Spirocyclic aminoacid derivatives, processes for their preparation, agents containing them and their use and new spirocyclic aminoacids as intermediates and processes for their preparation

The invention relates to new spirocyclic aminoacid derivatives of the formula I ##STR1## in which m denotes 1 or 2, n denotes 0 or 1, R denotes hydrogen, alkyl or aralkyl, R.sup.1 denotes hydrogen or alkyl which can be optionally substituted by amino, acylamino or benzoylamino, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl or partially hydrogenated aryl, each of which can be substituted by alkyl, alkoxy or halogen, arylalkyl or aroylalkyl, both of which can be substituted as defined above in the aryl radical, an S- or O- and/or N-heterocyclic radical or a side chain of an .alpha.-aminoacid, R.sup.2 denotes hydrogen, alkyl, alkenyl or aralkyl, Y denotes hydrogen or hydroxyl, Z denotes hydrogen, or Y and Z together denote oxygen and X denotes alkyl, alkenyl, cycloalkyl, aryl, which can be monosubstituted, disubstituted or trisubstituted by alkyl, alkoxy, hydroxyl, halogen, nitro, amino, alkylamino, dialkylamino and/or methylenedioxy, or 3-indolyl, processes for their preparation, agents containing them and their use and new spirocyclic aminoacids as intermediates and a process for their preparation.

The invention relates to new spirocyclic amino-acid derivatives of the 
formula I 
##STR2## 
in which m denotes 1 or 2, 
n denotes 0 or 1, 
R denotes hydrogen, (C.sub.1 to C.sub.6)-alkyl or aralkyl having 7 to 9 
carbon atoms, 
R.sup.1 denotes hydrogen or (C.sub.1 to C.sub.6)-alkyl which can optionally 
be substituted by amino, (C.sub.1 to C.sub.6)-acylamino, in particular 
(C.sub.1 to C.sub.6)-alkanoylamino or BOC-NH, or benzoylamino, (C.sub.2 to 
C.sub.6)-alkenyl, (C.sub.5 to C.sub.9)-cycloalkyl, (C.sub.5 to 
C.sub.9)-cycloalkenyl, (C.sub.5 to C.sub.7)-cycloalkyl-(C.sub.1 to 
C.sub.4)-alkyl, (C.sub.6 to C.sub.12)-aryl or partially hydrogenated 
(C.sub.6 to C.sub.12)-aryl, each of which can be substituted by (C.sub.1 
to C.sub.4)-alkyl, (C.sub.1 or C.sub.2)-alkoxy or halogen, (C.sub.6 to 
C.sub.12)-aryl-(C.sub.1 to C.sub.4)-alkyl or (C.sub.7 to 
C.sub.13)-aroyl-(C.sub.1 to C.sub.2)-alkyl, both of which can be 
substituted in the aryl radical as defined above, a monocyclic or bicyclic 
heterocyclic radical having 5 to 7 or 8 to 10 ring atoms respectively, 1 
to 2 ring atoms representing sulfur of oxygen atoms and/or 1 to 4 ring 
atoms representing nitrogen atoms, or an optionally protected side chain 
of a naturally occurring .alpha.-aminoacid, 
R.sup.2 denotes hydrogen, (C.sub.1 to C.sub.6)-alkyl, (C.sub.2 to 
C.sub.6)-alkenyl or (C.sub.6 to C.sub.12)-aryl-(C.sub.1 to C.sub.4)-alkyl, 
Y denotes hydrogen or hydroxyl, 
Z denotes hydrogen or 
Y and Z together denote oxygen and 
X denotes (C.sub.1 to C.sub.6)-alkyl, (C.sub.2 to C.sub.6)-alkenyl, 
(C.sub.5 to C.sub.9)-cycloalkyl, (C.sub.6 to C.sub.12)-aryl which can be 
monosubstituted, disubstituted or trisubstituted by (C.sub.1 to 
C.sub.4)-alkyl, (C.sub.1 to C.sub.4)-alkoxy, hydroxyl, halogen, nitro, 
amino, (C.sub.1 to C.sub.4)-alkylamino, di-(C.sub.1 -C.sub.4)-alkylamino 
and/or methylenedioxy, or 3-indolyl, and their physiologically acceptable 
salts. 
When R.sup.1 represents a protected side chain of a naturally occurring 
.alpha.-aminoacid, such as, for example, protected Ser, Thr, Asp, Asn, 
Glu, Gln, Arg, Lys, Hyl, Cys, Orn, Cit, Tyr, Trp, His or Hyp, the 
preferred protective groups are the groups customary in peptide chemistry 
(compare Houben-Weyl, Vol. XV/1 and XV/2). In the case where R.sup.1 
denotes the protected side chain of lysine, the known amino protective 
groups, but particularly (C.sub.1 -C.sub.6)-alkanoyl, are preferred. In 
the case where R.sup.1 denotes the protected side chain of tyrosine, the 
ether protective group on the oxygen, especially (C.sub.1 -C.sub.6)-alkyl, 
is preferred; particularly preferred protective groups are methyl and 
ethyl. 
Particularly suitable salts are alkali metal and alkaline earth metal 
salts, salts with physiologically tolerated amines and salts with 
inorganic or organic acids, such as, for example, HCl, HBr, H.sub.2 
SO.sub.4, maleic acid and fumaric acid. 
In this context and in the following text, aryl is preferably understood to 
be optionally substituted phenyl or naphthyl. Aroyl is especially 
understood to be benzoyl. Alkyl can be straight-chain or branched. 
A monocyclic or bicyclic heterocyclic radical having 5 to 7 or 8 to 10 ring 
atoms respectively, 1 to 2 ring atoms representing sulfur or oxygen atoms 
and/or 1 to 4 ring atoms representing nitrogen atoms, is understood to be, 
for example, thienyl, benzo[b]thienyl, furyl, pyranyl, benzofuryl, 
pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, 
indazolyl, isoindolyl, indolyl, purinyl, quinolizinyl, isoquinolinyl, 
phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolyl, cinnolinyl, 
pteridinyl, oxazolyl, isoxazolyl, thiazolyl or isothiazolyl. These 
radicals can also be partially or completely hydrogenated. 
Compounds of the formula I have chiral carbon atoms. The invention relates 
to both the R and the S configurations at all centers of asymmetry. Thus 
the compounds of the formula I can exist as optical isomers, as 
diastereomers, as racemates or as mixtures of these. However, compounds of 
the formula I in which the carbon atoms labeled with an asterisk (*) have 
the S configuration are preferred. However, when (--CO--CHR.sup.1 --NH--) 
is Cys, the R configuration at this center is preferred. 
Particularly preferred compounds of the formula I are those in which 
m denotes 1 or 2, 
n denotes 1, 
R denotes hydrogen or alkyl having 1 to 4 carbon atoms, 
R.sub.1 denotes hydrogen, (C.sub.1 to C.sub.3)-alkyl, (C.sub.2 or 
C.sub.3)-alkenyl, benzyl, 4-methoxybenzyl, 4-ethoxybenzyl, phenethyl, 
4-aminobutyl or benzoylmethyl, 
R.sub.2 denotes hydrogen, (C.sub.1 to C.sub.4)-alkyl or benzyl and 
X denotes cyclohexyl or phenyl which can be monosubstituted or 
disubstituted, or in the case of methoxy, trisubstituted, by (C.sub.1 or 
C.sub.2)-alkyl, (C.sub.1 or C.sub.2)-alkoxy, hydroxyl, fluorine, chlorine, 
bromine, amino, (C.sub.1 to C.sub.4)-alkylamino, di-(C.sub.1 to 
C.sub.4)-alkylamino, nitro and/or methylenedioxy, 
especially those compounds of the formula I in which m denotes 1 or 2, n 
denotes 1, R denotes hydrogen, R.sup.1 denotes methyl, 4-methoxybenzyl or 
4-ethoxybenzyl, R.sup.2 denotes hydrogen or ethyl, and the chiral carbon 
atoms which are identified with an asterisk (*) have the S configuration. 
The --COOR group in the tricyclic aminoacid radical can be located exo or 
endo with respect to the bicyclic radical; thus the preferred compounds of 
the invention contain one of the two partial structures of the formulae Ia 
and Ib 
##STR3## 
and their mirror images. 
The invention also relates to processes for the preparation of compounds of 
the formula I. One process variant comprises reacting, by methods of amide 
formation known in peptide chemistry, a compound of the formula II 
##STR4## 
in which n, R.sup.1, R.sup.2, X, Y and Z have the same meaning as in 
formula I, with a compound of the formula III 
##STR5## 
in which W denotes hydrogen or a radical which can be split off with acid 
or by hydrogenolysis, especially a tert.-butyl radical or a benzyl 
radical, and, where appropriate, subsequently splitting off, by acid 
treatment or hydrogenation, the radical W and, where appropriate, by 
additional acid or base treatment also splitting off the radical R.sup.2, 
the free carboxylic acids being obtained in each case. 
Further synthetic processes for the preparation of the compounds of the 
formula I in which Y and Z together denote oxygen comprise reacting, in a 
known manner in a Michael reaction (Organikum, 6th edition, page 492, 
1967), a compound of the formula IV 
##STR6## 
in which m and R.sup.1 have the same meaning as in formula I and W has the 
same meaning as in formula III, with a compound of the formula V 
EQU R.sup.2 O.sub.2 C--CH.dbd.CH--CO--X (V) 
in which R.sup.2 and X have the same meanings as in formula I, and, where 
appropriate, splitting off the radical W and/or the radical R.sup.2, as 
described above, or comprise reacting, in a known manner in a Mannich 
reaction (Bull. Soc. Chim. France 1973, page 625), a compound of the 
abovementioned formula IV with a compound of the general formula VI, in 
which R.sup.2 has the same meaning as in formula I, and with a compound of 
the general formula VII 
EQU OHC--CO.sub.2 R.sup.2 (VI) 
EQU X--CO--CH.sub.3 (VII) 
in which X has the same meaning as in formula I, and then, where 
appropriate, splitting off the radical W and/or the radical R.sup.2 as 
described above, with the formation of the free carboxyl groups. 
Furthermore, compounds of the formula I with Y and Z each being hydrogen 
can also be prepared in a manner such that a compound of the 
abovementioned formula IV is reacted in accordance with the procedure 
described in J. Amer. Chem. Soc. 93, 2897 (1971) with a compound of the 
formula VIII 
##STR7## 
in which R.sup.2 and X have the same meanings as in formula I, the 
resulting Schiff's bases are reduced and then, where appropriate, the 
radical W and/or the radical R.sup.2 are split off as described above, 
with the formation of the free carboxyl groups. The reduction of the 
Schiff's bases can be carried out electrolytically or with reducing 
agents, such as, for example, sodium borohydride or sodium 
cyanoborohydride. 
Compounds of the formula I with Y being hydroxyl and Z being hydrogen can 
also be obtained, for example, by reduction of a compound I, with Y and Z 
together being oxygen, obtained in accordance with the above procedures. 
This reduction can be carried out with a reducing agent, such as sodium 
borohydride and other complex boranates or, for example, borane-amine 
complexes. 
Compounds of the formula I in which R represents hydrogen can, where 
appropriate, be converted by methods which are known per se into their 
esters of the formula I in which R denotes (C.sub.1 to C.sub.6)-alkyl or 
(C.sub.7 to C.sub.9)-aralkyl. 
The invention also relates to compounds of the formula III 
##STR8## 
in which m denotes 1 or 2 and W denotes hydrogen or a radical which can be 
split off with acid or by hydrogenolysis, such as tert.-butyl or benzyl. 
These compounds are used in accordance with the invention as starting 
materials for the synthesis of compounds of the formula I and can be 
prepared according to the invention by hydrolyzing a compound of the 
formula XIV 
##STR9## 
with a mineral acid, such as hydrochloric acid or hydrobromic acid, or 
with a strong base, such as an alkali metal hydroxide, at 20.degree. C. to 
150.degree. C., particularly at 60.degree. to 120.degree. C., preferably 
in water as the solvent, and esterifying the resulting aminoacids 
(III/W=hydrogen), where appropriate, by customary methods of aminoacid 
chemistry. The aminoacids (III/W=hydrogen) or the resulting esters 
(III/W.noteq.hydrogen) can be separated, for example by chromatography or 
fractional crystallization of suitable salts, into stereoisomers. 
The tricyclic nitriles of the formula XIV can be prepared according to the 
invention by reacting a bicyclic nitrile of the formula (IX) 
##STR10## 
in which m is 1 or 2, in the presence of a strong base, such as an alkali 
metal amide, preferably lithium diisopropylamide, lithium diethylamide or 
lithium hexamethyldisilazide, with a compound of the formula (X) 
##STR11## 
in which X denotes halogen, particularly chlorine, bromine or iodine, and 
R.sup.3 denotes identical or different (C.sub.1 to C.sub.4)-alkyl groups, 
or both radicals R.sup.3 together form an ethylene or propylene bridge, in 
an aprotic solvent, such as tetrahydrofuran, at -100.degree. C. to 
+50.degree. C., preferably -80.degree. C. to 0.degree. C., to give a 
compound of the formula (XI) 
##STR12## 
in which m and R.sup.3 have the above meanings, reducing the latter with a 
suitable reducing agent, such as, for example, lithium aluminum hydride in 
an aprotic solvent, preferably diethyl ether or tetrahydrofuran at 
0.degree. C. to 80.degree. C., preferably at 20.degree. C. to 60.degree. 
C., or in an alcoholic solvent, preferably ethanol or n-butanol at 
0.degree. C. to 120.degree. C., preferably at 20.degree. C. to 80.degree. 
C., or by catalytic hydrogenation in an alcoholic solvent with the 
addition of ammonia at 0.degree. C. to 80.degree. C., preferably 
20.degree. C. to 50.degree. C., in the presence of a noble metal or Ni 
catalyst, preferably Raney nickel or rhodium on aluminum oxide, to give a 
compound of the formula (XII) 
##STR13## 
in which m and R.sup.3 have the above meanings, cyclizing the latter by 
treatment with a mineral acid, preferably hydrochloric acid, in water at 
20.degree. C. to 140.degree. C., preferably 40.degree. C. to 100.degree. 
C., to give a compound of the formula (XIII) 
##STR14## 
in which m is 1 or 2, and which is produced as a mixture with its trimer, 
and converting this compound by reaction with an alkali metal cyanide, 
preferably sodium or potassium cyanide, in water, with the addition of a 
mineral acid, preferably hydrochloric acid or sulfuric acid, at 0.degree. 
C. to 60.degree. C., preferably at 10.degree. C. to 40.degree. C., into 
the nitrile of the formula (XIV). 
The nitriles of the formula IX are known. 
The compounds of the formula II with n=1, Y and Z=hydrogen, R.sup.1 =methyl 
and R.sup.2 =methyl or ethyl and X=phenyl which are used as starting 
materials for the preparation of the compounds of the formula I are known 
(European Patent Application No. 37,231). The compounds of the formula II 
can be prepared by a variety of procedures. One synthesis variant starts 
from a ketone of the abovementioned formula VII, which is reacted, by 
known procedures in a Mannich reaction, with a compound of the 
abovementioned formula VI, together with aminoacid esters of the formula 
XV 
##STR15## 
in which R.sup.1 has the abovementioned meaning and W' denotes a radical 
which can be split off by hydrogenolysis or with acid, in particular a 
benzyl or a tert.-butyl radical, to give a compound of the formula XVI, in 
which R.sup.1, R.sup.2, X and W' have the abovementioned meanings, with 
the proviso that, when W' denotes a radical which can be split off by 
hydrogenolysis, in particular benzyl, R.sup.2 must not have the meaning of 
W'. If the radical W' is split off by hydrogenolysis with the aid of, for 
example, palladium, when 3 mole equivalents of hydrogen have been taken 
up, compounds of the formula II with X and Z=hydrogen are obtained. If the 
uptake of hydrogen is stopped at 1 mole equivalent, compounds of the 
formula II with n=1 and Y and Z together=oxygen are obtained, and these 
are also obtained if the radical W' in formula XVI is split off with 
acids, such as, for example, trifluoroacetic acid or hydrochloric acid, in 
an inert organic solvent, such as, for example, dioxane. 
Compounds of the formula XVI are also accessible by known procedures by 
Michael addition reactions of a compound of the abovementioned formula V 
with a compound of the abovementioned formula XV. This process is suitable 
preferably for the preparation of those compounds of the formula XVI in 
which R.sup.1 denotes methyl, R.sup.2 denotes ethyl and X denotes aryl. 
The compounds of the formula XVI are produced as mixtures of diastereomers. 
Preferred diastereomers of the formula XVI are those in which the chiral 
carbon atoms marked with an asterisk each have the S configuration. These 
can, for example, be resolved by crystallization or by chromtography, for 
example on silica gel. The configurations of the chiral carbon atoms are 
maintained when the radical W' is subsequently split off. 
The compounds of the abovementioned formula IV used as starting materials 
for the preparation of the compounds of the formula I are obtained from 
the compounds of the abovementioned formula III by reaction, by knownw 
procedures, with a N-protected 2-aminocarboxylic acid of the formula XVII 
##STR16## 
in which V is a protective group and R.sup.1 has the abovementioned 
meaning. An example of a suitable protective group V, which is split off 
again after reaction is complete, is tert.-butoxycarbonyl. 
The reaction of a compound of the formula II with a compound of the formula 
III for the preparation of a compound of the formula I is effected in 
accordance with a condensation reaction known in peptide chemistry, 
dicyclohexylcarbodiimide and 1-hydroxybenzotriazole, for example, being 
added as the condensing agent. Trifluoroacetic acid or hydrogen chloride 
are preferably employed as the acids when the radical W is subsequently 
split off by acids. 
The compounds of the formula III obtained in accordance with the procedure 
described above are produced as a mixture and can be separated from one 
another, for example, by recrystallization or by chromatography. 
The compounds of the formula III are obtained as racemic mixtures and can 
be employed as such in the synthesis described above. However, they can 
also be employed as the pure enantiomers after separating the racemates 
into the optical antipodes by customary methods, for example via salt 
formation with optically active bases or acids. 
If the compounds of the formula I are obtained as racemates, these can also 
be resolved into their enantiomers by the customary methods, such as, for 
example, via salt formation with optically active bases or acids, or are 
separated by chromatography. 
When R is hydrogen, the compounds of the formula I according to the 
invention exist as internal salts. Since they are amphoteric compounds, 
they can form salts with acids or bases. These salts are prepared in a 
customary manner by reaction with one equivalent of acid or base. 
The compounds of the formula I and their salts have a long-lasting and 
powerful hypotensive effect. They are strong inhibitors of the angiotensin 
converting enzyme (ACE inhibitors). They can be employed for the control 
of high blood pressure of various etiologies. It is also possible to 
combine them with other compounds having hypotensive, vasodilator or 
diuretic activity. Typical representatives of these classes of active 
compounds are described, for example, in Erhardt-Ruschig, Arzneimittel 
("Drugs") 2nd edition, Weimheim, 1972. They can be administered 
intravenously, subcutaneously or orally. 
The dosage on oral administration is 0.01-7 mg/kg/day, in particular 
0.07-0.5 mg/kg/day. This can also be increased in severe cases, since no 
toxic properties have hitherto been observed. It is also possible to 
decrease the dose and this is particularly appropriate when diuretics are 
administered concurrently. 
The compounds according to the invention can be administered orally or 
parenterally in appropriate pharmaceutical formulations. For a form for 
oral use, the active compounds are mixed with the additives customary for 
this purpose, such as vehicles, stabilizers or inert diluents, and 
converted by conventional methods into suitable forms for administration, 
such as tablets, coated tablets, hard capsules, aqueous, alcoholic or oily 
suspensions or aqueous, alcoholic or oily solutions. Examples of inert 
vehicles which can be used are gum arabic, magnesium carbonate, potassium 
phosphate, lactose, glucose or starch, especially corn starch. In this 
context, the formulation can be as either dry or moist granules. Examples 
of suitable oily vehicles or solvents are vegetable and animal oils, such 
as sunflower oil and codliver oil. 
For subcutaneous or intravenous administration, the active compounds or 
their physiologically tolerated salts 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 for the new active compounds and the corresponding 
physiologically tolerated salts are: water, physiological sodium chloride 
solutions or alcohols, for example ethanol, propanediol or glycerol, but 
also sugar solutions, such as glucose or mannitol solutions, as well as a 
mixture of the various solvents mentioned. 
The extremely strong effect of the compounds according to formula I is 
demonstrated by the pharmacological data in the table below: Intraduodenal 
administration to the anesthetized rat, 50% inhibition of the pressor 
reaction induced by 310 ng of angiotensin I 30 min after administration at 
the dose . . . -ED.sub.50 : 
TABLE 
______________________________________ 
(The compounds listed have the S configuration at the 
carbon atoms indicated by an asterisk): 
Configuration 
of the COOR 
ED 
m n X Y Z R.sup.1 
R.sup.2 
R group (.mu.g/kg) 
______________________________________ 
2 1 C.sub.6 H.sub.5 
H H CH.sub.3 
C.sub.2 H.sub.5 
H exo 50 
2 1 C.sub.6 H.sub.5 
H H CH.sub.3 
C.sub.2 H.sub.5 
H endo 500 
2 1 C.sub.6 H.sub.5 
H H CH.sub.3 
H H exo 200 
2 1 C.sub.6 H.sub.5 
H H CH.sub.3 
H H endo 850 
2 1 C.sub.6 H.sub.5 
O CH.sub.3 
C.sub.2 H.sub.5 
H exo 80 
2 1 C.sub.6 H.sub.5 
O CH.sub.3 
C.sub.2 H.sub.5 
H endo 650 
1 1 C.sub.6 H.sub.5 
H H CH.sub.3 
C.sub.2 H.sub.5 
H exo/endo 80 
1 1 C.sub.6 H.sub.5 
H H CH.sub.3 
H H exo/endo 240 
1 1 C.sub.6 H.sub.5 
O CH.sub.3 
C.sub.2 H.sub.5 
H exo/endo 140 
______________________________________ 
The symbols n, m, X, Y, Z, R, R.sup.1 and R.sup.2 relate to the compounds 
of the formula I. 
The examples which follow serve to illustrate the invention without 
restricting it to the compounds which are mentioned as representative.

EXAMPLE 1 
5'-Cyanospiro[bicyclo[2.2.2]octane-2,3'-pyrrolidine] 
(a) 2-Cyano-2-(1,3-dioxolan-2-yl)methylbicyclo[2.2.2]octane 
84 ml of diisopropylamine are dissolved in 300 ml of absolute 
tetrahydrofuran. 39.9 ml of n-butyllithium (1.5 molar in hexane) are added 
at -20.degree. C. under dry argon. After 30 minutes at room temperature, 
the mixture is cooled down to -78.degree. C. and 8.1 g of 
2-cyanobicyclo[2.2.2]octane in 30 ml of absolute tetrahydrofuran are 
stirred in, and, after 30 minutes at 0.degree. C., the mixture is again 
cooled down to -78.degree. C. and 10 g of 2-bromomethyl-1,3-dioxolane in 
30 ml of tetrahydrofuran are added dropwise. The mixture is stirred for a 
further 45 minutes at -78.degree. C., warmed up to room temperature and 
evaporated, and the residue is taken up in 2N acetic acid and ether, 
washed three times with water and dried over sodium sulfate and the 
solvent is removed. The crude product is chromatographed on silica gel 
with ethyl acetate/cyclohexane (1:6) as the mobile phase. 7.9 g of the 
title compound are obtained as a colorless oil. 
.sup.1 H-NMR data (CDCl.sub.3): 5.02+4.95 (2t, J=6 Hz, 1H); 4.1-3.7 (m, 
4H); 1.95 (d, J=6 Hz, 2H); 2.2-1.3 (m, 12H) ppm. 
(b) 2-Aminomethyl-2-(1,3-dioxolan-2-yl)methylbicyclo[2.2.2]octane 
3.7 g of lithium aluminum hydride are suspended in 60 ml of dry ether; 7.4 
g of 2-cyano-2-(1,3-dioxolan-2-yl)methylbicyclo[2.2.2]octane, dissolved in 
80 ml of dry ether, are added dropwise so that gentle boiling is 
maintained. The mixture is then boiled under reflux for 2 hours, then 
cooled in ice and, in sequence, 2.1 ml of water, 2.1 ml of 1N sodium 
hydroxide solution and 15 ml of water are added dropwise. The aluminum 
hydroxide is filtered off with suction and thoroughly washed with ether. 
5.5 g of the title compound are obtained as a colorless oil. 
.sup.1 H-NMR data (CDCl.sub.3): 4.87 (t, J=6 Hz, 1H); 4.0-3.6 (m, 4H); 2.63 
(s, 2H); 2.0-1.0 (m, 14H) ppm. 
(c) Spirobicyclo[2.2.2]octane-2,3'-pyrroline-.DELTA.3' 
5.5 g of 2-aminomethyl-2-(1,3-dioxolan-2-yl)methylbicyclo[2.2.2]octane are 
boiled under reflux with 5N hydrochloric acid for 1.5 hours. After 
extraction with ethyl acetate, the aqueous phase is cooled in ice and 4N 
potassium hydroxide is added, then it is extracted with ether, the extract 
is dried with sodium sulfate and the solvent is removed. 3 g of the title 
compound are obtained as a mixture of the monomer and the trimer 
(s-triazine derivative). 
(d) 5'-Cyanospiro[bicyclo[2.2.2]octane-2,3'-pyrrolidine] 
3 g of spiro[bicyclo[2.2.2]octane-2,3'-pyrroline-.DELTA.3'] are dissolved 
together with 2.25 g of potassium cyanide in 100 ml of water. While 
cooling in ice, 24 ml of 2N hydrochloric acid are added dropwise and the 
mixture is stirred at room temperature for 72 hours. After extraction with 
ethyl acetate, the aqueous phase is made alkaline, with 1N sodium 
hydroxide solution and extracted with ether and the extract is dried over 
sodium sulfate. After evaporation, the crude product is chromatographed on 
silica gel with ethyl acetate/cyclohexane (1:1) as the mobile phase, thus 
separating the endo and exo isomers. 
Endo isomer: 0.83 g, melting point 78.degree.-80.degree. C. 
.sup.1 H-NMR data (CDCl.sub.3): 4.0 (t, J=14 Hz, 1H); 2.8 (s, 2H); 2.4 (s, 
1H); 2.0 (d, 2H); 1.5 (br. s, 12H). 
Exo isomer: 1.5 g, melting point 38.degree.-40.degree. C. 
.sup.1 H-NMR data (CDCl.sub.3): 4.02 (X part of an ABX system, 1H); 2.85 
(AB system, J=15 Hz, 2H); 2.5-1.0 (m, 15H) ppm. 
EXAMPLE 2 
Endo-spiro[bicyclo[2.2.2]octane-2,3'-pyrrolidine]-5'-carboxylic acid 
0.8 g of endo-5'-cyanospiro[bicyclo[2.2.2]octane-2,3'-pyrrolidine] are 
boiled under reflux with 20 ml of 5N hydrochloric acid for 5 hours. After 
evaporation to dryness, the residue is taken up with water, the pH is 
adjusted to 5.7 by the addition of Amberlite.RTM. IRA 93 (OH.sup.- form), 
the latter is filtered off and the solution is evaporated. The residue is 
triturated with methylene chloride/isopropyl ether. 0.9 g of the title 
compound is obtained as colorless crystals of melting point 236.degree. C. 
.sup.1 H-NMR data (D.sub.2 O): 4.2 (X part of a ABX system, 1H); 3.2 (s, 
2H); 3.2 (s, 2H); 2.5-1.5 (AB part of a ABX system, 2H); 1.5 (br. s, 12H) 
ppm. 
Mass spectrum (m/e): 209 (M.sup.+, 0.8%); 165 (13%); 164 (M-COOH, 100%); 87 
(14%), 69 (10%). 
EXAMPLE 3 
Exo-spiro[bicyclo[2.2.2]octane-2,3'-pyrrolidine]-5'-carboxylic acid 
1.5 g of exo-5'-cyanospiro[bicyclo[2.2.2]octane-2,3'-pyrrolidine] are 
reacted with 30 ml of 5N hydrochloric acid by the procedure described in 
Example 2. 1.68 g of the title compound are obtained as colorless crystals 
of melting point 242.degree. C. 
.sup.1 H-NMR data (D.sub.2 O): 4.15 (X part of a ABX system, 1H); 3.2 (AB 
system, J.sub.AB =15 Hz, 2H); 2.5-1.7 (AB part of an ABX system, 2H); 1.5 
(br. s, 12H) ppm. 
Mass spectrum (m/e): 209 (M.sup.+, 0.5%); 165 (15%); 164 (M-COOH, 100%); 87 
(10%); 69 (8%). 
EXAMPLE 4 
5'-Cyanospiro[bicyclo[2.2.1]heptane-2,3'-pyrrolidine] 
(a) 2-Cyano-2-(1,3-dioxolan-2-yl)methylbicyclo[2.2.1]heptane 
7.2 g of norbornane-2-carbonitrile are reacted with 60 mmoles of lithium 
diisopropylamide (prepared from 8.2 ml of diisopropylamine and 40 ml of 
n-butyllithium) and with 7 g of 2-bromomethyl-1,3-dioxolane in analogy to 
Example 1a. After chromatography on silica gel with ethyl 
acetate/cyclohexane (1:6) as the mobile phase, 8.0 g of the title compound 
are obtained as an oil. 
.sup.1 H-NMR data (CDCl.sub.3): 4.95 (t, J=6 Hz, 1H); 4.0-3.7 (m, 4H); 
2.6-2.2 (m, 2H) 2.0-1.2 (m, 10H) ppm. 
(b) 2-Aminomethyl-2-(1,3-dioxolan-2-yl)methylbicyclo[2.2.1]heptane 
8 g of 2-cyano-2-(1,3-dioxolan-2-yl)methylbicyclo[2.2.1]heptane are reduced 
with 4.4 g of lithium aluminum hydride in analogy to Example 1b. 6.9 g of 
a colorless oil are obtained. 
.sup.1 H-NMR data (CDCl.sub.3): 4.07 (t, J=6 Hz, 1H); 4.0-3.6 (m, 4H); 2.6 
(s, 2H); 2.4-0.7 (m, 14H) ppm. 
(c) Spiro[bicyclo[2.2.1]heptane-2,3'-pyrroline-.DELTA.3'] 
6.9 g of 2-aminomethyl-2-(1,3-dioxolan-2-yl)methylbicyclo[2.2.1]heptane are 
cyclized with 125 ml of 5N hydrochloric acid by the method of Example 1c. 
4.6 g of the title compound are obtained as a mixture of monomer and 
trimer. 
(d) 5'-Cyanospiro[bicyclo[2.2.1]heptane-2,3'-pyrrolidine] 
4.6 g of spiro[bicyclo[2.2.1]heptane-2,3'-pyrrolidine-.DELTA.3'] are 
reacted with 3.85 g of potassium cyanide and 42.8 ml of 2N hydrochloric 
acid in analogy to the procedure described in Example 1d. 4.4 g of the 
title compound are obtained as a mixture of isomers. 
.sup.1 H-NMR data (CDCl.sub.3): 3.98 (X part of an ABX system, 1H); 3.2-1.0 
(m, remaining H) ppm. 
EXAMPLE 5 
Spiro[bicyclo[2.2.1]heptane-2,3'-pyrrolidine]-5'-carboxylic acid 
4.4 g of 5'-cyanospiro[bicyclo[2.2.1]heptane-2,3'-pyrrolidine] are 
hydrolyzed with 120 ml of 5N hydrochloric acid by the procedure described 
in Example 2. 4.35 g of the title compound are obtained as a colorless 
powder. 
.sup.1 H-NMR data (D.sub.2 O): 4.3-4.0 (m, 1H); 3.5-3.0 (m, AB system, 2H); 
2.5-1.0 (m, 12H) ppm. 
EXAMPLE 6 
Benzyl endo-spiro[bicyclo[2.2.2]octane-2,3'-pyrrolidine]-5'-carboxylate 
hydrochloride 
0.9 g of endo-spiro[bicyclo[2.2.2]octane-2,3'-pyrrolidine]-5'-carboxylic 
acid are added to a solution of 0.9 ml of thionyl chloride in 9 ml of 
benzyl alcohol, prepared at -5.degree. C. After 1 hour at -5.degree. C. 
and 18 hours at room temperature, the mixture is diluted with water and 
extracted with ethyl acetate. The ethyl acetate phase is dried over 
magnesium sulfate and evaporated. The benzyl alcohol is removed under high 
vacuum. The oily residue is triturated with diisopropyl ether, whereupon 
the product crystallizes, yield 0.92 g, melting point 
139.degree.-142.degree. C. 
.sup.1 H-NMR data (CDCl.sub.3): 7.3 (s, 5H); 5.25 (s, 2H); 4.52 (t, 1H); 
3.4 (s, 2H); 2.5-1.1 (m, 14H) ppm. 
EXAMPLE 7 
Benzyl exo-spiro[bicyclo[2.2.2]octane-2,3'-pyrrolidine]-5'-carboxylate 
hydrochloride 
1.6 g of exo-spiro[bicyclo[2.2.2]octane-2,3'-pyrrolidine]-5'-carboxylic 
acid are esterified with 1.6 ml of thionyl chloride and 16 ml of benzyl 
alcohol in analogy to the procedure described in Example 6, yield 1.68 g, 
melting point 149.degree.-151.degree. C. 
.sup.1 H-NMR data (CDCl.sub.3): 7.3 (s, 5H); 5.4-5.0 (AB system, 2H); 4.55 
(t, 1H); 3.35 (s, 2H); 2.4-1.2 (m, 14H) ppm. 
EXAMPLE 8 
Benzyl spiro[bicyclo[2.2.1]heptane-2,3'-pyrrolidine]-5'-carboxylate 
hydrochloride 
4.3 g of spiro[bicyclo[2.2.1]heptane-2,3'-pyrrolidine]-5'-carboxylic acid 
are esterified with 43 ml of thionyl chloride and 43 ml of benzyl alcohol 
is analogy to the procedure described in Example 6, yield 6.7 g, 
.sup.1 H-NMR data (DMSO-d.sub.6): 7.4 (s, 5H); 5.2 (s, 2H); 4.6-4.2 (m, 
1H); 3.5-3.0 (m, 2H); 2.4-1.0 (m, 12H) ppm. 
Mass spectrum (m/e): 285 (M.sup.+, 0.1%); 150 (M.sup.+ -CO.sub.2 Bzl, 
100%). 
EXAMPLE 9 
Benzyl 
N-(1-S-carboethoxy-3-phenylpropyl)-S-alanyl-exospiro[bicyclo[2.2.2]octane- 
2,3'-pyrrolidine]-5'-S-carboxylate (diastereomer A9) and benzyl 
N-(1-S-carboethoxy-3-phenylpropyl)-S-alanyl-exo-spiro[bicyclo[2.2.2]octane 
-2,3'-pyrrolidine]-5'-R-carboxylate (diastereomer B9) 
1.6 g of the benzyl ester from Example 7 are dissolved together with 1.39 g 
of N-(1S-carboethoxy-3-phenylpropyl S-alanine, 0.59 g of 
1-hydroxybenzotriazole and 0.66 ml of N-ethylmorpholine in 15 ml of 
absolute dimethylformamide. 1.08 g of dicyclohexylcarbodiimide are added 
and the mixture is stirred at room temperature for 2 hours. The 
precipitate is filtered off, the filtrate is diluted with ethyl acetate, 
washed with 10 percent citric acid solution, 1N sodium bicarbonate 
solution, water and saturated brine, once with each, dried over sodium 
sulfate and evaporated. Chromatography of the crude product on silica gel 
with ethyl acetate/cyclohexane (1:2) as the mobile phase provides the two 
title compounds. 
Diastereomer A9: R.sub.f value 0.26 (ethyl acetate/cyclohexane 1:1). 
.sup.1 H-NMR data (CDCl.sub.3):=7.3 (s, 5H); 7.15 (s, 5H); 5.15 (AB system, 
2H); 4.55 (X part of an ABX system, 1H); 4.2 (s, 2H); 3.7-3.1 (m, 3H); 
2.9-2.4 (m, 2H); 2.3-1.0 (m, 18H); 1.2 (d+t, 6H) ppm. 
Mass spectrum (m/e): 560 (M.sup.+, 1%), 487 (4%), 355 (3%), 234 (100%). 
Diastereomer B9: R.sub.f value 0.20 (ethyl acetate/cyclohexane 1:1). 
.sup.1 H-NMR data (CDCl.sub.3):=7.3 (s, 5H); 7.15 (s, 5H); 5.2 (s, 2H); 
4.6-4.0 (m, 4H); 3.8-3.0 (m, 4H); 2.9-1.0 (m, 18H); 1.2 (d+t, 6H) ppm. 
Mass spectrum (m/e): 560 (M.sup.+, 1%); 487 (4%); 355 (3%), 348 (5%), 234 
(100%). 
EXAMPLE 10 
Benzyl 
N-(1-S-carboethoxy-3-phenylpropyl)-S-alanyl-endospiro[bicyclo[2.2.2]octane 
-2,3'-pyrrolidine]-5'-(RS)-carboxylate 
0.91 g of the benzyl ester from Example 6 are reacted with 0.8 g of 
N-(1-S-carboethoxy-3-phenylpropyl)-S-alanine, 0.34 g of 
1-hydroxybenzotriazole, 0.38 ml of N-ethylmorpholine and 0.62 g of 
dicyclohexylcarbodiimide by the procedure described in Example 9. 
Chromatography on silica gel with ethyl acetate/cyclohexane (1:2) as the 
mobile phase provides 0.96 g of the title compound as a mixture of 
diastereomers. 
.sup.1 H-NMR data (CDCl.sub.3):=7.3 (s, 5H); 7.15 (s, 5H); 5.2 (s, 2H); 
4.7-4.0 (m, 3H); 3.6-3.0 (m, 4H); 2.9-2.4 (m, 2H); 2.4-1.0 (m, 24H) ppm. 
EXAMPLE 11 
Benzyl 
N-(1-S-carboethoxy-3-phenylpropyl)-S-alanylspiro[bicyclo[2.2.1]heptane-2,3 
'-pyrrolidine]-5'-carboxylate (Diasteromers A11 to C11) 
2.0 g of the benzyl ester from Example 8 are reacted with 1.83 g of 
N-(1-S-carboethoxy-3-phenylpropyl)-S-alanine, 0.78 g of 
1-hydroxybenzotriazole, 0.87 ml of N-ethylmorpholine and 1.43 g of 
dicyclohexylcarbodiimide by the procedure described in Example 9. Three 
fractions can be separated by chromatography on silica gel with ethyl 
acetate/cyclohexane as the mobile phase. 
Diastereomer A11 (0.28 g) R.sub.f value (ethyl acetate/cyclohexane 1:1) 
0.36. 
.sup.1 H-NMR data (CDCl.sub.3):=7.3 (s, 5H); 7.15 (s, 5H); 5.2 (AB system, 
2H); 4.6-3.9 (m, 4H); 3.6-3.0 (m, 4H); 2.9-2.6 (m, 2H); 2.4-1.0 (m, 22H) 
ppm. 
Diastereomer B11 (0.89 g) R.sub.f value (ethyl acetate/cyclohexane 1:1) 
0.32. 
.sup.1 H-NMR data (CDCl.sub.3):=7.3 (s, 5H); 7.15 (s, 5H); 5.15 (AB system, 
2H); 4.55 (X part of an ABX system, 2H); 4.2 (q, 2H); 4.4-4.0 (m, 1H); 
3.7-3.0 (m, 4H); 2.9-2.5 (m, 2H); 2.4-1.0 (m, 22H) ppm. 
Diastereomer C11 (0.86 g) R.sub.f value (ethyl acetate/cyclohexane 1:1) 
0.29. 
.sup.1 H-NMR data (CDCl.sub.3):=7.3 (s, 5H); 7.15 (s, 5H); 5.2 (s, 2H); 
4.7-4.0 (m, 4H); 3.8-3.1 (m, 4H); 2.9-2.5 (m, 2H); 2.4-1.0 (m, 22H) ppm. 
EXAMPLE 12 
N-(1-S-Carboethoxy-3-phenylpropyl)-S-alanyl-exo-spiro[bicyclo[2.2.2]octane- 
2,3'-pyrrolidine]-5'-S-carboxylic acid hydrochloride 
553 mg of the diastereomer A9 from Example 9 are dissolved in 50 ml of 
ethanol and, after the addition of 0.3 g of Pd/C (10%), are hydrogenated 
at room temperature and under normal pressure. After filtration, the 
solution is acidified with 2.5N ethanolic hydrochloric acid and evaporated 
and the residue is triturated with isopropyl ether. 
0.42 g of the title compound, of melting point 128.degree.-130.degree. C. 
(decomposition), is obtained. 
.sup.1 H-NMR data (DMSO-d.sub.6):=7.25 (s, 5H); 4.6-3.0 (m, 7H); 3.0-2.0 
(m, 2H); 2.0-1.0 (m, 24H) ppm. 
IR data (KBr): 3400, 2930, 2860, 1740, 1650, 1500, 1220, 750, 700 
cm.sup.-1. 
EXAMPLE 13 
N-(1-S-Carboethoxy-3-phenylpropyl)-S-alanyl-exo-spiro[bicyclo[2.2.2]octane- 
2,3'-pyrrolidine]-5'-R-carboxylic acid hydrochloride 
0.62 g of the diasteromer B9 from Example 9 is hydrogenated by the 
procedure described in Example 12. 0.41 g of the title compound, of 
melting point 120.degree. C. (decomposition), is obtained. 
.sup.1 H-NMR data (DMSO-d.sub.6):=7.25 (s, 5H); 4.6-3.0 (m, 7H); 3.3-2.0 
(m, 2H); 2.0-1.0 (m, 18H); 1.2 (d+t, 6H) ppm. 
IR data (KBr): 3400, 2930, 2860, 1740, 1650, 1500, 1225, 750, 700 
cm.sup.-1. 
EXAMPLE 14 
N-(1-S-Carboethoxy-3-phenylpropyl)-S-alanyl-endo-spiro[bicyclo[2.2.2]octane 
-2,3'-pyrrolidine]-5'-(RS)-carboxylic acid hydrochloride 
0.94 g of the compound from Example 10 is hydrogenated by the process of 
described in Example 12. 0.7 g of the title compound, of melting point 
186.degree.-189.degree. C. (decomposition), is obtained. 
.sup.1 H-NMR data (DMSO-d.sub.6):=7.2 (s, 5H); 4.6-3.1 (m, 7H); 3.0-2.0 (m, 
2H); 2.0-1.0 (m, 18H); 1.2 (d+t, 6H) ppm. 
IR data (KBr): 3420, 2930, 2860, 1740, 1653, 1545, 1500, 1208, 750, 705 
cm.sup.-1. 
Mass spectrum (m/e): 470 (M.sup.+, 0.01%); 452 (M.sup.+ -H.sub.2 O, 16%), 
348 (100%), 302 (47%), 263 (16%). 
EXAMPLE 15 
tert.-Butyl 
endo-spiro[bicyclo[2.2.2]octane-2,3'-pyrrolidine]-5'-carboxylate hydrochlo 
ride 
1 ml of concentrated sulfuric acid and 6 g of isobutylene are added to a 
solution of 1.3 g of the aminoacid from Example 2 in 12 ml of dioxane, 
cooled to -10.degree. C. After warming up to 25.degree. in an autoclave, 
the mixture is stirred at this temperature for 20 hours. The mixture is 
then added to ice-cold 50% strength sodium hydroxide and this mixture is 
extracted with methylene chloride. The combined organic phases are washed 
with water and dried with sodium sulfate, the residue is dissolved in 
ether and gaseous hydrogen chloride is passed in. 0.95 g of the title 
compound is obtained. 
.sup.1 H-NMR data (DMSO-d.sub.6):=4.0-3.5 (m, 1H); 3.2-2.6 (s, 2H); 2.0-1.1 
(m, 14H); 1.3 (s, 9H) ppm. 
EXAMPLE 16 
tert.-Butyl exo-spiro[bicyclo[2.2.2]octane-2,3'-pyrrolidine]-5'-carboxylate 
hydrochloride 
Prepared from 0.7 g of the aminoacid from Example 3 by the procedure 
described in Example 15. 0.6 g of the title compound is obtained. 
.sup.1 H-NMR data (DMSO-d.sub.6):=3.9-3.5 (m, 1H); 3.2-2.6 (m, 1H); 2.0-1.1 
(m, 14H); 1.3 (s, 9H) ppm. 
EXAMPLE 17 
tert.-Butyl spiro[bicyclo[2.2.1]heptane-2,3'-pyrrolidine]-5'-carboxylate 
hydrochloride 
Prepared from 0.6 g of the aminoacid from Example 5 by the procedure 
described in Example 15; 0.52 g of the title compound is obtained. 
.sup.1 H-NMR data (DMSO-d.sub.6):=3.8-3.5 (m, 1H); 3.2-2.5 (m, 1H); 2.0-1.1 
(m, 12H); 1.3 (s, 9H) ppm. 
EXAMPLE 18 
tert.-Butyl 
N-(1-S-carboethoxy-3-phenylpropyl)-S-alanylendo-spiro[bicyclo[2.2.2]octane 
-2,3'-pyrrolidine]-5'-S-carboxylate 
(Diastereomer A18) 
In analogy to the procedure in Example 9, 0.28 g of the title compound is 
obtained as a colorless oil from 0.58 g of the tert.-butyl ester from 
Example 15, 0.57 g of N-(1-S-carboethoxy-3-phenylpropyl)-S-alanine, 0.27 g 
of N-hydroxybenzotriazole and 0.41 g of dicyclohexylcarbodiimide with the 
addition of 0.23 g of N-ethylmorpholine. 
.sup.1 H-NMR data (CDCl.sub.3):=7.1 (s, 5H); 4.5-4.1 (m, 1H); 4.2 (q, J=7 
Hz, 2H); 3.9-1.9 (m, 22H); 1.3 (s, 9H); 1.2 (d+t, J=7H.sub.2, 6H) ppm. 
EXAMPLE 19 
N-(1-S-Carboethoxy-3-phenylpropyl)-S-alanyl-endo-spiro[bicyclo[2.2.2]octane 
-2,3'-pyrrolidine]-5'-S-carboxylic acid hydrochloride 
0.28 g of the tert.-butyl ester from Example 18 is dissolved in 1.5 ml of 
trifluoroacetic acid and stirred at 0.degree. C. for 3 hours. The 
trifluoroacetic acid is evaporated in vacuo, toluene is added and 
evaporation is repeated. After filtration through a short column of silica 
gel with methylene chloride/ethanol (10:1) as the mobile phase, the 
filtrate is acidified with ethanolic hydrochloric acid and evaporated. 
After dissolving in a little methylene chloride, the title compound is 
precipitated with diisopropyl ether. 0.21 g is obtained, which is 
identical with the compound from Example 12. 
EXAMPLE 20 
N-(1-S-Carboxy-3-phenylpropyl)-S-alanyl-exo-spiro[bicyclo[2.2.2]octane-2,3' 
-pyrrolidine]-5'-S-carboxylic acid 
Two equivalents of potassium hydroxide and a 10% excess of 4N potassium 
hydroxide solution are added to a solution of 0.25 g of the compound from 
Example 12 in 2 ml of water. After stirring at 20.degree. to 25.degree. C. 
for 8 hours, the reaction solution is adjusted to a pH of 4 with 2N 
hydrochloric acid and evaporated in vacuo. The residue is taken up in 
ethyl acetate and the precipitated salt is filtered off. The ethyl acetate 
solution is evaporated, and the residue is triturated with diisopropyl 
ether and filtered off with suction. 
.sup.1 H-NMR data (DMSO-d.sub.6):=7.1 (s, 5H); 4.4-4.0 (m, 1H); 3.9-1.3 (m, 
22H); 1.2 (d, 3H) ppm. 
EXAMPLE 21 
N-(1-S-Carboxy-3-phenylpropyl)-S-alanyl-endo-spiro[bicyclo[2.2.2]octane-2,3 
'-pyrrolidine]-5'-(RS)-carboxylic acid 
0.32 g of the compound from Example 14 are reacted by the process described 
in Example 20. 
.sup.1 H-NMR data (DMSO-d.sub.6):=7.15 (s, 5H); 4.4-3.9 (m, 1H); 3.9-1.3 
(m, 22H); 1.2 (d, 3H) ppm. 
EXAMPLE 22 
N-(1-S-Carboethoxy-3-phenylpropyl)-S-alanyl-spiro[bicyclo[2.2.1]heptane-2,3 
'-pyrrolidine]-5'-carboxylic acid hydrochloride 
(Diastereomers A22 to C22) 
The diastereomers A11 to C11 from Example 11 are hydrogenated by the 
procedure described in Example 12. The free carboxylic acids are obtained 
in each case. 
Diastereomer A22 0.17 g, melting point 189.degree. C. (decomposition). 
.sup.1 H-NMR data (DMSO-d.sub.6):=7.2 (s, 5H); 4.6-3.0 (m, 7H); 3.0-2.0 (m, 
2H); 2.1-1.0 (m, 22H) ppm. 
Diastereomer B22 0.79 g, melting point 126.degree. C. (decomposition). 
.sup.1 H-NMR data (DMSO-d.sub.6):=7.2 (s, 5H); 4.5-3.1 (m, 7H); 3.1-2.0 (m, 
2H); 2.2-1.0 (m, 22H) ppm. 
Diastereomer C22 0.63 g, melting point 125.degree. C. (decomposition). 
.sup.1 H-NMR data (DMSO-d.sub.6):=7.15 (s, 5H); 4.5-3.1 (m, 7H); 3.0-2.0 
(m, 2H); 2.2-1.0 (m, 22H) ppm. 
EXAMPLE 23 
tert.-Butyl 
N-(1-S-carboethoxy-3-phenyl-3-oxopropyl)-S-alanyl-exo-spiro[bicyclo[2.2.2] 
octane-2,3'-pyrrolidine]-5'-S-carboxylate 
0.28 g of the tert.-butyl ester from Example 16 is dissolved together with 
0.14 g of 1-hydroxybenzotriazole, 0.29 g of 
N-(1-S-carboethoxy-3-phenyl-3-oxopropyl)-S-alanine, 0.22 g of 
dicyclohexylcarbodiimide and 0.2 g of N-ethylmorpholine in 3 ml of DMF and 
the solution is stirred at 20.degree. C. for 3 hours. After dilution with 
ethyl acetate, the mixture is filtered, and the filtrate is washed twice 
with water, dried and evaporated. The residue is chromatographed on silica 
gel with cyclohexane/ethyl acetate (1:1) as the mobile phase; 0.16 g of 
the title compound is obtained. 
.sup.1 H-NMR data (CDCl.sub.3):=8.2-7.1 (m, 5H); 4.7-4.1 (m, 1H); 4.1 (q, 
2H); 3.9-1.3 (m, 20H); 1.3 (s, 9H); 1.2 (d+t, 6H) ppm. 
EXAMPLE 24 
tert.-Butyl 
N-(1-S-carboethoxy-3-phenyl-3-oxopropyl)-S-alanyl-endo-spiro[bicyclo[2.2.2 
]octane-2,3'-pyrrolidine]-5'-S-carboxylate 
0.28 g of the tert.-butyl ester from Example 15 is reacted by the procedure 
of Example 23. 0.18 g of the title compound is obtained. 
.sup.1 H-NMR data (CDCl.sub.3):=8.2-7.2 (m, 5H); 4.7-4.1 (m, 1H); 4.15 (q, 
2H); 3.9-1.2 (m, 20H); 1.3 (s, 9H); 1.2 (d+t, 6H) ppm. 
EXAMPLE 25 
tert.-Butyl 
N-(1-S-carboethoxy-3-phenyl-3-oxopropyl)-S-alanylspiro[bicyclo[2.2.1]hepta 
ne-2,3'-pyrrolidine]-5'-S-carboxylate 
0.27 g of the tert.-butyl ester from Example 17 is reacted by procedure of 
Example 23. 
.sup.1 H-NMR data (CDCl.sub.3):=8.1-7.2 (m, 5H); 4.7-4.0 (m, 1H); 4.1 (q, 
2H); 3.9-1.2 (m, 18H); 1.3 (s, 9H); 1.2 (d+t, 6H) ppm. 
EXAMPLE 26 
N-(1-S-Carboethoxy-3-phenyl-3-oxopropyl)-S-alanyl-exospiro[bicyclo[2.2.2]oc 
tane-2,3'-pyrrolidine]-5'-S-carboxylic acid hydrochloride 
0.12 g of the compound from Example 23 are reacted in analogy to the 
procedure described in Example 19 to give 0.1 g of the title compound. 
.sup.1 H-NMR data (DMSO-d.sub.6):=8.2-7.1 (m, 5H) 4.7-4.1 (m, 1H) 4.1 (q, 
2H) 3.9-1.3 (m, 20H) 1.2 (d+t, 6H) ppm. 
EXAMPLE 27 
N-(1-S-Carboethoxy-3-phenyl-3-oxopropyl)-S-alanyl-endospiro[bicyclo[2.2.2]o 
ctane-2,3'-pyrrolidine]-5'-S-carboxylic acid hydrochloride 
0.14 g of the compound from Example 24 are reacted in analogy to the 
procedure described in Example 19 to give 0.11 g of the title compound. 
.sup.1 H-NMR data (DMSO-d.sub.6):=8.2-7.1 (m, 5H); 4.7-4.1 (m, 1H); 4.1 (q, 
2H); 3.9-1.3 (m, 20H); 1.2 (d+t, 6H) ppm. 
EXAMPLE 28 
N-(1-S-Carboethoxy-3-phenyl-3-oxopropyl)-S-alanylspiro[bicyclo[2.2.1]heptan 
e-2,3'-pyrrolidine]-5'-S-carboxylic acid hydrochloride 
0.23 g of the compound from Example 25 are reacted in analogy to the 
procedure described in Example 19 to give 0.19 g of the title compound. 
.sup.1 H-NMR data (DMSO-d.sub.6):=8.2-7.1 (m, 5H); 4.7-4.1 (m, 1H); 4.2 (q, 
2H); 3.8-1.2 (m, 18H); 1.2 (d+t, 6H) ppm. 
EXAMPLE 29 
tert.-Butyl 
S-alanyl-exo-spiro[bicyclo[2.2.2]octane-2,3'-pyrrolidine]-5'-carboxylate 
(a) tert.-Butyl 
N-methylsulfonylethoxycarbonyl-(MSC)-S-alanyl-exo-spiro[bicyclo[2.2.2]octa 
ne-2,3'-pyrrolidine]-5'-carboxylate 
6.7 g of 1-hydroxybenzotriazole and 16.0 g of tert.-butyl 
exo-spiro[bicyclo[2.2.2]octane-2,3'-pyrrolidine]-5'-carboxylate are added 
to a solution of 10 g of MSC-Ala-OH in 50 ml of dimethylformamide. The pH 
is adjusted to 8.0 with N-ethylmorpholine. The mixture is cooled in an 
icebath and 10.5 g of dicyclohexylcarbodiimide are added. The mixture is 
stirred at 20.degree.-25.degree. C. for 15 hours. The precipitated urea is 
filtered off with suction, the filtrate is evaporated in vacuo and the 
residue is taken up in ethyl acetate. The organic phase is washed 
consecutively with potassium bisulfate, potassium bicarbonate and sodium 
chloride solutions, dried and evaporated. The residue is chromatographed 
on silica gel with 1:1 ethyl acetate/cyclohexane. 
Yield: 10 g. 
.sup.1 H-NMR data (CDCl.sub.3):=4.8-3.8 (m, 2H); 3.8-3.1 (m, 8H); 3.0 (s, 
3H); 2.9-1.2 (m, 14H); 1.4 (s, 9H); 1.2 (d, 3H) ppm. 
(b) tert.-Butyl 
S-alanyl-exo-spiro[bicyclo[2.2.2]octane-2,3'-pyrrolidine]-5'-carboxylate 
2.0 g of the compound from Example 29a are dissolved in 15 ml of methanol 
and 1.5 ml of water. The pH is adjusted to 13 with 2N sodium hydroxide 
solution and the mixture is stirred at room temperature for 2 hours. It is 
then neutralized with 2N hydrochloric acid, the methanol is evaporated in 
vacuo, the aqueous phase is extracted with ethyl acetate, and the ethyl 
acetate solution is washed with water, dried and evaporated. The residue 
is filtered through silica gel with ethyl acetate as the eluting agent. 
Yield: 0.8 g. 
.sup.1 H-NMR data (CDCl.sub.3):=4.7-4.2 (m, 1H); 3.9-3.3 (m, 3H); 2.9-1.2 
(m, 19H); 1.4 (s, 9H); 1.2 (d, 3H) ppm. 
EXAMPLE 30 
tert.-Butyl 
N-(1-S-carboethoxy-3-oxo-3-phenylpropyl)-S-alanyl-exo-spiro[bicyclo[2.2.2] 
octane-2,3'-pyrrolidine]-5'-carboxylate 
5 mmoles of the compound from Example 29b are dissolved together with 5 
mmoles of ethyl 3-benzoylacrylate and 5 drops of triethylamine in 50 ml of 
anhydrous ethanol and the mixture is stirred at 20.degree. to 25.degree. 
C. for 24 hours. It is then evaporated to dryness and the residue is taken 
up in ethyl acetate. The solution is now washed with water, dried and 
evaporated. The mixture of diastereomers is chromatographed on silica gel 
with ethyl acetate/cyclohexane as the eluting agent. The .sup.1 H-NMR data 
agree with the data for the compound from Example 23. 
EXAMPLE 31 
tert.-Butyl 
N-(1-S-carboethoxy-3-phenylpropyl)-S-alanylexo-spiro[bicyclo[2.2.2]octane- 
2,3'-pyrrolidine]-5'-S-carboxylate 
5 mmoles of the compound from Example 29b are dissolved in 15 ml of 
anhydrous ethanol. The pH of the solution is adjusted to 7.0 with 
ethanolic potassium hydroxide, and 0.7 g of powdered molecular sieve (4 
.ANG.) and then 5 mmoles of ethyl 2-keto-4-phenylbutyrate are added. A 
solution of 0.6 g of sodium cyanoborohydride in 6 ml of anhydrous ethanol 
is slowly added dropwise. After a reaction time of 20 hours at 20.degree. 
to 25.degree. C., the solution is filtered and the solvent is distilled 
off. The residue is taken up in ethyl acetate/water. After evaporating the 
ethyl acetate phases, the residue is chromatographed on silica gel with 
1:4 ethyl acetate/cyclohexane 1:4. 
The .sup.1 H-NMR data agree with the data for the compound from Example 18. 
EXAMPLE 32 
tert.-Butyl 
N-(1-S-carboethoxy-3-phenyl-3-oxopropyl)-S-alanyl-exo-spiro[bicyclo[2.2.2] 
octane-2,3'-pyrrolidine]-5'-S-carboxylate 
10 mmoles of acetophenone, 10 mmoles of ethyl glyoxylate and 10 mmoles of 
the compound from Example 23b in 30 ml of glacial acetic acid are heated 
at 45.degree. C. for 36 hours. After evaporation in vacuo, the residue is 
neutralized with sodium carbonate solution and extracted with ethyl 
acetate. The ethyl acetate phase is evaporated and chromatographed on 
silica gel with 1:1 ethyl acetate/cyclohexane 1:1 as the eluting agent. 
The NMR data agree with the data for the compound from Example 23. 
EXAMPLE 33 
N-(1-S-Carboethoxy-3-R,S-hydroxy-3-phenylpropyl)-S-alanyl-exo-spiro[bicyclo 
[2.2.2]octane-2,3'-pyrrolidine]-5'-S-carboxylic acid 
0.5 g of the compound from Example 23 are dissolved in 5 ml of aqueous 
ethanol and 0.1 g of sodium borohydride is added. The mixture is stirred 
at room temperature for 14 hours. Then ethyl acetate is added, and the 
ethyl acetate solution is washed with water, dried and evaporated. The 
crude product is filtered through silica gel with 9:1 ethyl 
acetate/methanol as the eluting agent. 
Yield: 0.3 g. 
.sup.1 H-NMR data (DMSO-d.sub.6):=7.3-6.9 (m, 5H); 5.4 (t, 1H); 4.7-4.2 (m, 
1H); 3.9-1.3 (m, 20H); 1.3 (d+t, 6H) ppm.