Novel compounds with angiotensin-converting enzyme inhibitory activity are disclosed. Such compounds are useful in the treatment of cardiovascular disorders, especially hypertension and congestive heart failure, and are useful in the treatment of glaucoma.

SUMMARY OF THE INVENTION 
The invention relates to compounds which are inhibitors of 
angiotensin-converting enzyme and useful in the treatment of 
cardiovascular disorders especially as antihypertensive agents and also in 
the treatment of congestive heart failure and of glaucoma. The compounds 
of this invention are represented by the formula 
##STR1## 
and the -pharmaceutically acceptable salts thereof, wherein R and R.sup.6 
are the same or different and are hydroxy, lower alkoxy, lower alkenoxy, 
diloweralkylamino lower alkoxy (e.g. dimethylaminoethoxy), acylamino lower 
alkoxy (e.g. acetylaminoethoxy), acyloxy lower alkoxy (e.g. 
pivaloyloxyethoxy), aryloxy (e.g. phenoxy), arylloweralkoxy (e.g. 
benzyloxy), amino, lower alkylamino, diloweralkylamino, hydroxyamino, 
aryllower alkylamino (e.g. benzylamino), or substituted aryloxy or 
substituted arylloweralkoxy wherein the substituent is methyl, halo or 
methoxy; 
R.sup.1 is hydrogen, alkyl of from 1 to 10 carbon atoms, including branched 
and cyclic and unsaturated (e.g. allyl) alkyl groups, substituted lower 
alkyl wherein the substituent is hydroxy, lower alkoxy, aryloxy (e.g. 
phenoxy), substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, 
amino, lower alkylamino, diloweralkylamino, acylamino, arylamino, 
substituted arylamino, guanidino, imidazolyl, indolyl, lower alkylthio, 
arylthio (e.g. phenylthio), substituted arylthio, carboxy, carbamoyl, 
lower alkoxycarbonyl, aryl (e.g. phenyl or naphthyl), substituted aryl, 
aralkyloxy, substituted aralkyloxy, aralkylthio, or substituted 
aralkylthio, wherein the aryl or heteroaryl portion of said substituted 
aryloxy, heteroaryloxy, arylamino, arylthio, aryl, aralkyloxy or 
aralkylthio groups is substituted with a group selected from halo, 
loweralkyl, hydroxy, lower alkoxy, amino, aminomethyl, carboxyl, cyano and 
sulfamoyl; and 
R.sup.3 is hydrogen, lower alkyl, phenyl lower alkyl, aminomethylphenyl 
lower alkyl, hydroxyphenyl lower alkyl, hydroxy lower alkyl, acylamino 
lower alkyl (e.g. benzoylamino lower alkyl or acetylamino lower alkyl), 
amino lower alkyl, dimethylamino lower alkyl, guanidino lower alkyl, 
imidazolyl lower alkyl, indolyl lower alkyl, or lower alkylthio lower 
alkyl. 
As used herein, acyl includes 
##STR2## 
wherein R.sup.12 is lower alkyl, lower alkenyl or aryl. The lower alkyl or 
lower alkenyl groups except where noted otherwise are represented by any 
of the variables including straight and branched chain hydrocarbon 
radicals from one to six carbon atoms, for example, methyl, ethyl, propyl, 
isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl or vinyl, 
allyl, butenyl and the like. Cycloalkyl groups include bridged and 
non-bridged groups. The aralkyl groups represented by any of the above 
variables have from one to four carbon atoms in the alkyl portion thereof 
and include for example, benzyl, p-methoxybenzyl and the like. Halo means 
chloro, bromo, iodo or fluoro. Aryl, where it appears in any of the 
radicals, except where noted, represents phenyl or naphthyl. Heteroaryl 
groups where they appear include for example pyridyl, thienyl, furyl, 
indolyl, benzothienyl, imidazolyl and thiazolyl. The R.sup.1 and R.sup.3 
substituted lower alkyl moieties are exemplified by groups such as 
##STR3## 
Preferred compounds of formula I are those in which R is hydroxy and lower 
alkoxy, R.sup.1 is lower alkyl and substituted lower alkyl wherein the 
substituent is aryl, R.sup.3 is lower alkyl and aminoloweralkyl and 
R.sup.6 is hydroxy. 
The aforementioned compounds of the formula I, as defined above, include 
all possible stereoisomers. Preferred stereoisomers are the 
cis,endo-octahydrocyclopenta[b]pyrrole-2(S)-carboxylic acids. Particularly 
preferred compounds are 
1-[N-(1(S)-carboxy-3-phenylpropyl)-(S)-alanyl]-cis,endo-octahydrocyclopent 
a[b]pyrrole-2(S)-carboxylic acid, 
1-[N-(1(S)-carboethoxy-3-phenylpropyl)-(S)-alanyl]-cis,endo-octahydrocyclo 
yclopenta[b]pyrrole-2(S)-carboxylic acid, 
1-[N.alpha.-(1(S)-carboethoxy-3-phenylpropyl)-(S)-lysyl]-cis,endo-octahydr 
ocyclopenta[b]pyrrole-2(S)-carboxylic acid, 
1-[N.alpha.-(1(S)-carboxy-3-phenylpropyl)-(S)-lysyl]-cis,endo-octahydrocyc 
lopenta[b]pyrrole-2(S)-carboxylic acid, 
1-[N-(1(S)-carboxybutyl)-(S)-alanyl]-cis,endo-octahydrocyclopenta[b]pyrrol 
e-2(S)-carboxylic acid, 
1-[N(1(S)-carboethoxybutyl)-(S)-alanyl]-cis,endo-octahydrocyclopenta[b]pyr 
role-2(S)-carboxylic acid, 
1-[N.alpha.-(1(S)-carboethoxybutyl)-(S)-lysyl]-cis,endo-octahydrocyclopent 
a[b]pyrrole-2(S)-carboxylic acid, and 
1-[N.alpha.-(1(S)-carboxybutyl)-(S)-lysyl]-cis,endo-octahydrocyclopenta[b] 
pyrrole-2(S)-carboxylic acid or their hydrochloride salts. A most preferred 
compound is 
1-[N-(1(S)-carboethoxy-3-phenylpropyl)-(S)-alanyl]-cis,endo-octahydrocyclo 
penta[b]pyrrole-2-(S)-carboxylic acid and its hydrochloride salt. 
The compounds of the present invention can be produced by methods known in 
the art using appropriate analogous reactants. 
One of ordinary skill in the art will appreciate that not all of the 
compounds of this invention may be readily prepared by any one process, 
but by selecting the appropriate process from those disclosed below, the 
skilled artisan may prepare all the compounds of this invention. 
The starting materials which are required for the processes herein 
described are known in the literature or can be made by known methods from 
known compounds. 
For example, the intermediate octahydrocyclopenta[b]pyrrole-2-carboxylate, 
III, 
##STR4## 
wherein R.sup.6 is as defined above, may be prepared by more than one 
method, including methods analogous to those known in the art, from 
starting materials described in the literature. 
Compounds of formula III consist of eight stereoisomers composed of four 
racemic pairs; the two cis epimers, IIIa and IIIb, and the two trans 
epimers, IIIc 
##STR5## 
If desired, each racemic pair may be separated into its component 
enantiomers by resolution methods well described in the art. 
A novel process for the synthesis of IIIa involves catalytic reduction of 
1-benzyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate, a compound 
of formula II wherein R.sup.6 is as defined above, which is prepared by 
reacting imine IV with a halo pyruvate ester such as ethyl bromopyruvate, 
as exemplified in the following process: 
##STR6## 
The above process preferably uses a lower alkyl ester of bromo pyruvate 
(e.g. R.sup.6 is ethoxy, methoxy or t-butoxy). Preferably, equimolar 
amounts of reactants are used. The reaction is carried out in an inert 
solvent such as an alcohol (e.g. ethanol), acetonitrile or 
dimethylformamide in the presence of a base such as triethylamine. The 
reaction may be carried out at from 0.degree.-100.degree. C. for 2-8 
hours, but is preferably carried out at low temperatures (e.g. 
0.degree.-5.degree. C.) for approximately 2 hours, then at reflux 
(temperature depends on solvent) for 2 hours. Catalytic reduction of the 
resultant 1-benzyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate to 
saturate the ring and remove the benzyl group is carried out in a solvent 
such as an alcohol (e.g. ethanol) in the presence of hydrogen gas and a 
catalyst such as Pd(OH).sub.2 on carbon or other appropriate catalysts. 
The resultant product may be isolated by methods well known to those 
skilled in the art, e.g. by treating with an acid such as HCl to prepare 
the salt, followed by removal of the salt (e.g. by basifying with sodium 
hydroxide) to obtain the compound of formula IIIa. 
Additional methods for synthesizing compounds of formula III will be 
described below. 
By utilizing intermediate III, the compounds of the present invention can 
be produced by various methods and subroutes, some of which are depicted 
in the following equations. Additional methods may be found in European 
Patent Application No. 50,800, published May 5, 1982. Reactive groups not 
involved in the condensation described below such as amino, carboxy, 
mercapto, etc., may be protected by methods standard in peptide chemistry 
prior to the coupling reactions and subsequently deprotected to obtain the 
desired products. Such reactions are demonstrated in the Examples. 
Compounds of the present invention may be prepared as follows: 
The intermediate III is coupled by known methods with a suitably 
N-protected alpha amino acid of formula VI wherein Pr is a protecting 
group, and the product is then deprotected by conventional means to 
produce the compound VII 
##STR7## 
wherein R.sup.3 is as defined hereinabove. 
Dipeptide VII is then condensed with keto acid (or ester) VIII in aqueous 
solution, optimally near neutrality or in a suitable organic solvent (for 
example, CH.sub.3 OH) in the presence of sodium cyanoborohydride to give 
I. 
##STR8## 
Alternatively, the intermediate Schiff base, enamine or aminol may be 
catalytically reduced to yield product I, for example, by hydrogen in the 
presence of 10% palladium on carbon or in the presence of Raney Nickel. 
The ratio of diastereomeric products formed may be altered by choice of 
catalyst. 
If R is a carboxy protecting group such as alkoxy or benzyloxy, it can be 
converted by well known methods such as hydrolysis or hydrogenation to I, 
wherein R is hydroxy. This is also the case in all of the methods referred 
to below. 
Alternatively VIII can be condensed with an amino acid VIa under the same 
conditions to yield amino acid IX. 
##STR9## 
The carboxylic acid function in VIa may be protected by removable ester 
groups such as benzyl, ethyl, t-butyl, and the like. Subsequent coupling 
of IX by known methods with amino acid derivative III gives I. 
##STR10## 
The known methods encompass reactive group protection during the coupling 
reactions, for example, amino groups in compounds VI and in substituents 
R.sup.1 and/or R.sup.3 may be protected by N-formyl, N-t-butoxycarbonyl 
and N-carbobenzyloxy groups followed by their removal to yield I and/or 
VII. Furthermore, the carboxylic acid function in III may be protected by 
removable ester groups such as benzyl, ethyl, t-butyl, and the like. As 
desired, protecting groups may be removed by known methods. Coupling 
agents in these synthetic routes are typically those useful in peptide 
chemistry such as dicyclohexylcarbodiimide (DCC) or diphenylphosphoryl 
azide (DPPA), and VI and/or IX may be activated via the intermediacy of 
active esters such as those derived from 1-hydroxy-benzotriazole or 
N-hydroxysuccinimide. 
The following additional non-exhaustive series of processes for preparing 
the cis,endo (IIIa) and cis,exo (IIIb) isomers of III, will exemplify some 
of the known methodology that may be employed by those of ordinary skill 
in the art in preparing intermediates of formula III. 
Analogy Process 1 
Conventional oxidation, using for example mercuric acetate, [e.g., see R. 
Bonnet, et al, J. Chem. Soc., 2087 (1959)]of the known 
cis-octahydrocyclopenta[b]pyrrole, X, wherein R.sup.7 is hydrogen, to 
imine XI, followed by addition of HCN to XI, affords the cis,endo and 
cis,exo nitriles, XIIa and XIIb. Nitriles XIIa and XIIb may be hydrolyzed 
under standard acidic or basic conditions to IIIa and IIIb, wherein 
R.sup.6 is OH. The reaction scheme is as follows: 
##STR11## 
Analogy Process 2 
IIIa and IIIb may be obtained by the known electrolytic oxidation of 
acylated amines such as XIII [M. Mitzlaff et al, Liebigs Ann. Chem. 1713 
(1978)], in the presence of an alcohol such as methanol, to ethers XIVa 
and XIVb, followed by conventional replacement of the ether group by HCN 
to afford compounds XVa and XVb. Alternatively XVa and XVb may be obtained 
by treatment of XIV with trimethylsilylcyanide in the presence of boron 
trifluoride etherate [V. Asher et al., Tetrahedron Lett., 141 (1981)]. 
Typical acyl groups are acetyl, trifluoroacetyl, benzoyl and the like. 
Compounds XVa and XVb may then be hydrolyzed by standard means to 
compounds IIIa and IIIb, or compounds XVa and XVb may first be partially 
hydrolyzed to XIIa and XIIb, a reaction which is known to be especially 
facile when the acyl group is trifluoroacetyl and the hydrolyzing agent is 
methanolic potassium carbonate. Compounds XIII are available by 
conventional acylation of compound X. 
The reaction schemes are as follows: 
##STR12## 
Compounds IIIa and IIIb, wherein R.sup.6 is OH, are readily esterified by 
standard methods to afford the corresponding esters as defined for R.sup.6 
above. Alternatively, many of the esters corresponding to IIIa and IIIb 
may be prepared by direct solvolysis of the nitriles XIIa and/or XIIb. 
Thus, for example, the ethyl esters corresponding to IIIa and/or IIIb 
(i.e., R.sup.6 =OCH.sub.2 CH.sub.3) may be directly obtained by reaction 
of XIIa and/or XIIb in ethanol, for example in the presence of an acid 
such as HCl. Conversely, the esters corresponding to IIIa and IIIb are 
convertible to their corresponding acids (i.e., wherein R.sup.6 is OH) by 
conventional hydrolytic methods. 
Analogy Process 3 
IIIa and IIIb can be obtained by the well-known Favorskii-type ring 
contraction of .alpha.-halo lactams, XVII, under a variety of basic 
conditions [see for example, G. B. R. deGraaf, et al., Rec. Trav. Chem., 
81, 786 (1962); K. Kariyone, Chem. Pharm. Bull., 8, 1110 (1960); Chem. 
Abstr., 53, 21940 (1959); H. T. Nagasawa et al., J. Med. Chem., 14, 501 
(1971); J. A. Elberling et al., J. Heterocycl. Chem., 9, 411 (1972); R. 
Henning et al., Tetrahedron Lett., 24, 5339 (1984)]. The .alpha.-halo 
lactams XVII, wherein X is chloro or bromo, may be prepared from the known 
lactam XVI [S. V. Kessar et al., J. Indian Chem. Soc., 40, 655 (1963)] by 
the process described by W. C. Francis et al [J. Amer. Chem. Soc., 80, 
6238 (1958)] and R. J. Wineman et al. [Ibid., 80, 6233 (1958)]. An example 
of the overall process, wherein X is chloro, is as follows: 
##STR13## 
Analogy Process 4 
Compounds IIIa and IIIb can be prepared from compound X, wherein R.sup.7 is 
hydrogen, by known methods of electrophilic substitution alpha to 
activated amines [for a review, see D. Sieback and D. Enders, Angew. Chem. 
Internat. Edit., 14, 15 (1975)]. Thus, for example, N-nitrosation of 
compound X, wherein R.sup.7 is hydrogen, with a reagent such as ethyl 
nitrite or the like affords the N-nitroso derivative XXIII. Treatment of 
compound XXIII with a strong base such as, for example, the lithium salt 
of diisoproplamine to remove the alpha hydrogen (intermediate XXIV), 
followed by carboxylation with carbon dioxide and subsequent removal of 
the N-nitroso group by known methods, such as with HBr in glacial acetic 
acid, affords compounds IIIa and IIIb, wherein R.sup.6 is hydrogen. 
##STR14## 
Analogy process 5 
Compounds of formula IIIa or IIIb may be prepared using any of several 
known processes for the preparation of compounds X wherein R.sup.7 is 
hydrogen, among which are those described in: (1) A. G. Anderson et al, J. 
Org. Chem., 43, 55 (1978); (2) M. G. Avetyan et al., U.S.S.R. Pat. No. 
761,462, Sept. 7, 1980; (3) H. Booth et al, J. Chem. Soc., 1050 (1959) and 
(4) F. E. King et al, Ibid., 250 (1953). Processes described in references 
(1) and (2) are essentially equivalent and involve as the first step the 
alkylation of cyclopentanone to intermediates of formula XX. 
Cyclopentanone is alkylated either as the free ketone of formula XVIII or 
as an enamine derivative of formula XXI, wherein Z is N-pyrrolidino or 
N-morpholino. The aforementioned pyrrolidine and morpholine groups 
exemplify the general enamine class of ketone "equivalents" [for a general 
reference, see (5) J. Smuzkowicz, "Advances in Organic Chemistry Methods 
and Results", Interscience, New York, N.Y. 1963, Vol. 4, Chapter 1]. 
Another general class of ketone "equivalents" are the enol ethers, 
represented by formula XXI, wherein Z is, for example, trimethylsilyloxy 
[i.e. Z=OSi(CH.sub.3).sub.3 ]. Such alkylations of cyclopentanone have 
been carried out with a variety of haloalkyl compounds of formula XIX, 
among which are compounds wherein Q is aminoalkyl [reference (2)], 
cyanoalkyl [reference (1)]and carboxyalkyl [(6) E.D. Bergman et al, J. 
Amer. Chem. Soc., 78, 1482 (1956); (7) E. D. Bergman et al, Ibid, 80, 3135 
(1958)]. These alkylations of cyclopentanone may be represented as 
follows: 
##STR15## 
The second step in the process from reference (1) is the reduction, by 
hydrogenation, of the nitrile intermediate XXb to the corresponding amine 
XXa. Amine XXa is not isolated in either of the processes described in 
references (1) and (2). 
##STR16## 
The third and fourth steps in the process from reference (1) involve the 
ring closure of intermediate XXa to the pyrroline(s) XXIIa, wherein 
R.sup.7 is hydrogen (without isolation) (Step 3), and its concommitant 
reduction to afford compound X, wherein R.sup.7 is hydrogen (Step 4). 
Similarly, the second and third steps in the process from reference (2) 
involve the ring closure of intermediate XXa to the pyrroline(s) XXIIa, 
wherein R.sup.7 is hydrogen (with isolation) (Step 2), followed by 
reduction of XXIIa with sodium in methanol to yield compound X, wherein 
R.sup.7 is hydrogen (Step 3). 
##STR17## 
Furthermore, one skilled in the art will recognize that using processes 
analogous to those exemplified by references (1), (2), (5), (6) and (7), 
compounds of formula III may be prepared by the alkylation of 
cyclopentanone (XVIII) or preferrably by a cyclopentanone equivalent of 
formula XXI, wherein Z is, for example, the N-pyrrolidino, N-morpholino or 
trimethylsilyl enol ether group, with compounds of formula XIX , wherein Q 
is CHR.sup.7 NHR.sup.8, and wherein R.sup.7 is COR.sup.6. The skilled 
artisan will appreciate that in the presence of a reactive carboxyl group, 
COR.sup.6, it is desirable to protect the basic amino group in compounds 
XIX during the alkylation (step 1). Such protection is obviously achieved 
by acylation, for example, to yield compounds XIX wherein R.sup.8 is acyl. 
A specific example is XIXe, wherein R.sup.7 is CO.sub.2 CH.sub.3 and 
R.sup.8 is acetyl. The alkylation of cyclopentanone via its reactive 
equivalent of formula XXI with compounds XIXe to afford intermediate XXe, 
wherein Q is CHR.sup.7 NHR.sup.8 and wherein R.sup.7 is CO.sub.2 CH.sub.3 
and R.sup.8 is acetyl may be exemplified as follows: 
##STR18## 
The Z function may be removed in a "one pot" process as is exemplified for 
the enamines in the referenced examples. Thus, the enamines are readily 
hydrolyzed under mild acid conditions to yield compound XXe. If the Z 
function is a silyl enol ether, e.g. compounds wherein Z is 
--OSi(CH.sub.3).sub.3, the alkylation of XXI with XIXe may be carried out 
in the presence of fluoride ion or Lewis acid catalysts such as 
TiCl.sub.4, ZnBr.sub.2, TiCl.sub.2 (i-PrO).sub.2 and the like, to generate 
compound XXe. 
As in the above described processes in references (1) and (2), intermediate 
XXe must be cyclized in step 2 to the pyrroline XXIIb, wherein R.sup.7 is 
COR.sup.6. Since the intermediate XXe in this example is N-protected by an 
acyl group, one skilled in the art will recognize that removal of the 
N-acyl protecting group may be readily accomplished by acid solvolysis, 
generally at elevated temperatures, which will concommitantly effect the 
previously exemplified cyclization reaction (i.e., XX.fwdarw.XXIIa) to 
afford compounds XXIIb. Compounds XXIIb are obtained as acids (i.e. 
wherein R.sup.7 is CO.sub.2 H) when aqueous conditions are used, or as 
esters, (i.e. wherein R.sup.7 is COR.sup.6, and R.sup.6 is as defined 
above, but not OH) when the solvolysis is carried out in an alcoholic 
solvent. The following reaction scheme exemplifies this process: 
##STR19## 
The methods described in the processes utilized in references (1) and (2) 
for the reduction of XXIIa represent only two of several methods for 
performing this reaction known to those skilled in the art. Thus, for 
example, to obtain cis-X, wherein R.sup.7 is COR.sup.6, (i.e. IIIa and/or 
IIIb) from XXIIb, it is obvious that catalytic hydrogenation procedures 
represent a preferred method, and such a procedure is exemplified as 
follows, utilizing a palladium on carbon catalyst: 
##STR20## 
Additional well known reduction methods include the use of NaBH.sub.4, 
NaBH.sub.3 CN and the like. 
A specific use of the analogy process described above is exemplified in 
European Patent Application No. 0079022 (1982) and German Patent 
Application Nos. 3226768 (1982) and 3143946 (1981). 
Analogy Process 6 
Those skilled in the art will appreciate that Compounds IIIa and IIIb are 
interconvertible, as are IIIc and IIId, by simple base catalyzed 
epimerization. Consequently, a synthesis of IIIa constitutes a synthesis 
of IIIb (and vice versa) and a synthesis of IIIc constitutes a synthesis 
of IIId (and vice versa). Such epimerizations are most conveniently 
carried out on the free base ester forms of these compounds in the absence 
or presence of additional basic catalysts such as potassium t-butoxide, 
triethylamine and the like. For example, 
##STR21## 
In the compounds of the formula I, the carbon atoms to which R.sup.1, 
R.sup.3 and COR.sup.6 are attached may be asymmetric. The compounds 
accordingly exist in disastereoisomeric forms or in mixtures thereof. The 
syntheses for making the compounds can utilize racemates, individual 
enantiomers or individual diastereomers as starting materials. 
Enantiomerically pure intermediates may be obtained by resolution methods 
known in the art. When diastereomeric products result from the synthetic 
procedures, the diastereomeric products can be separated by conventional 
chromatographic or fractional crystallization methods. 
In general, the starred chiral centers in the amino acid part-structures, 
i.e., 
##STR22## 
of Formula I are preferred in the configuration most similar to that of 
natural L-amino acids. Usually, natural L-amino acids are assigned the 
S-configuration. A notable exception is the natural amino acid L-cysteine 
which is assigned the R-configuration. 
The compounds of this invention form salts with various inorganic and 
organic acids and bases which are also within the scope of the invention. 
Such salts include ammonium salts, alkali metal salts such as sodium and 
potassium salts (which are preferred), alkaline earth metal salts such as 
the calcium and magnesium salts, salts with organic bases e.g., 
dicyclohexylamine or N-methyl-D-glucamine, salts with amino acids such as 
arginine, lysine and the like. Also, salts with organic and inorganic 
acids may be prepared, e.g., HCl, HBr, H.sub.2 SOhd 4, H.sub.3 PO.sub.4, 
methanesulfonic acid, toluenesulfonic acid, maleic acid, fumaric acid and 
camphorsulfonic acid. The non-toxic physiologically acceptable salts are 
preferred, although other salts are also useful, e.g., in isolating or 
purifying the product. 
The salts may be formed by conventional means, as by reacting the free acid 
or free base forms of the product with one or more equivalents of the 
appropriate base or acid in a solvent or medium in which the salt is 
insoluble, or in a solvent such as water which is then removed in vacuo or 
by freeze-drying or by exchanging the cations of an existing salt for 
another cation on a suitable ion exchange resin.

The following examples illustrate the preparation of the compounds of the 
present invention. The diasterioisomers prepared as set forth below may be 
isolated by column chromatography or by fractional crystallization. 
EXAMPLE 1 
PREATION OF ETHYL CIS-OCTAHYDROCYCLOPENTA[b]PYRROLE-2-CARBOXYLATE 
A. GENERAL PROCEDURE 
Heat under reflux cis-octahydrocyclopenta[b]pyrrole [prepared by the 
methods of A. Bertho, et al, Chem. Ber. 92, 2218 (1959), wherein 
2-oxo-cyclopentyl acetic acid is cyclized by reduction with Raney 
Nickel/H.sub.2 in the presence of ammonia to obtain 
2-keto-octahydrocyclopenta[b]pyrrole, which is then reduced with lithium 
aluminum hydride in etheral solution to yield 
ciso-octahydrocyclopenta[b]pyrrole, or by the method of A. G. Anderson, 
Jr., et al, J. Org. Chem. 43, 55 (1978), discussed above] and mercuric 
acetate in water or up to 10% aqueous acetic acid for twenty hours or 
more, to obtain cis-3,3a,4,5,6,6a-hexahydrocyclopenta[b]pyrrole. Dissolve 
this compound in water and treat with potassium cyanide followed by 2N 
hydrochloric acid at 0.degree. C. for two hours and at room temperature 
for approximately twenty hours to obtain 
2-cyano-cis-octahydrocyclopenta[b]pyrrole. Heat this resultant compound in 
6N hydrochloric acid under reflux for 6 hours followed by concentration of 
the reaction mixture to obtain 
cis-octahydrocyclopenta[b]pyrrole-2-carboxylic acid. If desired, adsorb 
the residue on an XAD-2 resin column and elute with methanol. Esterify by 
reaction with ethanol to obtain ethyl 
cis-octahydrocyclopenta[b]pyrrole-2-carboxylate, as a mixture of two 
epimers. 
B. DETAILED PROCEDURES 
1. Cis-3,3a,4,5,6,6a-Hexahydrocyclopenta[b]pyrrole 
Method I 
Heat under reflux 3.00 g (27 mmol) of cis-octahydrocyclopenta[b]-pyrrole 
(obtained from the recrystallized 3,5-dinitrobenzoate salt [ See H. Booth 
et al, J. Chem. Soc., 1050 (1959)] by basification with sodium hydroxide 
to pH 11, extraction with ether and removal of the ether in vacuo) and 35 
g (110 mmol) of mercuric acetate in 50 ml of 6% aqueous acetic acid for 
six days. Cool the reaction mixture to ambient temperature, basify with 
NaOH to pH 11, filter and extract the solids with ether continuously for 
six days in a soxhlet apparatus. Combine the ethereal extract with the 
basic aqueous filtrate from the original filtration and extract 
continuously with ether for two days. Dry the ether layer over K.sub.2 
CO.sub.3, filter through a sintered glass funnel, and remove the ether in 
vacuo to obtain approximately 1.03 g of the crude title compound of Part 1 
as a light amber oil. Gas liquid chromatography-(R.sub.t 2.29 min. 
(instrument: Varian Vista Series 6000; 3% OV-1 on 80 Supelcoport; column 
dimensions 6'.times.2 mm I.D.; column temp. 110.degree. C.; He flow rate, 
ca 20 ml/min). Mass spectrum (GLC/MS): 109 (M.sup.+, 20%), 108 (15%), 82 
(57% MHCN), 81 (20%), 80 (12%), 67 [100% M-(CH.sub.2).sub.3 ]. 
Method II 
Heat under reflux 7.39 g (66.1 mmol) of cis-octahydrocyclopenta[b]pyrrole 
and 86 g (264.4 mmol) of mercuric acetate in 125 ml. of water for six days 
and extract as described in Method I to obtain approximately 3.4 g of the 
crude title compound of Part 1 as a light amber oil. 
Method III 
Heat under reflux 10.5 g (32.5 mmol) of octahydrocyclopenta[b]-pyrrole 
3,5-dinitrobenzoate and 41.5g (130 mmol) of Hg(OAc).sub.2 in 300 ml of 10% 
aqueous acetic acid for seven days and extract as described in Method I to 
obtain approximately 5.9 g of the crude title compound of Part 1 as a 
light amber oil. 
2. Cis,Endo- and Cis,Exo-2-Cyanooctahydrocyclopenta[b]pyrrole 
Method I 
Dissolve 1.03 g of the crude reaction product from part 1 in 10 ml of water 
and 2 ml of methanol. Cool to approximately 0.degree. C. and add 2 g of 
KCN. With stirring, add 2NHCl periodically over 3 hours to pH 6. Remove 
the cooling bath and stir overnight at ambient temperature. Warm to 
approximately 40.degree. C. for one hour, cool to ambient temperature, 
remove the methanol in vacuo, cool to approximately 0.degree., basify with 
KOH to pH 11 and continuously extract with ether for 24 hours. Dry the 
ether extract over K.sub.2 CO.sub.3, filter and remove the ether to obtain 
0.84 g of a light amber oil which is a crude mixture of the two title 
compounds of Part 2, readily identified by gas liquid chromatographic 
(glc) analysis as a single peak for the binary mixture (instrument: Varian 
3700; column length: 30m; i.d.: 0.25 mm; film thickness: 0.25 .mu.m; flame 
ionization detection temp: 300.degree. C.; injector temp: 200.degree. C.; 
injector mode: split; He flow rate: 0.5 ml/min); on Carbowax 20M, R.sub.t 
6.34 min (column temp. 70.degree. C. for 3 min., then increase 4.degree. 
C./min) or R.sub.t 7.6 min. (column temp 60.degree. C. for 3 min., then 
increase 2.degree. C./min.), and on 100% biscyanopropylsilicone (SP 
2340-Supelco Inc., Bellefonte, Pa.), R.sub.t 5.7 min (column temp. 
120.degree. C.) or 4.6 min (column temp. 150.degree. C.). The two title 
compounds of Part 2 are also readily detected by TLC as individual 
components, R.sub.f 0.25 and 0.33 (0.25 mm silica, ether:hexanes-1:1). 
Method II 
To a stirred mixture of 1.5 g of the crude reaction product from Part 1, 
and 2 g of KCN in 15 ml of water at approximately 0.degree. C., add 2N HCl 
periodically to pH6. Remove the cooling bath and stir overnight at ambient 
temperature. Warm to 40.degree. C. for one hour, cool to approximately 
0.degree. C., basify with KOH to pH 11 and extract as in Method I of Part 
2 to obtain a crude mixture of the two title compounds as a light amber 
oil. 
Isolation 
Isolate the two epimeric products of Part 2 by any of the following 
methods: 
(a) Isolate a binary mixture of the two epimeric products from Method I or 
II, Part 2 by preparative glc on an OV-17 column [1/8".times.6'; 
140.degree. C.; He pressure 20 lbs.; R.sub.t 3.25 min (R.sub.t 
octahydrocyclopenta[b]pyrrole--2.50 min)]. 
Similarly, Carbowax 20M or 100% biscyanopropylsilicone columns can be 
employed. If desired, separate the individual isomers by chromatography on 
silica gel. 
(b) Dissolve 1.5 g of the crude products from Methods I or II, Part 2 in 23 
ml of dry methylene chloride. Add 2.5 ml of pyridine, cool to 
approximately 0.degree. C. and add dropwise 3.5 ml of trifluoroacetic 
anhydride. Allow the mixture to warm to ambient temperature overnight. 
Quench the reaction by slowly adding approximately 10 ml of 6N HCl. Remove 
the volatiles in vacuo and partition the residue between ether and 1N HCl. 
Wash the combined ether layers to neutrality with saturated sodium 
bicarbonate, dry over MgSO.sub.4, filter and remove the ether in vacuo. 
Distill the residue in a kugelrohr oven (bulb to bulb, 70-120.degree. 
C./2.5 mm-0.3 mm) to obtain a mixture of the cis,endo- and 
cis,exo-2-cyano-1-trifluoroacetyloctahydrocyclopenta[b]pyrroles which is 
separated from the 1 -trifluoroacetyl-cis-octahydrocyclopenta[b]pyrrole 
and other products by preparative thin layer chromatography (i.e., 
TLC--200.times.200.times.1 mm silica; elute with ether:hexanes (2:3); two 
developments), column chromatography (silica gel), or by preparative glc 
on an OV-17 column (1/8".times.6"; 210.degree. C.); He pressure 20 lbs.; 
R.sub.t (isomeric mixture) 6.4 min. 
If desired, separate the cis,endo and 
cis,exo-1-trifluoroacetyl-octahydrocyclopenta[b]pyrroles from each other 
by preparative TLC (200.times.200.times.1 mm silica eluted with 
ether:hexanes-2:3); two developments) or by column chromatography (silica 
gel). 
Cis,endo-2-cyano-1-trifluoroacetyloctahydrocyclopenta[b]pyrrole: 
TLC: R.sub.f 0.5 (0.25 mm silica; ether:hexanes--1:1); GLC (see Method I of 
Part 2 for additional details): 
Carbowax 20M--R.sub.t 10.3 min (column temp. 200.degree. C. for 3 min then 
raise 10.degree. C./min); 100% Biscyanopropylsilicone--R.sub.t 7.4 min 
(column temp. 245.degree. C.). 
MS: 232 (M.sup.+ ; 13%), 205 (M-HCN; 2%), 204 (M-H,HCN; 9%); 203 
(M-H.sub.2, HCN; 69%); 190 (M-(CH.sub.2).sub.3 ; 11%); 179 (M-CH.sub.2 
=CHCN; 11%); 163 (m-CF.sub.3 ; 10%; 135 (M-COCF.sub.3 ; 8%); 43 (100%) 
NMR (200 MHz-CDC.sub.3): .delta.4.95 (1H, doublet of doublets J=9Hz, 4Hz); 
4.61 (1H, multiplet) 
Cis,exo-2-cyano-1-trifluoroacetyl-octahydrocyclopenta[b]pyrrole: 
TLC: R.sub.f 0.4 (0.25 mm silica; ether:hexanes-1:1,); 
GLC: (see Method 1 of Part 2 for further details): Carbowax 20M--R.sub.t 
10.7 min (column temp. 200.degree. C. for 3 min then raise 10.degree. 
C./min); 100% Biscyanopropylsilicone--R.sub.t 7.8 min (column temp. 
245.degree. C.). 
MS: 232 (M.sup.+ ; 19%); 205 (M-HCN; 4%); 204 (M-H,HCN; 6%); 203 
(M-H.sub.2, HCN; 100%); 190 (M-(CH.sub.2).sub.3 ; 7%); 179 (MCH.sub.2 
=CHCN; 6%); 163 (M-CF.sub.3 ; 14%) 
NMR: (200 MHz-CDC.sub.13): .delta.4.94 (1H, triplet J=8Hz); 4.54 (1H, 
multiplet) 
Hydrolyze a mixture of cis,endo and 
cis,exo-2-cyano-1-trifluoroacetyloctahydrocyclopenta[b]pyrrole as obtained 
above, or hydrolyze the individual epimers as obtained above. For example, 
dissolve 2.5 g of cis,endo isomer in 20 ml of methanol containing 
approximately 2 g of K.sub.2 CO.sub.3. Stir for seven hours, filter 
through celite, wash with ether and remove the solvents in vacuo. 
Partition the residue between CH.sub.2 Cl.sub.2 and aqueous K.sub.2 
CO.sub.3 and wash the organic layer with additional aqueous K.sub.2 
CO.sub.3. Dry over K2C.sub.3, filter, and remove the solvent in vacuo to 
obtain a mixture of 1.77 g of the cis,endo- (major component) and 
cis,exo-(minor component)2-cyano-octahydrocyclopenta[b]pyrrole epimers as 
an oil. 
MS: 136 (M.sup.+ ; 29%); 135 (5%); 110 (M-CN; 100%); 109 (MHCN; 24%); 108 
(M-H,HCN; 17%); 107 (M-H2, HCN; 46%); 93 (M-H(CH.sub.2).sub.3 ; 20%); 82 
(M-CH.sub.2 =CHCN; 43%); 81 (M-H,CH.sub.2 =CHCN; 22%); 80 (M-H.sub.2, 
CH.sub.2 =CHCN; 19%); 68 (M-CN,(CH.sub.2).sub.3 ; 24%); 67 
(M-HCN,(CH.sub.2).sub.3 ; 88%); 54 (M-C.sub.5 H.sub.9 N; 35%) 
NMR (200 MH.sub.2 -CDCl.sub.3): .delta.5.05 (1H, broad) 4.55 (1H, 
multiplet) 4.13 (1H, multiplet) 2.81 (1H, multiplet) 2.62 (1H, multiplet) 
2.27 (1H, multiplet) 
3. Cis,Endo- and Cis,Exo-Octahydrocyclopenta[b]pyrrole-2-Carboxylic Acid 
Hydrochloride 
Reflux a solution of 0.85 g (6.2 mmol) of a mixture of cis,endo- and 
cis,exo-2-cyano octahydrocyclopenta[b]pyrrole (from Method I or II of Part 
2) in 10 ml of 6N HCl for eight hours. Cool the reaction mixture to 
ambient temperature, remove the solvent under high vacuum and obtain the 
two title compounds of Part 3 as a mixture, which appears as a single spot 
on TLC, R.sub.f 0.12 (0.25 mm silica; CHC.sub.3 : isopropanol:7% NH.sub.4 
OH-1:1:1-lower phase). 
4. Ethyl Cis,Endo- and Ethyl 
Cis,Exo-Octahydrocyclopenta[b]pyrrole-2-Carboxylate 
a. Preparation of Hydrochloride salts 
Dissolve the crude carboxylic acid hydrochloride obtained in Part 3 in 20 
ml of absolute ethanol and 3 ml of triethyl orthoformate. Cool to 
approximately 0.degree. C., bubble in HCl gas for 5 minutes and then 
reflux overnight (CaSO.sub.4 drying tube). Cool the reaction mixture to 
ambient temperature and remove the volatiles in vacuo. Suspend the 
resultant residue in 50 ml. of boiling THF, filter through celite, and 
remove the solvent in vacuo to obtain approximately 0.86 g of a mixture of 
the hydrochlorides of the two title compounds of Part 4, as a light tan 
solid. TLC (0.25 mm silica; 94.5% CH.sub.2 Cl.sub.2 : 5% MeOH:0.5% 
NH.sub.4 OH, developed 3 times): 
R.sub.f --cis,endo-isomer: 0.60 
R.sub.f --cis,exo-isomer: 0.67 
b. Separation of Epimers 
Chromatograph the mixture of the ester hydrochlorides of Part 4a on silica 
gel (elute with ether: NH.sub.4 OH--99:1)). Ethyl 
cis,exo-octahydrocyclopenta[b]pyrrole-2-carboxylate elutes first [MS: 183 
(M.sup.+); 110 PG,29 (M-CO.sub.2 CH.sub.2 CH.sub.3, 100%); NMR (200 
MHz-CDCl.sub.3): .delta. 3.89 (1H br. triplet, J=5.6 Hz), .delta. 3.81 (1H 
triplet, J=6.4 Hz)], followed by ethyl 
cis,endo-octahydrocyclopenta[b]pyrrole2-carboxylate [MS: 183 (M.sup.+), 
110 (M-CO.sub.2 CH.sub.2 CH.sub.3, 100%); NMR (200 MHz-CDC.sub.3): .delta. 
3.68 (1H br. multiplet), 3.62 (1H doublet of doublets, J=10 Hz, 6 Hz)]. 
The two epimeric products of this example are also readily assayed by glc 
on 100% biscyanopropylsilicone (170.degree. C.), R.sub.t cis,exo isomer 
6.2 min, R.sub.t cis,endo isomer 6.7 min (see Method I, Part 2 for 
additional details). 
c. Preparation of Ethyl 
Cis,Endo-Octahydrocyclopenta[b]pyrrole-2-Carboxylate Hydrochloride 
Dissolve in ether the ethyl cis,endo-free base obtained in Part 4b and add 
2.86 N ethereal HCl dropwise until precipitation is complete. Filter and 
recrystallize from CH.sub.2 Cl.sub.2 /CCl.sub.4 or ethanol/ether to obtain 
the hydrochloride of the cis,endo-epimer of the product of Example 1, m.p. 
170.degree.-171.degree. C. 
NMR (400 MHz-d.sub.6 DMSO): .delta. 4.37 (1H, doublet of doublets J=11 Hz, 
7 Hz); 4.22 (2H, doubled quartet J=7 Hz, 2 Hz); 4.00 (1H broad triplet J=7 
Hz); 3.38 (2H singlet); 2.89 (1H multiplet); 2.43 (1H multiplet); 1.99 (1H 
multiplet); 1.85-1.53 (5H multiplet); 1.49 (1H multiplet); 1.24 (3H 
triplet J=7 Hz). 
d. Preparation of Ethyl Cis,Exo-Octahydrocyclopenta[b]pyrrole-2-Carboxylate 
Hydrochloride 
Treat the cis,exo-free base obtained in Part 4b in a manner identical to 
that described in Part 4c to obtain the hydrochloride of the 
cis,exo-epimer of the product of Example 1, m.p. 
111.5.degree.-113.5.degree. C. 
NMR (400 MHz - d.sub.6 DMSO): .delta. 4.49 (1H, triplet J=8 Hz); 4.24 (2H, 
quartet J=7 Hz); 4.13 (1H doublet of doublets J=7 Hz, 1.5 Hz); 3.34 (2H 
singlet); 2.77 (1H multiplet); 2.21 (1H multiplet); 1.99 (1H multiplet); 
1.87 (2H multiplet); 1.75 (2H multiplet); 1.50 (2H multiplet); 1.25 (3H 
triplet 
J=7 Hz). 
EXAMPLE 2 
ETHYL CIS,ENDO-OCTAHYDROCYCLOPENTA[b]PYRROLE-2-CARBOXYLATE 
Method I 
See Example 1, B(4)(b) (free base) and Example 1, B(4)(c) (hydrochloride). 
Method II 
A. Ethyl 1-Benzyl-1,4,5,6-Tetrahydrocyclopenta[b]Pyrrole-2-Carboxylate 
Add dropwise 3.9 gm of ethyl bromopyruvate in 50 ml of ethanol to a flask 
containing 3.46 gm of benzyliminocyclopentane and 2.0 g of triethylamine 
in 50 ml of ethanol at 0.degree. C., stir for 2 hours, then heat to reflux 
for 2 hours. Concentrate the reaction mixture and partition between 1N HCl 
and ether. Dry the ether extract over magnesium sulfate, filter, 
concentrate under high vacuum to obtain a brown oil and distill in a 
kugelrohr at 190.degree.-210.degree./0.1 mm to obtain the title compound 
of Part A as a yellow oil. 
B. Ethyl Cis,Endo-octahydrocyclopenta[b]pyrrole-2-Carboxylate Hydrochloride 
Introduce hydrogen gas to a mixture of 2.3 gm of the pyrrole compound 
produced in Method II, part A of this Example and 1.5 gm of 20% 
Pd(OH).sub.2 /C in 200 ml of ethanol, and stir the reaction mixture. After 
24 hours add an additional 0.8 gm of the palladium catalyst. After 600 ml 
of hydrogen gas is absorbed, filter the reaction mixture and concentrate 
to obtain a liquid and a solid. Take up the liquid in ether and filter. 
Treat the filtrate with 2.86N HCl/ether to obtain an oil which solidifies. 
Filter off the solid to obtain the hydrochloride salt of the title 
compound of Part B as a beige solid, m.p. 163.degree.-7.degree. C. 
Recrystallization from CH.sub.2 Cl.sub.2 and hexane raises the melting 
point to 171.degree.-2.degree. C. 
C. Cis,Endo-Octahydrocyclopenta[b]pyrrole-2-Carboxylic Acid 
Stir a mixture of 10.7 g of ethyl 
cis,endo-octahydrocyclopenta[b]pyrrole-2-carboxylate hydrochloride (from 
Part B above) and 175 ml of 1N sodium hydroxide at room temperature for 20 
hours and then concentrate in vacuo. Place the residue on a silica gel 
(1000 g, 60-200 mesh) column and elute with chloroform:isopropanol:7% 
ammonium hydroxide 1:1:1 (organic layer) to give 
cis,endo-octahydrocyclopenta[b]pyrrole-2-carboxylic acid, as a white 
solid, m.p. 220.degree.-222.degree. C.; TLC: R.sub.f 0.12 (0.25 mm silica; 
CHCl.sub.3 :isopropanol:7% NH.sub.4 OH-1:1:1-lower phase); MS: 156, 155 
(M.sup.+), 126 (M-HCO), 111 (M-CO.sub.2), 110 (MO.sub.C.sub.2 H; 100%), 93 
[M-H(CH.sub.2).sub.3 ], 82 (M-CH.sub.2 =CHCO.sub.2 H), 80 
(M-H.sub.2,CH.sub.2 =CHCO.sub.2 H), 68 [M-CO.sub.2 H, (CH.sub.2).sub.3 ], 
67 [M-HCO.sub.2 H,(CH.sub.2).sub.3 ] . 
NMR (400 MHz-D.sub.2 O); .delta. 4.39 (1H doublet of doublets J=11 Hz, 8 
Hz); 4.20 (1H multiplet); 3.00 (1H multiplet); 2.66 (1H multiplet); 
2.03-1.78 (6H multiplet); 1.57 (1H multiplet). 
Method III 
Dissolve 0.058 g of ethyl 
cis,exo-octahydrocyclopenta[b]pyrrole-2-carboxylate (from Example 1, 
B(4)(b) or from Example 5) in 20 ml of ethanol and 2 ml of triethylamine. 
Reflux under nitrogen for two days to obtain an equilibrium mixture 
consisting of approximately 25% of the cis,endo epimeric product of this 
method and 75% of the cis,exo epimeric starting material of this method. 
Remove the volatiles in vacuo and isolate the product of this Example as 
in Example 1, B(4)(b). To obtain the hydrochloride salt of the product of 
this example, treat the free base with etheral HCl as exemplified in 
Method II, Part B above, and in Example 1, B(4)(c). 
Method IV 
Dissolve 0.5 g of ethyl cis,exo-octahydrocyclopenta[b]pyrrole-2-carboxylate 
in 20 ml of absolute ethanol contain 0.66 g of potassium t-butoxide. 
Reflux under nitrogen for 18 hours, cool to ambient temperature and quench 
with solid NH.sub.4 Cl. Remove the solvent in vacuo, suspend the residue 
in 50 ml of boiling THF, filter through celite, remove the THF in vacuo 
and separate the product of this example from its cis,exo epimer as in 
Example 1, B(4)(b). The hydrochloride salt of the product of this Example 
may be obtained as in Method III. 
Method V 
Allow 0.5 g of ethyl cis,exo-octahydrocyclopenta[b]pyrrole-2-carboxylate in 
20 ml of absolute ethanol to stand at room temperature for one to two 
weeks. Remove the ethanol in vacuo and isolate the product of this example 
as in Example 1, B(4)(b). The hydrochloride salt of the product may be 
obtained as in Method III. 
The product of Example 2 is used in part A of Example 3 as the intermediate 
for producing the title compound of Example 3. 
EXAMPLE 3 
1-[N-(1(R,S)-CARBOETHOXY-3-PHENYLPROPYL)-(S)-ALANYL]-CIS,ENDO-OCTAHYDROCYCL 
OPENTA[b]PYRROLE-2(S)-CARBOXYLIC ACID 
A. To a solution of 10.0 g of 
ethyl-cis,endo-octahydrocyclopenta[b]pyrrole-2-carboxylate in 400 ml of 
ethyl acetate add 17.0 g of N-benzyloxycarbonyl-(S)-alanine, 
N-hydroxysuccinimide ester. Stir the reaction mixture at room temperature 
for 20 hours and concentrate it in vacuo. Place the residue on a column of 
silica gel (3000 g, 60-200 mesh) and elute with chloroform:ethyl acetate 
10:1 to obtain 
1-[N-benzyloxycarbonyl-(S)-alanyl]-cis,endo-octahydrocyclopenta[b]pyrrole- 
2-carboxylic acid, ethyl ester, a colorless oil [.alpha.].sub.D.sup.26 
-32.6.degree. (C=0.5, ethanol). 
B. To a solution of 3.22 g of 
1-[N-benzyloxycarbonyl-(S)-alanyl]-cis,endo-octahydrocyclopenta[b]pyrrole- 
2-carboxylic acid, ethyl ester in 150 ml of methanol, add 20 ml of 2.5 N 
sodium hydroxide and stir the mixture at room temperature for 18 hours. 
Concentrate the mixture under nitrogen, dilute the residue with ice-water 
and then make the mixture acidic with concentrated hydrochloric acid. 
Extract the aqueous solution with ethyl acetate and dry the organic phase 
over magnesium sulfate. Concentrate the organic phase and place it on a 
column of silica gel (500 g., 60-200 mesh). Elute with chloroform:glacial 
acetic acid 9:1 and isolate 
1-[N-benzyloxycarbonyl-(S)-alanyl]-cis,endo-octahydrocyclopenta 
[.beta.]pyrrole-2(S)-carboxylic acid, as a colorless oil, 
[.alpha.]D.sup.26 -26.4.degree. (C=0.5, ethanol). 
C. Dissolve 1.70 g of 
1-[N-benzyloxycarbonyl-(S)-alanyl]-cis,endo-octahydrocyclopenta[b]pyrrole- 
2(S)-carboxylic acid in 100 ml of methanol. Add 0.40 g 10% 
palladium-on-charcoal and hydrogenate the mixture at atmospheric pressure. 
Filter the mixture and concentrate in vacuo to obtain 
1-[(S)-alanyl]-cis,endo-octahydrocyclopenta[b]pyrrole-2(S)-carboxylic 
acid. 
D. Dissolve 
1-[(S)-alanyl]-cis,endo-octahydrocyclopenta[b]pyrrole-2(S)-carboxylic acid 
in 100 ml of absolute methanol. Add 1.10 g 2-oxo-4-phenylbutyric acid, 
ethyl ester and 20 ml of 3 Angstrom molecular sieve pellets, and stir the 
resulting mixture at room temperature for eighteen hours. Filter the 
reaction mixture and treat the filtrate with 0.68 g sodium 
cyanoborohydride at room temperature for two hours. Concentrate the 
mixture under nitrogen and dilute the oil with dilute hydrochloric acid 
and stir at room temperature for one hour. Absorb the aqueous solution on 
200 ml of a XAD-2 (Rohm & Haas Co. resin). Elute the resin with 2000 ml of 
water and then with 2000 ml of methanol. Concentrate the methanol solution 
and place the residue on a column of silica gel (400 g, 60-200 mesh) and 
elute with chloroform:isopropanol:7% ammonium hydroxide (1:1:1) (organic 
layer) to give 
1-[N-(1(R,S)-carboethoxy-3-phenylpropyl)-(S)-alanyl]-cis,endo-octahydrocyc 
lopenta[b]pyrrole-2(S)-carboxylic acid, as a colorless oil, 
[.alpha.]D.sup.26 - 5.8.degree. (C=10.6, ethanol). 
EXAMPLE 4 
1-[N-(1(S)-CARBOETHOXY-3-PHENYLPROPYL)-(S)-ALANYL]-CIS,ENDO-OCTAHYDROCYCLOP 
ENTA[b]PYRROLE-2(S)-CARBOXYLIC ACID, AND THE HYDROCHLORIDE SALT THEREOF 
Method I 
A. Cis,endo-Octahydrocyclopenta[b]pyrrole-2-Carboxylic Acid Hydrochloride 
Method I Add a 20% HCl in dioxane solution (100 ml) to 5 g. of 
cis,endo-octahydrocyclopenta[b]pyrrole-2-carboxylic acid. Stir the 
resulting mixture at room temperature for 30 min. and then concentrate it 
in vacuo. Wash the white residue with anhydrous ether and dry in vacuo to 
obtain the title compound of Part A as a white solid, m.p. 
209.degree.-211.degree.. 
Method II Dissolve 0.2 g of ethyl 
cis,endo-octahydrocyclopenta[b]pyrrole-2-carboxylate (free base or 
hydrochloride from Example 2 in 20 ml of 6N hydrochloric acid and reflux 
overnight. Cool the reaction mixture, remove the volatiles under high 
vacuum and obtain the title product of Part A. 
B. To 5.0 g of the product of Part A, add 50 ml of benzyl alcohol and 50 ml 
of thionyl chloride and stir at room temperature. Concentrate the reaction 
mixture in vacuo and recrystallize the residue from chloroform/isopropanol 
to give benzyl cis,endo-octahydrocyclopenta[b]pyrrole-2-carboxylate 
hydrochloride, m.p. 175.degree.. 
C. To 5.5 g of the product of Part B, add 2.6 g of 1-hydroxybenzotriazole, 
5.4 g of N[1(S)-carboethoxy-3-phenylpropyl]-(S)-alanine and 4.0 g of 
dicyclohexylcarbodiimide in 80 ml of dimethyl formamide. Stir the reaction 
mixture at room temperature for 18 hours. Filter the reaction mixture, and 
add ethyl acetate to the filtrate. Extract the ethyl acetate solution (3 
.times.200 ml) with 5% aqueous sodium bicarbonate. Concentrate the dried 
(MqSO.sub.4) ethyl acetate solution in vacuo. Chromatograph the residue on 
a silica gel column (400 g, 60-200 mesh) and elute with ethyl 
acetate/petroleum ether (30.degree.-60.degree.) 2:1. Isolate, as the first 
eluted material, 
1-[N-(1(S)-carboethoxy-3-phenylpropyl)-(S)-alanyl]-cis,endo-octahydrocyclo 
penta[b]pyrrole-2(S)-carboxylic acid benzyl ester. 
D. Hydrogenate 3.0 g of 1-[N-(1(S)-carboethoxy-3- 
phenylpropyl)-(S)-alanyl]-cis,endo-octahydrocyclopenta[b]pyrrole-2(S)-carb 
oxylic acid benzyl ester in 40 ml of ethanol containing 0.5 g of 10% Pd/C. 
Remove the catalyst by filtration and concentrate the filtrate in vacuo. 
Add absolute ether to crystallize 
1-[N-(1(S)-carboethoxy-3-phenylpropyl)-(S)-alanyl]-cis,endo-octahydrocyclo 
penta[b]pyrrole-2(S)-carboxylic acid, m.p. 110.degree.-112.degree. C.(d). 
E. Add dropwise, with stirring, a solution of 1.3 M hydrochloric acid in 
ether to the product of Part D until the mixture is pH2. Add 100 ml of 
ether and continue to stir for 30 minutes, then filter to obtain 
1-[N-1(S)-carboethoxy-3-phenylpropyl)-(S)-alanyl]-cis,endo-octahydrocyclop 
enta[b]pyrrole-2(S)-carboxylic acid hydrochloride. 
Method II 
A. Stir a solution of 4.56 g of 
N-[1(S)-carboethoxy-3-phenylpropyl]-(S)-alanine, 2.20 g of 
N-hydroxysuccinimide and 3.80 g of 
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 30 ml of 
dimethylformamide for 18 hours at room temperature. Dilute the reaction 
mixture with ethyl acetate and wash the ethyl acetate layer with saturated 
aqueous sodium chloride. Concentrate the dried (MqSO.sub.4) ethyl acetate 
solution to give N-[1(S)-carboethoxy-3-phenylpropyl]-(S)-alanine 
N-hydroxysuccinimide ester. 
B. To a mixture of 3.76 g of the product of Part A and 1.55 g of 
cis,endo-octahydrocyclopenta[b]pyrrole-2-carboxylic acid in 30 ml of 
dimethylformamide, add 1.5 ml of triethylamine and stir the resulting 
mixture at room temperature for 18 hours. Concentrate the reaction mixture 
in vacuo and partition between ethyl acetate and H.sub.2 O (adjusted to pH 
4). Wash the ethyl acetate solution with saturated aqueous sodium 
chloride. Concentrate the dried (MgSO.sub.4) ethyl acetate solution in 
vacuo and chromatograph the residue on a silica gel (1000 ml) column using 
CHCl.sub.3 /iso-PrOH/7% NH.sub.4 OH-1:1:1 (organic phase). Isolate 
1-[N-(1(S)-carboethoxy-3-phenylpropyl)-(S)-alanyl]-cis,endo-octahydrocyclo 
penta[b]pyrrole-2(S)-carboxylic acid as a foam. 
EXAMPLE 5 
ETHYL CIS,EXO-OCTAHYDROCYCLOPENTA[b]PYRROLE-2-CARBOXYLATE 
Method I 
See Example 1, B(4)(b) (free base) and Example 1, B(4)(d) (hydrochloride 
salt). 
Method II 
Dissolve 0.4 g of ethyl 
cis,endo-octahydrocyclopenta[b]pyrrole-2-carboxylate (as prepared in 
Example 1, B(4)(b) or Example 2) in 40 ml of ethanol and 7 ml of 
triethylamine. Reflux under nitrogen for five days. Remove the volatiles 
in vacuo and isolate the product of this example as in Example 1, B(4)(b). 
To obtain the hydrochloride salt of the product of this example, treat the 
free base with ethereal HCl as exemplified in Example 1 B(4)(d). 
Method III 
Substituting 0.5 g of ethyl 
cis,endo-octahydrocyclopenta[b]pyrrole-2-carboxylate for the cis,exo 
epimer, follow the procedure described in Method IV of Example 2 to obtain 
the product of this example. The hydrochloride salt may be obtained as in 
Method II. 
Method IV 
Substituting 0.5 g of ethyl 
cis,endo-octahydrocyclopenta[b]pyrrole-2-carboxylate for the cis,exo 
epimer, follow the procedure described in Method V of Example 2 to obtain 
the product of this example. The hydrochloride salt may be obtained as in 
Method II. 
EXAMPLE 6 
CIS,EXO-OCTAHYDROCYCLOPENTA[b]PYRROLE-2-CARBOXYLIC ACID 
Substituting ethyl cis,exo-octahydrocyclopenta[b]pyrrole-2-carboxylate 
(from Example 5 or from Example 1, B(4)(d) for the cis,endo-epimer, follow 
the hydrolysis procedure of Example 2C, Method II to obtain the product of 
this example. TLC: R.sub.f 0.12 (0.25 mm silica; CHCl.sub.3 
:isopropanol:7% NH.sub.4 OH-1:1:1-lower phase). 
EXAMPLE 7 
CIS,EXO-OCTAHYDROCYCLOPENTA[b]PYRROLE-2-CARBOXYLIC ACID HYDROCHLORIDE 
Method I 
Substituting the cis,exo-acid product of Example 6 for the cis,endo-epimer, 
follow the procedure of Example 4A, Method I to obtain the product of this 
example. 
NMR (400 MHz-D.sub.2 O): .delta. 4.50 (1H triplet J=5 Hz); 4.29 (1H doubled 
triplet J=9 Hz, 3.5 Hz); 2.96 (1H multiplet); 2.38 (1H multiplet); 2.14 
(1H multiplet); 2.05 (1H multiplet); 1.88 (1H multiplet); 1.80-1.60 (3H 
multiplet); 1.53 (1H 
multiplet). 
Method II 
Dissolve 0.2 g of ethyl cis,exo-octahydrocyclopenta[b]pyrrole-2-carboxylate 
[free base or hydrochloride from Example 5 or Example 1, B(4)(b) or (d)]in 
20 ml of 6N hydrochloric acid and reflux overnight. Cool the reaction 
mixture and remove the volatiles under high vacuum to obtain the product 
of this example. MS (FAB): 311 (2M+H; 5%), 156 (M+H; 100%), 112 
(M+H-CO.sub.2 ; 12%), 110 (M-CO.sub.2 H; 42%). 
EXAMPLE 8 
BENZYL CIS,EXO-OCTAHYDROCYCLOPENTA[b]-PYRROLE-2-CARBOXYLATE 
To 5.0 g of the product of Example 7, add 50 ml of benzyl alcohol and 50 ml 
of thionyl chloride and stir at room temperature. Concentrate the reaction 
mixture in vacuo and recrystallize the residue from chloroform/isopropanol 
to give benzyl cis,exo-octahydrocyclopenta-[b]pyrrole-2-carboxylate 
hydrochloride. 
EXAMPLE 9 
1-[N-(1(S)-CARBOETHOXY-3-PHENYLPROPYL)-(S)-ALANYL]-CIS,EXO-OCTAHYDROCYCLOPE 
NTA[b]PYRROLE-2(S)-CARBOXYLIC ACID AND THE HYDROCHLORIDE SALT THEREOF 
Method I 
Substituting the product of Example 8 for the cis,endo-epimer, follow the 
procedures of Example 4, Parts C, D and E of Method I to obtain the 
product of this example, as the free amino acid or as its hydrochloride 
salt. 
Method II 
Substituting the product of Example 6 for the cis,endo-epimer, follow the 
procedures in Method II of Example 4 to obtain the product of this 
example. 
EXAMPLE 10 
1-[N-(1(S)-CARBOXY-3-PHENYLPROPYL)-(S)-ALANYL]-CIS, 
ENDO-OCTAHYDROCYCLOPENTA[b]PYRROLE-2(S)-CARBOXYLIC ACID AND THE 
HYDROCHLORIDE SALT THEREOF 
A. To a solution of 0.80 g of 
1[N-(1(S)-carboethoxy-3-phenylpropyl)-(S)-alanyl]-cis,endo-octahydrocyclop 
enta[b]pyrrole-2(S)-carboxylic acid from Example 4 in 100 ml of methanol at 
0.degree.-5.degree. C., add 2.0 ml of 2.5 N sodium hydroxide solution and 
stir at room temperature for 24 hours. Concentrate this solution in vacuo 
and absorb on 350 ml of AG50W-X2 Bio-Rad resin (100-200 mesh, hydrogen 
form). Wash the column with water until the eluate is neutral and elute 
the product with pyridine:H.sub.2 O (1:24). Concentrate the uluate in 
vacuo and chromatograph on a Lobar RP-8, size B column (E. Merck) using 
acetonitrile:water (2:3) as eluant to obtain the title compound of this 
example as the free amino acid. 
B. Treat an ethanol solution of the product of Part A with one equivalent 
of a 1N solution of ethanolic hydrogen chloride. Remove the solvent in 
vacuo at room temperature to obtain the hydrochloride salt of the title 
compound of this example. 
Similarly, prepare the following compounds: 
1[N.alpha.-(1(S)-carboethoxy-3-phenylpropyl)-(S)-lysyl]-cis,endo-octahydroc 
yclopenta[b]pyrrole-2(S)-carboxylic acid. 
1[N.alpha.-(1(S)-carboethoxy-3-phenylpropyl)-(S)-lysyl]-cis,endo-octahydroc 
yclopenta[b]pyrrole-2(S)-carboxylic acid hydrochloride. 
1[N.alpha.-(1(S)-carboethoxy-3-phenylpropyl)-(S)-lysyl]-cis,endo-octahydroc 
yclopenta[b]pyrrole-2(S)-carboxylic acid dihydrochloride. 
1-[N.alpha.-(1(S)-carboxy-3-phenylpropyl)-(S)-lysyl]-cis,endo-octahydrocycl 
openta[b]pyrrole-2(S)-carboxylic acid. 
1-[N.alpha.-(1(S)-carboxy-3-phenylpropyl)-(S)-lysyl]-cis,endo-octahydrocycl 
openta[b]pyrrole-2(S)-carboxylic acid hydrochloride. 
1-[N.alpha.-(1(S)-carboxy-3-phenylpropyl)-(S)-lysyl]-cis,endo-octahydrocycl 
openta[b]pyrrole-2(S)-carboxylic acid dihydrochloride. 
1-[N-(1(S)-carboethoxybutyl)-(S)-alanyl]-cis,endo-octahydrocyclopenta[b]pyr 
role-2(S)-carboxylic acid. 
1-[N-(1(S)-carboethoxybutyl)-(S)-alanyl]-cis,endo-octahydrocyclopenta[b]pyr 
role-2(S)-carboxylic acid hydrochloride. 
1-[N-(1(S)-carboxybutyl)-(S)-alanyl]-cis,endo-octahydrocyclopenta[b]pyrrole 
-2(S)-carboxylic acid. 
1-[N-(1(S)-carboxybutyl)-(S)-alanyl]-cis,endo-octahydrocyclopenta[b]pyrrole 
-2(S)-carboxylic acid hydrochloride. 
1-[N.alpha.-(1(S)-carboethoxybutyl)-(S)-lysyl]-cis,endo-octahydrocyclopenta 
[b]pyrrole-2(S)-carboxylic acid. 
1-[N.alpha.-(1(S)-carboethoxybutyl)-(S)-lysyl]-cis,endo-octahydrocyclopenta 
[b]pyrrole-2(S)-carboxylic acid hydrochloride. 
1-[N.alpha.-(1(S)-carboethoxybutyl)-(S)-lysyl]-cis,endo-octahydrocyclopenta 
[b]pyrrole-2(S)-carboxylic acid dihydrochloride. 
1-[N.alpha.-(1(S)-carboxybutyl)-(S)-lysyl]-cis,endo-octahydrocyclopenta[b]p 
yrrole-2(S)-carboxylic acid. 
1-[N.alpha.-(1(S)-carboxybutyl)-(S)-lysyl]-cis,endo-octahydrocyclopenta[b]p 
yrrole-2(S)-carboxylic acid hydrochloride. 
1-[N.alpha.-(1(S)-carboxybutyl)-(S)-lysyl]-cis,endo-octahydrocyclopenta[b]p 
yrrole-2(S)-carboxylic acid dihydrochloride. 
1-[N-(1(S)-carboxy-3-phenylpropyl)-(S)-alanyl]-cis,exo-octahydrocyclopenta[ 
b]pyrrole-2(S)-carboxylic acid. 
1-[N-(1(S)-carboxy-3-phenylpropyl)-(S)-alanyl]-cis,exo-octahydrocyclopenta[ 
b]pyrrole-2(S)-carboxylic acid hydrochloride. 
1[N.alpha.-(1(S)-carboethoxy-3-phenylpropyl)-(S)-lysyl]-cis,exo-octahydroc 
yclopenta[b]pyrrole-2(S)-carboxylic acid. 
1[N.alpha.-(1(S)-carboethoxy-3-phenylpropyl)-(S)-lysyl]-cis,exo-octahydrocy 
clopenta[b]pyrrole-2(S)-carboxylic acid hydrochloride. 
1[N.alpha.-(1(S)-carboethoxy-3-phenylpropyl)-(S)-lysyl]-cis,exo-octahydrocy 
clopenta[b]pyrrole-2(S)-carboxylic acid dihydrochloride. 
1-[N.alpha.-(1(S)-carboxy-3-phenylpropyl)-(S)-lysyl]-cis,exo-octahydrocyclo 
penta[b]pyrrole-2(S)-carboxylic acid. 
1-[N.alpha.-(1(S)-carboxy-3-phenylpropyl)-(S)-lysyl]-cis,exo-octahydrocyclo 
penta[b]pyrrole-2(S)-carboxylic acid hydrochloride. 
1-[N.alpha.-(1(S)-carboxy-3-phenylpropyl)-(S)-lysyl]-cis,exo-octahydrocyclo 
penta[b]pyrrole-2(S)-carboxylic acid dihydrochloride. 
1-[N-(1(S)-carboethoxybutyl)-(S)-alanyl]-cis,exo-octahydrocyclopenta[b]pyrr 
ole-2(S)-carboxylic acid. 
1-[N-(1(S)-carboethoxybutyl)-(S)-alanyl]-cis,exo-octahydrocyclopenta[b]pyrr 
ole-2(S)-carboxylic acid hydrochloride. 
1-[N-(1(S)-carboxybutyl)-(S)-alanyl]-cis,exo-octahydrocyclopenta[b]pyrrole- 
2(S)-carboxylic acid. 
1-[N-(1(S)-carboxybutyl)-(S)-alanyl]-cis,exo-octahydrocyclopenta[b]pyrrole 
-2(S)-carboxylic acid hydrochloride. 
1-[N.alpha.-(1(S)-carboethoxybutyl)-(S)-lysyl]-cis,exo-octahydrocyclopenta[ 
b]pyrrole-2(S)-carboxylic acid. 
1-[N.alpha.-(1(S)-carboethoxybutyl)-(S)-lysyl]-cis,exo-octahydrocyclopenta[ 
b]pyrrole-2(S)-carboxylic acid hydrochloride. 
1-[N.alpha.-(1(S)-carboethoxybutyl)-(S)-lysyl]-cis,exo-octahydrocyclopenta[ 
b]pyrrole-2(S)-carboxylic acid dihydrochloride. 
1-[N.alpha.-(1(S)-carboxybutyl)-(S)-lysyl]-cis,exo-octahydrocyclopenta[b]py 
rrole-2(S)-carboxylic acid. 
1-[N.alpha.-(1(S)-carboxybutyl)-(S)-lysyl]-cis,exo-octahydrocyclopenta[b]py 
rrole-2(S)-carboxylic acid hydrochloride. 
1-[N.alpha.-(1(S)-carboxybutyl)-(S)-lysyl]-cis,exo-octahydrocyclopenta[b]py 
rrole-2(S)-carboxylic acid dihydrochloride. 
The compounds of this invention are useful in view of their pharmacological 
properties. In particular, they possess activity as antihypertensive 
agents as evidenced by their ability to reduce blood pressure in mammals, 
including humans, in which the blood pressure has become abnormally 
elevated. 
The compounds of the present invention can be combined with pharmaceutical 
carriers and administered in a variety of well known pharmaceutical forms 
suitable for oral or parenteral administration to provide compositions 
useful in the treatment of cardiovascular disorders and particularly 
mammalian hypertension. 
The effective dose (ED.sub.50) of the compounds of this invention will 
typically be in the range of about 0.01 to about 30 mg/kg, preferably 
about 0.1 to about 10 mg/kg, of mammalian weight, administered in single 
or divided doses. The exact dose to be administered is determined by the 
attending clinician and is dependent upon where the particular compound 
lies within the above quoted range, as well as upon the age, weight and 
condition of the individual. 
Generally, in treating humans, the compounds of this invention may be 
administered to patients in need of such treatment in a dosage range of 5 
to 500 mg per patient generally given several times, thus giving a total 
daily dose of from 5 to 2000 mg per day. Also, the compounds of this 
invention may be given in combination with diuretics or other 
antihypertensives. Typically, these are combinations whose individual per 
day dosages range from one-fifth of the minimally recommended clinical 
dosages to the maximum recommended levels for the entities when they are 
given singly. Examples of such diuretics or other antihypertensives are 
hydrochlorothiazide, chlorothiazide, ethacrynic acid, amiloride, 
furosemide, propanolol, timolol and methyldopa. 
Since the compounds of the present invention are believed to act as 
angiotensin converting enzyme inhibitors, it is also contemplated that 
they may be used in treating other cardiovascular disorders, for example 
congestive heart failure, in the same manner as other ACE inhibitors such 
as captopril and enalapril may be used. In addition, the compounds of this 
invention may be used in the treatment of glaucoma by topical application. 
The composition containing the compounds of this invention will preferably 
contain about 5 to about 250 mg of the active compound per dosage unit. 
These compositions are most preferably administered orally. Typical 
formulations for oral administration are those such as tablets, capsules, 
syrups, elixirs or suspensions. Typical injectable formulations include 
solutions and suspensions. 
Typical acceptable pharmaceutical carriers for use in the formulations 
described above are exemplified by: sugars such as lactose, sucrose, 
mannitol and sorbitol; starches such as corn starch, tapioca starch and 
potato starch; cellulose and derivatives such as sodium carboxymethyl 
cellulose, ethyl cellulose and methyl cellulose; calcium phosphates such 
as dicalcium phosphate and tri-calcium phosphate; sodium sulfate; calcium 
sulfate, polyvinylpyrrolidone, polyvinyl alcohol; stearic acid; alkaline 
earth metal stearates such as magnesium stearate and calcium stearate, 
stearic acid vegetable oils such as peanut oil, cottonseed oil, sesame 
oil, olive oil and corn oil; non-ionic, cationic and anionic surfactants; 
ethylene glycol polymers; beta-cyclodextrin; fatty alcohols and hydrolyzed 
cereal solids; as well as other non-toxic compatible fillers, binders, 
disintegrants, buffers, preservatives, antioxidants, lubricants, flavoring 
agents, and the like commonly used in pharmaceutical formulations. 
For treatment of glaucoma, a compound of this invention is preferably 
administered in the form of ophthalmic pharmaceutical compositions adapted 
for topical administration to the eye, such as solutions, ointments or 
solid inserts. Formulations of these compounds may contain from 0.01 to 5% 
and especially 0.25 to 2% of medicament. Other concentrations may be 
employed provided the dose is effective in lowering intraocular pressure. 
As a unit dosage form, between 0.01 to 2.5 mg., preferably 0.05 to 2.5 
mg., and especially 0.1 to 1.0 mg. of the active compound is applied to 
the human eye, generally on a daily basis. Individual dosage requirements 
are variable, however, and must be administered on the basis of the 
severity of the disease and the response of the patient. 
Typical pharmaceutical carriers for topical opthalmological administration 
are well known in the art, see for example U.S. Pat. No. 4,312,863, the 
relevant portions of which are herein incorporated by reference. 
The following examples describe in detail compositions that are 
illustrative of the present invention. It will be apparent to those 
skilled in the art that many modifications, both of materials and methods, 
may be practiced without departing from the purpose and intent of this 
disclosure. 
In the following examples, the active ingredient is 
1-{[N-[1(S)-carboethoxy-3-phenylpropyl]-(S)-alanyl}cis,endo-octahydrocyclo 
penta[b]pyrrole-2(S)-carboxylic acid or equivalent amounts of its 
pharmaceutically acceptable salts. 
EXAMPLE 11 
______________________________________ 
Capsule Amount (mg) 
______________________________________ 
Active ingredient 250.0 125.0 
Lactose 173.0 86.5 
Corn Starch 75.0 37.5 
Magnesium Stearate 
2.0 1.0 
500.0 250.0 
______________________________________ 
Blend the active ingredient, lactose and corn starch until uniform; then 
blend the magnesium stearage into the resulting powder. Encapsulate the 
mixture into suitably sized two-piece hard gelatin capsules. 
EXAMPLE 12 
______________________________________ 
Tablet Amount (mg) 
______________________________________ 
Active ingredient 
250.0 125.0 
Lactose 161.0 80.5 
Corn Starch 12.0 6.0 
Water (per thousand tablets) 
120 ml 60 ml 
(evaporates) 
(evaporates) 
Corn Starch 75.0 37.5 
Magnesium Stearate 
2.0 1.0 
500.0 250.0 
______________________________________ 
Blend the active ingredient with the lactose until uniform. Blend the 
smaller quantity of corn starch with the water and add the resulting corn 
starch paste, then mix until a uniform wet mass is formed. Add the 
remaining corn starch to the remaining wet mass and mix until uniform 
granules are obtained. Screen the granules through a suitable milling 
machine, using a 3/4 inch stainless steel screen. Dry the milled granules 
in a suitable drying oven until the desired moisture content is obtained. 
Mill the dried granules through a suitable milling machine using a 16 mesh 
stainless steel screen. Blend in the magnesium stearate and compress the 
resulting mixture into tablets of desired shape, thickness, hardness and 
disintegration. 
EXAMPLE 13 
______________________________________ 
Injectable Solution 
mg/ml 
______________________________________ 
Active ingredient 5.00 
Methyl -p-hydroxybenzoate 
0.80 
Propyl -p-hydroxybenzoate 
0.10 
Disodium Edetate 0.10 
Citric Acid Monohydrate 
0.08 
Dextrose 40.0 
Water for injection qs. ad 
1.0 ml 
______________________________________ 
Dissolve the p-hydroxybenzoates in a portion of water for injection at 
60.degree.-70.degree. C. and cool the solution to 25.degree.-35.degree. C. 
Charge and dissolve all other excipients and the active ingredient. Bring 
the solution to final volume, filter it through a sterilizing membrane and 
fill into sterile containers. 
EXAMPLE 14 
______________________________________ 
Ophthalmic Solution Amount (mg) 
______________________________________ 
Active ingredient 1 
Sodium phosphate monobasic.2H.sub.2 O 
9.38 
Dibasic sodium phosphase.12H.sub.2 O 
28.48 
Benzalkonium chloride 
0.10 
Sodium hydroxide q.s. 
pH 6.8 
Water q.s. ad. 1.0 ml 
______________________________________ 
The active ingredient, phosphate buffer salts and benzalkonium chloride are 
added to and dissolved in water. The pH of the solution is adjusted to 6.8 
with sodium hydroxide and the final solution diluted to volume. The 
solution is rendered sterile by filtration through a sterilizing filter. 
Following the procedures of Examples 11, 12, 13 and 14, substitute other 
compounds of the present invention for 
1-{[N-[1(S)-carboethoxy-3-phenylpropyl]-(S)-alanyl}-c is 
endo-octahydrocyclopenta [b]pyrrole-2(S)-carboxylic acid to prepare other 
compositions of the present invention.