A compound of the formula ##STR1## and the pharmaceutically acceptable acid addition salts thereof are potent antihypertensive agents and are therefore useful as cardiovascular system regulators. These compounds are also useful as bronchodilators.

BACKGROUND OF THE INVENTION 
1. Field of the invention 
This invention concerns 
.+-.2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-hydroxy)-.alpha. 
-hydroxybenzyl]pyrrolidines which affect the cardiovascular system and 
which are particularly effective as antihypertensive agents. The invention 
is directed mainly toward orally active, long lasting cardiovascular 
regulators of hypertension. However, the compounds of this invention are 
also potent bronchodilators. 
The invention is also directed toward pharmaceutical compositions useful 
for management of hypertension and toward the method of use for regulating 
the cardiovascular system in mammals. 
2. Related Disclosures 
The invention herein concerns cyclic analogs of compounds known to possess 
molecular segments which affect peripheral nervous system receptors 
regulating the cardiovascular system. These compounds are also effective 
as bronchodilators. 
Various physiological responses result from administering pharmaceuticals 
which affect the cardiovascular system regulating receptors. These 
responses may vary from vasodilation, vasoconstriction, tachycardia, 
bradycardia, positive or negative inotropic effect. Secondary effects such 
as bronchodilation or bronchoconstriction can also appear. 
The physiological response depends on the exact nature of the drug. 
Therefore, various members of the same general class of compounds may be 
used in the treatment of cardiac disorders such as hypertension, cardiac 
arrhythmia, and vasal congestion. 
The following resume represents a compilation of the known compounds which 
most closely resemble, in molecular structure, the compounds of the 
present invention, and which are useful in treating cardiovascular 
disorders and in other therapeutic applications. 
Practolol and prenalterol which are amino-alcohol aryl ethers are well 
known and commercially available compounds which affect the .alpha..sub.1 
adrenergic receptors of the peripheral system. 
Sulfinolol, (British Pat. No. 1,544,872, published Apr. 25, 1979) and its 
relatives, are known antihypertensive/antiarrhythmic agents. 
Deliberate attempts to combine .alpha..sub.1 affectors with vasodilators 
resulted in compounds such as naphthalenone phthalazinylhydrazones. 
Naphthalenone phthalazinylhydrazones may be hydrolyzed in the body to form 
a well known peripheral vasodilator hydralazine, and a general .alpha. 
adrenergic blocker bunolol, (see U.S. Pat. No. 4,061,636). 
Cyclic compounds containing a 5 or 6 membered saturated nitrogen-containing 
ring, linked through a hydroxymethyl group to an aromatic nucleus, such 
as, for example, rimeterol (Pinder, R. M. et al, Drugs, 14:81 (1977)) and 
other compounds disclosed in European Pat. No. 10460, published Apr. 30, 
1980 are known psychotropic and hypolipaemic agents. Rimeterol, itself, is 
a known .alpha..sub.2 agonist which is effective when given parentherally, 
but not effective when administered orally. Some of these compounds have 
recently been described as having hypotensive effect (See European Pat. 
No. 22408). 
British Pat. No. 1,392,674, published Apr. 30, 1975, discloses compounds 
related in structure to those of the current invention which are useful 
for treatment of acute slowdown cardiac contractility. 
U.S. Pat. No. 4,342,692 and its EPO counterpart disclose a family of 
compounds which may be interpreted to be similar to the compounds of the 
current invention. U.S. Pat. No. 3,655,693 discloses salicylic acid 
derivatives useful in the treatment of inflammation. U.S. Pat. No. 
3,984,200 discloses mono or dihydroxyphenylalkyl dopamine derivatives 
useful as inotropic agents. 
The present invention is directed toward orally active, long acting 
cardiovascular regulators. The compounds combine, in a sterically 
controlled way, two segments related to structures showing analogous 
activities (i.e. an arylhydroxymethyl or benzyl moiety bridged through a 
short chain to nitrogen and another aromatic group also linked to a 
nitrogen), by joining these through a common nitrogen atom cyclized to 
form a pyrrolidine ring. 
The compound of this invention have a strong antihypertensive activity. The 
antihypertensive activity of the compounds of this invention is best shown 
by their effect on the systolic blood pressure. The compounds of this 
invention decrease significantly the systolic blood pressure without at 
the same time increasing heart rates. Moreover, the dosage which is needed 
to decrease systolic blood pressure is very low and the secondary, often 
undesirable, side effects are thus avoided. Thus, this invention offers 
the effective management of hypertension without submitting the treated 
subject to the undesirable secondary effects which would be unavoidable if 
large doses are needed. 
SUMMARY OF THE INVENTION 
One aspect of this invention relates to compounds of the formula 
##STR2## 
and their pharmaceutically acceptable acid addition salts. These compounds 
are potent antihypertensive agents and are therefore useful as 
cardiovascular system regulators. 
The other aspect of this invention relates to the mixture of and to 
individual stereoisomers, namely cis erythro, cis threo, trans erythro and 
trans threo isomers of the above compounds. 
Yet another aspect relates to the method of use of the compounds of this 
invention as cardiovascular regulators and to the pharmaceutical 
composition useful in regulating cardiovascular disorder, particularly in 
managing hypertension. 
DETAILED DESCRIPTION OF THE INVENTION 
Definitions 
As used hereinafter: 
"Noble metal catalyst" is a catalyst such as platinum on carbon, platinum 
oxide, palladium on carbon, or rhodium on carbon, but other noble metal 
catalysts suitable to effect catalytic reductions are also included. 
"Protection" or "Protecting group" refer to the protection of phenolic 
hydroxyl groups. A phenolic hydroxyl group is present in compounds 
prepared by the process of this invention. In order to preserve the 
phenolic hydroxyl group during the catalytic reduction, O-protection is 
often required for phenols, which react readily with oxidizing agents, 
electrophiles, or even with mild alkylating and acylating agents. The 
protection of phenolic hydroxyl groups can be achieved with any suitable 
protecting group such as an alkyl ether, for example methyl ether, 
isopropyl ether, t-butyl ether; alkoxymethyl ether, for example 
methoxymethyl ether; alkoxyethoxymethyl ether, for example 
methoxyethoxymethyl ether; cycloalkylmethyl ether, for example 
cyclopropylmethyl ether; alkyldimethylsilyl ether, for example 
t-butyldimethylsilyl ether, 9-anthrylmethyl ether, preferably substituted 
or unsubstituted benzyl ether. [Protective Groups in Organic Synthesis, 
John Wiley & Sons, New York, pp:87-100(1980); Synthesis, (II): 987 
(1982)]. 
"N-Protection" or "N-Protecting groups" refer to electron withdrawing 
groups which make pyrrole less aromatic and more susceptible to the 
reduction. Electron withdrawal achieved through the utilization of 
N-protection of the nitrogen atom of the pyrrole can be best illustrated 
by attachment of the acyl N-protecting group, i.e. 
##STR3## 
where R may be aryl, phenyl, substituted phenyl, alkyl of 1-4 carbons with 
branched alkyl preferred, alkoxy of 1-4 carbons with branched alkoxy 
preferred. Exemplary N-protecting groups for the pyrrole nitrogen atom are 
alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 
t-butoxycarbonyl and the like, or alkylcarbonyl such as methylcarbonyl, 
ethylcarbonyl, propylcarbonyl and the like, or alkanoyl such as ethanoyl, 
propanoyl, butanoyl and the like, or aroyl. 
"Aroyl" means the radical ZCO-- wherein Z is an aromatic group such as, for 
example, benzoyl or naphthoyl. 
"Wt %" (weight percent) used for solids means the weight of one solid 
relative to the total weight of all reactants. For example, if 10 wt % of 
catalyst is given, then 10 g of catalyst are added for 90 g of other 
reactants. 
"Mild reaction conditions" means that the reaction is run at the low 
temperature between 10.degree.-35.degree. C., preferably ambient and at 
pressures of 1-5 atmospheres, preferably at atmospheric pressure, in the 
presence of a suitable organic solvent. 
"Organic solvent" means liquid organic compound with the power to dissolve 
solids or liquids at mild reaction conditions. The term is meant to 
include cyclic and acyclic compounds such as alcohols of 1-4 carbons, 
lower alkyl ester of alkanoic acids, ethers, cyclic ethers and the like. 
Examplary solvents are methanol, ethanol, ethyl acetate, tetrahydrofuran, 
benzene or mixtures thereof. 
"Lower alkyl" means a branched or unbranched saturated hydrocarbon chain 
containing from one to four carbon atoms, such as, for example, methyl, 
ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl and the like. 
"Cycloalkyl" means a saturated monocyclic hydrocarbon of 3-7 carbons 
without side chains, such as cyclopropane, cyclobutane, cyclopentane, 
cyclohexane and cycloheptane. 
"Alkoxy" means --OR wherein R is lower alkyl as defined hereinabove. 
"Alkoxycarbonyl" means --C(O)--OR wherein R is lower alkyl as defined 
hereinabove. 
"Alkylcarbonyl" means --C(O)--R wherein R is lower alkyl as defined 
hereinabove. 
Hereinafter ".alpha.-hydroxybenzyl" or "phenylhydroxymethyl" mean compounds 
of the formula 
##STR4## 
"Strong acid" means an organic or inorganic, water soluble, easily 
dissociable Bronsted Lowry acid, such as methanesulfonic, trifluoroacetic, 
hydrochloric, sulfuric, phosphoric acid and the like. 
"Strong base" means an inorganic, water soluble base such as sodium 
hydroxide, sodium carbonate, potassium carbonate, and the like. 
"N-acylating" means the formation or introduction of acyl radical 
##STR5## 
to the N-atom of the pyrrole ring. 
"Ph" in Reaction Schemes drawings means phenol. 
STEREOCHEMICAL CONTROL 
The 
.+-.2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-hydroxy)-.alpha. 
-hydroxybenzyl]pyrrolidines have three chiral centers. Two chiral centers 
are at the 2- and 5-positions of the pyrrolidine ring at which the side 
chains are substituted. The third chiral center is introduced in 
pyrrolidines where the side chain attached to the 5-position is 
.alpha.-hydroxybenzyl. 
Compounds with three chiral centers can be obtained as four 
diastereoisomeric racemates or as eight optical isomers in total. The 
nomenclature (.+-.)cis erythro, (.+-.)cis threo, (.+-.)trans erythro and 
(.+-.)trans threo is used to describe individual diastereoisomers. 
Embodiments wherein hydrogens at 2- and 5-positions are on the same side of 
the plane of the pyrrolidine ring are designated "cis". Embodiments where 
hydrogens at 2- and 5-position are on opposite sides are "trans." 
##STR6## 
"Erythro/threo" terminology is used to designate the relationship between 
the configurations of the group attached to the carbon atom bearing the 
hydroxyl substituent and of the number 5 carbon of the pyrrolidine ring to 
which it is attached. 
"Erythro" indicates those embodiments wherein the hydrogen of carbon atom 5 
of the ring and the hydrogen of the hydroxylated carbon occupy the same 
side of the molecule. 
"Threo" indicates those embodiments where the hydrogen of carbon atom 5 of 
the ring and the hydrogen of the hydroxylated carbon are on the opposite 
sides of the molecule. For the numbering system, see below. 
##STR7## 
See Stereochemistry of Carbon Compounds, McGraw-Hill, pp. 16-86 (1962); 
RECUEIL, 83:535, (1964); and Morison and Boyd, Organic Chemistry, 3d Ed., 
pp. 148-153, (1974). 
Numbering on the phenyl rings of the pyrrole or pyrrolidine molecule is 
illustrated below. 
##STR8## 
It is to be understood that this invention discloses and encompasses each 
of the racemates, racemic mixtures, diastereomer and enantiomers. 
PREFERRED EMBODIMENTS 
Presently preferred embodiments of this invention are compounds of the 
formula 
##STR9## 
namely, .+-.trans threo 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-hydroxy)-.alpha.-hyd 
roxybenzyl]pyrrolidine. 
More preferred embodiments are compounds of the formula 
##STR10## 
namely, .+-.trans erythro 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-hydroxy)-.alpha.-hyd 
roxybenzyl]pyrrolidine. 
Other more preferred embodiments are compounds of the formula 
##STR11## 
namely, .+-.cis threo 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-hydroxy)-.alpha.-hyd 
roxybenzyl]pyrrolidine. 
Most preferred embodiments are compounds of the formula 
##STR12## 
namely, .+-.cis erythro 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-hydroxy)-.alpha.-hyd 
roxybenzyl]pyrrolidine. 
PREATION PROCEDURES 
A compounds of this invention are prepared by the reaction sequence 
illustrated in Reaction Scheme 1-4. Reaction Scheme 1 illustrates the 
preparation of .+-.cis erythro 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-hydroxy)-.alpha.-hyd 
roxybenzyl]pyrrolidine. Reaction Scheme 2 illustrates the preparation of 
.+-.cis threo 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-hydroxy)-.alpha.-hyd 
roxybenzyl]pyrrolidine. Reaction Scheme 3 illustrates preparation of 
.+-.trans erythro 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-hydroxy)-.alpha.-hyd 
roxybenzyl]pyrrolidine and Reaction Scheme 4 illustrates preparation of 
.+-.trans threo 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-hydroxy)-.alpha.-hyd 
roxybenzyl]pyrrolidine. 
##STR13## 
Step 1. Step 1 describes the preparation of 
2-[(3,4-methylenedioxy)phenylacetyl]pyrrole (III) from pyrrole (IIb) and 
[(3,4-methylenedioxy)phenylacetyl]morpholide (IIa). 
Pyrrole (IIb) is commercially available from Aldrich. 
[(3,4-methylenedioxy)phenylacetyl]morpholide (IIa) is prepared by reacting 
phenylacetic acid with thionyl chloride and with a small amount of 
dimethylformamide for 10-60 minutes at the temperature of 
10.degree.-30.degree. C., preferably at room temperature. The resulting 
mixture is reacted with morpholine dissolved in an organic solvent, 
preferably in dry dichloromethane, to give 
[(3,4-methylenedioxy)phenylacetyl]morpholide (IIa). 
[(3,4-methylenedioxy)phenylacetyl]morpholide (IIa) in the presence of an 
acylating agent, such as acid halides, preferably phosphorous oxychloride, 
is reacted under the constant stirring for 3-10 hours, preferably for 6 
hours. Pyrrole (IIb) dissolved in a chlorinated hydrocarbon solvent, 
preferably in anhydrous 1,2-dichloroethane, is added. The reaction mixture 
is stirred for 12-20 hours, alkalized, and purified by methods known in 
the art to obtain 2-[(3,4-methylenedioxy)phenylacetyl]pyrrole (III). 
Step 2. Step 2 describes the conversion of 
2-[(3,4-methylenedioxy)phenylacetyl]pyrrole (III) to 
2-[(3,4-methylenedioxy)phenethyl]pyrrole (IV). 
Compound (III) is dissolved in an ethereal solvent, preferably dry 
tetrahydrofuran, and a complex metal hydride, preferably lithium aluminum 
hydride, is added. The mixture is reacted at reflux temperature for 35-55 
hours, preferably 48 hours. Excess of hydride is destroyed with an organic 
solvent and the reaction mixture is purified by methods known in the art 
to afford 2-[(3,4-methylenedioxy)phenethyl]pyrrole (IV). 
Step 3. Step 3 describes the preparation of 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy)benzoyl]py 
rrole (V). 
[(3-carboxamido-4-benzyloxy)benzoyl]morpholide (I) is prepared from 
(3-carboxamido-4-benzyloxy)benzoic acid by procedure similar to that of 
Step 1. (3-carboxamido-4-benzyloxy)benzoic acid, in turn, is prepared from 
(3-carboxamido-4-hydroxy)benzoic acid which is a known compound of which 
preparation is described in Brit. Pat. No. 802,841, issued Oct. 15, 1958, 
in J. Chem. Soc., pp. 4678 (1956), and in Chem. in Industry, pp. 417 
(1955)). 
It should be noted that in order to prepare .+-.cis erythro 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-hydroxy)benzoyl]pyrr 
ole (X), 4-hydroxy phenolic group of the compounds undergoing reaction 
steps 3-7, 9-10, 12-14 and 16-17 must be protected. Usually, such 
protection is achieved with benzylation of phenolic hydroxy group. 
Therefore, compound I with benzyloxy protecting group must be prepared. 
Benzylation of phenolic hydroxy group begins with dissolving methyl ester 
of (3-carboxamido-4-hydroxy)benzoic acid in an organic solvent, preferably 
in dimethylformamide, and treating it with metal hydride, preferably with 
1 equivalent of sodium hydride, at a temperature of 10.degree.-30.degree. 
C., preferably at room temperature. The mixture is stirred until the 
compounds dissolve, for about 5-6 minutes and benzyl halide, preferably 
benzyl bromide or chloride is added. The mixture is again stirred at a 
temperature of 15.degree.-50.degree. until reaction is complete, usually 
for 1-3 hours. The mixture is purified with methods known in the art and 
the methyl ester (3-carboxamido-4-benzyloxy)benzoic acid is hydrolyzed 
with aqueous bicarbonate or carbonate in lower alcohol such as methanol or 
ethanol to obtain (3-carboxamido-4-benzyloxy)benzoic acid which is then 
submitted to the same procedure as described in Step 1 to obtain 
[(3-carboxamido-4-benzyloxy)benzoyl]morpholide (I). 
Alternately, the compound (X) may also be prepared from the 
(3-nitrile-4-hydroxy)benzoic acid. This compound is known and is described 
in German Patent No. 2,224,681, issued on Oct. 10, 1970, and in 
corresponding Brit. Applic. 16197-7), published on May 21, 1971. 
(3-nitrile-4-hydroxy)benzoic acid is benzylated using the procedure 
described above for (3-carboxamido-4-hydroxy)benzoic acid and as such, 
i.e. (3-nitrile-4-benzyloxy)benzoic acid, (3-nitrile-4-benzyloxy)benzoyl 
and (3-nitrile-4-benzyloxy).alpha.-hydroxybenzyl is carried through the 
Steps 3-7, 9-10, 12-14 and 16-17. Before debenzylating Steps 8, 11, 15 and 
18, a nitrile compound is hydrolyzed to the carboxamido with 10-20% 
aqueous hydrochloric acid in a polar solvent such as, for example, 
methanol for about 0,5-5 hours. The nitrile compound can also be 
hydrolyzed to its corresponding carboxamido compound with 1 equivalent of 
aqueous sodium hydroxide in a polar solvent. 
[(3-carboxamido-4-benzyloxy)benzoyl]morpholide is reacted with an acylating 
agent, preferably phosphorous oxychloride, at a room temperature for 2-4 
hours. Then the compound (IV), dissolved in an organic solvent, preferably 
in 1,2-dichloroethane, is added and the mixture is stirred for 15-21 
hours, preferably for 18 hours. The mixture is purified by methods known 
in the art to give 
.+-.2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy)benzoy 
l]pyrrole (V). 
Step 4. Step 4 describes the attachment of the protective group R.sub.2 to 
the N atom of the pyrrole compound (V). 
Compound (V) is dissolved in a suspension of an ethereal or dipolar 
solvent, preferably in dry dimethylformamide, and mixed with sodium 
hydride. The mixture is heated to 45.degree.-60.degree. for 1-3 hours, 
preferably 2 hours. Suitble N-protecting agent R.sub.2, such as 
aroylchloride, alkanoylchloride, alkylchloroformate, preferably 
di-t-butylcarbonate, is added and the mixture is stirred at 
60.degree.-70.degree. for 1-3 hours. After purification and 
crystallization by methods known in the art, 
.+-.N-protected-2-[(3,4-methylenedioxy)phenethyl]-5-[3-carboxamido-4-benzy 
loxy)benzoyl]pyrrole, preferably 
.+-.1-t-butoxycarbonyl-2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido 
-4-benzyloxy)benzoyl]pyrrole (VI) is obtained. 
Step 5. Step 5 describes a catalytic reduction of 
.+-.1-t-butoxycarbonyl-2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido 
-4-benzyloxy)benzoyl]pyrrolidine (VII). 
Pyrrole (VI) is reduced in the presence of the noble metal catalyst, such 
as rhodium on carbon, rhodium on aluminum, platinum oxide, preferably with 
platinum on carbon, in the solvent or solvent mixture containing lower 
alcohol, lower alkyl ester or ethereal solvent. The preferred solvent is 
ethyl acetate. Reduction is carried on under the mild reaction conditions, 
at the room temperature and pressure of 1-3 atmospheres, preferably at 
atmospheric pressure for 15-28 hours, preferably for 22 hours. The reduced 
compound is purified and crystallized by the methods known in the art to 
give .+-.cis 
1-t-butoxycarbonyl-2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-b 
enzyloxy)benzoyl]pyrrolidine (VII). 
Step 6. Step 6 describes the removal of the N-protecting R.sub.2 group from 
the compound (VII). 
A solution of .+-.cis 
1-t-butoxycarbonyl-2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-b 
enzyloxy)benzoyl]pyrrolidine (VII) in chlorinated hydrocarbon, preferably 
dry dichloromethane, is added to a strong protic acid, preferably 
trifluoroacetic acid. The reaction is carried on for 1-3 hours at room 
temperature. After purification and crystallization by methods known in 
the art, .+-.cis 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy)benzoyl]py 
rrolidine trifuoroacetate (VIII) is obtained. 
Step 7. Step 7 describes the reduction of .+-.cis 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy)benzoyl]py 
rrolidine trifluoroacetate (VIII) to .+-.cis erythro 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy)-.alpha.-h 
ydroxybenzyl]pyrrolidine (IX). 
Compound (VIII) is reduced to compound (IX) with a metal borohydride, 
preferably sodium borohydride dissolved in lower alcohol, preferably in 
ethanol at 0.degree. temperature. The mixture is reacted for 0.5-3 hours 
and the solvent is removed. The aqueous residue is diluted with base such 
as sodium carbonate and the product is extracted with an organic solvent, 
preferably with ethyl acetate. The extract is washed with water, dried 
over sodium sulfate, purified, and crystallized by the methods known in 
the art to give .+-.cis erythro 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy)-.alpha.-h 
ydroxybenzyl]pyrrolidine (IX). 
Step 8. Step 8 describes the conversion of compound (VIII) in which hydroxy 
group is protected phenolic hydroxyl, for example benzyloxy, to the 
compound (X) with unprotected hydroxyl. 
The reduction is conducted in alcohol, preferably methanol, in the presence 
of 5-50 wt % of the noble metal catalyst, preferably 5-20% palladium on 
carbon. Reduction proceeds at temperatures of 10.degree.-36.degree., 
preferably at room temperature, and at atmospheric pressure for 1-100 
hours. Purification by methods known in the art and recrystallization from 
a suitable solvent, preferably acetonitrile, gives compound (X) with 
unprotected hydroxyl group, namely .+-.cis erythro 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-hydroxy)-.alpha.-hyd 
roxybenzyl]pyrrolidine. 
Reaction Scheme 2 illustrates preparation of cis threo 
.+-.2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-hydroxy)-.alpha. 
-hydroxybenzyl]pyrrolidine. 
##STR14## 
Step 9. Step 9 describes the reduction of keto compound (VII) to the 
mixture of .alpha.-hydroxybenzyl compounds (XI') and (XI), and subsequent 
separation of the obtained mixture into .+-.cis erythro isomer (XI') and 
.+-.cis threo isomer (XI) of 
N-protected-2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzylox 
y)-.alpha.-hydroxybenzyl]pyrrolidine. 
Step 9A. .+-.N-protected cis 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy)benzoyl]py 
rrolidine (VII) (see Reaction Scheme 1) is reduced with metal borohydride, 
preferably with sodium borohydride, in lower alcohol, preferably ethanol 
or methanol, at -10.degree. to +20.degree. C., for 0.5-50 hours. The 
product obtained after purification by methods known in the art is the 
mixture of both .+-.cis erythro (XI') and .+-.cis threo 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy)-.alpha.-h 
ydroxybenzyl]pyrolidines (XI). 
Step 9B. Obtained mixture of cis erythro and cis threo isomers (XI') and 
(XI) is separated by thin layer chromatography (TLC), column 
chromatography, crystallization, or any other common separation technique, 
preferably by TLC, to obtain .+-.cis erythro 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy)-.alpha.-h 
ydroxybenzyl]pyrrolidine (XI') and .+-.cis threo 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy)-.alpha.-h 
ydroxybenzyl]pyrrolidine (XI). 
Cis erythro compound (XI') is then submitted to Step 6 (Reaction Scheme 1) 
to remove N-protecting group R.sub.2. 
Step 10. Step 10 describes the removal of the N-protecting group from 
.+-.cis threo 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy)-.alpha.-h 
ydroxybenzyl]pyrrolidine. 
A solution of cis threo compound (XI) in chlorinated hydrocarbons, 
preferably dichloromethane, is added to a strong protic acid, such as 
hydrochloric acid or hydrobromic acid, preferably trifluoroacetic acid. 
The mixture is reacted for 1-50 hours at -10.degree. to +20.degree. C. 
temperature. The solvent is evaporated and the residue is purified to 
obtain .+-.cis threo 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy)-.alpha.-h 
ydroxybenzyl]pyrrolidine trifluoroacetate (XII). 
Step 11. Step 1 describes the debenzylation of compound (XII) wherein 
hydroxy group is protected phenolic hydroxyl, for example benzyloxy, to 
the compound (XIII). 
The reduction is conducted in alcohol, preferably methanol, in the presence 
of 5-50 wt% of the noble metal catalyst, preferably 5-20% palladium on 
carbon. Reduction proceeds at temperatures of 10.degree.-36.degree., 
preferably at room temperature, and at atmospheric pressure for 1-100 
hours. Purification by methods known in the art and recrystallization from 
a suitable solvent, preferably acetonitrile, gives compound (XIII) with 
unprotected hydroxyl group. 
##STR15## 
Reaction Scheme 3 illustrates the preparation of .+-.trans erythro 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-hydroxy)-.alpha.-hyd 
roxybenzyl]pyrrolidine (XVII). 
Step 12. Step 12 illustrates the isomerization of .+-.cis 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-hydroxy)benzoyl]pyrr 
olidine compound (VII) to the .+-.trans 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy)benzoyl]py 
rrolidine compound (XIV). 
.+-.Cis-2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy)ben 
zoyl]pyrrolidine is dissolved in higher alcohol, for example, propanol, 
butanol, heptanol, pentanol, preferably in t-butanol and potassium in 
higher alcohol, preferably in t-butanol is added. The mixture is reacted 
for 1-6 hours, preferably for 2 hours at a temperature of 
10.degree.-30.degree., preferably at room temperature. The mixture is 
quenched with ammonium salt, preferably with saturated ammonium chloride, 
poured in the water and extracted with organic solvent, preferably with 
ethyl acetate, Purification and crystallization of methods known in the 
art gave the mixture rich in the .+-.trans isomer 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy)benzoyl]py 
rrolidine (XIV). 
Step 13. Step 13 describes the removal of the N-protecting group from 
.+-.trans 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy)benzoyl]py 
rrolidine. 
A solution of trans compound (XIV), is added to a strong protic acid, such 
as hydrochloric acid or hydrobromic acid, preferably to 1 ml of 
trifluoroacetic acid cooled on ice. The mixture is reacted for 1 minute to 
5 hours at -10.degree. to +20.degree. C. temperature. The solvent is 
evaporated and the residue is purified to obtain .+-.trans 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy)benzoyl]py 
rrolidine trifluoroacetate (XV). 
Step 14. Step 14 describes the reduction of .+-.trans 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy)benzoyl]py 
rrolidine compound (XV) to .+-.trans erythro 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy)-.alpha.-h 
ydroxybenzyl]pyrrolidine (XVI). 
.+-.Trans 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy)benzoyl]py 
rrolidine trifluoroacetate (XV) is reduced with metal borohydride, 
preferably with sodium borohydride, in a lower alcohol, preferably ethanol 
or methanol, at -35.degree. to +10.degree. C. The solution is evaporated 
and the residue is stirred with the solution of an organic solvent, 
preferably ethyl acetate, and water. The organic layer is evaporated and 
the residue dissolved in lower alcohol, such as methanol, ethanol, 
propanol, butanol, preferably in methanol, and acidified with a solution 
of hydrogen chloride in the same solvent as above, i.e., preferably in 
methanol to afford .+-.trans erythro 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy)-.alpha.-h 
ydroxybenzyl]pyrrolidine compound (XVI). 
Step 15. Step 15 describes the debenzylation of compound (XVI) with 
protected phenolic hydroxyl, for example benzyloxy, to the compound (XVII) 
where hydroxyl is unprotected. 
The reduction is conducted in alcohol, preferably methanol, in the presence 
of 5-50 wt % of the noble metal catalyst, preferably 5-20% palladium on 
carbon, in a hydrogen atmosphere. Reduction proceeds at temperatures of 
10.degree.-36.degree., preferably at room temperature, and at atmospheric 
pressure for 1-100 hours. Purification by methods known in the art and 
recrystallization from a suitable solvent, preferably acetonitrile, gives 
compound (XVII) with unprotected phenolic hydroxyl group, namely, 
.+-.trans erythro 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-hydroxy)-.alpha.-hyd 
roxybenzyl]pyrrolidine compound (XVI). 
##STR16## 
Step 16. Step 16 describes the reduction of N-protected .+-.trans 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy)benzoyl]py 
rrolidine compound (XIV) into the N-protected .+-.trans erythro 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy)-.alpha.-h 
ydroxybenzyl]pyrrolidine (XVIII) and .+-.trans threo 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy)-.alpha.-h 
ydroxybenzyl]pyrrolidine (XIX). 
Step 16A. The reaction begins with the reduction of compound (XIV) with 
metal borohydride, preferably with sodium borohydride, in lower alcohol, 
preferably ethanol or methanol, at -10.degree. to +20.degree. C. for 
0.5-50 hours. The mixture obtained after purification by methods known in 
the art consist of both .+-.trans erythro and .+-.trans threo 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy)-.alpha.-h 
ydroxybenzyl]pyrrolidine compounds (XVIII) and (XIX). 
Step 16B. The mixture obtained in Step 16A is separated by TLC, column 
chromatography, crystallization or any other common separation technique, 
preferably by TLC, to obtain .+-.trans erythro 
2-[(3,4-methylenedioxy)-phenethyl]-5-[(3-carboxamido-4-benzyloxy)-.alpha.- 
hydroxybenzyl]pyrrolidine (XVIII) and .+-.trans threo 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy)-.alpha.-h 
ydroxybenzyl]pyrrolidine (XIX). 
N-protected .+-.trans erythro 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy)-.alpha.-h 
ydroxybenzyl]pyrrolidine (XVIII) is submitted to the procedure of Step 13 
(Reaction Scheme 3). 
Step 17. Step 17 describes the removal of the N-protecting group from the 
.+-.trans threo 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy)-.alpha.-h 
ydroxybenzyl]pyrrolidine compound (XIX). 
A solution of .+-.N-protected trans 
2-[(3,4-methylene-dioxy)phenethyl]-5-[(3-carboxamido-4-hydroxy)-.alpha.-hy 
droxybenzyl]pyrrolidine compound (XIX) in chlorinated hydrocarbons, 
preferably dichloromethane, is added to a strong protic acid, such as 
hydrochloric acid or hydrobromic acid, preferably trifluoroacetic acid. 
The mixture is reacted for 1-50 hours at -10.degree. to +20.degree. C. 
temperature. The solvent is evaporated and the residue is purified to 
obtain the trifluoroacetic acid salt of .+-.trans threo 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy)-.alpha.-h 
ydroxybenzyl]pyrrolidine (XX). 
Step 18. Step 18 describes the debenzylation of compound (XX) with 
protected phenolic hydroxyl, for example benzyloxy, to the compound (XXI). 
The reduction is conducted in alcohol, preferably methanol, in the presence 
of 5-50 wt % of the noble metal catalyst, preferably 5-20% palladium on 
carbon. Reduction proceeds at temperatures of 10.degree.-36.degree., 
preferably at room temperature, and at atmospheric pressure for 1-100 
hours. Purification by methods known in the art and recrystallization from 
a suitable solvent, preferably acetonitrile, gives compound (XXI) with 
unprotected phenolic hydroxyl group, namely .+-.trans threo 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-hydroxy)-.alpha.-hyd 
roxybenzyl]pyrrolidine. 
ISOLATION, SEATION, AND PURIFICATION 
Isolation, separation, and purification of the desired final compounds and 
their intermediates from the reaction mixture can be effected by any 
suitable separation or purification procedure, such as, for example, 
extraction, filtration, evaporation, distillation, crystallization, 
thin-layer chromatography, column chromatography, high pressure liquid 
chromatography, and the like, or by a combination of these procedures. If 
not otherwise described above, illustrations of suitable isolation, 
separation and purification procedures can be had by reference to the 
Examples herein below. However, other isolation, separation and isolation 
procedures could, of course, also be used. 
In summary, compounds of this invention are prepared by the following 
steps: 
N-protecting 
.+-.2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy)benzyl 
]pyrrole; 
reducing .+-.N-protected 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy)benzoyl]py 
rrole with noble metal catalyst under the mild reaction conditions to 
.+-.N-protected cis 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy)benzoyl]py 
rrolidine; 
removing N-protecting group from .+-.cis 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy)benzoyl]py 
rrolidine; 
reducing .+-.cis 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy)benzoyl]py 
rrolidine to .+-.cis erythro 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy)-.alpha.-h 
ydroxybenzyl]pyrrolidine; 
optionally converting .+-.cis N-protected 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy)benzoyl]py 
rrolidine to N-protected .+-.cis threo 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy)-.alpha.-h 
ydroxybenzyl]pyrrolidine and subsequently removing N-protecting group; 
optionally isomerazing N-protected .+-.cis 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy)benzoyl]py 
rrolidine to N-protected .+-.trans 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy)benzoyl]py 
rrolidine; and subsequently removing N-protecting group and reducing to 
.+-.trans erythro 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy)-.alpha.-h 
ydroxybenzyl]-pyrrolidine; 
optionally converting.+-.trans N-protected 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy)benzoyl]py 
rrolidine to N-protected .+-.trans threo 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy)-.alpha.-h 
ydroxybenzyl]pyrrolidine and subsequently removing N-protecting group; 
debenzylating phenolic protected group from 
.+-.2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy)-.alph 
a.-hydroxybenzyl]pyrrolidine (all isomers) to obtain 
.+-.2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-hydroxy)-.alpha. 
-hydroxybenzyl]pyrrolidine; 
optionally converting base to a salt; and 
optionally converting salt to a base. 
UTILITY AND ADMINISTRATION 
Utility 
The compounds of the invention are active antihypertensives. When 
administered orally or subcutaneously, they relieve hypertension in 
spontaneously hypertensive rats (SHR) but, at the same time they do not 
affect rate and force of the heart beat. Accordingly, they are potentially 
useful as drugs for management of hypertension. They are also active as 
bronchodilators. 
Administration 
Administration of the active compounds and salts described herein can be 
via any of the accepted modes of administration for cardiovascular system 
regulating agents. These methods include oral or parenteral routes. 
Parenteral routes include intravenous, subcutaneous, intradermal, or 
intramuscular administration. 
Oral mode of administration is referred for daily administration which is 
necessary in management of hypertension. 
Parenteral route of administration is the administration of drugs to a 
patient by injection under or through one or more layers of the skin or 
mucous membrane. Parenteral administration would preferably be reserved 
for crisis situations, wherein the subject is unable to swallow or 
administer the medication to himself. 
The amount of active ingredient administered will, of course, be dependent 
on the subject being treated, on the severity of the affliction, on the 
manner of administration and on the judgment of the prescribing physician. 
However, an effective dosage is in the range of 0.001-50 mg/kg/day, 
preferably 0.01-1 mg/kg/day. For an average 70 kg human, this would amount 
to 0.07-3500 mg per day, preferably 0.7-70 mg/day. 
For oral administration, a pharmaceutically acceptable non-toxic 
composition is formed by the incorporation of any of the normally employed 
excipients, such as, for example pharmaceutical grades of mannitol, 
lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, 
glucose, sucrose, magnesium, carbonate, and the like. Such compositions 
take the form of solutions, suspensions, tablets, pills, capsules, 
powders, sustained release formulations and the like. Such compositions 
may contain 0.1%-95% active ingredient, preferably 1%-70%. 
For parenteral administration, such as, for example, intravenous 
injections, the compound is dissolved in a vehicle. Vehicle may be, for 
example, aqueous vehicle, such as sodium chloride injection, Ringer's 
injection, dextrose injection and others, water miscible vehicle, such as 
ethyl alcohol, polyethylene glycol of the liquid series or propylene 
glycol, or nonaqueous vehicles such a corn oil, peanut oil or sesame oil. 
Vehicle will be buffered to the proper pH in order to stabilize a solution 
against chemical degradation and formed in such a way as to control 
isotonicity of injection. Other substances may also be added as 
antimicrobial or antioxidant agents. 
For use as bronchodilators, administration of the active compounds and 
salts described herein can be via any of the accepted modes for 
bronchodilation, i.e., any mode described above can be used and compounds 
may also be administered in aerosol form. 
PHARMACEUTICAL COMPOSITION 
Depending on the intended mode of administration, the pharmaceutical 
compositions may be in the form of solid, semi-solid or liquid dosage 
forms, such as, for example, tablets, pills, capsules, powders, liquids, 
suspensions, or the like, preferably in unit dosage forms suitable for 
single administration of precise dosages. The pharmaceutical compositions 
will include a conventional pharmaceutical carrier or excipient, and a 
compound of this invention or the pharmaceutically acceptable salt as an 
active ingredient thereof. In addition, it may include other medicinal or 
pharmaceutical agents, carriers, adjuvants, etc. 
The composition or formulation to be administered will, in any event, 
contain a quantity of the active ingredient(s) in an amount effective to 
alleviate the symptoms of the subject being treated. 
For solid pharmaceutical compositions, conventional non-toxic solid 
carriers include, for example, pharmaceutical grades of mannitol, lactose, 
starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, 
sucrose, magnesium carbonate, and the like. The active ingredient as 
defined above may also be formulated as suppositories, using as the 
carrier for example polyalkylene glycols, such as propylene glycol. 
Liquid pharmaceutically administerable compositions can be prepared by 
dissolving or dispersing, or otherwise preparing an active ingredient (as 
defined above), and mixing it optionally with a pharmaceutical adjuvant in 
a carrier, such as, for example, water, saline, aqueous dextrose, 
glycerol, ethanol, and the like, to thereby form a solution or suspension. 
If desired, the pharmaceutical composition to be administered may also 
contain minor amounts of nontoxic auxiliary substances such as wetting or 
emulsifying agents, pH buffering agents and the like, such as for example, 
sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, 
sorbitan monolaurate, triethanolamine oleate, etc. 
Methods of preparing various pharmaceutical compositions with certain 
amount of active ingredient are known, or will be apparent, to those 
skilled in this art. For examples, see Remington's Pharmaceutical 
Sciences, Mack Publishing Company, Easton, Penna., 15th Edition (1975).

EXAMPLE 1 
Preparation of [(3-Carboxamido-4-Benzyloxy)Benzoyl]Morpholide (I) 
This example illustrates the preparation of 
[(3-carboxamido-4-benzyloxy)benzoyl]morpholide. This compound can be 
prepared from the corresponding [(3-carboxamido-4-hydroxy)benzoic acid by 
protecting the phenolic hydroxy group. 
A. Methyl ester (3-carboxamido-4-hydroxy)benzoic acid was prepared 
according to the procedure described in J. Chem. Soc., pp. 4678 (1956). 
The procedure is also described in Brit. Pat. No. 802,841. 
B. Methyl ester(3-carboxamido-4-hydroxy)benzoic acid is dissolved in 
dimethylformamide (10 ml/mmol) and treated with 1 equivalent of sodium 
hydride at room temperature under constant stirring for about 5 minutes. 
Then 1 equivalent of benzyl bromide is added and the mixture is stirred at 
room temperature until reaction is complete, usually for 1 hour. The 
mixture is poured into water and extracted with ethyl acetate. The extract 
is washed with water to eliminate dimethylformamide, evaporated in vacuo 
to afford methyl ester (3-carboxamido-4-benzyloxy)benzoic acid. Methyl 
ester [(3-carboxamido-4-benzyloxy)benzoic acid is hydrolyzed to benzoic 
acid with bicarbonate in methanol for about 12 hours to give 
(3-carboxamido-4-benzyloxy)benzoic acid. 
C. To a suspension of 11.15 g of (3-carboxamido-4-benzyloxy)benzoic acid in 
250 ml of dichloromethane was added 2.87 ml of thionyl chloride and 1 ml 
of dimethylformamide. The mixture is stirred at room temperature for 
approximately 15 min. or until solution occurred. The solvent was removed 
in vacuo. The residual acid chloride was dissolved in ether, and 5.8 ml of 
morpholine was added slowly with stirring. The precipitate was removed by 
filtration. The ether was evaporated in vacuo to give 11.4 g of an oil 
which was purified by column chromatography in silica gel with ethyl 
acetate-hexane (2:3) as the eluting solvent to give in 
[(3-carboxamido-4-benzyloxy)benzoyl]morpholide (I). (Step 3) 
EXAMPLE 2 
Preparation of [(3,4-Methylenedioxy)-Phenylacetyl]Morpholide (IIa) 
4 ml of thionyl chloride and 0.5 ml of dry dimethylformamide were added to 
a solution of 12.5 g of (3,4-methylenedioxy)phenylacetic acid (Trans World 
Chemical) in 200 ml of dry dichloromethane. The solution was stirred for 
15 minutes and evaporated to dryness in vacuo. The residual acid chloride 
was dissolved in 100 ml of dry dichloromethane. A solution of 5.35 ml of 
morpholine in 100 of dichloromethane was added dropwise with stirring. 
When the addition was ended, the mixture was evaporated to dryness in 
vacuo and the residue was percolated through a short silica gel column 
using ethyl acetate-hexane (3:7) as the percolating solvent. 13.7 g of 
[(3,4-methylenedioxy)phenylacetyl]morpholide (IIa) was obtained. (Step 1) 
EXAMPLE 3 
Preparation of 2-[(3,4-Methylenedioxy)Phenylacetyl]Pyrrole (III) 
Vilsmeier-Haack reaction was carried out according to the method of J. 
White and G. McGillivray, J. Org. Chem., 42:4248 (1979). 
A mixture of 30 g (0.146 mole) of 
[(3,4-methylenedioxy)phenylacetyl]morpholide and 27 ml (0.295 mole) of 
phosphorous oxychloride was stirred magnetically at room temperature in a 
nitrogen atmosphere for 6 h. A solution of 10 ml (0.149 mole) of pyrrole 
in 700 ml of anhydrous 1,2-dichloroethane was added at a rate such that 
the temperature did not exceed 30.degree.. The reaction mixture was 
stirred at room temperature for 18 h. The mixture was cautiously mixed 
with a solution of 700 ml of 10% sodium carbonate in water and the mixture 
was heated at reflux temperature with stirring for 1.5 h. The cooled 
mixture was filtered through celite. The organic phase was separated and 
combined with dichloromethane extracts (3.times.500 ml) of the aqueous 
phase, the organic phases were dried over sodium sulfate and evaporated in 
vacuo. The residue was subjected to column chromatography over silica gel 
(1 kg). 2[(3,4-methylenedioxy)phenylacetyl]pyrrole (III) was eluted with 
dichloromethane and crystallized from acetone-hexane. (Step 1) 
EXAMPLE 4 
Preparation of 2-[(3,4-Methylenedioxy)Phenethyl]-Pyrrole (IV) 
A solution of 6.00 g (0.032 mole) of the 
2-[(3,4-methylenedioxy)phenylacetyl]pyrrole (III) in 200 ml of anhydrous 
tetrahydrofuran was added to a suspension of 600 g (0.153 mole) of lithium 
aluminum hydride in dry tetrahydrofuran. The mixture was stirred at reflux 
temperature for 48 h. The mixture was cooled to 0.degree., and ethyl 
acetate was cautiously added to destroy the excess hydride. Then the 
saturated aqueous sodium sulfate was added, the organic phase was 
decanted, dried over sodium sulfate and evaporated in vacuo. The residue 
was subjected to column chromatography on neutral alumina (Fluka, Act II). 
2-[(3,4-methylenedioxy)phenethyl]pyrrole (IV) was eluted with hexane-ethyl 
acetate and crystallized from (hexane). (Step 2). 
EXAMPLE 5 
Preparation of 
.+-.2-[(3,4-Methylenedioxy)Phenethyl]-5-[(3-Carboxamido-4-Benzyloxy)Benzoy 
l]Pyrrole (V) 
A mixture of 12,3 g (0.046 mole) of 
[(3-carboxamido-4-benzyloxy)benzoyl]morpholide (I) (Example 1) and 12 ml 
(0.13 mole) of phosphorous oxychloride was stirred at room temperature for 
3 hours in a nitrogen atmosphere. A solution of 10.0 g (0.058 mole) of 
2-[(3,4-methylenedioxy)phenethyl]pyrrole (IV) in 200 ml of dry 
1,2-dichloroethane was added and the mixture was stirred at room 
temperature for 18 h. The reaction mixture was stirred at room temperature 
for 18 h. The mixture was cautiously mixed with a solution of 700 ml of 
10% sodium carbonate in water and the mixture was heated at reflux 
temperature with stirring for 1.5 h. The cooled mixture was filtered 
through celite. The organic phase was separated and combined with 
dichloromethane extracts (3.times.500 ml) of the aqueous phase, the 
organic phases were dried over sodium sulfate and evaporated in vacuo. The 
residue was submitted to column chromatography on neutral alumina (Fluka, 
Act II). The crude product was purified by column chromatography on silica 
gel (1 kg). The desired material was eluted with dichloromethane to give 
.+-.2-[(3,4-methylenedioxy)phenethyl]-5-(3-carboxamido-4-benzyloxy)benzoyl 
]pyrrole (V) which was crystallized from dichloromethane-acetone. (Step 3) 
EXAMPLE 6 
Preparation of 
1-t-Butoxycarbonyl-2-[(3,4-Methylenedioxy)Phenethyl]-5-[(3-Carboxamido-4-B 
enzyloxy)Benzoyl]Pyrrole (VI) 
4.10 g (0.012 mole) of 
.+-.2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy)benzoy 
l]pyrrole (V) was added to a 1.40 g of suspension (0.05 mole; 60% 
dispersion in mineral oil) of sodium hydride in 100 ml of dry 
dimethylformamide. The mixture was heated at 45.degree.-60.degree. for 2 
h. 4.51 g (0.02 mole) of di-t-butyl dicarbonate was added rapidly and the 
solution was stirred at 60.degree.-70.degree. for 2 h. The reaction 
mixture was cooled, poured onto ice-water and the product was extracted 
into ethyl acetate. The extract was washed with water, dried over sodium 
sulfate and evaporated in vacuo. Then it was purified by column 
chromatography on alumina (300 g, Fluka, Neutral Act. II). The crude 
product was crystallized from acetone-hexane to give 
.+-.1-t-butoxycarbonyl-2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido 
-4-benzyloxy)benzoyl]pyrrole (VI). (Step 4) 
EXAMPLE 7 
Preparation of .+-.Cis 1-t-Butoxycarbonyl 
2-[(3,4-Methylenedioxy)Phenylethyl]-5-[(3-Carboxamido-4-Benzyloxy)Benzoyl] 
Pyrrolidine (VII) 
A solution of 4.50 g, (0.01 mole) 
1-t-butoxycarbonyl-2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-b 
enzyloxy)benzoyl]pyrrole (VI) in 300 ml of ethyl acetate (2:1) containing 
1.8 g of suspended platinum on carbon was hydrogenated at room temperature 
and atmospheric pressure for 22 hours. The reaction mixture was filtered, 
the filtrate was evaporated in vacuo and the residue was subjected to 
column chromatography on neutral alumina (Fluka, Act II). The product was 
eluted with hexane-ethyl acetate (95:5). The crude .+-.cis 
1-t-butoxycarbonyl 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy)benzoyl]py 
rrolidine (VII) was obtained in quantitative yield as an oil. (Step 5) 
The above hydrogenation procedure, however, may result in partial or 
complete debenzylation of phenolic hydroxyl. If such is the case the 
phenolic hydroxyl must be again protected by benzylation. The process of 
benzylation has been described in Example 1. 
EXAMPLE 8 
Preparation of .+-.Cis 
2-[(3,4-Methylenedioxy)Phenethyl]-5-[(3-Carboxamido-4-Benzyloxy)Benzoyl]Py 
rrolidine Trifluoroacetate (VIII) 
50 ml of trifluoroacetic acid was added to a solution of 3.60 g (0.0085 
mole) of .+-.cis 
1-t-butoxycarbonyl-2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-b 
enzyloxy)benzoyl]pyrrolidine (VII) in 200 ml of dry dichloromethane. The 
reaction solution was stirred at room temperature for 0.5 h. The solvent 
was removed in vacuo and the residue was crystallized from 
dichloromethane-ether to give .+-.cis 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy)benzoyl]py 
rrolidine trifluoroacetate (VIII). (Step 6) 
EXAMPLE 9 
Preparation of .+-.Cis Erythro 
2-[(3,4-Methylenedioxy)-Phenethyl]-5-[(3-Carboxamido-4-Benzyloxy)-.alpha.- 
Hydroxybenzyl]Pyrrolidine (IX) 
1.35 g (0.035 mole) of sodium borohydride was added to a stirred solution 
of 2.70 g (0.0057 mole) of .+-.cis 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy)-.alpha.-h 
ydroxybenzyl]pyrrolidine in 270 ml ethanol, at 0.degree. temperature. After 
1 hour at 0.degree., the mixture was poured into 100 ml of 10% ammonium 
chloride solution. The mixture was evaporated in vacuo to remove the 
ethanol, the residue was cooled to 0.degree., and 50 ml of a saturated 
sodium carbonate solution was added. The product was extracted into ethyl 
acetate, the extract was washed with water, dried over sodium sulfate and 
evaporated in vacuo. The residue was crystallized from ethyl 
acetate-hexane to give 1.72 g (93%) of the desired .+-.cis erythro 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy)-.alpha.-h 
ydroxybenzyl]pyrrolidine (IX). (Step 7) 
EXAMPLE 10 
Debenzylation of .+-.Cis Erythro 2-[(3,4-Methylenedioxy)Phenethyl]-5-[( 
3-Carboxamido-4-Benzyloxy)-.alpha.-Hydroxybenzyl]Pyrrolidine 
A solution of the .+-.cis erythro 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy)-.alpha.-h 
ydroxybenzyl]pyrrolidine (0.600 g 0.0012 mole) in absolute methanol (20 ml) 
containing suspended 10% palladium on carbon catalyst (0.30 g) was 
hydrogenated at room temperature and atmospheric pressure for 1 hour. The 
mixture was filtered through Celite, the filtrate was evaporated in vacuo 
and the residue was triturated with acetone and crystallized from 
methanol-acetone, to give .+-.cis erythro 
2-[3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-hydroxy).alpha.-hydro 
xybenzyl]pyrrolidine, m.p. 189-191. 
Other compounds may be similarly debenzylated: 
.+-.trans erythro 
2-[3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-hydroxy).alpha.-hydro 
xybenzyl]pyrrolidine, m.p. 189-191. 
.+-.cis threo 
2-[3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-hydroxy).alpha.-hydro 
xybenzyl]pyrrolidine, m.p. 193-193,5. 
EXAMPLE 11 
A. Preparation of .+-.Cis Erythro and .+-.Cis Threo 
1-t-Butoxycarbonyl-2-[(3,4-Methylenedioxy)Phenethyl]-5-[(3-Carboxamido-4-B 
enzyloxy).alpha.-Hydroxybenzyl]Pyrrolidine (XI') and (XI) 
A solution of 3.20 g (4.5 mmole) of the .+-.cis 
1-t-butoxycarbonyl-2[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-be 
nzyloxy)benzoyl]pyrrolidine (VII), prepared in Example 7 and 6.4 g (16.9 
mmole) of sodium borohydride in 300 ml ethanol is heated at a reflux 
temperature for 45 min. The solvent is removed in vacuo and the residue is 
partitioned between water and ethyl acetate. The organic phase is 
evaporated in vacuo and the residue is percolated through a short column 
of silica gel using ethyl acetate-hexane (1:3) as the percolating solvent. 
The resulting mixture is separated by TLC with ethyl acetate/hexane (1:3) 
into two isomers: 
.+-.cis erythro 1-t-butoxycarbonyl 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy)-.alpha.-h 
ydroxybenzyl)pyrrolidine; and 
.+-.cis threo 1-t-butoxycarbonyl 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy)-.alpha.-h 
ydroxybenzyl]pyrrolidine. 
B. Preparation of .+-.Trans Erythro and .+-.Trans Threo 
1-t-Butoxycarbonyl-2-[(3,4-Methylenedioxy)Phenethyl]-5-[(3-Carboxamido-4-B 
enzyloxy).alpha.-Hydroxybenzyl]Pyrrolidine (XI') and (XI) 
The same procedure as described in Section A is used for the preparation of 
.+-.trans erythro (XVIII) and .+-.trans threo (XIX) compounds shown in 
Reaction Scheme 4 (Step 16) except that the starting compound is a trans 
isomer (XIV). 
The resulting compounds are: 
.+-.trans erythro 1-t-butoxycarbonyl 
2[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy)-.alpha.-hy 
droxybenzyl]pyrrolidine, m.p. 115.degree.-116.degree.; and 
.+-.trans threo 1-t-butoxycarbonyl 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy)-.alpha.-h 
ydroxybenzyl]pyrrolidine. 
EXAMPLE 12 
Removal of N-Protecting Group from .+-.Cis Erythro or .+-.Cis Threo 
1-t-Butoxycarbonyl-2-[(3,4-Methylenedioxy)Phenethyl]-5-[(3-Carboxamido-4-B 
enzyloxy)-.alpha.-Hydroxybenzyl]Pyrrolidine (XI')(XI) 
50 ml of trifluoroacetic acid is added to a solution of .+-.cis erythro 
1-t-butoxycarbonyl 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy)-.alpha.-h 
ydroxybenzyl]pyrrolidine (XI') or to a solution of 3.60 g (0.0085 mol) 
.+-.cis threo 
1-t-butoxycarbonyl-2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-b 
enzyloxy)-.alpha.-hydroxybenzyl]pyrrolidine (XI) in 200 ml of 
dichloromethane. The reaction mixture is stirred at room temperature for 
0.5-1 hour. The solvent is removed in vacuo and the residue is 
crystallized from dichloromethane-ether to give trifluoroacetic acid salt 
of compounds (XI') and (XI). 
Resulting compounds are: 
.+-.cis erythro 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy)-.alpha.-h 
ydroxybenzyl]pyrrolidine trifluoroacetate; and 
.+-.cis threo 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-hydroxy)-.alpha.-hyd 
roxybenzyl]pyrrolidine trifluoroacetate (XII). (Step 10) 
The same procedure is used for the removal of N-protecting group from 
compounds (XIV), (XV), (XVIII) and (XIX), shown in Reaction Schemes 3 and 
4. 
EXAMPLE 13 
Isomerization of .+-.Cis 
1-t-Butyloxycarbonyl-2-[(3,4-Methylenedioxy)Phenethyl]-5-[(3-Carboxamido-4 
-Benzyloxy)Benzoyl]Pyrrolidine to 
.+-.Trans-1-t-Butyloxycarbonyl-2-[(3,4-Methylenedioxy)Phenethyl]-5-(3-Carb 
oxamide-4-Benzyloxy)Benzoyl]Pyrrolidine 
550 mg of .+-.cis 
1-t-butyloxycarbonyl-2-[(3,4-methylenedioxy)phenethyl-5-[(3-carboxamido-4- 
benzyloxy)benzoyl]pyrrolidine is dissolved in 50 ml of t-butanol and 1 ml 
of a solution prepared by dissolving 3-4 g of potassium in 60 ml of 
t-butanol, is added. After 2 hours at room temperature, the reaction 
mixture is quenched by adding 1 ml of saturated ammonium chloride. The 
solution is then poured into water and extracted with ethyl acetate. The 
ethyl acetate layer is washed, dried and evaporated to yield a residue. 
The analysis of the residue showed it to be a 50:50 mixture of starting 
material and a new slightly more polar compound. The more polar compound 
was isolated by chromatography on silica gel eluting twice with ethyl 
acetate/hexane (1:2)(2:1) to yield .+-.trans 
N-t-butyloxycarbonyl-2-[(3,4-methylenedioxy)phenethyl-5-(3-carboxamido-4-b 
enzyloxy)benzoyl]pyrrolidine, m.p. 115.degree.-116.degree.. 
EXAMPLE 14 
Conversion of .+-.Trans 
1-t-Butyloxycarbonyl-2-[(3,4-Methylenedioxy)Phenethyl]-5-[(3-Carboxamido-4 
-Benzyloxy)Benzoyl]Pyrrolidine to .+-.Trans Erythro 
2-[(3,4-Methylenedioxy)Phenethyl]-5-[(3-Carboxamido-4-Benzyloxy)-.alpha.-H 
ydroxybenzyl]Pyrrolidine Hydrochloride 
40 mg of .+-.trans 
1-t-butyloxycarbonyl-2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4 
-benzyloxy)benzoyl]pyrrolidine was dissolved in 1 ml of trifluoroacetic 
acid cooled on an ice bath. After about 1 minute, the solution was 
evaporated in vacuo and the residue dissolved in 1 ml of ethanol and added 
to a solution of 25 mg of sodium borohydride in 5 ml of ethanol cooled to 
-35.degree.. After warming to room temperature, the solution was 
evaporated and the residue stirred with ethyl acetate and water. The 
organic layer was separated, washed, dried, and evaporated to leave a 
residue which was dissolved in methanol. The solution was acidified with a 
solution of hydrogen chloride in methanol. The solvent was removed by 
evaporation and the residue stirred with ethyl acetate to give 28 mg of 
.+-.trans 
erythro-2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy)-. 
alpha.-hydroxybenzyl]pyrrolidine hydrochloride, m.p. 
178.degree.-179.degree.. 
EXAMPLE 15 
Conversion of .+-.Trans Erythro 
2-[(3,4-Methylenedioxy)Phenethyl]-5-[(3-Carboxamido-4-Benzyloxy)-.alpha.-H 
ydroxybenzyl]Pyrrolidine Hydrochloride to .+-.Trans Erythro 
2-[(3,4-Methylenedioxy)Phenethyl]-5-[(3-Carboxamido-4-Hydroxy)-.alpha.-Hyd 
roxybenzyl]Pyrrolidine Hydrochloride 
25.9 mg of .+-.trans erythro 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-benzyloxy-.alpha.-hy 
droxybenzyl]pyrrolidine hydrochloride is dissolved in methanol and 3 mg of 
5% palladium on carbon catalyst is added. The mixture is stirred overnight 
in a hydrogen atmosphere. The solution is filtered, the filtrate 
evaporated and the residue triturated with ethyl acetate. The .+-.trans 
erythro-2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-hydroxy)-.al 
pha.-hydroxybenzyl]pyrrolidine hydrochloride is collected by filtration and 
dried. After recrystallization from ethanol it had m.p. 
189.degree.-190.degree.. 
EXAMPLE 16 
Conversion of Free Base to Salt Preparation of .+-.Cis Erythro 
2-[(3,4-Methylenedioxy)Phenethyl]-5-[(3-Carboxamido-4-Hydroxy)-.alpha.-Hyd 
roxybenzyl]Pyrrolidine Hydrochloride 
Excess 3% hydrogen chloride in methanol is added to a solution of 1.0 g of 
.+-.cis erythro 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-hydroxy)-.alpha.-hyd 
roxybenzyl]pyrrolidine in 20 ml of methanol. Diethyl ether is added until 
precipitation is complete. .+-.Cis erythro 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-hydroxy)-.alpha.-hyd 
roxybenzyl]pyrrolidine hydrochloride is filtered, washed with ether, air 
dried and recrystallized. 
Other isomers may be similarly converted to various salts. 
EXAMPLE 17 
Conversion of Salt to Free Base Preparation of .+-.Cis Erythro 
2-[(3,4-Methylenedioxy)Phenethyl]-5-[(3-Carboxamido-4-Hydroxy)-.alpha.-Hyd 
roxybenzyl]Pyrrolidine 
1.0 l g of .+-.cis erythro 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-hydroxy)-.alpha.-hyd 
roxybenzyl]pyrrolidine hydrochloride or trifluoroacetate is dissolved in 50 
ml of water. A solution of sodium bicarbonate is added, and the pH 
adjusted to about pH 5. The resulting free base is extracted with ethyl 
acetate, the organic layer is then separated, washed twice with water, 
dried over magnesium sulfate and evaporated to yield .+-.cis erythro 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-hydroxy)-.alpha.-hyd 
roxybenzyl)]pyrrolidine as the free base. 
EXAMPLE 18 
Direct interchange of acid addition salts 
1 g of .+-.cis erythro 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-hydroxy)-.alpha.-hyd 
roxybenzyl]pyrrolidine hydrochloride, prepared according to Example 13, is 
dissolved in a solution of 1 ml 50% aqueous sulfuric acid in 10 ml ethanol 
and the resulting precipitate is harvested. The product is suspended in 
ethanol and filtered, air dried, and recrystallized from methanol/acetone 
to yield .+-.cis erythro 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-hydroxy)-.alpha.-hyd 
roxybenzyl]pyrrolidine bisulfate. 
In Examples 16-23, the active ingredient is .+-.cis erythro 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-hydroxy)-.alpha.-hyd 
roxybenzyl]-pyrrolidine hydrochloride. 
EXAMPLE 19 
______________________________________ 
Quantity per 
Ingredients tablet, mgs. 
______________________________________ 
Active ingredient 
25 
cornstarch 20 
lactose, spray-dried 
153 
magnesium stearate 
2 
______________________________________ 
The above ingredients are thoroughly mixed and pressed into single scored 
tablets. 
EXAMPLE 20 
______________________________________ 
Quantity per 
Ingredients tablet, mgs. 
______________________________________ 
Active ingredient 
100 
lactose, spray-dried 
148 
magnesium stearate 
2 
______________________________________ 
The above ingredients are mixed and introduced into a hard-shell gelatin 
capsule. 
EXAMPLE 21 
______________________________________ 
Quantity per 
Ingredients tablet, mgs. 
______________________________________ 
Active ingredient 
200 
cornstarch 50 
lactose 145 
magnesium stearate 
5 
______________________________________ 
The above ingredients are mixed intimately and pressed into single scored 
tablets. 
EXAMPLE 22 
______________________________________ 
Quantity per 
Ingredients tablet, mgs. 
______________________________________ 
Active ingredient 
108 
lactose 15 
cornstarch 25 
magnesium stearate 
2 
______________________________________ 
The above ingredients are mixed and introduced into a hard-shell gelatin 
capsule. 
EXAMPLE 23 
______________________________________ 
Quantity per 
Ingredients tablet, mgs. 
______________________________________ 
Active ingredient 
150 
lactose 92 
______________________________________ 
The above ingredients are mixed and introduced into a hard-shell gelatin 
capsule. 
EXAMPLE 24 
An injectable preparation buffered to a pH of 7 is prepared having the 
following composition: 
______________________________________ 
Ingredients 
______________________________________ 
Active ingredient 0.2 g 
KH.sub.2 PO.sub.4 buffer (0.4 M solution) 
2 ml 
KOH (1 N) q.s. to pH 7 
water (distilled, sterile) 
q.s. to 20 
ml 
______________________________________ 
EXAMPLE 25 
An oral suspension is prepared having the following composition: 
______________________________________ 
Ingredients 
______________________________________ 
Active ingredient 0.1 g 
fumaric acid 0.5 g 
sodium chloride 2.0 g 
methyl paraben 0.1 g 
granulated sugar 25.5 g 
sorbitol (70% solution) 
12.85 g 
Veegum K (Vanderbilt Co.) 
1.0 g 
flavoring 0.035 ml 
colorings 0.5 mg 
distilled water q.s. to 100 
ml 
______________________________________ 
EXAMPLE 26 
______________________________________ 
Active ingredient 3.0% 
Span.sup.R 85 (sorbitan trioleate) 
1.0% 
Freon 11 (trichloromonofluoromethane) 
30.0% 
Freon 114 (dichlorotetrafluoroethane) 
41.0% 
Freon 12 (dichlorodifluoromethane) 
25.0% 
______________________________________ 
EXAMPLE 27 
Antihypertensive Activity of .+-.Cis Erythro 
2-[(3,4-Methylenedioxy)Phenethyl]-5-[(3-Carboxamido-4-Hydroxy)-.alpha.-Hyd 
roxybenzyl]Pyrrolidine 
This example illustrates superiod antihypertensive activity of compounds of 
this invention. In this Example, compounds I and II mean the compounds 
defined in Table 1. 
24 previously trained adult male spontaneously hypertensive rats were 
distributed into 6 groups (5 animals per group) with approximately equal 
mean systolic blood pressures. The 6 groups were then studied concurrently 
in a 2-day compound screening procedure. 
Test compounds were randomly assigned to each group. 5 groups received 
potential antihypertensive agents and 1 control group received vehicle 
only (water and Tween). 
At approximately 17 hours prior to the first day of dosing food was removed 
from the rat cages. On the morning of Day 1, a group of 4 rats was orally 
dosed (by gavage) with 6.25 mg/kg, 12.5 mg/kg or 25 mg/kg of .+-.cis 
erythro 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-hydroxy)-.alpha.-hyd 
roxybenzyl)pyrrolidine or other tested compound dissolved/suspended in 
water (using 2-3 drops Tween 80) with a homogenizer at concentrations such 
that 0.1 ml of solution was administered per 10 g of body weight. At 41/2 
hours post dose, food was put back in the cages and the rats were allowed 
to eat for 21/2 hours, after which food was again removed. On the morning 
of Day 2, rats were orally dosed as described above. Immediately after 
dosing, the rats were put in restrainers and placed in a heated chamber 
(30.+-.1.0.degree. C.) for four hours. Normal feeding resumed at the end 
of the study on Day 2. 
Systolic blood pressure (i.e., pressure at the appearance of the first 
pulse) were recorded using photoelectric transducers. The coccygeal 
arteries of 3 rats (in a horizontal group) were simultaneously occluded by 
pump-inflated tail cuffs that were automatically inflated to 300 mmHg and 
then deflated. A pressure curve and tail pulses were simultaneously 
monitored on an MFE recorder. Four consecutive (at 30 second intervals) 
traces were recorded for each rat in a given horizontal group at one, two, 
three and four hours post compound administration. Subsequent horizontal 
groups were automatically tested in the same manner. 
The mean systolic blood pressure (SBP) of each rat at each observation time 
was calculated. The SBP of the animals in each dose group were compared to 
the SBP of the animals in the control group (vehicle only) at each 
observation time using a one-way analysis of variance test. A compound 
exhibiting p.ltoreq.0.05 at any observation time was considered to exhibit 
significant antihypertensive activity. Compounds significantly decreasing 
blood pressure 20 mmHg or more from control values at all four observation 
times were considered worthy of further examination. In these instances 
heart rates were calculated and tested for significant change from control 
heart rate values using the two-tailed test. Pressures were read at hours 
1, 2, 3 and 4 after dosing on both days 1 and 2. 
A. Table 1 summarizes the results obtained by testing two structurally 
similar compounds, namely, .+-.cis erythro 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-hydroxy)-.alpha.-hyd 
roxybenzyl]pyrrolidine (I) and .+-.cis erythro 
2-[(4-methoxy)phenethyl]-5-[(3-carboxamido-4-hydroxy)-.alpha.-hydroxybenzy 
l]pyrrolidine (II). 
TABLE 1 
__________________________________________________________________________ 
Compound 
.+-.cis erythro .+-.cis erythro 
2-[(3,4-methylenedioxy)- 2-[(4-methoxy) 
phenethyl]-5-[(3-carboxamido- 
phenethyl]-[(3-carboxamido- 
4-hydroxy)-.alpha.-hydroxybenzyl] 
4-hydroxy)-.alpha.-hydroxybenzyl] 
pyrrolidine pyrrolidine 
Compound I Compound II 
Test 
Systolic Systolic 
Blood Heart Blood Heart 
Pressure Rates Pressure Rates 
mm mm 
% .DELTA. 
P Hg % .DELTA. 
P BPM 
% .DELTA. 
P Hg % .DELTA. 
P BPM 
__________________________________________________________________________ 
Dose 
per os 25 mg/kg per os 25 mg/kg 
Hours 
1 -54 
0.05 
-119 
-12 
0.05 
-40 
-38 
0.05 
-71 
-2 NS -7 
Past 
2 -42 
0.05 
-87 -13 
0.05 
-41 
-32 
0.05 
-66 
-5 NS -16 
Dosing 
3 -40 
0.05 
-80 -13 
NS -37 
- 23 
0.05 
-47 
-14 0.05 
-39 
4 -40 
0.05 
-83 -15 
NS -43 
-23 
0.05 
-49 
-15 0.05 
-45 
Dose 
per os 12,5 mg/kg per os 12,5 mg/kg 
Hours 
1 -45 
0.05 
-98 -13 
0.05 
-45 
-32 
0.05 
-54 
-1 NS -4 
Past 
2 -39 
0.05 
-81 -14 
0.05 
-45 
-9 
NS -15 
ND ND 
Dosing 
3 -32 
0.05 
-64 -15 
NS -41 
-10 
NS -18 
4 -38 
0.05 
-80 -30 
0.05 
-93 
-10 
NS -17 
__________________________________________________________________________ 
BPM means beats per minute 
.DELTA.mmHg means difference in blood pressure expressed in mmHg 
% .DELTA. means difference in blood pressure expressed in % 
p = significance 
NS = not significant 
ND = no data available 
Table 1 illustrates the superiority of compound I .+-.cis erythro 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-hydroxy)-.alpha.-hyd 
roxybenzyl]pyrrolidine over compound II .+-.cis erythro 
2-[4-methoxyphenyl]-5-[3-carboxamido-4-hydroxy)-.alpha.-hydroxybenzyl]pyrr 
olidine. 
Two dosages, 25 mg/kg and 12,5 mg/kg were tested on spontaneous 
hypertensive rats to determine their effect on systolic blood pressure and 
heart beat. At the dosage of 25 mg/kg, both compounds show significant 
decrease in the systolic blood pressure. However, Compound I is more 
potent and has longer lasting effect. The decrease in systolic blood 
pressure persist for the whole testing period of four hours. At the same 
time heart rates are also decreased. Compound II shows lesser effect on 
systolic blood pressure and, during the first two hours, does not effect 
heart rates significantly. 
At the lower dosage of 12,5 mg/kg, compound I shows its superiority even 
more clearly. The decrease in systolic blood pressure is significant and 
similar, in absolute numbers, to that seen with the higher dose. Again, 
heart rates are lowered. Compound II, on the other hand, at dosage 12,5 
mg/kg decreases the systolic blood pressure only during the first hour. 
Then, the decrease is small and insignificant. 
B. Table 2 summarizes the results obtained by testing four doses of .+-.cis 
erythro 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-hydroxy)-.alpha.-hyd 
roxybenzyl]pyrrolidine for period of 1-24 hours after gavage. Doses 
administered using the procedure described above were 50 mg/kg, 25 mg/kg, 
12,5 mg/kg and 6,5 mg/kg. 
TABLE 2 
______________________________________ 
Compound 
.+-.cis erythro 2-[(3,4-methylenedioxy) 
phenethyl]-5-[(3-carboxamido-4-hydroxy)- 
.alpha.-hydroxybenzyl]pyrrolidine 
TEST 
Systolic Blood 
Hours Pressure 
Past mm Heart Rates 
Dose: Dosing % .DELTA. 
P Hg % .DELTA. 
P BPM 
______________________________________ 
50 mg/kg/per os 
1 -39 0.05 -76 -- -- -- 
2 -34 0.05 -65 -18 0.05 -50 
3 -28 0.05 -54 -- -- -- 
4 -34 0.05 -66 -21 0.05 -60 
8 -28 0.05 -57 -- -- -- 
12 -7 NS -13 -- -- -- 
24 -10 0.05 -21 -- -- -- 
25 mg/kg/per os 
1 -42 0.05 -82 -- -- -- 
2 -32 0.05 -61 -12 0.05 -33 
3 -33 0.05 - 64 -- -- -- 
4 -30 0.05 -57 -20 0.05 -57 
8 -17 0.05 -35 -- -- -- 
12 -3 NS -5 -- -- -- 
24 -8 NS -17 -- -- -- 
12,5 mg/kg/per os 
1 -38 0.05 -72 -- -- -- 
2 -21 0.05 -38 -8 -- -23 
3 -25 0.05 -51 -- -- -- 
4 -20 0.05 -38 -19 -- -56 
8 -9 NS -18 
12 -7 NS -13 
24 -14 NS -30 
6.25 mg/kg/per os 
1 -30 0.05 -58 -- -- -- 
2 -15 NS -28 -10 -- -12 
3 -19 0.05 -38 -- -- -- 
4 -15 NS -29 -12 -- - 37 
8 -1 NS -1 -- -- -- 
12 +9 NS +16 -- -- -- 
24 -11 NS -25 -- -- -- 
______________________________________ 
% .DELTA., p, .DELTA.mmHg and BPM are as in Table 1. 
Table 2 illustrates long-lasting antihypertensive effect of compound 
.+-.cis erythro 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-hydroxy)-.alpha.-hyd 
roxybenzyl]pyrrolidine. 
All tested doses of the above compound are effectively decreasing the 
systolic blood pressure. Although for the lowest dose (6,5 mg/kg) such 
decrease is not significant after 2 hours, it reapears again in the 3rd 
hour. 
The dosage 12,5 mg/kg shows significant lowering of systolic blood pressure 
up to 4 hours after gavage. 
At 25 mg/kg dose the compound has extended systolic blood lowering effect 
which is significant for more than 8 hours. 
In dosage 50 mg/kg the lowering of systolic blood pressure can be seen up 
to 24 hours. 
At 12 hours the decrease is insignificant for any tested dosage. 
Heart rates are not increased but are overall, mostly significantly, 
decreased. 
From the above it is clear that the compound .+-.cis erythro 
2-[(3,4-methylenedioxy)phenethyl]-5-[(3-carboxamido-4-hydroxy)-.alpha.-hyd 
roxybenzyl]pyrrolidine has long-lasting antihypertensive effect. The effect 
occur without, at the same time, increase in the heart rate. Such increase 
is an undesirable side effect of many antihyrpertensives which could cause 
cardiovascular complications and ultimately could lead to heart failure.