cycloalkyl and (C3-Cg)-cyclo-
alkyl-(Cy-C4)-alkyl;
5. di-(C1-Cat)-alk;ylamino-(C5-Cg)-alkyl;
6. (C1-CS>-alkano;yloxy-(C5-Cg)-alkyl;
7. (C1-C6)-alkoxycarbonyloxy-(C5-C8)-alkyl;
8. (C7-C13)--aroyloxy-(C5-Cg)-alkyl;
9. (C6-C12)--arylo:xycarbonyloxy-(C5-C8)-alkyl;
10. (C16-C20%'-arallkyl;
it being possible for the radicals mentioned under d)8., 9.
and 10. to be substituted in the aryl moiety as described
above under A.I.~b)5.; or one of the radicals R2 and R3
denotes hydrogen and the other is as defined above.
In addition, preferred compounds of the formula II are
those in which F;2 and R3 are identical or different and
denote propyl, isopropyl, n-butyl, isobutyl, sec.-butyl,
n-pentyl, sec.-pentyl,, isopentyl, neopentyl, n-hexyl, iso-
hexyl, cyclobuty~l, cyclopentyl, cyclohexyl, cycloheptyl,
cyclooctyl, cyclohexenyl, cycloheptenyl, menthyl, phenyl,
a- or S-naphthyl, 2-, 3- or 4-biphenylyl, phenethyl, 3-
phenylpropyl, be~nzhydn~yl, a-methylbenzyl, a-methylenebenzyl,
2-, 3- or 4-phenylbenzyl, bibenzyl-a-yl, styryl, 1-indanyl
or 9-fluorenyl, with phenyl, and phenyl as a part-structure
of one of the said radicals, optionally being substituted
1 X41 064
- 39 -
as defined above under A.I.b)5., or one of the radicals
R2 and R3 denotes hyclrogen and the other is as defined
above, or R2 represents benzyl, and R3 represents benzyl,
hydrogen or one of the abovementioned definitions.
The invention also relates to a process for the preparation
of a compound of the formula II, which comprises reacting
together its fragments in a suitable solvent, where appro-
priate in the presence of a base and/or of a coupling aid,
reducing, where appropriate, unsaturated compounds which
have formed as intermediates, such as Schiff's bases, elim-
inating protective groups which have been introduced tempo-
rarity to protect reactive groups, esterifying, where appro-
priate, compounds of the formula II having one or more free
carboxyl groups, and converting, where appropriate, the re-
sulting compounds into their physiologically tolerated salts.
It is possible, for example, in the said manner to react
compounds of the formula V with compounds of the formula
VI.
R300C-Cli-l~-H HOOC-CH-AH-CH-( CH ) R
R~~ R5 R~ COOR2 2 ri
(9) (VI)
The reaction of these compounds can be carried out, for
example, in analogy to known peptide coupling methods in
an organic solvent such as DMF, CH2Cl2 or DMA in the pre-
sence of coupling aids such as carbodiimides (for example
dicyclohexylcarbodiimide), diphenylphosphoryl azide,
alkanephosphoric anhydrides, dialkylphosphinic anhydrides
or N,N-succinimidyl carbonate, in a solvent such as CH3CN.
Amino groups in compounds of the formula V can be acti-
vated with tetraethyl diphosphite. The compounds of the
formula VI can be converted into active esters (for
example with 1-hydroxybenzotriazole), mixed anhydrides
(for example with chloroformic esters), azides or carbo-
diimide derivatives and thus activated (cf. Schroder,
X341064
- 40 -
Lubke, The Peptides, volume 1, New York 1965, pages 76 -
136). The reaction is preferably carried out between -
20°C and the boiling point of the reaction mixture.
It is likewise possible to react compounds of the formula
VII with compounds of the formula VIII with the formation
of compounds of the formula II
R300C-Chi-N-~;-C~Ii-Y1 Y2-CH-(CH2)ri R
R4 R5 0 R1 COOR2
(VII) (VIII)
;r, ~h;rh either Y1 represents amino and Y2 represents a
leaving group, or Y1 represents a leaving group and YZ
represents amino. Examples of suitable leaving groups are
Cl, Br, I, alkylsulfonyloxy or arylsulfonyloxy.
Alkylations of this type are expediently carried out in
water or an organic solvent such as a lower aliphatic
alcohol (such as ethanol>, benzyl alcohol, acetonitrile,
nitromethane or glycol ethers, at a temperature between
-20°C and the boiling point of the reaction mixture, in
the presence of a base such as an alkali metal hydroxide
or an organic amine.
Furthermore, it is possible to condense compounds of the
formula IX with compounds of the formula X
R300C-CFi-N-C~-C-=Q~ Q2sC-( CH ) -R
~~~ R5 0 R1 COOR22 n
(7:R) (x)
in which either 41 represents amino + hydrogen and 42
represents oxo, or 41 represents oxo and 42 represents
amino + hydrogen. The condensation is expediently carried
out in water or an organic solvent such as a lower alipha-
tic alcohol, at a temperature between -20°C and the boiling
point of the reactions mixture, in the presence of a reducing
~ 341 O6 4
- 41 -
agent, such as NaBH3CN, compounds of the formula I being
obtained directly. However, it is also possible to reduce
Schiff's bases or enamines which are produced as inter-
mediates, where appropriate after previous isolation, with
the formation of compounds of the formula II, for example
by hydrogenation in the presence of a transition metal
catalyst.
Finally, reaction of compounds of the formula IX (41 -
H + NH2) with compounds of the formula XI, or their reac-
tion with compounds of the formula XII and XIII, expediently
in the presence of a base such as sodium alcoholate, in an
organic solvent such as a lower alcohol, at a temperature
between -10°C and the boiling point of the reaction mixture,
also results in compounds of the formula II (n = 2),
R200C~-CH=CH-COR (%I ) .
OCH-C00R2 (%II )
R-CO-t:H3 (%II I )
with Schiff's bases which have been produced as inter-
mediates being reduced as described above, and a carbonyl
group being converted by reduction (for example with a
complex hydride) into methylene.
In the abovementioned formulae V - XIII, R - RS and n are
as defined in formula II. Protective groups temporarily
introduced to protect reactive groups not involved in the
reaction are eliminated in a manner known per se after the
reaction is complete (cf. Schroder, Lubke, l~oc. cit.,
pages 1 - 75 and 24b - 270; Greene, "Protective Groups in
Organic Synthesis", New York 1981).
The new compounds of the general formula I or II can also
be prepared, for example, using methods of esterification
familiar to the expert (see, for example, Buchler, Pearson,
Survey of Organic Syntheses, vol. 1, New York 1970, pages
1 341 d6 4
- 42 -
802 - 825; Hoube~n-Weyl, Methoden der Organischen Chemie,
(Methods of Organic Clhemistry), volume E5, 1985, pages 656
- 773).
a) Reaction of a mono- or dicarboxylic acid of the general
formula I or II in which at least one of the radicals
R2 and R3 denotes hydrogen with an appropriate alcohol
with acid catalysis (mineral acid or acid ion exchanger).
b) Alkylation of a mono- or dicarboxylic acid of the gen-
eral formula I or II in which at least one of the radi-
cals R2 and F;3 denotes hydrogen with a compound R2Z or
R3Z, in which Z denotes a leaving group which can be
displaced nuc:leophilically (such as halogen, tosylate>,
in a polar erotic or Bipolar aprotic solvent, in the
presence of a base such as an alkali metal hydroxide or
alcoholate.
c) Reaction of a mono- or dicarboxylic acid of the general
formula I or II in which at least one of the radicals
R2 and R3 denotes hydrogen with a diazoalkene in an
inert organic. solvent such as CH2Cl2.
The cognition adjuvant action of the compounds according
to the invention has been tested in the inhibitory (pas-
sive) avoidancer test (step-through model) in mice having
a body weight of 20-25 g. A modified form of the test
method describerd by .J. KOPP, Z. BODANECKY and M.E. JARVIK
has been described by J. BURES, 0. BURESOVA and J. HUSTON
in "Techniques and B~~sic Experiments for the Study of
Brain and BehaL~ior", Elsevier Scientific Publishers,
Amsterdam (198'_.).
According to the statements in this literature, a sub-
stance is said to have cognition adjuvant activity when it
is able to abolish the amnesia induced in the experimental
animals by an erlectroconvulsive shock or the amnesia in-
duced by scopolamine.
1 3t~~ p6 4
- 43 -
The experiments were carried out by modified test methods.
The comparison compound used was the known cognition ad-
juvant 2-oxo-1-pyrrolidinylacetamide (piracetam). The
marked superiority of the compounds according to the in-
s vention over the comparison substance was evident from the
fact that the scopolamine-induced amnesia in the inhibi-
tory avoidance 'test can be abolished with an oral MED
(minimal effective dose) of 1.0-30 mg/kg. The comparison
substance has an oral MED of about 500-1,000 mg/kg.
Most of the compounds according to the invention have
only low toxicity.
By reason of their pharmacological properties, the com-
pounds accordin~~ to the invention are suitable not only
for the treatment of high blood pressure but also for
the treatment of cognitive dysfunctions of various etiologies,
as occur with, for example, Alzheimer's disease or senile
dementia.
Hence the invention also relates to the use of the com-
pounds accordin~~ to the invention for the treatment and
prophylaxis of cognitive dysfunctions in patients with
high blood pressure.
The invention furthermore embraces medicaments containing
the said compounds, processes for their preparation and
the use of the compaunds according to the invention for
the preparation of medicaments which can be used for the
treatment and prophylaxis of the abovementioned diseases.
It is possible, in practicing the method according to the
invention, to u:,e the angiotensin converting enzyme in-
hibitors which :ire described above in mammals such as
monkeys, dogs, cats, rats, humans etc.
The medicaments are prepared by processes which are known
per se and fami~Liar to those skilled in the art. The
~ 341 06 4 '
- 44 -
pharmacologically active compounds (= active compound)
according to the invention are used as medicaments either
as such or, preferably, combined with suitable pharma-
ceutical auxiliaries, in the form of tablets, coated
tablets, capsules, suppositories, emulsions, suspensions
or solutions, the content of active compound being up to
about 95%, preferably between 10 and 75%.
The auxiliaries suitable for the desired medicament for-
n~ulation are familiar to those skilled in the art by
reason~of their expert knowledge. Apart from solvents,
gel-forming agents, suppository bases, tabletting auxi-
liaries and other active compound vehicles, it is pos-
sible to use, for example, antioxidants, dispersing
agents, emulsifiers, antifoam agents, masking flavors,
preservatives, solubilizers or colorants.
The active compounds can, for example, be administered
orally, rectally or parenterally (for example intravenously
or subcutaneously>, oral administration being preferred.
For a form for oral use, the active compounds are mixed
with the additives suitable for this purpose, such as
excipients, stabilizers or inert diluents, and converted
by the customary methods into suitable presentations such
as tablets, coated tablets, hard gelatin capsules, aqueous,
alcoholic or oily suspensions, or aqueous, alcoholic or
oily solutions. Examples of inert vehicles which can be
used are gum arabic, magnesia, magnesium carbonate, lac-
tore, glucose or starch, in particular corn starch. This
formulation can take the form of dry and of moist gran-
ules. Examples of suitable oily excipients or solvents
are vegetable or animal oils such as sunflower oil or fish-
liver oil.
For subcutaneous or intravenous administration, the
active compounds or their physiologically tolerated salts
are converted into solutions, suspensions or emulsions, if
appropriate with the substances customary for this purpose
~ 349 064
- 45 -
such as solubilizers, emulsifiers or other auxiliaries.
Examples of suitable solvents are water, physiological
saline solution or alcohols such as ethanol, propanol,
glycerol, and in addition also sugar solutions such as
glucose or mannitol solutions, as well as a mixture of
the various solvents mentioned.
The following examples 1-6 indicate the forms used for the
prophylaxis and treatment of cognitive dysfunctions by the
method according to the invention. The compounds accord-
ing~to the invention can be converted into the appropriate
use forms in analogy to the examples.
Example 1
Preparation of the agent used according to the invention
for oral use in the treatment and prophylaxis of cognitive
dysfunctions.
1000 tablets each containing 10 mg of 2-CN-(1-S-carbethoxy-
3-phenylpropyl>-S-alanylJ-1S,3S,5S-2-azabicycloC3.3.OJ-
octane-3-carboxylic acid are prepared using the following
auxiliaries:
2-CN-(1-S-carbethoxy-3-phenylpropyl)- 10 g
S-alanylJ-(1S,3.S,5S)-2-azabicycloC3.3.OJoctane-
3-carboxylic acid
corn starch 140 g
gelatin 7.5 g
microcrystallin~e cellulose ~ 2.5 g
magnesium stearate 2.5 g
2-CN-(1-S-Carbethoxy-3-phenylpropyl>-S-alanylJ-(1S,3S,5S)-
2-azabicycloC3.3.OJactane-3-carboxylic acid and corn starch
are mixed with .an aqueous gelatin solution. The mixture is
dried and milled to form granules. Microcrystalline cellu-
lose and magnesium stearate are mixed with the granules.
~ 341 06 4
- 46 -
The resulting granules are compressed to form 1000 tab-
lets, each tablet containing 10 mg of the ACE inhibitor.
These tablets can be used for the treatment and prophy-
laxis of cognitive dysfunctions.
Example 2
In analogy to Example 1, 1000 tablets each containing
mg of 1'-CN-(1-S-carbethoxy-3-phenylpropyl)-S-alanylJ-
10 (3'S,5'S)-spirobicycloC2.2.2Joctane-2,3'-pyrrolidine-5'-
carboxylic acid are prepared.
Example 3
Gelatin capsules each containing 10 mg of 1'-CN-(1-S-carb-
ethoxy-3-phenylpropyl)-S-alanylJ-(3'R,5'S)-spirobicyclo-
C2.2.2Joctane-2,3'-pyrrolidine-5'-carboxylic acid are
filled with the folla~Wing mixture:
1'-CN-(1-S-Carbethoxy-3-phenylpropyl)-S-alanylJ-(3'R,5'S)-
spirobicycloC2.2.2Joctane-2,3'-pyrrolidine-5'-carboxylic
acid 10 mg
Magnesium stearate 1 mg
Lactose 214 mg
These capsules can be used for the treatment and prophy-
laxis of cognitive dysfunctions.
Example 4
The preparation of an injection solution is described
below:
2-CN-(1-S-Carboxy-3-phenylpropyl)-S-alanylJ-
(1S,3S,5S)-2-azabicycloC3.3.OJoctane-2-carb-
oxylic acid 250 mg
Methylparaben 5 g
1 341 06 4
- 47 -
Propylparaben 1 9
Sodium chloride 25 g
Water for injections 5 l
2-CN-(1-S-Carboxy-3-phenylpropyl)-S-alanylJ-(1S,3S,5S)-
2-azabicycloC3.3.OJoctane-3-carboxylic acid, the preserva-
tives and sodium chloride are dissolved in 3 l of water
for injections, and the solution is made up to 5 l with
water for injections. The solution is filtered sterile
and dispensed aseptically into presterilized vials, which
are closed with sterilized rubber caps. Each vial con-
tains 5 ml of solution.
Example 5
Tablets which can be used for the treatment or prophylaxis
of cognitive dysfunctions are prepared as described in
Example 1 with the exception that in place of 2-CN-(1-S-
carbethoxy-3-phenylpropyl)-S-alanylJ-(1S,3S,5S>-2-azabi-
cycloC3.3.OJoctane-3S-carboxylic acid use is made of 2-CN-
(1-S-carboxy-3-phenylpropyl>-S-alanylJ-(1S,3S,5S)-2-azabi-
cycloC3.3.Oloctane-3-carboxylic acid or 1-CN-(1-S-carboxy-
3-phenylpropyl)-S-alanylJ-(2S,3aR,7aS)-octahydroindole-2-
carboxylic acid or 1-CN-(1-S-carbethoxy-3-phenylpropyl)-
S-alanyll-cis-2,3,3a,4,5,7a-hexahydroClHJindole-2-S-endo-
carboxylic acid or 1-tN-(1-S-carboxy-3-phenylpropyl)-S-
alanylJ-cis-2,3,3a,4,5,7a-hexahydroClHJindole-2S-endo-
carboxylic acid or 2-CN-(1-S-carboxy-3-phenylpropyl)-S-
lysylJ-(1S,3S,5S)-2-azabicycloC3.3.OJoctane-3-carboxylic
acid or 2-CN-(1-S-carbethoxy-3-cyclohexylpropyl)-S-alanylJ-
1S,3S,5S)-2-azabicycloC3.3.OJoctane-3-carboxylic acid or
N-(1-S-carboxy-3-cyclohexylpropyl>-S-lysyl-(1S,3S,5S)-2-
azabicycloC3.3.OJoctane-3-carboxylic acid or 1'-CN-(1-S-
carbethoxy-3-phenylpropyl)-S-alanylJ-exo-spirobicyclo-
C2.2.2Joctane-2,3'-pyrrolidin-5'-S-ylcarboxylic acid or
(S,S,S)-1-methyl-2-(1-carbethoxy-3-phenylpropyl)-2H-un-
decahydrocyclopentaC4.5JpyrroloCl,2-aJpyrazine-3,8-dione
or 1'-CN-(1-S-carbethoxy-3-phenylpropyl)-S-alanylJ-endo-
spirobicycloC2.2.2Joctane-2,3'-pyrrolidin-5'-S-ylcarb-
oxylic acid.
- ~ 3 4 1 0' 6 4
- 48 -
Example 6
An injection sa~lution is prepared in analogy to the pro-
cedure described in Example 4 with the exception that in
place of 2-CN-(1-S-carbethoxy-3-phenylpropyl)-S-alanyl7
(1S,3S,5S)-2-azabicyc;loC3.3.07octane-3-carboxylic acid
use is made of 2-CN-I.1-S-carboxy-3-phenylpropyl)-S-alanylJ-
(1S,3S,5S)-2-azabicycloC3.3.07octane-3-carboxylic acid or
1-CN-(1-S-carbethoxy-~3-phenylpropyl>-S-alanylJ-(2S,3aR,
7aS)-octahydroindole-~2-carboxylic acid hydrochloride or
1-CN-(1-S-carboxy-3-p~henylpropyl)-S-alanyl7-(2S,3aR,7aS)-
octahydroindole-2-carboxylic acid or 1-CN-(1-S-carbethoxy-
3-cyclohexylpropyl)-S-alanyl7-cis-2,3,3a,4,5,7a-hexahydro-
C1H7indole-2-S-endo-carboxylic acid or 1-CN-(1-S-carboxy-
3-phenylpropyl)-S-alanyl7-cis-2,3,3a,4,5,7a-hexahydroClH7-
indole-2-S-endo-carboxylic acid or 2-CN-(1-carboxy-3-
phenylpropyl)-S-lysyl7-(1S,3S,5S)-2-azabicycloC3.3.07-
octane-3-carboxylic acid or 2-CN-(1-S-carbethoxy-3-cyclo-
hexylpropyl)-S-alanyl7-(1S,3S,5S)-2-azabicycloC3.3.OJoctane-
3-carboxylic acid or 2-CN-(1-S-carboxy-3-cyclohexylpropyl>-
S-lysyl7-(1S,3S,,5S)-2-azabicycloC3.3.117octane-3-carboxylic
acid or 1'-CN-(1-S-carboxy-3-phenylpropyl)-S-alanyl7-endo-
spirobicycloC2.~?.27octane-2,3'-pyrrolidine-5'-S-carboxylic
acid or 1'-CN-(1-S-carboxy-3-phenylpropyl)-S-alanyl7-exo-
spirobicycloC2.~'_.27octane-2,3'-pyrrolidine-5'-S-carboxylic
acid.
The Examples which now follow are intended to illus-
trate the proce::s according to the invention for the prepa-
ration of the nelw compounds of the formula I and II , with-
out confining the inmention to them.
Example 7:
Octadecyl 2-CN-(1S)-ethoxycarbonyl-3-phenylpropyl-S-alanyl7-
cis,endo-2-azabicycloC3.3.07octane-3-S-carboxylate
23 g of octadecyl cis"endo-2-azabicycloC3.3.07octane-3-
carboxylate prepared in analogy to European Patent A-79022
1 341 06 4
- 49 -
are reacted with 6.7 g of H08t, 13.8 g of N-(1S)-carbethoxy-
3-phenylpropyl-:S-alanine and 10.2 g of dicyclohexylcarbodi-
imide in 200 ml of dimethylformamide. After stirring at room
temperature for 3 hours, the precipitated dicyclohexylurea
is filtered off with suction, the filtrate is concentrated,
the residue is taken up in 1 l of ethyl acetate, and the
solution is extracted by shaking with 3 x 500 ml of 5%
strength NaHC03 solution. The organic phase is concen-
trated and chromatographed on a column of 1 kg of silica
gel with ethyl ~~cetate/petroleum ether in the ratio 2:1, and
in this way is :,eparated into the title compound and the
diastereomeric (S,S,R) compound.
Example 8:
1-CN-(1S)-Dodec;~loxycarbonyl-3-phenylpropyl-S-alanyll-2S,
3aR,7aR-octahydn~oindole-2-carboxylic acid
a) 8enzyl 1-CN-(1S)-dodecyloxycarbonyl-3-phenylpropyl-S-
alanylJ-2S,3~~R,7aR-octahydroindole-2-carboxylate
10 mmol of benzyl S-alanyl-2S,3aR,7aR-octahydroindole-2-
carboxylate '(prepared as in European Patent A-84164) are
dissolved in 30 ml of anhydrous ethanol. Ethanolic potas-
sium hydroxide is used to adjust the pH of the solution
to 7.0, and t g of powdered molecular sieve (4A), and
then 10 mmol of do~decyl 2-keto-4-phenylbutyrate, are
added. A so~'~.utian of 1 g of sodium cyanoborohydride in
10 ml of anhydrous ethanol is slowly added dropwise.
After a reaction time of 20 hours at 20 to 25°C, the
reaction solution is filtered, and the solvent is removed
by distillation. The residue is taken up in ethyl
acetate/watei~. After the ethyl acetate phase has been
evaporated, 'the residue is chromatographed on silica gel
with ethyl acetate/cyclohexane (1:4).
b) The compound obtained as in a) is hydrogenated in ethanol
in the presence of palladium/animal charcoal (10%) at
20-25oC undei~ atmospheric pressure. After the catalyst
os
- 50 -
has been removed, 0.5 N ethanolic hydrogen chloride is
added to the solution until it gives an acid reaction.
The solution is concentrated in vacuo, and the residue is
crystallized by trituration with diisopropyl ether.
Example 9:
Isobutyl 2-CN-C(2S)-ethoxycarbonyl-3-phenylpropylJ-L-
alanylJ-(1S,3S,'.iS>-2-azabicycloC3.3.OJoctane-3-carboxylate
2.00 g (4.80 mmol) of 2-CN-C(1S)-ethoxycarbonyl-3-phenyl-
propylJ-L-alanyl~J-(1S,3S,5S>-2-azabicycloC3.3.OJoctane-
3-carboxylic acid were dissolved in 100 ml of isobutanol,
0.1 ml of concentrated sulfuric acid was added, and the
mixture was boin,ed under reflux for 15 hours. After cool-
ing, the solvewt was removed in a rotary evaporator, and
the residue was taken up in methylene chloride. This sol-
ution was washed once with water, once with saturated
aqueous NaHC03 :~oluti~on and again with water, dried over
MgS04, and conc~antrat~ed, and impurities were removed by
chromatography on 200 g of silica gel (mobile phase
methylene chloridelethyl acetate 8:2).
Yield: 51% of theory ~of oily product.
CaJpO = -28.2~~ (c - 1, methanol)
This product was dissolved in ether, the pH was adjusted to
2 with saturated ethereal hydrochloric acid, the solvent was
evaporated off, and the residue was crystallized from diiso-
propyl ether.
data on the hydrochloride:
Melting point 1.?3- 124°C
CaJpO = +17.7° '(c - 1, methanol)
Example 10:
Benzhydryl 2-CN-C(1S>-ethoxycarbonyl-3-phenylpropylJ-L-
alanylJ-(1S,3S,!iS)-2-azabicycloC3.3.OJoctane-3-carboxylate
2.07 g (4.97 mmol) of 2-CN-C(1S)-ethoxycarbonyl-3-phenyl-
propylJ-L-alanylJ-(1S,3S,5S>-2-azabicycloC3.3.OJoctane-3-
1341064-'
- 51 -
carboxylic acid were dissolved in 50 ml of acetone and,
while cooling i~n ice, a solution of 1.16 g (5.98 mmol) of
diphenyldiazomethane in 50 ml of acetone was added dropwise.
The solution was then stirred at room temperature for 26
hours, the solvent was evaporated off in a rotary evapo-
rator, and the residue was purified by flash chromatography
on 150 g of silica gel (mobile phase toluene/ethanol 98:2).
Yield: 2.55 g (B8 %) of oily product
Ca7p0 - -33.8° Cc - 1, methanol>.
Example 11:
Octadecyl 2-CN-C(1S)-ethoxycarbonyl-3-phenylpropyl7-L-
alanyll-(1S,3S,5S)-2-azabicycloC3.3.07octane-3-carboxylate
2.08 g (5.00 mmol) of 2-CN-C(1S>-ethoxycarbonyl-3-phenyl-
propyl7-L-alanyl7-(1S,3S,5S)-2-azabicycloC3.3.07octane-3-
carboxylic acid were dissolved in 25 ml of absolute dimethyl-
formamide, 1.00 g (10.0 mmol) of potassium bicarbonate was
added, and the mixture was stirred at 40°C for 90 minutes.
After cooling to room temperature, a solution of 4.00 g
(12.0 mmol) of 1-bromooctadecane in 20 ml of absolute di-
methylformamide was added dropwise, and the mixture was
stirred at 40°C for 4 hours. The solvent was removed in
a rotary evaporator at about 1 torr, and the residue was
partitioned between water and methylene chloride. The or-
ganic phase was separated off, dried over MgS04 and concen-
trated. 3.05 g (92 %) of the product were isolated from the
crude product (5.40 g) after column chromatography on 200 g
of silica gel (mobile phase toluene/ethanol 99:1).
Ca7p0 = -19.6° Cc - 1, methanol)
Example 12:
8enzyl 2-CN-C(1S)-benzyhydroloxycarbonyl-3-phenylpropyl7-L-
alanyl7-(1S,3S,5S)-2-azabicycloC3.3.Oloctane-3-carboxylate
a) eenzhydryl (2R)-hydroxy-4-phenylbutyrate
A solution of 10.1 g (52.1 mmol) of diphenyldiazomethane
in 400 ml of absolute acetone was added dropwise over
-52- 141064
20 minutes t~ a solution of 7.40 g (41.1 mmol) of (2R)-
hydroxy-4-phenylbutyric acid in 200 ml of absolute ace-
tone while cooling in ice, and the reaction mixture was
stirred at room temperature for 20 hours. The solvent
was evaporated off, and the residue was triturated with
100 ml of petroleum ether. 6.4 g of crystalline product
were obtained. The mother liquor was concentrated, and
a further 6.0 g of the product were isolated by column
chromatography on 700 g of silica gel (mobile phase
toluene/ethanol 99:1).
Total yield: 12.4 g (87 %).
Melting point 88 - 89°C.
CaJpO - -1.8° (c - 5, methanol).
b) Benzyl 2-CN-C(1S)-benzhydryloxycarbonyl-3-phenylpropylJ-
L-alanylJ-(1S,3S,SS)-2-azabicycloC3.3.OJoctane-3-carboxy-
late
b1) 1.80 g (4.33 mmol) of benzyl 2-(N-tert.butoxycarbonyl-
L-alanyl)-(1S,3S,SS)-2-azabicycloC3.3.OJoctane-3-car-
boxylate were dissolved in 4.5 ml of trifluoroacetic
:ZO acid, and the reaction solution was stirred at room
temperature for 90 minutes. It was then concentrated
and, to remove trifluoroacetic esters, toluene was
evaporated off three times in a rotary evaporator.
The residue, which comprised 1.90 g of benzyl 2-(L-
ZS alanyl)-(1S,3S,SS)-2-azabicycloC3.3.OJoctane-3-carboxy-
late trifluoroacetate, was dissolved in 10 ml of abso-
lute methylene chloride (solution A).
b2) 1.63 g (4.71 mmol) of benzhydryl (2R)-hydroxy-4-phenyl-
butyrate from Example 12 a) were dissolved together
30 with 0.4 ml of absolute pyridine in 25 ml of absolute
methylene chloride and, at -10°C, 1.41 g (5.00 mmol)
of trifluoromethanesulfonic anhydride were added drop-
wise within 20 minutes. The cooling bath was then
removed and, after room temperature had been reached,
35 the solvent was evaporated off. The residue was
-53- 1341064
filtered through 50 g of silica gel using methylene
chloride, and the filtrate was concentrated. 1.70 g
of benzhydryl 4.-phenyl-(2R)-trifluoromethylsulfonyloxy-
butyrate were obtained and were dissolved in 10 ml of
absolute methylene chloride (solution B).
b3) 1.0 ml (7.40 mmol) of triethylamine was added to
solution A and then, at 0°C, solution B was slowly
added dropwise. The cooling bath was removed and
the reaction solution was stirred at room temperature
for 19 hours, then washed three times with water,
dried over MgS0~4 and concentrated. The residue
was purified by chromatography on 80 g of silica gel
(mobile phase cyclohexane/ethyl acetate 8:2 and 7:3),
and 0.95 g (30%) of the desired product was obtained.
Melting point 81-85oC.
CaJpO = -55.2° (c - 1, methanol)
By suitable combinations of the methods described in the
foregoing examples, the following additional compounds are
prepared (the designation of the ring systems corresponds
to that for the compounds of the general formulae I and II):
1~41~64
- 54 -
R300C - ~H - t - C --~H - FA - CH - CH2 - CH2
R4 ~t5 0 CH COOR2
3
R300C-~A-Nf-
E x a m p l a R4 Ft5 R2 R3
13a Ring system- A -C2A5 -CH(CH3)2
14 Ring system H -C2H5 -CH2-CH(CH3)2
15 Ring system C -CH3 -CH2
16 Ring systee C -C2H5 -CH(C6H5)2
1? Ring system D -C2H5 -Q
18 Ring system'D -C2H5
-_
19 Ring system D -C2H5
_.-_
20 Ring system D -C2H5 0
21 Ring system D -C2H5
* 22 Ring system D -C2H5 -(CH2)3
23 Ring system E -C2H5 -(CH2)5-CH3
24 Ring system F -CH3 -CH(C6H5)2
25 Ring system d -C2H5 -CH(CH3)2
-_
26 Ring system t3 -C2H5 CH(C6H5~2
* [a]p= -21.5° [c=1, CH3nH]
1341064
- 55 -
R300C - C' H - » - ~~ ~ I H ~ - ~A - CH2 - CH2 /
R4 ~t5 0 CH3 COOR2
R300C-~A-t~-
E x a m p l a R4 135 R2 R3
2T Ring systern 0 -C2H5 '(CH2)2~
28 Ring system H C2H5 CH(CH3)2
29 Ring systern H C2H5 CH2 CH(CH3)2
30 Ring system H C2H5 -(CH2)5 CH3
3~ Ring system H C2H5
~r
32 Ring system H C2H5 -~-CH3
33 Ring systernH C2H5
-
34 Ring - H C2H5 0 0
systern
35 Ring systernA H -CH2-O
36 Ring systernH C2H5 CH(C6H5)2
r
3? Ring system H C2H5 -(CH2)8~
38 Ring systam I CH3
39 Ring system J C2H5 -CH(C6H5)2
r
40 Ring system K C2H5 -(CH2)4 CH3
_
41 Ring systern- C2H5 -C(CH3)3
Ir
,
1 341 Ofi 4 _
- 56 -
R300C - C H - 1Q - C ~-CH - NH - ~H - CH2 - CH2 r
R4 1~5 ~ CH3 COOR2
R300C-CH-lT-
E x a m p l a R4 1~5 R2 R3
42 Ring system M C2H5 -(CH2)2-CH(CH3)3
43 Ring system. A C2H5. -CH(4-F-C6H4)2
44 Ring system_~ 1~ C2H5 -CH(CH3)2
45 Ring system 0 C2H5 -(CHZ)2-
46 Ring system p C2H5
--
4T Ring system Q C2H5
__
48 Ring system _ CH2CH(CH3)2 -CH2-~
A
49 Ring system H CH(CH3)2 -C(CH3)3
50 Ring system C CH(C6H5)2 -H
51 R i s y s D CH2 -CH2-
n g t a
m .
* 52 Ring system D CH2-CH(CH3)2 -CA2
ir*
53 Ring system D CH2 CH(CH3)2 -H
_
54 Ring system - CH2-CH(CH3)2 -CH(C6H5)2
D
55 Ring system. D CH(C6Ii5)2 -C(CH3)3
56 Ring system D CH(C6A5)2 -H
* [aJ~ _ -39.3° [c=1, CH30H]
** [aJ n° _ +2.2° [c=1, CH~O:H]; mp:162-163°C
1 341 06 4
- 57 -
R300C - CH - 'N - C -~A - NH - ~H - CA2 - CA2 ~ \
R4' R5 0 CA3 COOR2
R300C-CH-;N-
R4 R5 R2 R3
Example
5? Ring system E --~--CA3 -(CA2)5-CH3
58 Ring system E -CAZ CA(CA3)2 -CA(4-F-C6A4)2
59 Ring system G -CA(C6A5)2 -CA2
60 Ring system G -CA(C6A5)2 -C(CA3)3
- _
61 Ring system A -CA2CA(CA3)2 -CH2-O
62 Ring system H -CH2CA(CA3)2 H
63 Ring system H -CH2CH(CH3)2 -CH(C6A5)2
--
64 Ring system H -CH2-O -CH2
_
65 Ring system - -CH2 -C(CH3)3
H
66 Ring system Ii -CA(C6A5)2 -CH2
6T Ring system H -CA(C6A5)2 -A
68 Ring system A -CH(C6A5)2 -C(CH3)3
69 Ring system A -CA(C6A5)2 -CH(C6H5)2
'l0 Ring system I -~ ~ 0
Z1 Ring system J -(CA2)5-CA3 -CA(CSAS)2
~ 349 06 4
_ 5g
R300C - FA - N - C -CH - NH - ~H - CH2 - CH2
R4 R5 0 CHj COOR2
R300C- 'H-N-
E x a m p l a ~~4 R5 R2 Rj
?2 Ring system K ~ -CH2
?3 Ring system '~ -CH2)2 -(CH2)5-CHj
?4 Ring system M -(CH2)2-CH(CHj)2 -CH(C6H5)Z
75 Ring system. p -CH(C6H5)2 -C(CHj)2-CH2CHj
?6 Ring system 0 -CH(CHj)2 -CA(C6H5)2
?? Ring system p -CH(CHj)2 -C(CHj)j
?8 Ring system ~ -~(~Hj)j -CH2-~
'
* ?8a Ring system D C2H5 Menthyl
?8b Ring system a Menthyl CH2C6H5
* [a]~ _ +27.0° [c=1, CF~30H]; malate mp: 118-120°C
- 58a -
1 341 06 4
"R300C-CH-N-C- CH -X2"
I 4 I S~I
R R 0 CH3 m
"Example R300C-~"H-N- R3 X2 m
~4 RS
7 9 Ring system O -CH (C6H5) 2 -C~i25H 1
80 Ring system 0 -(CH2) 5-CH3 -(~i2SH 1
81 R30CC-CH2-N._ -C~i (C6H5) 2 -(~i2-S-OO-~ (CH3) 3 1
82 R300C-C'Fi2-N._ -C~i(CH3) 2 -CH2-S~-(CH3) 3 1-
83 CH30 OOR'; .-Cgi (C6H5) 2 -NH~EI-(C~i2) 2 / \
CH3
- ~ -59- 1341064
nR300C-CH-N-C- CH -X2n
~ 4 ~ 5~~
R R 0 CH3 m
"Example R300C-Cfi-N- R3 X2 m
R4 RS
84 R300C-CHf2-N- -CH ( 4-F-C6H4 ) 2 -NH-i H- ( CH2 ) 2.~ 1
COOCZHS
r
85 R300C-CH2,-1~- -Cg2~ -HH-CH- CH2 ) 2-
1 C 1
CC10-CH (C2H5) Z
86 Ring syste~a~ H H 'CH2-b (CHZ)4~
~(CH312CH-CH-O-C-C2H5 0
Y
* ~ NH - ~H - CH2 - CHZ
O COOR2
CHZ-CCIOR3
Example T~ R2 R3
_.
8? CH2 -.C2H5 -CH(C6H5)2
-_
88 s -~CH(C6H5)2 -(cH2)5-cH3
-_
89 CH2 -,CH2-CH ( CH3 ) 2 -CH2-
-60- 1341pfi4
'' rf-'1
J> ~ _
p '~ NH - CH -2CH2 CH2 -O
C OOR
Example R2 R3
90 -CH(C6FI5)2 -C(CH3)3
g1 -CH(C6H5)2 -CH(C6H~)2
Example 92
4-CN-(1S>-Carboethoxy-3-phenylpropyl)-S-benzyl7-exospiro-
(bicycloC2.2.27octane-2,3-pyrrolidine)-5-carboxylic acid
a) eenzyl ester of N-(1S-carbethoxy-3-phenylpropyl>-S-
leucine
3.4 g (10 mmol) of ethyl 2-(D)-trifluoromethylsulfonyl-
oxy-4-phenylhutyrate and 5.9 g (15 mmol) of the benzyl
ester of L-l~eucine tosylate were mixed in 50 ml of abs.
CH2Cl2 and, .after addition of 4.2 ml of triethylamine,
the mixture ~~as stirred at room temperature for 6.5
hours. After concentration of the solution, the pro-
duct was isolated by column chromatography (silica gel,
cyclohexane/ethyl acetate 9:1). 3.2 g of colorless oil
were obtained.
'H ~MR a~ 0.95 (a.. ~3). ~.2 (t, cH3) ~.e (m, CH2)
2.6 (m,. CH2) 3.3 (m. CH) 4.1 (q, CH2)
5.1(s, CH2) 7.3 (e, CH) ppm.
b) N-(1-S-Carboethoxy-3-phenylpropyl)-S-leucine
3.1 g of the benzyl ester obtained in a) were cleaved by
1 341 06 4
- 61 -
hydrogenolys~is with 500 mg of Pt/C (10%) in 200 ml of
ethanol. Afr:er removal of the catalyst by filtration
and concentr<~tion of the solution, 2.3 g of colorless
crystals of l:he carboxylic acid of melting point 120
121°C were obtained.
tg NMR b~ 0.!~ (d, CH3), 1.25 (t, CH3y 1.8-2,1 (m,CH2),
2.~ (~m~ CH2), 3~3 (Q. CR). 4.25 (Q~ CR2~~
?.2 (s, CH) ppm.
c) 4-CN-(1S)-Carbethoxy-3-phenylpropyl)-S-leucylJ-exo-
spirobicyclol:2.2.2Joctane-2,3-pyrrolidine-5-carboxylic
acid
2 g (6.2 mmol.) of N-(1-S-carboethoxy-3-phenylpropyl)-
S-leucine and 1.9 g (3.9 mmol) of benzyl exo-spiro-
(bicycloC2.2,.2J-octane-2,3-pyrrolidine)-5-carboxylate
were stirred in 100 ml of dimethylformamide with 4.3 ml
of triethylarnine and 6.5 ml of n-propylphosphonic
anhydride at room temperature overnight. The reaction
solution was taken up in ethyl acetate and shaken twice
with aqueous NaHC03 solution and once each with 10 %
aqueous citric acid, saturated aqueous NaHC03 solution
and saturated aqueous NaCI solution. The organic phase
was then sep~~rated off, dried and concentrated. The
crude product, with a yield of 2.8 g, was separated into
the two diastereomers by column chromatography (silica
gel, toluene,~ethyl acetate 95:5). 1 g of pure product
was obtained for each benzyl ester. 1 g of the first
diastereomer was hydrogenated with Pd/C in 40 ml of
ethanol. 780 mg of crystalline carboxylic acid of melt-
ing point 131-132°C were obtained.
Rotation CaJp - -2.8° (c - 1, methanol)
860 mg of the second diastereomer were hydrogenated with
Pd/C in 35 ml of ethanol and, after removal of the cata-
lyst by filtration and concentration of the solution, the
yield was 721) mg.
Melting point: the substance sinters above 65°C
Rotation CaJp - -22.2° (c - 1, methanol)
- 62 - 1 341 06 4
Example 93
4-CN-(1S)-Carboxyl-3-phenylpropyl)-S-leucylJ-exo-spiro-
(bicycloC2.2.27octane-2,3-pyrrolidine)-5-carboxylic acid
102 mg (0.2 mmol) of the carboxylic acid from Example 92c)
were stirred in aqueous 4N KOH solution until all the sub-
stance had diss;olved,. The solution was applied to an ion
exchanger ((R)Amberlite R 120) and eluted with a 2X strength
solution of pyridine in water. The yield was 70 mg.
Rotation Ca7p0 = +3,90 (c - 1, methanol)
'10 The following compounds of the formula II are prepared in
analogous manner (the designations of the ring systems
correspond to tlhose for the compounds of the general for-
mulae I and II)
s
HOOC - C~ - p5- c; - Cg - CH - CH2 - CH2
R 0' R COOC2H5
R1 HOOC - CH - AH
R4 R5
CH(CH3)Z A
CH ( CI33 ) CH2 CH3 A
CH2C6H5 A
CH2-C6H1 > (CH2-Cyclc~heayl) C
CH2-C6H4 OCH3 Q
CH2-C6A4 OCZHS C
CH2-C6H4-OC3H? C
CH2-C6H4-OC4H9 ~ A
* (CH2)4-NH2 D
CH2 )3-HH2 A
CH2~H~- 8 CH3 A
CH- CH
w N
CH2 - C CH A
~9~
* [a] p° _ -23.7° [c=0.1.52, CH30H]
- ~ 3t~~ Ofi 4
- 63 -
HOOC - CH - N - h - CH - CH - CH2 - CH2 -
R4 R5 0 R~ COOC2H5
R~ HOOC - CH - NH
R4 R5
CH(CH3)2 B
CH(CH3)CH2CH3 B
CH2C6H5 E
CH2 C6H D
CH2-C6H4 OCH:3 H
CH2-C6H4 OC2~H5 G
CH2-C6H~-On-~C3H7 G
CH2-C6H4 On-,C4H9 ~ C
( CH2 ) 4..~I2 C
(CH2)3-NH2 G
CH2-CHI s-C~;~3 D
CH - cH
CH C C;A B
~ si
- ~34~064
~ - 64 -
HOOC - CH ~- N - ~~ - CH - CH - CH2 - CH2
R4 R5 ~D R~ COOC2H5
R~ HOOC - CH - AH
R4 R5
CH(CH3)2 C
CH ( CH3 ) CH2CH~~ C
CH2C6H5 C
CH2- C6H11
CH2-C6H4- OCBj, I
*CH2-C6H4 OC2H',5 H less polar diastereomer
[a] _ -28.6 [c=1, CH30H]
o
more polar diastereomer
[ a _ +20 . 7 [ c=1,
] CH30H ]
p
MS
(FAH):591
(M'
+
1)
CH2-C6H~-On-C-~HT H mp:53-57°C MS ( FAH) :605 (M' + 1 )
CH2-C6H4-On-C,~H9 G
( CHZ ) i-~t G
( CHZ ) 3-~z H
CH2-CH2-S-CH3 H
CH - C:fi
CH2 - C \ j~H C
S
. ~ 341 06 4
' - 65 -
HOOC - CH - P - ~ - CH - CH - CHZ - CH2
R4 R5 0 R~ COOC2H5
R~ HOOC - CH - NH
R4 R5
CH(CH3)2 D
CH ( CH3 ) CH2CH,3 D
CHZC6H5 D
CH2-C6H11
CH2-C6H~ OCH,3 N
CH2-C6H4 OC2;H5 I
CH2--E6H4-On-C3H? I
CH2-C6H4- On-C4H9 H
(CH2)4-NH2 H mp: 142C
(CH2)3-NH2 0
CH2-CHI 8-CH,3 I
CH -Cli
CH2 - C C13 D
mss'
~ 341 06 4
- 66 -
HOOC - CH -~ N - C - CH - CH - CH2 - CHZ -
R4 R5 ~D R~ COOC2H5
R~ HOOC - CH - NH
R4 R5
CH(CH3)2 0
CH(CH3)CH2CHj~ E
CH2C6H5 H 1st diastereomer:
[a]n°= +1fi.4 [c=1, CH30HJ
2nd diastereomer:
( t - HuNH2 salt )
(a]~ _ +29.9 [c=1, CH30H]
CHZ-C6H11 C'
CH2-C6H,~-OCH3 0
CHZ-C6H4-OCziiS ~ N
CHZ-C6H~-On-CjH~ N
CHZ-C6H~-On-C~Ii9 I
CHZ ) ~-NH2 N
C CHz ) 3-NH2 P
CH2-CH2-S-CH3 P
~~H - CIi
CHZ - C ~ %H; R
S
1341064
. - 67 -
HOOC - CH - N - C - CH - CH - CH2 - CH2
R4 R5 0 R~ COOC2H~
R~ HOOC - CH - NH
R4 R5
CH(CH3)2 H
CH(CH3)CH2CH3 F
CH2C6H5 I
CH2-C6H11 H
CH2-C6H4 OCH3 P
CH2-C6H4-OC2H5 0
CH2-C6H4 On-C3H? 0
cH2-C6H4- on-c4H9 N
(CH2)4 NH2 Q
(CH2)3'NH2 Q
CHZ-CH2 s CH3 Q
CH- C:Ei
a
CH2 - C C:H Q
~s~
1 X41 064
_6$_
HOOC - CH - N - C - CH - CH - CH2 - CH2
R4 R5 0 R~ COOC2H5
R~ HOOC - CH - 1QH
R4 R5
CH(CH3)2 I
CH(CH3)CHZCH3 G
CH2C6H5 N
CHZ C6H» I
CH2-C6H4- OCH3 Q
CH2-C6H4-OC2H5 P
CH2-C6H4-On-C3H7
CH2-C6H4 On-C4H9 0
(CH2)4 NH2 P
CH2-CH2 S-CH;3 N
CH- CH
CH2 - ' j~H H
S
1 341 06 4
- 69 -
HOOC - CH ~- N - C - CH - CH - CH CH
2 - 2
R4 R5 0 R~ COOC2H5
R~ HOOC - CH - NIi
R4 R5
CH(CH3)Z 0
* CH ( CH3 ) CH2CH;f E
CH2C6R5 0
cH2 c6H» ~ z
CH2-C6H4- OC2~i5 Q
CH2-C6H4 On-~:3H7 Q
CH2~C6A4- On-(:4H9 P
CHI CH2- 8-CH,~ (~
CH- CH
r
CH - C CH I
2
* [a]~ _ -7.3° [c=1, ~CH30H]
mp s 117°C
1341064
- 70 -
HOOC - CH - N - C - CH - CH - CH2 - CH2
R4 R5 0 R~ COOC2H5
R~ HOOC - CH - NH
R4 R5
CH(CH3)2 P
CH2- C6H~ P
CH2~C6H~~ M
CH2-C6H4-OCH3 D
CH2-C6H4- OC2H5 D
CH2-C6H4- On-C3H? D
CH2 C6H4-On-C4H9 Q
CH- CH
w N
CH2 - C CH N
~S~
1 - 1 341 06 4
HOOC - CH - N - C - CH - CH - CH2 - CH2 ~
R4 R5 0 R1 COOC2H5
R1 HOOC - CH - NH
R4 R5
CH(CH3)2 N
CH(CH3)CH2CH3 P
CH2 C6H5 Q
CH2-C6H11 N
CH2-C6H4~ On-C4~H9 D
CH- CH
a a
CH C CH P
2 -
S
CH(CH3)CH2CH3 Q
CH(CH3)CH3CH3 I
CH2 C6H11 0
CH2-C6H11 Q
Example 94:
1-CN-(1S)-Carboethoxybutyl)-S-alanyl7-octahydrocyclopenta-
Cb7pyrrole)-2-carboxylic acid
a) Ethyl DL-2-trifluo~romethylsulfonyloxypentanoate
5 g (34 mmol) of ethyl 2-hydroxyvalerate and 2.85 g
(35.9 mmol) of absolute pyridine were dissolved in 100 ml
of absolute CHZCl2 under protective gas, the solution
was cooled to 0°C and 9.66 g (34 mmol) of trifluoro-
methanesulfonic anhydride were added. The mixture was
warmed to room temperature and stirred for 6 hours. The
solution was concentrated and the resulting crude product
was purified by column chromatography (silica gel, petro-
leum ether/CH2Cl2 6:1). The yield was 9.3 g of a
1 341 O6 4
- 72 -
colorless, slightly viscous liquid.
IR: 2880 -~ 3000 1??0, 1420,
1200 -~ 1220 1150, 620 em 1
b) 8enzyl ester of N-(1-S-carboethoxybutyl)-S-alanine
4.9 g (17.6 mmol) of the trifluoromethanesulfonic ester
thus obtained were dissolved, under nitrogen, in 70 ml
of absolute ~~H2C12 with 4.08 g of the benzyl ester of
L-alanine hydrochloride (19 mmol) with the addition of
5.4 ml of triethylamine, and the solution was stirred
at room temperature for 3 hours. It was then concentra-
ted, the crude product was taken up in ethyl acetate,
and the solution was washed three times with water, dried
and concentr;3ted. The diastereomers were separated by
column chrom;stography (silica gel, cyclohexane/ethyl
acetate 5:1>. The yield of each isomer was 500 mg. The
diastereomer isolated in the first filtration had the
S,S conf igur~at ion.
1H NMR
a = 0.9 (t.CH3). 1~3 (t.CH3). 1.35 (d.CH3). 1.4 (m,CH2).
1.6 (m,CH2). 1.9 (s.~H). 3.3 (t.CH). 3~4 (Q.CH).
4.2 (m,CH2), 5.15 (q,CH2 Ph), 7.4 (e, CH sromet.)
ppm.
c) N-(1-S-Carboethoxybutyl)-S-alanine
600 mg (1.95 mural) of benzyl ester (diastereomer A>
were hydrogenated with Pd on charcoal in 34 ml of etha-
nol. The catalyst was then filtered off, and the sol-
ution was concentrated in vacuo. The product was then
obtained as ~j white solid with a melting point of 137°
and a yield of 430 mg.
d) 430 mg (1.98 mmol) of N-(1-S-carboethoxybutyl)-S-alanine
and 486 mg (1.98 mmol) of benzyl L(-)-octahydrocyclo-
pentaCb7pyrrole-2-carboxylate were dissolved, under nitro-
gen, in 20 m'l of dimethylformamide, the solution was
cooled to -11)°C, and 1.5 ml of triethylamine and 2 ml
of n-propylphosphonic anhydride were added. The solution
1 X41 Ofi 4
73
was stirred ~~t -10°C for 1 hour and then at room tem-
perature overnight. It was then taken up in 200 ml of
ethyl acetate and washed with saturated aqueous NaHC03
solution, 10;K aqueous citric acid and saturated aqueous
NaCI solution. After the solution had been dried and
concentrated,, the diastereomeric compounds were separa-
ted by column chromatography (silica gel, cyclohexane/
ethyl acetate 9:1). The yield was 360 mg. Both dia-
stereomers ware hydrogenated with Pd/C in ethanol as
described in Example 94 c) and, after concentration of
the solution,, they were obtained as~white solids.
Example 95:
1-CN-(1S)-Carbo;Kybutyl)-S-alanyl7-(octahydrocyclopenta-
Cb7pyrrole)-2-c~3rboxylic acid
60 mg (0.17 mmol) of carboxylic acid (Example 94 d) were
stirred into 2 ml of 4 N aqueous KOH solution until the
substance had completely dissolved. The solution was then
applied to a strongly acid ion exchanger and eluted with a
2% strength solution of pyridine in water. The yield after
concentration of the solution was 39 mg.
In analogy to tihe compounds prepared in Examples 94 and 95,
it is possible to synthesize the following additional com-
pounds of the f~°rmula II
H
R300C - CH - N - C - CIi - N - CH (CH2)ri R
R~ COOR2
in which, with n = 2, R1 is CH3, R2 is C2H5, R3
is H, and R and the part of the molecule
R OOC-CH-N
R4 R3
are substituted as indicated in the table detailed below.
- 74 -
1341064
R HOOC-CH-NH
R4 R5
CH3 A
-CA2CH2CH3 A
-(CH2)9-CH3 C
2-Naphthyl D
4-Biphenylyl A
-(CH2)~3-CH3 A
R HOOC-CH-NH
R4 R5
CH3 B
-CH2CH2CH~~ B
- ( CH2 ) 9-CH3 D
2-Naphthy7.
4-Bipheny7lyl ~ C
- ( cH2 ) ~ 3-c;H3 B
1 341 06 4
- 7s -
R HOOC-CH-NH
R4 R5
CH3 C
-CH2CH2CH3 C
-(CH2)9-CH3 G
2-Naphthyl G
4-Biphenylyl D
-(CH2)~3-CH3 C
R HOOC-CH-NH
R4 R5
CH3 D
-CH2CH2CH3 D
-(CH2)9-CH3 H
2-Nephthyl H
4-Biphenylyl H
- ( CH2 ) ~ 3-CH,3 D
R HOOC-CH-NH
4 5
CH3 G
-CH2CH2CH3 G
-(CH2)9-CH3 K
2-Naphthyl I
4-Biphenyly;l Z
- ( CH2 ) ~ 3-CH;3 G
1 341 46 4
- 76 -
R HOOC-CH-NH
R4 R5
CH3 H
-CH2cH2cH3 H
-(CH2)9-CH3 N
2-Naphthyl M
4-Biphenylyl N
- ( CH2 ) ~ 3-C~3.3 N
R HOOC-CH-PH
R4 R5
CH3 N
-CH2CH2CH3 N
-(CH2)9-CH3, 0
2-Naphthyl N
4-Biphenylyl P
- ( CH2 ) ~ 3-CH~3 0
R HOOC-CH-NH
R4 R5
CH3 Q
-CH2CH2CH3 Q
-(CH2)9-CH~~ P
4-Hiphenyl3~l Q
-(CH2)~3-CH3 P
1 341 06 4
- 77 -
R HOOC-CH-NH
R4 R5
CH3 P
-CH2CH2CH3 P
-(CH2)9-CH3 Q
4-Biphenylyl G
-(CH2)~3-CH3 Q
4-Biphenylyl H
- 1 341 06 4
Example 96a
eenzyl 2-(S-alanyl)~-(1S,3S,SS)-2-azabicycloC3.3.0J-
octane-3-carboxylate trifluoroacetate
a) Benzyl 1-(N-t:ert.butyloxycarbonyl-S-alanyl)-(1S,3S,SS)-
2-azabicycloC3.3.OJoctane-3-carboxylate
61.5 g (0.251 mot) of benzyl (1S,3S,SS)-2-azabicyclo-
C3.3.OJoctane-3-carboxylate, 47.5 g (0.251 mol) of 80C-l-
alanine and 173 ml (1..?6 .mol> of absolute triethylamine
are dissolved in 1,025 ml of absolute dimethylformamide,
252 ml of a SOX strength solution of propanephosphonic
anhydride in dich~loromethane are added dropwise at -5°C,
and the mixture is stirred at -5°C for 30 minutes and at
room temperature for four hours. The reaction solution
is partitioned be~tveen water and ethyl acetate, the
aqueous phase is extracted once more with ethyl acetate,
and the combined organic phases are washed With saturated
sodium bicarbonate solution, 10X strength citric acid solu-
tion Water and saturated sodium chloride solution, dried
and concentrated.
Yield: 93.2 g (8S~X) of oily product.
b) eenzyl 2-(S-alanyl)-(1S,3S,SS)-2-azabicycloC3.3.0J-
octane-3-carboxylate trifluoroacetate
235 ml of absolute trifluoroacetic acid are poured over
93.2 g (0.224 mol) of 130C derivative from
above, at 0°C, wind the mixture is stirred at 0°C for 2.5
hours. Excess acrid is removed by evaporation in vacuo at
25°C and the residue is crystallized from 1,000 ml of _.
absolute diisopropyl ether. _
Yield: 82.6 g (86X), melting point 148-150°C. -
I
_ _
~9 - 1 341 O6 4
Example 966
n-Octyl (1S,3S,,5S)-2-azabicycloC3.3.OJoctane-3-carboxy-
late
a) eenzyl 2-tert.butyloxycarbonyl-(1S,3S,5S)-2-azabi-
cycloC3.3.OJo~:tane-3-carboxylate
A solution of 39..? g (0.180 mol) of di-tert.butyl dicarbo-
pate in 60 ml of ;absolute methylene chloride is slowly
added dropwise at 0°C to a solution of 40.0 g (0.163 mol)
of benzyl (1S,3S,'.iS)-2-azabicycloC3.3.OJoctane-3-carboxy-
late and 23.4 ml (0.169 mot) of absolute triethylamine in
300 ml of absolute methylene chloride, and the mixture is
stirred at 0°C for 15 minutes and at room temperature
for one hour. Thin reaction solution is crashed with 10X
strength citric acid solution, saturated sodium bicarbonate
solution and Water, dried and concentrated.
Yield: 55.6 g of oily product,
CaJpS - -1.20 (c ~_ 2, methanol).
b) 2-Tert.butyloxycarbonyl-(1S,3S,5S)-Z-azabicycloC3.3.OJ-
octane-3-carboxylic acid
55.6 g (0.161 mol) of benzyl ester from a) above
are hydrogena~:ed on 4 g of palladium/charcoal (10X)
in 2 liters of ethanol at room temperature for 2.5 hours.
The catalyst is filtered off vith suction, and the fil-
trate is concentrated.
Yield: 37.3 g (90~:);
CaJpS - +22.7° (c - 1, methanol).
c) n-Octyl 2-tert.butyloxycarbonyl-(1S,3S,5S)-2-azabi-
cycloC3.3.OJoc:tane-3-carboxylic acid
32.3 g (0.121 mol:n of acid from b) above and
25.3 g (0.253 mol) of potassium bicarbonate are stirred
'~41 Os4
in 500 ml of dimethylformamide at 40°C for l.S hours.
After cooling, 48.9 g 00.253 mol) of 1-bromooctane are
added dropwise, and they mixture is stirred at room tem-
perature overnight. The reaction mixture is poured into
water, extracted three times with ethyl acetate, and the
combined organic phases are washed with saturated sodium
bicarbonate solution and water, dried and concentrated,
and the crude product (44.3 g) is purified by flash chro-
matography on silica gel (900 g, mobile phase toluene/
ethanol 95:5 or 99.5:0.5) in two portions.
Yield: 35.4 g (76X) of oily product,
Caps = +5.7° (c - 1, methanol).
The following are obtained in an analogous way:
n-octyl 2-tert.butyloxycarbonyl-(1RS,3RS,SRS)-2-azabicyclo-
03.3.07-7-octene-3-carboxylate;
n-octyl ester of N-tert.butyloxycarbonyl-S-praline.
d) n-Octyl (1S,3S,SS)-2-azabicycloC3.3.OJoctane-3-car-
boxylate
2.6 g (7.0 mmol) of e0C compound from c1 above
are stirred with 9 ml of trifluoroacetic acid at 0°C
for 1.5 hours. The excess acid is removed by evaporation
in vacuo, the residue is taken up in water, the solution
is basified with sodium bicarbonate and extracted with
ethyl acetate, an~~ the organic phase is washed once more
with water, dried and concentrated, and the product is
rapidly reacted further.
Yield: 1.8 g (95X) of oily product.
The following are obtained in an analogous way:
n.-octyl (1RS,3RS,:iRS)-2-azabicycloC3.3.OJ-7-octene-3-car-
boxylate;
n-octyl ester of :i-praline.
- 81 -
Example 96c ~ ~ t~ ~ 0 6 4 ,
3-Octynyl methanesul,fonate
7.47 g (65 mmol) of me!thanesulfonyl chloride are added
dropwise to a solution of 7.56 g (60 mmol) of 3-octyn-1-of
and 12.45 ml (90 mmol) of triethylamine in 225 ml of
methylene chloride at '10°C within 30 minutes, and the
mixture is stirred for one hour. The reaction solution
is washed with water, <.~aturated sodium bicarbonate solu-
tion and again with wat:er, dried and concentrated.
lrield: 11.9 g (97X) of oily product.
Example 96d
n-Octyl 2-CN-(1S-ethoxycarbonyl-3-phenylpropyl)-S-alanylJ-
(1S,3S,SS)-2-azabicycloC3.3.OJoctane-3-carboxylate
2.07 g (5 mmol) of 2-CN-(1S-ethoxycarbonyl-3-phenylpropyl)-
S-alanylJ-(1S,3S,5S)-2-~azabicycloC3.3.OJoctane-3-carboxy-
lic acid (ramipril> ancf 0.50 g (5 mmol) of potassium
bicarbonate are stirred in 25 ml of dimethylformamide at
40°C for 1.5 hours and,, after cooling to room temperature,
a solution of 1.16 g (E~ mmol) of 1-bromooctane in 20 ml
of dimethylformamide is. added dropwise, and the mixture
is stirred at room temperature overnight. The pH is ad-
justed to 6 by addition of 0.1N HCI, the mixture is
diluted with water and extracted three times with methylene
chloride, and the combiined organic phases are dried, con-
centrated and purified by column chromatography on 120 g
of silica gel (mobile phase toluene/ethanol 95:5).
Yield: 2.35 g (89X) of oily product;
CaJps - -23.9° (c - 1, methanol>. .. . - .-
Example 97:
n-Octyl 2-CN-(1S-ethoxycarbonyl-3-phenylpropyl)-S-alanylJ-
(1S,3S,SS)-2-azabicycloC3.3.OJoctane-3-carboxylate
' f
.. - 82 -
1 341 0~ 4
~ydrogen maleate
528 mg (1 mmol) of the ester obtained in Example 96d are ;
dissolved in 20 ml of ether, and a solution of 116 mg
(1 mmol) of malefic acid in 4 ml.of acetone is added. The
solvents are removed by evaporation, and the residue is
~:rystallized With diisopropyl ether.
'field: 0.51 g (79X) of colorless crystals,
melting point 89-90oC.
Example 98:
c'.=Octenyl 2-CN-(1S-ethoxycarbonyl-3-phenylpropyl)-S-ala-
nylJ-(1S,3S,5S)-2-azabicycloC3.3.OJoctane-3-carboxylate
hydrogen maleate
2.08 g (5 mmol) of 2-CN-(1S-ethoxycarbonyl-3-phenylpropyl>-
S-alanyl7-(1S,3S,SS)-2-azabicycloC3.3.07octane-3-carboxy-
lic acid (ramipril) and 1.00 g (10 mmol) of potassium bi-
carbonate are stirred in 25 ml of dimethylformamide at 40°C
for 1.5 hours, the mixture is cooled to 0°C, and a solu-
tion of 2.3 g (12 mmol) of E-1-bromo-2-octene in 20 ml of
dimethylformamide is added dropwise. The reaction solu-
tion is stirred at O~~C for 4 hours, poured in 500 ml of
water and extracted i:hree times with ethyl acetate, the
combined extracts are. washed twice with saturated sodium
bicarbonate solution and three times with water, dried
and concentrated, and the crude product (3.4 g) is puri-
fied by flash chromat:ograp~hy on 125 g of silica gel
(mobile phase cyclohE~xane/~ethyl acetate 8:2 and 1:1).
1.93 g (73X) of an oi~ty product are obtained and converted
into the hydrogen mal.eate in analogy to Example-97.
Yield: 2.0 g of colorless .crystals, melting-point.81-84°C. .-.
E;Kample 99:
3-Octynyl Z-CN-(1S-ethoxycarbonyl-3-phenylpropyl)-S-ala-
nylJ-(15,3S,5S)-2-azabicycl,oC3.3.OJoctane-3-carboxylate
hydrogen maleate . '
~ 34 ~ os 4
- 83 -
4.9 g (11.8 mmol) of 2-CPS-(1S-ethoxycarbonyl-3-phenyl-
propyl)-S-alanyl7-(1S,3S,,SS)-2-azabicycloC3.3.O7octane-3-
carboxylic acid (ramiprit.) and 2.4 g (23.6 mmol) of potas-
sium bicarbonate are stirred in 90 ml of dimethylformamide
S at 40°C for 2 hours, and then a solution of 2.41 g
(11.8 mmol) of mesylate i'rom Example 96c in 30 ml
of dimethylformamide is added, and the mixture is stirred
at 40°C for a further 9 Flours. The reaction solution
is diluted with 250 ml oi' water and extracted three times
with ethyl acetate, the combined organic phases are washed
with saturated sodium bicarbonate solution and with water,
dried and concentrated, and the crude product (5.6 g) is
purified by chromatography on 200 g of silica gel (mobile
phase toluene/ethanol 99:1). 3.45 g (56X) of oily product
are obtained, and 1.3 g of this are converted into the
hydrogen maleate in analogy to Example 97.
Yield: 0.8 g of colorless. crystals, melting point 68-70°C.
Example 100:
Ethyl 2-CN-(1S-n-octyloxycarbonyl-3-phenylpropyl)-S-ala-
nylJ-(1S,3S,SS)-2-azabicycloC3.3.OJoctane-3-carboxylate
hydrogen maleate
1.43 g (2.8 mmvl) of carboxylic acid from Example 106 are
stirred in 25 ml of ethan~olic hydrochloric acid at room
temperature. After 5 days, a further 25 ml of ethanolic
hydrochloric acid are addled, the mixture is stirred over-
night and concentrated, the residue is taken up in ethyl
acetate, the solution is washed three times with saturated
sodium bicarbonate solution and once with water, dried
and concentrated, and the crude product (1.16 g). is puri-
fled by flash chromatography on 80 g of silica gel -(mobile
phase toluene/ethanol 99:1). 0.62 g (42X) of oily product
is obtained and converted) into the hydrogen maleate in
analogy to Example 97. . ._. _ _ _
Yield: 0.50 g of colorless crystals, melting point _ _.
84-86°C.
84- 1341064
Example 101:
5-Nonyl 2-CN-(1S-e~thoxycarbonyl-3-phenylpropyl)-S-alanylJ-
(1S,3S,5S)-2-azabi~:ycloC3.3.OJoctane-3-carboxylate hydro-
gen maleate
A solution of 1.31 g (7.5 mmol) of diethyl azodicarboxylate
in 10 ml of absolute tetrahydrofuran is added dropwise at
0oC to a solution of 1.97 g (7.5 mmol) of triphenylphos-
phine and 0.72 g <.'i mmol) of 5-nonanol in 100 ml of abso-
lute tetrahydrofur~rn, the mixture is stirred for 10
minutes and then, at 0°C, a solution of 2.08 g (5 mmol)
of 2-CN-(1S-ethoxyc:arbon;yl-3-phenylpropyl)-S-alanylJ-
(15,35,5S)-2-azabic:ycloC:3.3.OJoctane-3-carboxylic acid
(ramipril) in 25 ml. of absolute tetrahydrofuran is added,
and the mixture is stirred at 0°C for one hour and at
room temperature overnight. The reaction solution is con-
centrated, the residue is taken up in ethyl acetate, the
solution is washed twice with 2N sodium hydroxide solution
and once with eater, dried and concentrated, and the crude
product (5.0 g) is purified by flash chromatography twice
on 200 g of silica gel (mobile phase a) toluene/ethanol
99:1, b) methylene chloride/ethyl acetate 9:1). The pro-
duct obtained in this way (1.74 g, 64X> is converted into
the hydrogen maleal:e in .analogy to Example 97.
Yield: 1.6 g (49X);. melting point 103-105°C.
Example 102:
8enzhydryl 2-CN-(1:~-menthyloxycarbonyl-3-phenylpropyl)-S-
alanylJ-(1S,3S,5S)-2-azabicycloC3.3.OJoctane-3-carboxylate
A solution of 0.59 g (3 mmol) of benzophenone hydrazone
in 12 ml of ether 'is added dropwise at room temperature
to a suspension of 2.95 !~ of nickel peroxide hydrate in
12 ml of ether and,. after stirring for one hour, the vio-
let solution is filtered with suction through Celite and
concentrated. The 3 mmol of diphenyldiazomethane obtained
in this way are dissolved in 32 ml of absolute acetone and
1 341 06 4
_ - 85 -
added dropwise, while cooling in ice, to a solution of
1.31 g (2.5 mmol) of 2-CN-(1S-menthyloxycarbonyl-3-phenyl-
propyl)-S-alanyl]-(1S,35,SS)-2-azabicycloC3.3.0]octane-3-
carboxylic acid (s~~e Example 132) in 32 ml of absolute
acetone. The mixture is subsequently stirred .at room
temperature for 38 hours and concentrated, and the crude
product is purified by column chromatography on silica
gel (mobile phase toluene/ethanol 99.5:0.5 or cyclohexane/
ethyl acetate 8:2).
Yield: 1.63 g (95X) of oily product;
Ca]p5 - -57.9° (c ~- 1, methanol).
Example 103:
n-Octyl 2-CN-(3-cy.lohexyl-1S-ethoxycarbonylpropyl)-S-
alanyl]-(1S,3S,SS)-2-azabicycloC3.3.0]octane-3-carboxylate
1.8 g (6.7 mmol> of octyl ester from Reference Example
2d), 1.92 g (6.7 mmol) of N-(3-cyclohexyl-1S-ethoxycarbon-
ylpropyl)-S-alanine and 4.6 ml of absolute triethylamine
are dissolved in 30 ml of absolute dimethylformamide, the
solution is cooled to -5°C, and 6.7 ml of a SOX strength
solution of propan~ephosphonic anhydride in methylene
chloride is slowly added dropwise. The reaction solution
is stirred at room temperature overnight, poured into
200 ml of water and extracted three times with ethyl ace-
tate, the combined organic phases are washed with water,
10X strength citric acid solution, saturated sodium
bicarbonate solution and saturated sodium chloride solu-
tion, dried and concentrated, and the crude product
(3.1 g) is purified by flash chromatography on 120 g of
silica gel (mobile phase toluene/ethanol 199:1). . . - ~ -
Yield: 2.48 g (69X) of colorless oil, - _ -
[a]25 - -26.40 ( c - 1, methanol).
D
-86- 1341064
Example 104:
eenzyl 2-CN-(1S-ethoxycarbonyl-1-tridecyl)-S-phenylala-
nylJ-(1S,3S,5S)-2-azabicycloC3.3.OJoctane-3-carboxylate
3.5 ml (25 mmol) of absolute triethylamine and 5.0 ml of
a SOX strength solution of propanephosphonic anhydride in
methylene chloride are successively added dropwise to a
solution of 2.1 g (5 mmol) of N-(1S-ethoxycarbonyl-n-tri-
decyl)-S-phenylalanine and 1.4 g (5 mmol) of benzyl
(15,3S,5S)-2-azabir:ycloC3.3.OJoctane-3-carboxylate in
80 ml of absolute dimeth;ylformamide, and the reaction
solution is stirred at room temperature overnight. It is
then poured into waiter and extracted several times with
ethyl acetate, the combined extracts are washed with
water, lOX citric acid solution, saturated sodium bicar-
bonate solution and saturated sodium chloride solution,
dried and concentrated, and the crude product (3.15 g) is
purified by flash chromatography on silica gel (mobile
phase cyclohexane/ethyl acetate 7:3).
Yield: 2.76 g (85X) of oily product
CaJpS - -8.0° (c - 0.97, ethanol).
25. Example 105:
Benzyl 2-CN-(1S-n-o~ctyloxycarbonyl-3-phenylpropyl)-S-
alanylJ-(1S,3S,5S>-~?-azabicycloC3.3.OJoctane-3-carboxylate
6.0 ml (43.4 mmol) of absolute triethylamine and 9.2 g of
n-octyl 4-phenyl-2R-trifluoromethanesulfonyloxybutyrate,
dissolved in 20 ml of absolute methylene chloride, are -
successively added dropwiae at 0°C to a-solution of
9.3 g (21.7 mmol) of trifiluoroacetate from Reference Exam- '-
ple 1b) in 100 ml of absollute methylene=chloride. The -
mixture is allowed to reach room temperature,-stirred for '- w - -
;?.5 hours, extracted three times with water, dried-and ' -
~:oncentrated, and the crude product (11.4 g)-is purified -' -
by flash chromatography on 450 g of silica gel (mobile ~ -
-8~- 134'p64
phase cyclohexane/ethyl acetate 9:1, 8:2, 7:3).
Yield: 6.95 g (54X) of oily product,
CaJpS - -35.1° (c ~- 1, methanol).
Example 106:
Tert.butylammonium 2-CN-(1S-n-octyloxycarbonyl-3-phenyl-
propyl)-S-alanylJ-~;1S,3S,5S)-2-azabicycloC3.3.OJoctane-
3-carboxylate
5.45 g (9.2 mmol) of benzyl ester from Example 105 are
hydrogenated on 1 c~ of palladium/charcoal (10X) in 300 ml
of ethanol at room temperature for 20 minutes. Removal
of the catalyst by filtration with suction, and concen-
tration result in ~~.1 g (89X) of 2-CN-(1S-n-octyloxycar-
bonyl-3-phenylpropyl)-S-alanylJ-(1S,3S,5S)-2-azabicyclo-
C3.3.OJoctane-3-carboxylic acid.
190 mg of tert.butylamime are added to 1.3 g of this acid
in ethanol, the solvent is evaporated off, and the residue
is crystallized with diisopropyl ether.
Yield: 1.27 g (86X) of colorless crystals,
melting point 141-143°C.
Example 107:
n-Octyl 2-CN-(1S-carboxy--3-phenylprvpyl)-S-alanylJ-
(1S,3S,5S)-2-azabicycloC'.S.3.OJoctane-3-carboxylate
' 2.65 g (5 mmol> of ethyl ester from Example 96dare dis-
solved in 18 ml of tetrahydrofuran, 7.5 ml of 1N sodium
hydroxide solution are added, and the mixture is stirred.
at room temperature for 48 hours. It is neutralized by
addition of 7.5 ml of 1N hydrochloric acid. The reaction
mixture is concentrated, the residue is suspended. in.
water, the mixture is exi:racted twice with ethyl acetate,
the combined organic pha<.ces are washed with saturated__
~ 349 06 4
_ 88 _
sodium chloride solution, dried and concentrated, and the
crude product (2.05 g) is purified by chromatography on
80 g of silica gel (toluene/ethanol 9:1). The product
obtained in this way (1.15 g; 46X) is triturated in 50 ml
of petroleum ether, left to stand in the cold, filtered
off With suction and dried.
Yield: 0.83 g of colorless crystals; melting point
56-61°C.
The following compounds according to the invention are
additionally obtained by use of suitable starting materi-
als and application of the processes described in Examples
96-107:
Example 108:
n-Octyl 2-CN-(1S-ethoxycarbonyl-n-heptyl)-S-alanylJ
(1S,3S,SS)-2-azabicycloC3.3.OJoctane-3-carboxylate.
Example 109:
n-Decyl 2-CN-(1S-ethoxycarbonyl-3-phenylpropyl)-S-alanyll-
(1S,3S,SS)-2-azabicycloC3.3.OJoctane-3-carboxylate;
CaJps - -25.8° (c - 1, methanol).
Example 110:
n-Tetradecyl 2-CN-(1S-ethoxycarbonyl-3-phenylpropyl)-S-
alanylJ-t15,3S,SS)-2-azabicycloC3.3.Oloctane-3-carboxylate;
CaJpS - -19.8° (c - 1, methanol).
Example 111:
2-Octynyl 2-CN-(1S-ethoxycarbonyl-3-phenylpropyl)-S-ala-
nylJ-(1S,3S,SS)-2-azabicycloC3.3.OJoctane-3-carboxylate
hydrogen maleate; melting 70-72°C.
- 89 -
Example 112: ~ ~ 4 1 0 6
n-Octyl 2-CN-(1S-isobutyl.oxycarbonyl-3-phenylpropyl)-S-
alanylJ-(1S,3S,5S)-2-azabicycloC3.3.OJoctane-3-carboxylate;
CaJpS - -23.7° (c - 1, methanol).
Example 113:
n-Octyl 2-CN-(1S-n-octyloxycarbonyl-3-phenylpropyl)-S-
alanylJ-(1S,3S,5S)-2-azabicycloC3.3.Oloctane-3-carboxylate;
CaJpS - -18.6° (c - 1, methanol).
Example 114:
n-Octyl 2-CN-(1S-n-~~ctadecyloxycarbonyl-3-phenylpropyl)-
S-alanylJ-(1S,3S,5S)-2-azabicycloC3.3.OJoctane-3-carboxy-
late; CaJps - -15.2" (c - 1, methanol).
Example 115:
n-Octyl 1'-CN-( 1S-e~:hoxyc~arbonyl-3-phenylpropyl )-S-ala-
nylJspiroCbicycloC3"3:OJoctane-2,3'S-pyrrolidineJ-5'S-
carboxylate.
Example 116:
n-Nonyl 1'-CN-(1S-et:hoxycarbonyl-3-phenylpropyl)-S-ala-
nylJspiroCbicycloC2.2.2Joctane-2,3'S-pyrrolidineJ-5'S-
carboxylate hydrogen maleate; melting point 110°C.
Example 117:
n-Decyl 1'-CN-(1S-ethoxycarbonyl-3-phenylpropyl)-S-ala-
nylJspiroCbicycloC2.2.2Joc;tape-2,3'S-pyrrolidineJ-5'S-
carboxylate hydrogen maleate; melting point 96°C.
- 90 - 1 341 06 4
Example 118:
n-Octyl 2-CN-(1S-ethoxycarbonyl-3-phenylpropyl)-S-alanylJ-
(1R,3R,5R)-2-azabicycloC3.3.07octane-3-carboxylate;
,CaJpS - -7.0° (c - 1.16,. methanol).
Example 119:
n-Octyl 2-CN-(1S-ethoxycarbonyl-3-phenylpropyl)-R-alanylJ-
(1S,3S,5S)-2-azabicycloC3.3.07octane-3-carboxylate;
CaJpS - +18.0° (c - 1, methanol).
Example 120:
n-Octyl 2-CN-(1R-ethoxycarbonyl-3-phenylpropyl)-R-alanylJ-
(1S,3S,5S)-2-azabicycloC3.3.07octane-3-carboxylate;
Ca7p5 - +9.4° (c - 1, methanol).
Example 121:
n-Octyl 2-CN-(1S-ethoxycarbonyl-3-phenylpropyl)-S-alanyll-
(1S,3S,5S>-2-azabicycloC3.3.07-7-octane-3-carboxylate;
CaJpS - +21.2° (c - 1, methanol).,
Example 122:
n-Octyl 2-CN-(1S-ethoxycarbonyl-3-phenylpropyl)-S-alanyl7-
(1R,3R,5R)-Z-azabi~cycloC3.3.07-7-octane-3-carboxylate;
CaJpS - -51.4° (c - 1, methanol).
Example 123:
n-Octyl ester of N~-CN-(1S-ethoxycarbonyl-3-phenylpropyl)-
S-alanylJ-S-proline hydrogen maleate; melting point
3 4 ~ 0 6 4
1os-1o7°c.
Example 124:
2-CN-(1S-Ethoxycarbonyl-n--tridecyl)-S-phenylalanylJ-
(1S,3S,SS)-2-azabicycloC3..3.OJoctane-3-carboxylic acid;
Ca7p5 - +27.2° (c - 1, methanol).
t:xample 125:
Elenzyl 2-CN-(1S-ethoxycarbonyl-n-tridecyl)-S-alanylJ-
(1S,3S,SS)-2-azabicycloC3.3.OJoctane-3-carboxylate.
Example 126:
Benzyl 2-CN-(1R-ethoxycarbonyl-n-tridecyl)-5-alanylJ-
(1S,3S,SS)-2-azabicyc:loC3.3.OJoctane-3-carboxylate.
Example 127:
8enzyl 2-CN-(1S-n-octadecyloxycarbonyl-3-phenylpropyl)-S-
alanylJ-(1S,3S,SS)-2-azabic:ycloC3.3.OJoctane-3-carbvxylate;
CaJpS - -28.6° (c - 1, methanol).
Example 128:
8canzyl 2-CN-(1S-menthyloxycarbonyl-3-phenylpropyl)-S-
al.anylJ-(1S,3S,SS)-2-azabicycloC3.3.OJoctane-3-carboxylate;
CaJpS - -63.2° (c - 1, methanol).
Example 129:
3s
3,3-Oiphenyl-n-propyl 2-CN-(1S-ethoxycarbonyl-3-phenylpro-
pyl)-S-alanylJ-(1S,3S"sS)-2-azabicycloC3.3.OJoctane-3-
carboxylate hydrogen analeate; melting point 122-124°C.
- 92 -
By..~~uitable combinations of the methods described in the foregoing
examples, the following additional compounds of the Formula I are prepared:
n, R . ~R1 ' , ~:2 R3 HOOC- CH- N-
. . . . R4 R5
1 ~CH2)lpCH3 CH3 C2,H5. H . D
les;S polardiasterevmer~ (a~~D = +0,5 (c=1, CH30H); MS (DCI) 481. (M++1)
more= polardiastereomer (a~2D = -22.5('c=1,CH30H) ; (DCI) 481 (M++1
MD )
1 CH2)lpCH3 H H D
(a~ DO - + 52.9° (c=~1, CH30H), MS (DCI) 529 (M++1)'
1 CH(.CH3)2 ~ CH3 CZH.g ~ CH2C6H5 D (diastereomers;
'?('a~ D~ ~_ -.29.8° (c=1., CH30H), ,MS (DCI) 459 (M++1)
~a~ DO = -0.6° (c=1, CH30H), MS (DCI) 459 (M++1)
2 CH3 ~ CH3 , C2H5 CH2C6H5 H
MS (DCI): 499 (M++:L) for both diastereomers
2. GH3 CH3 . C2H5 ~ H ~ H
less .polar diaster~=omer (a) DO = -40.8° (c=1, CH30H)
more polar diastereomen (a~DO = -4.5° (c=l, CH30H)
2 , C6H5 ~CHZ-C6H4-0-»C3H~ C2H5 H . H mp: 53°C
. . MS (DCI): 605 (M++1)
2 .C6H5 ~~ CH2-C6H4-0-nC3H7 H H ~~ . . H
, , (a~ DO - +32.0° (c=l, CH2(:12), mp: 120-127°C
2 C6H5 CH2-C6H5 H . H ' H
+32.6° (c=1, CH2C;12)~ mp: 145° (decamp.) .
. .
.. .. : I
. . . , ~,' . .
' ~ . ..
. . . . , . . , . , ~ . 1
. ,
~,~ . - 93 -
. . ~ ~ ~ . ~ 1 341 06 4
Compounds of the formula I ' ,
. n ~ . . R ~ v R1. R2 , R3 HOOC- CH- N-
I I
R4 RS
2 C6H5 CH2CH(CH3)2 H H H mp: 156°C
(decamp.)
other diastereomer mp: 137° (decamp.), (a~ DO = +3.9° (c=1,
CH30H)
. 2 C6H5. CH(CH3)-CZHS H H . H
mp: 127°C.(decomp.); M:i (DCI): 485 (M++1)
2 a- C4Hg CH3 C;ZHS CHZ- C6H5 D
less polar diasterevmer (a~DO -51.6° (c=1, CH30H)
. t,~
. more polar diastereome:~ (a~2D = -26.8° (c=1, CH30H)
2 a-C4Hg ~ CH3 C:ZHS ~ H H
less polar diastereome=- (a~2D = +6.9° (c=1, CH30H)
more polar diastereomer (a~20= +4.4° (c=1, CH30H);. MS (DCI): 597
. D (M++1=
' 2' a- C4Hg CH3 FI H' D
1st diasterevmer (a~DO = +10.4° (c=1, CH30H)
2nd diastereomer mp: 104-108°C
.,..-. .:_ . . . - . . . . ~ . , .
;; ..; . .-,
