Amino acid esters, pharmaceuticals containing them, and the use thereof in learning disorders

The invention relates to amino acid esters of the formula I ##STR1## in which n is 2 and R, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 have the meaning indicated in the description, to a process and intermediates for the preparation thereof, to agents containing them, and the use thereof.

DESCRIPTION 
EP-A 243645 discloses the use of ACE inhibitors for the treatment of 
cognitive dysfunctions. 
The invention relates to new amino acid esters of the formula I 
##STR2## 
in which 
n is 2, 
R denotes an optionally substituted aliphatic radical having 1-18 carbon 
atoms, an optionally substituted alicyclic radical having 3-20 carbon 
atoms, or an optionally substituted aromatic radical having 6-12 carbon 
atoms, 
R.sup.1 denotes the side-chain, which is protected if necessary, of a 
naturally occurring .alpha.-amino acid of the formula R.sup.1 
--CH(NH.sub.2)--COOH, 
R.sup.2 denotes hydrogen, an optionally substituted aliphatic radical 
having 1-18 carbon atoms, benzyl or an optionally substituted alicyclic 
radical having 3-20 carbon atoms, 
R.sup.3 denotes hydrogen, an optionally substituted aliphatic radical 
having 1-18 carbon atoms or an optionally substituted araliphatic radical 
having 7-20 carbon atoms, and 
R.sup.4 and R.sup.5 form, together with the atoms carrying them, a mono-, 
bi- or tricyclic heterocyclic ring system having 3 to 15 carbon atoms, 
with the proviso that 
A: R.sup.2 denotes an optionally substituted aliphatic radical having 7-18 
carbon atoms or an optionally substituted alicyclic radical having 7-20 
carbon atoms, and otherwise n, R, R.sup.1, R.sup.3, R.sup.4 and R.sup.5 
have the abovementioned meaning, or 
B: R.sup.3 denotes an optionally substituted aliphatic radical having 7-18 
carbon atoms or an optionally substituted araliphatic radical having 7-20 
carbon atoms, and otherwise n, R, R.sup.1, R.sup.2, R.sup.4 and R.sup.5 
have the abovementioned meaning, or 
C: R denotes an optionally substituted aliphatic radical having 9-18 carbon 
atoms, and otherwise n, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 
have the abovementioned meaning, 
and the physiologically tolerated salts thereof, excepting n-octyl 2-[N-(1S 
ethoxycarbonyl-3-phenylpropyl)-S-alanyl]-(1S,3S,5S)-2-azabicyclo[3.3.0]oct 
ane-3-carboxylate, n-octyl2-N-(1S-carboxyl-3-phenylpropyl)-S-alanyl]-(1S, 
3S,5S)-2-azabicyclo[3.3.0]octane-3-carboxylate, and the physiologically 
tolerated salts thereof. 
An optionally substituted aliphatic radical is to be understood to be an 
aliphatic acyclic radical, i.e. a radical having an open, straight or 
branched carbon chain, such as, for example, alkyl, alkenyl, alkynyl and 
corresponding polyunsaturated radicals. 
An optionally substituted alicyclic radical is a preferably mono- to 
pentacyclic isocyclic non-aromatic radical which has single bonds or 
unsymmetrically 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. Several rings as components of a radical 
of this type are fused-on, spiro-linked or isolated. Examples of radicals 
of this type are cycloalkyl, cycloalkenyl, bicycloalkyl, tricycloalkyl and 
radicals derived from mono-, bi- or oligocyclic terpenes, such as menthyl, 
isomenthyl, bornyl, caranyl, epibornyl, epiisobornyl, isobornyl, 
norbornyl, neomenthyl, neoisomenthyl, pinanyl and thujanyl; they are 
preferably unsubstituted (aliphatic side-chains are not substituents 
according to the present definition). 
An optionally substituted aromatic radical is preferably aryl such as 
henyl, biphenylyl or naphthyl, which is optionally mono-, di- or 
trisubstituted. Radicals derived from aryl, such as aralkyl, can be 
substituted like aryl. 
An optionally substituted araliphatic radical is to be understood to be, in 
particular, aralkyl radicals such as arylalkyl, diarylalkyl, indanyl or 
fluorenyl, in which aryl is as defined above and can be substituted in the 
manner indicated there. 
R.sup.4 and R.sup.5 can form, with the atoms carrying these, a mono-, bi- 
or tricyclic heterocyclic ring system having 3 to 15 ring carbon atoms. 
Particularly suitable ring systems of these types are those from the 
following group: 
Octahydrocyclopenta[b]pyrrole (D); 
Spiro[(bicyclo[2.2.2]octane)-2,3'-pyrrolidine](H); 
Pyrrolidine (O); 1,2,3,3a,4,6a-hexahydrocyclopenta[b]-pyrrole (P). 
The suitable heterocyclic ring systems have the following structural 
formulae: 
##STR3## 
Examples of naturally occurring .alpha.-amino acids are Ala, Val, Leu, Ile, 
Ser, Thr, Asp, Asn, Glu, Gln, Arg, Lys, Hyl, Orn, Cit, Tyr, Phe, Trp and 
His. 
If R.sup.1 represents a side-chain of a protected naturally occurring 
.alpha.-amino acid, such as, for example, protected Ser, Thr, Asp, Asn, 
Glu, Gln, Arg, Lys, Hyl, Cys, Orn, Cit, Tyr, Trp or His, the preferred 
protective groups are the groups customary in peptide chemistry (cf. 
Houben-Weyl, Vol. XV/1 and XV/2). In the case where R.sup.1 denotes the 
protected lysine side-chain, the known amino protective groups are 
preferred, but especially Z, Boc or (C.sub.1 -C.sub.6)alkanoyl. Suitable 
and preferred as O-protective groups for tyrosine are (C.sub.1 
-C.sub.6)alkyl, especially methyl or ethyl. 
The compounds of the formula I have asymmetric carbon atoms and can 
therefore occur as enantiomers and diastereomers. The invention embraces 
both the pure enantiomers and the racemates. 
In the case of 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. 
Suitable salts of the compounds of the formula I are, depending on the 
acidic or basic nature of these compounds, alkali metal or alkaline earth 
metal salts or salts with physiologically tolerated amines or salts with 
inorganic or organic acids such as, for example, HCl, HBr, H.sub.2 
SO.sub.4, maleic acid, fumaric acid, tartaric acid and citric acid. 
Preferred compounds of the general formula I are those in which 
n is 2, 
R denotes an aliphatic radical having 4-10 carbon atoms, an alicyclic 
radical having 6 carbon atoms or an aromatic radical having 6 carbon 
atoms, 
R.sup.1 denotes methyl or benzyl, 
R.sup.2 denotes hydrogen, an aliphatic radical having 1-18 carbon atoms, 
benzyl or an alicyclic radical having 6-10 carbon atoms, 
R.sup.3 denotes hydrogen, an aliphatic radical having 2-14 carbon atoms or 
an araliphatic radical having 7-15 carbon atoms, and 
R.sup.4 and R.sup.5 form, together with the atoms carrying them, a mono-, 
bi- or tricyclic heterocyclic ring system having 3-11 carbon atoms, 
with the proviso that 
A: R.sup.2 denotes an aliphatic radical having 7-18 carbon atoms or an 
alicyclic radical having 7-10 carbon atoms, and otherwise n, R, R.sup.1, 
R.sup.3, R.sup.4 and R.sup.5 have the abovementioned meaning, or 
B: R.sup.3 denotes an aliphatic radical having 7-14 carbon atoms or an 
araliphatic radical having 7-15 carbon atoms, and otherwise n, R, R.sup.1, 
R.sup.2, R.sup.4 and R.sup.5 have the abovementioned meaning, or 
C: R denotes an aliphatic radical having 9 or 10 carbon atoms, and 
otherwise n, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 have the 
abovementioned meaning, 
and the physiologically tolerated salts thereof. 
Particularly preferred compounds of the general formula are those in which 
n is 2, 
R denotes n-butyl, n-decyl, cyclohexyl or phenyl, 
R.sup.1 denotes methyl or benzyl, 
R.sup.2 denotes hydrogen, methyl, ethyl, isobutyl, n-octyl, n-octadecyl, 
benzyl or menthyl, 
R.sup.3 denotes hydrogen, ethyl, n-octyl, n-nonyl, 5-nonyl, n-decyl, 
n-tetradecyl, 2-octenyl, 2-octynyl, 3-octynyl, benzyl, benzhydryl or 
3,3-diphenylpropyl, and 
R.sup.4 and R.sup.5 form, together with the atoms carrying them, a 
heterocyclic ring system from the series comprising 
octahydrocyclopenta[b]pyrrole, 
spiro[(bicyclo[2.2.2]octane)-2,3,-pyrrolidine], pyrrolidine or 
1,2,3,3a,4,6a-hexahydrocyclopenta[b],-pyrrole, 
with the proviso that 
A: R.sup.2 denotes n-octyl, n-octadecyl or menthyl, and otherwise n, R, 
R.sup.1, R.sup.3, R.sup.4 and R.sup.5 have the above-mentioned meaning, or 
B: R.sup.3 denotes n-octyl, n-nonyl, 5-nonyl, n-decyl, n-tetradecyl, 
2-octenyl, 2-octynyl, 3-octynyl, benzhydryl or 3,3-diphenylpropyl, and 
otherwise n, R, R.sup.1, R.sup.2, R.sup.4 and R.sup.5 have the 
abovementioned meaning, or 
C: R denotes n-decyl, and otherwise n, R.sup.1, R.sup.2, R.sup.3, R.sup.4 
and R.sup.5 have the stated meaning, 
and the physiologically tolerated salts thereof. 
Very particularly preferred are the following compounds of the formula I, 
and the physiologically tolerated salts thereof. 
n-Octyl 2-[N-(1S-ethoxycarbonyl-n-heptyl)-S-alanyl]-(1S, 
3S,5S)2-azabicyclo[3.3.0 ]octane-3-carboxylate; 
n-Octyl 
2-[N-(1S-ethoxycarbonyl-3-cyclohexylpropyl)-S-alanyl]-(1S,3S,5S)-2-azabicy 
clo[3.3.0]octane-3carboxylate; 
Benzyl 
2-[N-(S-ethoxycarbonyl-n-tridecyl)-S-alanyl](1S,3S,5S)-2-azabicyclo[3.3.0] 
octane-3-carboxylate; 
Benzyl 2-[N-(1R-ethoxycarbonyl-n-tridecyl)-S-alanyl]-(1S, 
3S,5S)-2-azabicyclo[3.3.0]octane-3-carboxylate; 
n-Decyl 
2-[N-(1S-ethoxycarbonyl-3-phenylpropyl)-S-alanyl]-(1S,3S,5S)-2-azabicyclo[ 
3.3.0]octane-3carboxylate; 
5-Nonyl 
2-[N-(1S-ethoxycarbonyl-3-phenylpropyl)-S-alanyl]-(1S,3S,5S)-2-azabicyclo[ 
3.3.0]octane-3-carboxylate; 
n-Octyl 
2-[N-(1S-isobutyloxycarbonyl-3-phenylpropyl)-S-alanyl]-(1S,3S,5S)-2-azabic 
yclo[3.3.0]octane-3carboxylate; 
2-[N-(1S-n-octyloxycarbonyl-3-phenylpropyl)-S-alanyl](1S,3S,5S)-2-azabicycl 
o[3.3.0]octane-3-carboxylic acid; 
Ethyl 
2-[N-(1S-n-octyloxycarbonyl-3-phenylpropyl)-S-alanyl]-(1S,3S,5S)-2-azabicy 
clo[3.3.0]octane-3carboxylate; 
n-Octyl 
2-[N-(1S-n-octyloxycarbonyl-3-phenylpropyl)-S-alanyl]-(1S,3S,5S)-2-azabicy 
clo[3.3.0]octane-3-carboxylate; 
Benzyl 
2-[N-(1S-n-octadecyloxycarbonyl-3-phenylpropyl)-S-alanyl]-(1S,3S,5S)-2-aza 
bicyclo[3.3.0]octane-3-carboxylate; 
n-Octyl 
2-[N-(1S-n-octadecyloxycarbonyl-3-phenylpropyl)-S-alanyl]-(1S,3S,5S)-2-aza 
bicyclo[3.3.0]octane-3-carboxylate; 
Benzyl 
2-[N-(1S-menthyloxycarbonyl-3-phenylpropyl)-S-alanyl]-(1S,3S,5S)-2-azabicy 
clo[3.3.0]octane-3carboxylate; 
Benzhydryl 
2-[N-(1S-menthyloxycarbonyl-3-phenylpropyl)-S-alanyl]-(1S,3S,5S)-2-azabicy 
clo[3.3.0]octane-3-carboxylate; 
n-Octyl 
2-[N-(1S-carboxy-3-phenylpropyl)-S-alanyl](1S,3S,5S)-2-azabicyclo[3.3.0]oc 
tane-3-carboxylate; 
n-Octyl 
2-[N-(1S-ethoxycarbonyl-3-phenylpropyl)-S-alanyl]-(1S,3S,5S)-2-azabicyclo[ 
3.3.0]-7-octene-3carboxylate; 
N-[N-(1S-ethoxycarbonyl-3-phenylpropyl)-S-alanyl]-S-proline n-octyl ester; 
n-Octyl 
2-[N-(1S-methoxycarbonyl-3-phenylpropyl)-S-alanyl]-(1S,3S,5S)-2-azabicyclo 
[3.3.0]octane-3carboxylate; 
n-Octyl 
2-[N-(1S-benzyloxycarbonyl-3-phenylpropyl)-S-alanyl]-(1S,3S,5S)-2-azabicyc 
lo[3.3.0]octane-3carboxylate; 
n-Decyl 
2-[N-(1S-carboxy-3-phenylpropyl)-S-alanyl](1S,3S,5S)-2-azabicyclo[3.3.0]oc 
tane-3-carboxylate. 
The invention also relates to a process for the preparation of compounds of 
the formula I, which comprises 
a) reacting a compound of the formula XIV 
##STR4## 
with a compound of the formula XV 
##STR5## 
where R, R.sup.1, R.sup.4, R.sup.5 and n in the abovementioned formulae 
XIV and XV have the same meaning as in formula I, and 
i. Q.sup.2 is defined as R.sup.2 in formula I but does not denote hydrogen, 
or represents a carboxyl protective group which can easily be eliminated 
by base, acid or hydrogenolysis, 
Q.sup.3 denotes hydrogen, 
Y denotes hydroxyl or a leaving group which can be displaced 
nucleophilically, and 
Q is defined as R.sup.3 in formula I but does not denote hydrogen, or 
Y denotes 
##STR6## 
and 
Q denotes an alkylidene radical having 1 to 18 carbon atoms, or 
ii. Q.sup.2 denotes hydrogen, 
Q.sup.3 is defined as R.sup.3 in formula I but does not denote hydrogen, or 
represents a carboxyl protective group which can easily be eliminated by 
base, acid or hydrogenolysis, 
Y denotes hydroxyl or a leaving group which can be displaced 
nucleophilically, and 
Q is defined as R.sup.2 in formula I but does not denote hydrogen, or 
Y denotes 
##STR7## 
and 
Q denotes an alkylidene radical having 1 to 18 carbon atoms, or comprises 
b) reacting a compound of the formula IX 
##STR8## 
in which R, R.sup.2 and n have the same meaning as in formula I, with a 
compound of the formula X 
##STR9## 
in which R.sup.1, R.sup.3, R.sup.4 and R.sup.5 have the same meaning as in 
formula I, or comprises 
c) reacting a compound of the formula XI 
##STR10## 
in which R.sup.3, R.sup.4 and R.sup.5 have the same meaning as in formula 
I, with a compound of the formula XII 
##STR11## 
in which n, R, R.sup.1 and R.sup.2 have the same meaning as in formula I, 
in analogy to known peptide-coupling processes, and where Q.sup.2 or 
Q.sup.3 in the compound obtained in this way represents a protective group 
which can be eliminated by base, acid or hydrogen-olysis, this protective 
group being eliminated, where appropriate by treatment with a base or an 
acid or by hydrogenation, and the compound of the formula I obtained in 
the above manner optionally being converted into the physiologically 
tolerated salt thereof. 
An alkylidene radical has the formula 
##STR12## 
in which R.sup.6 and R.sup.7 are as defined below in process variant 
a.sub.5). 
According to process variant a), preferably 
a.sub.1) a compound of the formula II 
##STR13## 
in which R, R.sup.1, Q.sup.2, R.sup.4, R.sup.5 and n have the same meaning 
as in formula XIV, is reacted with a compound of the formula III 
EQU R.sup.3 --OH (III) 
in which R.sup.3 has the same meaning as in formula I, except that of 
hydrogen, using esterification methods familiar to those skilled in the 
art (see, for example, Buehler, Pearson, Survey of Organic Synthesis, Vol. 
1, New York 1970, pages 802-825; Houben-Weyl, Methoden der Organischen 
Chemie (Methods of Organic Chemistry), volume E5, 1985, pages 656-773), 
for example with acid catalysis or after activation of the carboxyl group 
of II or the hydroxyl group of III, in particular under the conditions of 
a Mitsunobu reaction, in a suitable solvent at a temperature up to the 
boiling point of the reaction mixture, 
or 
a.sub.2) a compound of the formula II in which R, R.sup.1, Q.sup.2, 
R.sup.4, R.sup.5 and n have the same meaning as in formula XIV is reacted 
with a compound of the formula IV 
EQU R.sup.3 --X (IV) 
in which R.sup.3 has the same meaning as in formula I, except that of 
hydrogen, and in which X denotes a leaving group which can be displaced 
nucleophilically, in particular a Cl, Br or I atom or a sulfonic acid 
residue, under the conditions of a nucleophilic substitution, preferably 
in a polar organic solvent such as an alcohol, preferably methanol, 
ethanol, propanol or isopropanol, or a lower ketone, preferably acetone, 
methyl ethyl ketone or methyl isobutyl ketone, or in acetonitrile, 
dimethylformamide, dimethyl sulfoxide or sulfolane, or a hydrocarbon, 
preferably toluene, with or without the presence of an auxiliary base to 
trap the acid which is formed, preferably in the presence of potassium 
bicarbonate, potassium carbonate, sodium bicarbonate, sodium carbonate, 
triethylamine, pyridine, 1,5-diazabicyclo[5.4.0]undec-5-ene or 
1,5-diazabicyclo-[4.3.0]non-5-ene, and with or without the presence of an 
alkali metal halide, preferably sodium iodide or potassium iodide, at a 
temperature between -50 and +100.degree. C., preferably between 
-20.degree.and +60.degree. C., or 
a.sub.3) a compound of the formula V 
##STR14## 
in which R, R.sup.1, Q.sup.3, R.sup.4, R.sup.5 and n have the same meaning 
as in formula XIV, is reacted with a compound of the formula VI 
EQU R.sup.2 --OH (VI) 
in which R.sup.2 has the same meaning as in formula I, except that of 
hydrogen, as described above under a.sub.1), or 
a.sub.4) a compound of the formula V in which R, R.sup.1, Q.sup.3, R.sup.4 
and n have the same meaning as in formula XIV is reacted with a compound 
of the formula VII 
EQU R.sup.2 --X (VII) 
in which R.sup.2 has the same meaning as in formula I, except that of 
hydrogen, and in which X has the same meaning as in formula IV, as 
described above under a.sub.2), or 
a.sub.5) a compound of the formula II or V is reacted with a diazoalkane of 
the formula (VIII) 
##STR15## 
in which R.sup.6 denotes a radical C.sub.x H.sub.2x+1, and R.sup.7 denotes 
a radical C.sub.y H.sub.2y+1, x and y are each an integer from 0 to 17, 
and x+y.ltoreq.17, in an inert organic solvent at temperatures between 
-80.degree. C. and the boiling point of the solvent. 
The reaction according to variant b) is carried out, for example, in 
analogy to the procedure described in U.S. Pat. No. 4,525,301, in a 
suitable solvent at a temperature up to the boiling point of the reaction 
mixture. 
Procedure c) is carried out, for example, in analogy to known 
peptide-coupling processes in an organic solvent such as DMF, CH.sub.2 
Cl.sub.2 or DMA in the presence of aids to coupling, such as carbodiimides 
(for example dicyclohexylcarbodiimide), diphenylphosphoryl azide, 
alkanephosphonic anhydrides, dialkylphosphinic anhydrides or 
N,N-succinimidoyl carbonate, in a solvent such as, for example, 
acetonitrile or after activation of the compounds of the formula XI, for 
example by reaction with tetraethyl diphosphite, or after activation of 
the compounds of the formula XII to active esters (for example with 
1-hydroxybenzotriazole), to mixed anhydrides (for example with 
chloroformic esters), to azides or to carbodiimide derivatives (cf. 
Schroder, Lubke, The Peptides, volume 1, New York 1965, pages 76-136) at 
temperatures preferably between -20.degree. C. and the boiling point of 
the solvent. A protective group which can be eliminated by hydrogenolysis 
is eliminated by hydrogenolysis on a suitable catalyst such as, for 
example, palladium on active charcoal under a pressure of 0.2 to 10 bar 
and at a temperature between 0.degree. C. and 100.degree. C. in an organic 
solvent to give a compound of the formula I (R.sup.3 =H). 
An easily hydrolyzable aliphatic radical can be eliminated using hydrolysis 
methods familiar to those skilled in the art (see, for example, 
Houben/Weyl, Methoden der Organischen Chemie, volume E 5/1, pages 
223-255), for example by acid or alkali hydrolysis with formation of the 
free carboxyl group. 
The invention also relates to compounds of the formula XI in which 
R.sup.3 denotes n-octyl, n-nonyl, 5-nonyl, n-decyl, n-tetradecyl, 
2-octenyl, 2-octynyl, 3-octynyl, benzyl, benzhydryl or 3,3-diphenylpropyl, 
and 
R.sup.4 and R.sup.5 form, together with the atoms carrying them, a 
heterocyclic ring system from the series comprising 
octahydrocyclopenta[b]pyrrole, 
spiro[(bicyclo-[2.2.2]octane-2,3'-pyrrolidine], pyrrolidine or 
1,2,3,3a,4,6a-hexahydrocyclopenta[b]pyrrole, excepting n-octyl 
(1S,3S,5S)-2-azabicyclo[3.3.0]octane-3-carboxylate, as well as the 
physiologically tolerated salts thereof, and to a process for the 
preparation of these compounds, which comprises reacting a compound of the 
formula XI in which R.sup.4 and R.sup.5 are defined as in formula XI, and 
R.sup.3 denotes hydrogen, in analogy to the abovementioned process variant 
a), with a compound of the formula XV in which Q is defined as R.sup.3 in 
formula XI, but does not denote hydrogen, and Y denotes hydroxyl or a 
leaving group which can be displaced nucleophilically. 
Compounds of the formula II and V are known (see, for example, EP-A 79022, 
EP-A 105102, EP-A 113880, EP-A 116270, EP-A 74164, EP-A 90362) or can be 
prepared by analogous routes. 
Compounds of the formula III, IV, VI, VII and VIII are known, and most of 
them can be bought. 
Compounds of the formula IX are obtained from compounds of the formula XIII 
##STR16## 
in which R, R.sup.2 and n have the same meaning as in formula in which R, 
R.sup.2 and n have the same meaning as in formula I, by conversion of the 
hydroxyl group into the --OSO.sub.2 CF.sub.3 group by conventional 
processes. 
Compounds of the formula X are dipeptides which can be built up from the 
individual amino acid components by methods of peptide chemistry known per 
se (see, for example, Houben-Weyl, Methoden der Organischen Chemie, vol. 
XV, part II, pages 1-364). 
Compounds of the formula XI, XII and XIII are known or can be prepared by 
routes analogous to those for the known compounds. 
The compounds of the formula I and the physiologically tolerated salts 
thereof have a nootropic effect, i.e. improving cognitive function. They 
are therefore suitable for the treatment of cognitive dysfunctions of 
various etiologies as occur, for example, in Alzheimer's disease or senile 
dimentia. The nootropic effect of the compounds according to the invention 
was tested in the inhibitory (passive) avoidance test (step-through model) 
on mice with a body weight of 20-25 g. A modified form of the test method 
described by J. KOPP, Z. BODANECKY and M.E. JARVIK has been described by 
J. BURES, O. BURESOVA and J. HUSTON in "Techniques and Basic Experiments 
for the Study of Brain and Behavior", Elsevier Scientific Publishers, 
Amsterdam (1983). 
According to the statements in this literature, a substance is designated 
as having nootropic activity when it is able to abolish the amnesia 
produced in the experimental animals by means of an electroconvulsive 
shock or the amnesia induced by scopolamine. 
The experiments were carried out by modified test methods. The comparison 
compound used was the known nootropic agent 2-oxo-1-pyrrolidinylacetamide 
according to the invention over the comparison substance was evident from 
the fact that it is possible to abolish the scopolamine-induced amnesia in 
the inhibitory avoidance test with an oral MED (minimal effective dose) of 
0.03-30 mg/kg. The comparison substance has an oral MED of about 500-1000 
mg/kg. 
The invention therefore also relates to the use of the compounds according 
to the invention for the treatment and prophylaxis of cognitive 
dysfunctions. 
The invention additionally embraces pharmaceuticals containing the said 
compounds, processes for the preparation thereof, and the use of the 
compounds according to the invention for the preparation of 
pharmaceuticals which are used for the treatment and prophylaxis of the 
above-mentioned diseases. 
The method according to the invention can be practiced by administering the 
compounds of the formula I described above to mammals such as monkeys, 
dogs, cats, rats, humans etc. 
The pharmaceuticals are prepared by processes which are known per se and 
familiar to those skilled in the art. As pharmaceuticals, the 
pharmacologically active compounds (=active substance) according to the 
invention are used either as such or, preferably, in combination with 
suitable pharmaceutical auxiliaries in the form of tablets, coated 
tablets, capsules, suppositories, emulsions, suspension or solutions, with 
the content of active substance being up to about 95%, advantageously 
between 10 and 75%. 
The particular auxiliaries suitable for the desired pharmaceutical 
formulation are familiar to those skilled in the art on the basis of their 
expert knowledge. Besides solvents, gel-formers, suppository bases, tablet 
auxiliaries and other active substance vehicles, it is possible to use, 
for example, antioxidants, dispersing agents, emulsifiers, antifoam 
agents, flavorings, preservatives, solubilizers or colorants. 
The active substances can be administered, for example, onto the mucous 
membranes (for example orally or rectally) or parenterally (for example 
intravenously or subcutaneously), with oral administration being 
preferred. 
For a form for oral administration, 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 a suitable 
dosage form, 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, lactose, glucose or starch, especially corn 
starch. This preparation can be carried out both as dry and as wet 
granules. 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 
the physiologically tolerated salts thereof, are converted into a 
solution, suspension or emulsion, if desired with the substances customary 
for this purpose, such as solubilizers, emulsifiers or other auxiliaries. 
Examples of suitable solvents are water, physiological saline solution or 
alcohols, for example ethanol, propanol or glycerol, as well as sugar 
solutions such as glucose or mannitol solutions, or else a mixture of the 
various solvents mentioned.

The examples which follow are intended to explain the compounds and 
processes according to the invention without confining the invention to 
the substances mentioned here as representative. 
A. INTERMEDIATES 
1) 
2-[N-(1S-Isobutyloxycarbonyl-3-phenylpropyl)-S-alanyl]-(1S,3S,5S)-2-azabic 
yclo[3.3.0]octane-2-carboxylic acid 
1a) Isobutyl 2R-hydroxy-4-phenylbutyrate 
8 g (44 mmol) of 2R-hydroxy-4-phenylbutyric acid are stirred together with 
100 ml of saturated isobutanol/HCl solution at room temperature for 5 
hours, the mixture is concentrated, the residue is taken up in ether, and 
the solution is washed with water, saturated NaHCO.sub.3 solution and 
again with water, dried and concentrated. 
Yield: 9.35 g (89%) [.alpha.].sub.D.sup.25 =-8.1.degree. (c=1, CH.sub.3 OH) 
The following are obtained analogously: 
Ethyl 2(RS)-hydroxytetradecanoate; 
Ethyl 2(RS)-hydroxyoctanoate; 
Methyl 2R-hydroxy-4-phenylbutyrate. 
1b) Isobutyl 4-phenyl-2R-(trifluoromethylsulfonyloxy)-butyrate 
11.28 g (40 mmol) of trifluoromethanesulfonic anhydride are slowly added at 
-10.degree. C. to 8.8 g (37.6 mmol) of the hydroxy ester from Example 1a) 
and 3.2 ml (40 mmol) of pyridine in 200 ml of absolute methylene chloride, 
and the mixture is then stirred at -10.degree. C. for 10 minutes and at 
room temperature for 30 minutes. The reaction solution is concentrated, 
the residue is dissolved in cyclohexane/ethyl acetate 95/5, filtered and 
purified by column chromatography on 320 g of silica gel (mobile phase 
cyclohexane/ethyl acetate 95/5). 
Yield: 11.85 g (86%). 
The following are obtained analogously: 
Ethyl 2(RS)-(trifluoromethylsulfonyloxy)octanoate; 
Ethyl 2(RS)-(trifluoromethylsulfonyloxy)tetradecanoate; 
n-Octyl 4-phenyl-2R-(trifluoromethylsulfonyloxy)butyrate; 
n-Octadecyl 4-phenyl-2R-(trifluoromethylsulfonyloxy)butyrate; 
Menthyl 4-phenyl-2R-(trifluoromethylsulfonyloxy)butyrate; 
Ethyl 4-phenyl-2(RS)-(trifluoromethylsulfonyloxy)butyrate; 
Methyl 4-phenyl-2R-(trifluoromethylsulfonyloxy)butyrate; 
Benzyl 4-phenyl-2R-2R-(trifluoromethylsulfonyloxy)butyrate. 
1c) Benzyl 
2-N-(1S-isobutyloxycarbonyl-3-phenylpropyl)-S-alanyl]-(1S,3S,4S)-2-azabicy 
clo[3.3.0]octane-3-carboxylate 
13.85 g (32.2 mmol) of benzyl 
N-(S-alanyl)-(1S,3S,5S)-2azabicyclo[3.3.0]octane-3-carboxylate 
trifluoroacetate (see Example 3) and 8.7 ml (64.4 mmol) of absolute 
triethylamine are dissolved in 85 ml of absolute methylene chloride and, 
at 0.degree. C., a solution of 11.85 g of the triflate from Example 1b) 
(32.2 mmol) in 85 ml of absolute methylene chloride is added dropwise. The 
mixture is then stirred at room temperature for 4 hours, the organic phase 
is extracted by shaking with water three times, dried and concentrated, 
and the residue (13.4 g) is chromatographed on 800 g of silica gel (mobile 
phase: cyclohexane/ethyl acetate 7:3 and 1:1, then toluene/ethanol) to 
remove byproducts. 
Yield: 9.65 g (56%) of oily product 
[.alpha.].sub.D.sup.25 =-39.3.degree.(c=1, methanol) 
1d) 
2-[N-(1S-Isobutyloxycarbonyl-3-phenylpropyl)-S-alanyl]-(1S,3S,5S)-2-azabic 
yclo[3.3.01]octane-3-carboxylic acid 
4.0 g (7.5 mmol) of the benzyl ester from Example 1c) in 220 ml of ethanol 
are hydrogenated on 0.6 g of palladium/charcoal (10%) within 30 minutes at 
room temperature. The catalyst is filtered off with suction, and the 
filtrate is evaporated to dryness. 
Yield: 3.32 g (100%) of oily product 
[.alpha.].sub.D.sup.25 =+6.8.degree.(c=1, methanol). 
The following are obtained analogously: 
2-[N-(1S-Ethoxycarbonyl-n-heptyl)-S-alanyl]-(1S,3S,5S)2-azabicyclo[3.3.0]oc 
tane-3-carboxylic acid 
2-[N-(1R-Ethoxycarbonyl-n-heptyl)-S-alanyl]-(1S,3S,5S)2-azabicyclo[3.3.0]oc 
tane-3-carboxylic acid 
2[N-(1S-Ethoxycarbonyl-3-phenylpropyl)-S-alanyl]-(1R,3R,5R)-2-azabicyclo[3. 
3.0]octane-3-carboxylic acid; 
2) n-Octyl 2R-hydroxy-4-phenylbutyrate 
9.0 g (50 mmol) of 2R-hydroxy-4-phenylbutyric acid are dissolved in 250 ml 
of absolute dimethylformamide, 10.0 g (0.1 mmol) of potassium bicarbonate 
are added, and the mixture is stirred at 50.degree. C. for one hour. After 
cooling to room temperature, a solution of 15.4 g (80 mmol) of 
1-bromooctane in 150 ml of absolute dimethylformamide is added dropwise, 
and the mixture is stirred at 50.degree. C. for three hours. The reaction 
solution is diluted with 1200 ml of water and extracted three times with 
ethyl acetate, the combined organic phases are extracted by shaking twice 
with water, dried over magnesium sulfate and evaporated in a rotary 
evaporator, and the crude product (21.3 g) is purified by chromatography 
on 480 g of silica gel (mobile phase methylene chloride/ethyl acetate 
100/0, 99:1, 95:5). 
Yield: 13.4 g (92%) of oily product. 
[.alpha.].sub.D.sup.25 =-6.3.degree.(c=2, methanol) 
The following are obtained analogously: 
n-Octadecyl 2R-hydroxy-4-phenylbutyrate, melting point 
42.degree.-43.degree. C. 
Benzyl 2R-hydroxy-4-phenylbutyrate. 
3) Benzyl 2-(S-alanyl) -(1S,3S,5S)-2-azabicyclo[3.3.0]octane-3-carboxylate 
trifluoroacetate 
3a) Benzyl 
2-(N-tert.butoxycarbonyl-S-alanyl)-(1S,3S,5S)-2-azabicyclco[3.3.0]octane-3 
-carboxylate 
61.5 g (0.251 mol) of benzyl 
(1S,3S,5S)-2-azabicyclo[3.3.0]octane-3-carboxylate, 47.5 g (0.251 mol) of 
BOC-L-alanine and 173 ml (1.26 mol) of absolute triethylamine are 
dissolved in 1025 ml of absolute dimethylformamide, 252 ml of a 50% 
strength dichloromethane solution of propanephosphonic anhydride are added 
dropwise at -5.degree. C., and the mixture is stirred at -5.degree. C. for 
30 minutes and at room temperature for four hours. The reaction solution 
is partitioned between 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, 10% strength citric 
acid solution, water and saturated sodium chloride solution, dried and 
concentrated. 
Yield: 93.2 g (39%) of oily product. 
3b) Benzyl 2-(S-alanyl)-(1S,3S,5S)-2-azabicyclo[3.3.0]-octane-3-carboxylate 
trifluoroacetate 
235 ml of absolute trifluoroacetic acid are poured onto 93.2 g (0.224 mol) 
of the BOC derivative from Example 3a) at 0.degree. C., and the mixture is 
stirred at 0.degree. C. for 2.5 hours. Excess acid is evaporated off in 
vacuo at 25.degree. C., and the residue is crystallized from 1000 ml of 
absolute diisopropyl ether. 
Yield: 82.6 g (86%), melting point 148.degree.-150.degree. C. 
4) N-(1R-Ethoxycarbonyl-3-phenylpropyl)-R alanine 
4a) N-(1R-Ethoxycarbonyl-3-phenylpropyl)-R-alanine benzyl ester 
6.07 g (60 mmol) of absolute triethylamine and a solution of 10.2 g (30 
mmol) of ethyl 3-phenyl-2(RS)-(trifluoromethylsulfonyloxy)butyrate are 
successively added drop-wise at 0.degree. C. to a solution of 10.5 g (30 
mmol) of D-alanine benzyl ester p-toluenesulfonate in 300 ml of absolute 
methylene chloride. The reaction mixture is stirred at 0.degree. C. for 10 
minutes and at room temperature for 2.5 hours, diluted with methylene 
chloride, washed three times with water, dried and concentrated, and the 
crude product (11.6 g) is fractionated into the diastereomers by flash 
chromatography on 770 g of silica gel (mobile phase cyclohexane/ethyl 
acetate 9:1). 
The following are obtained successively: 
4.78 g (45%) of the RS diastereomer, 
[.alpha.].sub.D.sup.25 =+20.8.degree. (c=1, methanol) 
3.07 g (29%) of the RR diastereomer, 
[.alpha.].sub.D.sup.25 =+19.7.degree. (c=1, methanol). 
The following are obtained analogously: 
N-(1S-Ethoxycarbonyl-3-phenylpropyl)-S-alanine benzyl ester, 
[.alpha.].sub.D.sup.25 =-18.4.degree. (c=1, methanol); 
N-(1R-Ethoxycarbonyl-3-phenylpropyl)-S-alanine benzyl ester, 
[.alpha.].sub.D.sup.25 =-21.7.degree. (c=1, methanol); 
N-(1S-Ethoxycarbonyl-n-heptyl)-S-alanine benzyl ester, 
[.alpha.].sub.D.sup.25 =-31.2.degree. (c=1, methanol); 
N-(1R-Ethoxycarbonyl-n-heptyl)-S-alanine benzyl ester; 
N-(1S-Ethoxycarbonyl-n-tridecyl)-S-phenylalanine benzyl ester; 
N-(1(RS)-Ethoxycarbonyl-n-tridecyl)-S-phenylalanine benzyl ester; 
4b) N-(1R-Ethoxycarbonyl-3-phenylpropyl)-R-alanine 
3.0 g (8.12 mmol) of the RR diastereomer from Example 4a) are dissolved in 
75 ml of ethanol and hydrogenated on 250 mg of palladium/charcoal (10%) at 
room temperature for one hour. The catalyst is filtered off with suction 
and the filtrate is concentrated. 
Yield: 2.2 g (96%) of colorless crystals, 
melting point 146.degree.-148.degree. C. 
The following are obtained by an analogous route: 
N-(1S-Ethoxycarbonyl-3-phenylpropyl)-S-alanine, melting point: 
134.degree.-136.degree. C.; 
N-(1R-Ethoxycarbonyl-3-phenylpropyl)-S-alanine, melting point: 
133.degree.-135.degree. C.; 
N-(1S-Ethoxycarbonyl-3-phenylpropyl)-S-alanine, melting point: 
148.degree.-150.degree. C.; 
N-(1S-Ethoxycarbonyl-n-heptyl)-S-alanine, 
[.alpha.].sub.D.sup.20 =+9.2.degree. (c=1, methanol); 
N-(1R-Ethoxycarbonyl-n-heptyl)-S-alanine, melting point: 122-124.degree. 
C.; 
N-(1S-Ethoxycarbonyl-n-tridecyl)-S-phenylalanine. melting point: 
116-118.degree. C.; 
N-(1(RS)-Ethoxycarbonyl-n-tridecyl)-S-phenylalanine, melting point: 
87-90.degree. C.; 
5) Benzyl 
2[N-(1S-ethoxycarbonyl-n-heptyl)-S-alanyl]-(1S,3S,5S)-2-azabicyclo[3.3.01] 
octane-3-carboxylate 
6.0 ml of absolute triethylamine and 8.2 ml of a 50% strength solution of 
propanephosphonic anhydride in methylene chloride are successively added 
dropwise at -8.degree. C. to a solution of 2.3 g (8.9 mmol) of 
N-(1S-ethoxy-carbonyl-n-heptyl)-S-alanine and 2.8 g (10.0 mmol) of benzly 
(1S,3S,5S)-2-azabicyclo[3.3.0]octane-3-carboxylate in 110 ml of absolute 
dimethylformamide. The reaction solution is left to stand at room 
temperature over the week-end and is diluted with ethyl acetate, washed 
with saturated sodium carbonate solution, 10% strength citric acid 
solution and saturated sodium chloride solution, dried and concentrated, 
and the residue (3.9 g) is purified by chromatography on silica gel 
(mobile phase cyclohexane/ethyl acetate 7:3). 
Yield: 1.2 g (28%) of oily product, 
[.alpha.].sub.D.sup.25 =-46.6.degree. (c=1, methanol). 
The following are obtained by an analogous route: 
Benzyl 
2-[N-(1R-ethoxycarbonyl-n-heptyl)-S-alanyl](1S,3S,5S)-2-azabicyclo[3.3.0]o 
ctane-3-carboxylate; 
[.alpha.].sub.D.sup.25 =-32.5.degree. (c=0.79, methanol), 
Benzyl 
2-[N-(1S-ethoxycarbonyl-3-phenylpropyl))-S-alanyl]-(1R,3R,5R)-2-azabicyclo 
[3.3.0]octane-3carboxylate; [.alpha.].sub.D.sup.25 =-1.9.degree. (c=1, 
methanol) 
6) n-Octyl (1S,3S,5S)-2-azabicyclo[3.3.01]octane-3-carboxylate 
6a) Benzyl 
2-tert.butyloxycarbonyl-(1S,3S,5S)-2-azabicyclo[3.3.0]octane-3-carboxylate 
A solution of 39.2 g (0.18 mmol) of di-tert.butyl dicarbonate in 60 ml of 
absolute methylene chloride is slowly added dropwise at 0.degree. C. to a 
solution of 40.0 g (0.163 mmol) of benzyl (1S,3S,5S)-2 
azabicyclo[3.3.0]-octane-3-carboxylate and 23.4 ml (0.169 mol) of absolute 
triethylamine in 300 ml of absolute methylene chloride, and the mixture is 
stirred at 0.degree. C. for 15 minutes and at room temperature for one 
hour. The reaction solution is washed with 10% citric acid solution, 
saturated sodium bicarbonate solution and water, dried and concentrated. 
Yield: 55.6 g of oily product, 
[.alpha.].sub.D.sup.25 -=1.2.degree. (c=2, methanol). 
6b) 
2-tert.Butyloxycarbonyl-(1S,3S,5S)-2-azabicyclo[3.3.0]octane-3-carboxylic 
acid 
55.6 g (0.161 mol) of the benzyl ester from Example 6a) in 2 1 of ethanol 
are hydrogenated on 4 g of palladium/ charcoal (10%) at room temperature 
for 2.5 hours. The catalyst is filtered off with suction, and the filtrate 
is concentrated. 
Yield: 37.3 g (90%); 
[.alpha.].sub.D.sup.25 =+22.7.degree. (c=1, methanol). 
6c) n-Octyl 
2-tert.butyloxyzarbonyl-(1S,3S,5S)-2-azabicyclo[3.3.0]octane-3-carboxylate 
32.3 g (0.127 mol) of the acid from Example 6b) and 25.3 g (0.253 mol) of 
potassium bicarbonate are stirred in 500 ml of dimethylformamide at 
40.degree. C. for 1.5 hours. After cooling, 48.9 g (0.253 mol) 
1-bromooctane are added dropwise, and the mixture is stirred at room 
temperature overnight. The reaction mixture is poured into water, 
extracted three times with ethyl acetate, 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 
chromatography in two portions on silica gel (900 g, mobile phase 
toluene/ethanol 95:5 and 99.5:0.5). 
Yield: 35.4 g (76% of oily product, 
[.alpha.].sub.D.sup.25 =+5.7.degree. (c=1, methanol). 
The following are obtained by an analogous route: 
n-Octyl 
2-tert.butyloxycarbonyl-(1RS,3RS,5RS)-2azabicyclo[3.3.0]-7-octene-3-carbox 
ylate; 
N-tert.butyloxycarbonyl-S-proline n-octyl ester 
6d) n-Octyl 1S,3S,5S)-2-azabicyclo[3.3.0]octane-3-carboxylate 
2.6 g (7.0 mmol) of the BOC compound from Example 6c) are stirred with 9 ml 
of trifluoroacetic acid at 0.degree. C. for 1.5 hours. The excess acid is 
evaporated off in vacuo, the residue is taken up in water, the solution is 
made basic with sodium bicarbonate and extracted with ethyl acetate, the 
organic phase is washed once more with water, dried and concentrated, and 
the product is rapidly reacted further. 
Yield: 1.8 g (95%) of oily product. 
The following are obtained by an analogous route: 
n-Octyl (1RS,3RS,5RS)-2-azabicyclo[3.3.0]-7-octene-3carboxylate; 
S-Proline n-octyl ester. 
7) 
2-tert.Butyloxycarbonyl-(1RS,3RS,5RS)-2-azabicyclo[3.3.0]-7-octene-3-carbo 
xylic acid 
6.26 g (28.7 mmol) of di-tert.-butyl dicarbonate are added, while cooling 
in ice, to 4.0 g (26.1 mmol) of 
(1RS,3RS,5RS)-2-azabicyclo[3.3.0]-7-octene-3-carboxylic acid (cis-endo 
racemate) in a mixture of 78 ml of dioxane/water 2:1 and 26.1 ml of 1 N 
sodium hydroxide solution, and the mixture is stirred at room temperature 
for one hour, keeping the pH continuously at pH 9 by addition of 1 N 
sodium hydroxide solution. The reaction solution is concentrated, the 
residue is dissolved in water, ethyl acetate is poured on, and the pH is 
adjusted to 2 with saturated potassium bisulfate solution. The phases are 
separated, the aqueous phase is extracted twice more with ethyl acetate, 
and the combined organic phases are washed with water and saturated sodium 
chloride solution, dried and concentrated. 
Yield: 6.3 g (96%). 
8) 3-Octynyl methanesulfonate 
7.47 g (65 mmol) of methanesulfonyl chloride are added dropwise within 30 
minutes at 10.degree. C. to a solution of 7.56 g (60 mmol) of 3-octyn-1-ol 
and 12.45 ml (90mmol) triethylamine in 225 ml of methylene chloride, and 
the mixture is stirred for one hour. The reaction solution is washed with 
water, saturated sodium bicarbonate solution and again with water, dried 
and concentrated. 
Yield: 11.9 g (97%) of oily product. 
B. FINAL PRODUCTS 
Example 9 
n-Octyl 
2-[N-(1S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl]-(1S,3S,5S)-2-azabicyclo 
[3.3.0]-octane-3-carboxylate 
2.07 g (5 mmol) of 
2-[N-(1S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl]-(1S,3S,5S)-2-azabicyclo 
[3.3.0]octane-3-carboxylic acid (ramipril) and 0.50 g (5 mmol) of potassium 
bicarbonate are stirred in 25 ml of dimethyl-formamide at 40.degree. C. 
for 1.5 hours and, after cooling to room temperature, a solution of 1.16 g 
(6 mmol) of 1-bromooctane in 20 ml of dimethylformamide is added dropwise, 
and the mixture is stirred at room temperature overnight. The pH is 
adjusted to 6 by addition of 0.1 N HCl, the mixture is diluted with water 
and extracted three times with methylene chloride, and the combined 
organic phases are dried, concentrated and purified by column 
chromatography on 120 g of silica gel (mobile phase toluene/ethanol 95:5). 
Yield: 2.35 g (89%) of oily product; 
[.alpha.].sub.D.sup.25 =-23.9 .degree. (c=1, methanol). 
Example 10 
n-Octyl 2-[N-(1S-ethoxycarbonyl-3-phenylpropyl)-S-alanyl] 
-(1S,3S,5S)-2-azabicyclo[3.3.0]octane-3carboxylate hydrogen maleate 
528 mg (1 mmol) of an amine obtained as in Example 9 are dissolved in 20 ml 
of ether, and a solution of 116 mg 1 mmol) of maleic acid in 4 ml of 
acetone is added. The solvents are evaporated off, and the residue is 
crystallized using diisopropyl ether. 
Yield: 0.51 g (79%) of colorless crystals, 
melting point 89.degree.-90.degree. C. 
Example 11 
2-Octynyl 
2-[N-(1S-ethoxycarbonyl-3-phenylpropyl)-S-alanyl]-(1S,3S,5S)-2-azabicyclo[ 
3.3.0]octane-3-carboxylate hydrogen maleate 
2.08 g (5 mmol) of 
2-[N-(1S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl]-(1S,3S,5S)-2-azabicyclo 
[3.3.0]octane-3-carboxylic acid (ramipril) and 1.00 g (10 mmol) of 
potassium bicarbonate are stirred in 25 ml of dimethylformamide at 
40.degree. C. for 1.5 hours, cooled to 0.degree. C., and a solution of 2.3 
g (12 mmol) of E-1-bromo-2-octene in 20 ml of dimethylformamide is added 
dropwise. The reaction solution is stirred at 0.degree. C. for 4 hours, 
poured into 500 ml of water and extracted three 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 purified by flash chromatography on 125 g of silica gel 
(mobile phase cyclohexane/ethyl acetate 8:2 and 1:1). 
1.93 g (73%) of an oily product are obtained and converted into the 
hydrogen maleate in analogy to Example 10. 
Yield: 2.0 g of colorless crystals, melting point 81.degree.-84.degree. C. 
Example 12 
3-Octynyl 
2-[N-(1S-ethoxycarbonyl-3-phenylpropyl)-S-alanyl]-(1S,3S,5S)-2-azabicyclo[ 
3.3.0]octane-3-carboxylate hydrogen maleate 
4.9 g (11.8 mmol) of 
2-[N-(1S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl]-(1S,3S,5S)-2-azabicyclo 
[3.3.0]octane3-carboxylic acid (ramipril) and 2.4 g (23.6 mmol) of 
potassium bicarbonate are stirred in 90 ml of dimethylformamide at 
40.degree. C. for 2 hours, then a solution of 2.41 g (11.8 mmol) of the 
mesylate from Example 8 in 30 ml of dimethylformamide is added, and the 
mixture is stirred at 40.degree. C. for a further 9 hours. The reaction 
solution is diluted with 250 ml of 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 (56%) of an oily product 
are obtained, and 1.3 g of this are converted into the hydrogen maleate in 
analogy to Example 10. 
Yield: 0.8 g of colorless crystals, melting point 68.degree.-70.degree. C. 
Example 13 
25 Ethyl 
2-[N-(1S-n-octyloxycarbonyl-3-phenylpropyl)-S-alanyl]-(1S,3S,5S)-2-azabicy 
clo[3.3.0]octane-3carboxylate hydrogen maleate 
1.43 g (2.8 mmol) of the carboxylic acid from Example 19 are stirred in 25 
ml of ethanolic hydrochloric acid at room temperature. After 5 days, a 
further 25 ml of ethanolic hydrochloric acid are added, the mixture is 
stirred overnight and concentrated, the residue is taken up in ethyl 
acetate, washed three times with saturated sodium bicarbonate solution and 
once with water, dried and concentrated, and the crude product (1.16 g) is 
purified by flash chromatography on 80 g of silica gel, (mobile phase 
toluene/ethanol 99:1). 0.62 g (42%) of oily product are obtained and 
converted into the hydrogen maleate in analogy to Example 10. 
Yield: 0.50 g of colorless crystals, melting point 84.degree.-86.degree. C. 
Example 14 
5-Nonyl 
2-[N-(1S-ethoxycarbonyl-3-phenylpropyl)-S-alanyl]-(1S,3S,5S)-2-azabicyclo[ 
3.3.0]octane-3--carboxylate hydrogen maleate 
A solution of 1.31 g (7.5 mmol) of diethyl azodicarboxylate in 10 ml of 
absolute tetrahydrofuran is added dropwise at 0.degree. C. to a solution 
of 1.97 g (7.5 mmol) of triphenylphosphine and 0.72 g (5 mmol) of 
5-nonanol in 100 ml of absolute tetrahydrofuran, the mixture is stirred 
for 10 minutes and then, at 0.degree. C., a solution of 2.08 g (5 mmol) of 
2-[N-(1S-ethoxycarbonyl-3-phenylpropyl)-S-alanyl](1S,3S,5S)-2-azabicyclo[3 
.3.0]octane-3-carboxyic acid (ramipril) in 25 ml of absolute 
tetrahydrofuran is added, and the mixture is stirred at 0.degree. C. for 
one hour and at room temperature overnight. The reaction solution is 
concentrated, the residue is taken up in ethyl acetate, the solution is 
washed twice with 2 N sodium hydroxide solution and once with water, 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 
product obtained in this way (1.74 g, 64%) is converted into the hydrogen 
maleate in analogy to Example 10. 
Yield: 1.6 g (49%); melting point 103.degree.-105.degree. C. 
Example 15 
Benzhydryl 2-[N-(1S-menthyloxycarbonyl-3-phenylpropyl)-S-alanyl]-(1S 3S 
5S)-2-azabicyclo[3.3.0]octane-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 g of nickel 
peroxide hydrate in 12 ml of ether, the mixture is stirred for one hour 
and the violet 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, while cooling in ice, added 
dropwise to a solution of 1.31 g (2.5 mmol) of 2-[N-(1S 
-menthyloxycarbonyl-3-phenylpropyl)-S-alanyl]-(1S,3S,5S)2-azabicyclo[3.3.0 
]octane-3-carboxylic acid (see Example 45) in 32 ml of absolute acetone. 
The mixture is then 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 and cyclohexane/ethyl 
acetate 8:2). 
Yield: 1.63 g (95%) of oily product; 
[.alpha.].sub.D.sup.25 =-57.9.degree. (c=1, methanol). 
Example 16 
n-Octyl 
2-[N-(3-cyclohexyl-1S-ethoxycarbonylpropyl)-S-alanyl]-(1S,3S,5S)-2-azabicy 
clo[3.3.0]octane-3-carboxylate 
1.8 g (6.7 mmol) of the octyl ester from Example 6d), 1.92 g (6.7 mmol) of 
N-(3-cyclohexyl-1S-ethoxycarbonylpropyl) -S-alanine and 4.6 ml of absolute 
triethylamine are dissolved in 30 ml of absolute dimethylformamide, cooled 
to -5.degree. C. and 6.7 ml of a 50% strength solution of 
propanephosphonic 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 acetate, the 
combined organic phases are washed with water, 10% strength citric acid 
solution, saturated sodium carbonate solution and saturated sodium 
chloride solution, dried and concentrated, and the crude product (3.1 g) 
is purified by flash chromatograpy on 120 g of silica gel (mobile phase 
toluene/ethanol 199:1). 
Yield: 2.48 g (69%) of colorless oil, 
[.alpha.].sub.D.sup.25 =-26.4.degree. (c=1, methanol). 
Example 17 
Benzyl 
2-[N-(1S-ethoxycarbonyl-n-tridecyl)-S-phenylalanyl]-(1S,3S,5S)-2-azabicycl 
o[3.3.0]octane-3-carboxylate 
3.5 ml (25 mmol) of absolute triethylamine and 5.0 ml of a 50% 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-tridecyl) -S-phenylalanine and 1.4 g (5 mmol) of 
benzyl (1S,3S,5S)-2-azabicyclo[3.3.0]octane-3-carboxylate in 80 ml of 
absolute dimethylformamide, and the reaction solution is stirred at room 
temperature overnight. It is then poured into water and extracted several 
times with ethyl acetate, the combined extracts are washed with water, 10% 
citric acid solution, saturated sodium bicarbonate 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 (85%) of oily product 
[.alpha.].sub.D.sup.20 =-8.0.degree. (c=0.97, ethanol). 
Example 18 
Benzyl 
2-[N-(1S-n-octyloxycarbonyl-3-phenylpropyl)-S-alanyl]-(1S,3S,5S)-2-azabicy 
clo[3.3.0]octane-3-carboxylate 
6 0 ml (43.4 mmol) of absolute triethylamine and 9.2 g of n-octyl 
4-phenyl-2R-(trifluoromethanesulfonyloxy)butyrate, dissolved in 20 ml of 
absolute methylene chloride, are successively added dropwise at 0.degree. 
C. to a solution of 9.3 g (21.7 mmol) of the trifluoroacetate from Example 
3b) in 100 ml of absolute methylene chloride. The mixture is allowed to 
reach room temperature, then stirred for 2.5 hours, extracted three times 
with water, dried and concentrated, and the crude product (11.4 g) is 
purified by flash chromatography on 450 g of silica gel (mobile phase 
cyclohexane/ethyl acetate 9:1, 8:2, 7:3). 
Yield: 6.95 g (54%) of oily product. 
[.alpha.].sub.D.sup.25 =-35.1.degree. (c=1, methanol). 
Example 19 
tert.Butylammonium 2-[N-(1S-n-octyloxycarbonyl-3-phenylpropyl) 
-S-alanyl]-(1S,3S,5S)-2-azbicyclo[3.3.0]octane-3carboxylate 
5.45 g (9.2 mmol) of the benzyl ester from Example 18 in 300 ml of ethanol 
are hydrogenated on 1 g of palladium/ charcoal (10%) at room temperature 
for 20 minutes. Removal of the catalyst by filtration with suction and 
concentration result in 4.1 g (89%) of 2-[N-(1S-n-octyloxycarbonyl 
-3-phenylpropyl)-S-alanyl]-(1S,3S,5S)-2azabicyclo[3.3.0]octane-3-carboxyli 
c acid. 
190 mg of tert.butylamine 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 (86%) of colorless crystals. 
melting point 141.degree.-143.degree. C. 
Example 20 
n-Octyl 
2-[N-(1S-carboxy-3-phenylpropyl)-S-alanyl](1S,3S,5S)-2-azabicyclo[3.3.0]oc 
tane-3-carboxylate 
2.65 g (5 mmol) of the ethyl ester from Example 9 are dissolved in 18 ml of 
tetrahydrofuran, 7.5 ml of 1 N sodium hydroxide solution are added, and 
the mixture is stirred at room temperature for 48 h. It is neutralized by 
addition of 7.5 ml of 1 N hydrochloric acid. The reaction mixture is 
concentrated, the residue is suspended in water and extracted twice with 
ethyl acetate, and the combined organic phases are washed with saturated 
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; 46%) is 
triturated in 50 ml of petroleum ether, placed in the cold, filtered off 
with suction and dried. 
Yield: 0.83 g of colorless crystals; melting point 56.degree.-61.degree. C. 
The following compounds according to the invention are also obtained by 
using suitable starting materials and employing the processes described in 
Examples 9-20: 
Example 21 
n-Octyl 
2-[N-(1S-ethoxycarbonyl-n-heptyl)-S-alanyl](1S,3S,5S)-2-azabicyclo[3.3.0]o 
ctane-3-carboxylate 
Example 22 
n-Decyl 
2-[N-(1S-ethoxycarbonyl-3-phenylpropyl)-S-alanyl]-(1S,3S,5S)-2-azabicyclo[ 
3.3.0]octane-3carboxylate; [.alpha.].sub.D.sup.25 =-25.8.degree. (c=1, 
methanol) 
Example 23 
n-Tetradecyl 
2-[N-(1S-ethoxycarbonyl-3-phenylpropyl)-S-alanyl]-(1S,3S,5S)-2-azabicyclo[ 
3.3.0]octane-3carboxylate; [.alpha.].sub.D.sup.25 =-19.8.degree. (c=1, 
methanol). 
2-Octynyl 
2-[N-(1S-ethoxycarbonyl-3-phenylpropyl)-S-alanyl]-(1S,3S,5S)-2-azabicyclo[ 
3.3.0]octane-3carboxylate hydrogen maleate; melting point 
70.degree.-72.degree. C. 
Example 25 
n-Octyl 
2-[N-(1S-isobutyloxycarbonyl-3-phenylpropyl)-S-alanyl]-(1S,3S,5S)-2-azabic 
yclo[3.3.0]octane-3carboxylate; [.alpha.].sub.D.sup.25 =-23.7.degree. (c=1, 
methanol). 
Example 26 
n-Octyl 
2-[N-(1S-n-octyloxyycarbonyl-3-phenylpropyl)-S-alanyl]-(1S,3S,5S)-2-azabic 
yclo[3.3.0]octane-3carboxylate; [.alpha.].sub.D.sup.25 =-18.6.degree. (c=1, 
methanol). 
Example 27 
n-Octyl 2-[N-(1S-n-octadecyloxycarbonyl-3-phenylpropyl) 
-S-alanyl]-(1S,3S,5S)-2-azabicyclo[3.3.0]octane-3carboxylate; 
[.alpha.].sub.D.sup.25 =-15.2.degree. (c=1, methanol). 
Example 28 
n-Octyl 
1'-[N-(1S-ethoxycarbonyl-3-phenylpropyl)-S-alanyl]-spiro[bicyclo[2.2.2]oct 
ane-2,3'-pyrrolidine]-5'S-carboxylate; 
Example 29 
n-Nonyl 
1'-[N-(1S-ethoxycarbonyl-3-phenylpropyl)-S-alanyl]-spiro[bicyclo[2.2.2]oct 
ane-2,3'-pyrrolidine]-5'-S-carboxylate hydrogen maleate; melting point 
110.degree. C. 
Example 30 
n-Decyl 
1'-[N-(1S-ethoxycarbonyl-3-phenylpropyl)-S-alanyl]-spiro[bicyclo[2.2.2]oct 
ane-2,3'-pyrrolidine]-5'S-carboxylate hydrogen maleate; melting point 
96.degree. C. 
Example 31 
n-Octyl 
2-[N-(1S-ethoxycarbonyl-3-phenylpropyl)-S-alanyl]-(1R,3R,5R)-2-azabicyclo[ 
3.3.0]octane-3-carboxylate; [.alpha.].sub.D.sup.25 =-7.0.degree. (c=1, 
methanol). 
Example 32 
n-Octyl 
2-[N-(1S-ethoxycarbonyl-3-phenylpropyl)-R-alanyl]-(1S,3S,5S)-2-azabicyclo[ 
3.3.0]octane-3carboxylate; [.alpha.].sub.D.sup.25 =+18.0.degree. (c=1, 
methanol). 
Example 33 
n-Octyl 
2-[N-(1R-ethoxycarbonyl-3-phenylpropyl)-R-alanyl]-(1S,3S,5S)-2-azabicyclo[ 
3.3.0]octane-3-carboxylate; [.alpha.].sub.D.sup.25 =+9.4.degree. (c=1, 
methanol). 
Example 34 
n-Octyl 
2-[N-(1S-ethoxycarbony13-phenylpropyl)-S-alanyl]-(1S,3S,5S)-2-azabicyclo[3 
.3.0]-7-octene-3carboxylate; [.alpha.].sub.D.sup.25 =+21.2.degree. (c=1, 
methanol). 
Example 35 
n-Octyl 
2-[N-(1S-ethoxycarbonyl-3-phenylpropyl)-S-alanyl]-(1R,3R,5R)-2-azabicyclo[ 
3.3.0]-7-octene-3-carboxylate; [.alpha.].sub.D.sup.25 =-51.4.degree. (c=1, 
methanol). 
Example 36 
N-[N'-(1S-Ethoxycarbonyl-3-phenylpropyl)-S-alanyl]-S-proline n-octyl ester 
hydrogen maleate; melting point 105.degree.-107.degree. C. 
Example 37 
2-[N-(1S-Ethoxycarbonyl-n-tridecyl)-S-phenylalanyl] 
-(1S,3S,5S)-2-azabicyclo[3.3.0]octane-3-carboxylic acid; 
[.alpha.].sub.D.sup.20 =+27.2.degree. (c=1, methanol). 
Example 38 
Benzyl 
2-[N-(1S-Ethoxycarbonyl-n-tridecyl)-S-alanyl](1S,3S,5S)-2-azabicyclo[3.3.0 
]octane-3-carboxylate; 
Example 39 
Benzyl 
2-[N-(1R-Ethoxycarbonyl-n-tridecyl)-S-alanyl](1S,3S,5S)-2-azabicyclo[3.3.0 
]octane-3-carboxylate; 
Example 40 
Benzyl 
2-[N-(1S-Octadecyloxycarbonyl-3-phenylpropyl)-S-alanyl]-(1S,3S,5S)-2-azabi 
cyclo[3.3.0]octane-3carboxylate; [.alpha.].sub.D.sup.25 =-28.6.degree. 
(c=1, methanol) 
Example 41 
Benzyl 
2-[N-(1S-Menthyloxycarbonyl-3-phenylpropyl)-S-alanyl]-(1S,3S,5S)-2-azabicy 
clo[3.3.0]octane-3-carboxylate; [.alpha.].sub.D.sup.25 =-63.2.degree. (c=1, 
methanol) 
Example 42 
3,3-Diphenylnpropyl 2-[N-(1S-ethoxycarbonyl-3-phenylpropyl) 
-S-alanyl]-(1S,3S,5S)-2-azabicyclo[3.3.0]-octane3-carboxylate hydrogen 
maleate; melting point 122.degree.-124.degree. C. 
Example 43 
5-Nonyl 
1'-[N-(1S-ethoxycarbonyl-3-phenylpropyl)-S-alanyl]-spiro[bicyclo[2.2.2]oct 
ane-2,3'-pyrrolidine)-5'S-carboxylate hydrogen maleate, melting point 
121.degree. C. 
Example 44 
tert.Butylammonium 2-[N-(1S-octadecyloxycarbonyl-3-phenylpropyl) 
-S-alanyl]-(1S,3S,5S)-2-azabicyclo[3.3.0]-octane-3-carboxylate; melting 
point 133.degree.-135.degree. C. 
Example 45 
tert.Butylammonium 2-[N-(1S-menthyloxycarbonyl-3-phenylpropyl) 
-S-alanyl]-(1S,3S,5S)-2-azabicyclo[3.3.0]-octane-3-carboxylate; melting 
point 164.degree.-167.degree. C. 
Example 46 
n-Octyl 
2-[N-(1R-ethoxycarbonyl-3-phenylpropyl)-S-alanyl]-(1S,3S,5S)-2-azabicyclo[ 
3.3.0]octane-3carboxylate; [.alpha.].sub.D.sup.25 =-30.8.degree. (c=1, 
methanol). 
Example 47 
n-Octyl 
2-[N-(1R-ethoxycarbonyl-3-phenylpropyl)-R-alanyl]-(1R,3R,5R)-2-azabicyclo[ 
3.3.0]octane-3carboxylate hydrogen maleate; melting point 
89.degree.-91.degree. C. 
Example 48 
n-Octyl 
2-[N-(1S-methoxycarbonyl-3-phenylpropyl)-S-alanyl]-(1S,3S,5S)-2-azabicyclo 
[3.3.0]octane-3-carboxylate; [.alpha.].sub.D.sup.25, =-18.0 (c=1, 
methanol). 
Example 49 
n-Octyl 
2-[N-(1S-benzyloxycarbonyl-3-phenylpropyl)-S-alanyl]-(1S,3S,5S)-2-azabicyc 
lo[3.3.0]octane-3carboxylate; [.alpha.].sub.D.sup.25, =-34.3.degree. (c=1, 
methanol). 
Example 50 
n-Decyl 
2-[N-(1S-carboxy-3-phenylpropyl)-S-alanyl]-(1S,3S,5S)-2-azabicyclo[3.3.0]o 
ctane-3-carboxylate, melting point 52.degree. .