(3-Aminopropoxy)bibenzyl derivatives are prepared and found useful as pharmaceutical agents, particularly as inhibitors of platelet aggregation.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
This invention relates to (3-aminopropoxy)bibenzyl derivatives which 
possess anticoagulant activity, especially activity against blood platelet 
aggregation. They enhance the prostaglandins I.sub.2 activity and are 
effective for the cure and prevention of thrombosis. 
More particularly, this invention relates to (3-aminopropoxy)bibenzyl 
derivatives and to pharmaceutical compositions containing the same 
effective for inhibiting platelet aggregation. 
This invention also relates to processes whereby said 
(3-aminopropoxy)bibenzyl derivatives are prepared and also to processes 
for inhibiting platelet aggregation. 
SUMMARY OF THE INVENTION 
In summary, the compounds of this invention can be represented by the 
formula (I): 
##STR1## 
wherein R.sup.1 and R.sup.2 independently are hydrogen, halogen, C.sub.1 
-C.sub.5 alkyl, C.sub.1 -C.sub.5 alkoxy or C.sub.2 -C.sub.6 dialkylamino; 
R.sup.3 is hydrogen, --(CH.sub.2).sub.n --COOH where n is an integer of 1 
to 5, or 
##STR2## 
where Y is --(CH.sub.2).sub.m -- (m is an integer of 1 to 3), 
##STR3## 
where r is an integer of 2 to 4, or 
##STR4## 
wherein R.sup.5 and R.sup.6 independently are C.sub.1 -C.sub.8 alkyl or 
(2) 
##STR5## 
wherein A is a divalent radical which consists of two or more groups 
selected from methylene --CH.sub.2 -- and monosubstituted 
##STR6## 
where R.sup.7 is C.sub.1 -C.sub.5 alkyl or carbamoyl --CONH.sub.2 and zero 
or one or more than one group selected from the group consisting of 
##STR7## 
and substituted 
##STR8## 
where R.sup.8 is C.sub.1 -C.sub.5 alkyl, which are combined in an arbitory 
order to form a ring, the number of the combined groups being up to 9, or 
a pharmaceutically acceptable acid addition salt thereof. 
DESCRIPTION OF THE PREFERRED EMBODIMENTS 
As summarized above, this invention relates to a group of compounds useful 
as pharmaceutical agents, the structure and numbering system of which are 
as follows: 
##STR9## 
In the above formula (I), R.sup.1 and R.sup.2 independently are hydrogen; 
halogen such as fluorine, chlorine and bromine (preferably fluorine and 
chlorine); C.sub.1 -C.sub.5 (preferably C.sub.1 -C.sub.3) alkyl such as 
methyl, ethyl, propyl, butyl or the like; C.sub.1 -C.sub.5 (preferably 
C.sub.1 -C.sub.3) alkoxy such as methoxy, ethoxy, propoxy, butoxy or the 
like; or C.sub.2 -C.sub.6 (preferably C.sub.2 -C.sub.4) dialkylamino such 
as dimethylamino, diethylamino or the like; R.sup.3 is hydrogen; 
--(CH.sub.2).sub.n COOH where n is an integer of 1 to 5 (preferably 1 to 
3); or 
##STR10## 
where Y is --(CH.sub.2).sub.m -- (m is an integer of 1 to 3), 
##STR11## 
where r is an integer of 2 to 4, or 
##STR12## 
wherein R.sup.5 and R.sup.6 are independently C.sub.1 -C.sub.8 (preferably 
C.sub.1 -C.sub.5) alkyl such as methyl, ethyl, propyl, iso-propyl, butyl, 
iso-butyl, pentyl, hexyl, heptyl, octyl or the like or (2) 
##STR13## 
wherein A is a divalent radical which consists of two or more groups 
selected from methylene --CH.sub.2 -- and monosubstituted 
##STR14## 
where R.sup.7 is C.sub.1 -C.sub.5 (preferably C.sub.1 -C.sub.3) alkyl such 
as methyl, ethyl, propyl, butyl or the like or carbamoyl --CONH.sub.2 ; 
and zero or one or more than one group selected from the group consisting 
of 
##STR15## 
and substituted 
##STR16## 
where R.sup.8 is C.sub.1 -C.sub.5 (preferably C.sub.1 -C.sub.3) alkyl such 
as methyl, ethyl, propyl, butyl or the like, which are combined in an 
arbitory order to form a ring, the number of the combined groups being up 
to 9 (preferably 7). 
Illustrative of the typical 
##STR17## 
groups are the following: 1-pyrrolidinyl, piperidino, 
1-hexamethyleneiminyl, 1-heptamethyleneiminyl, 3-methyl-1-pyrrolidinyl, 
2,5-dimethyl-1-pyrrolidinyl, 2-ethylpyrrolidinyl, 2-methylpiperidino, 
3-methylpiperidino, 4-methylpiperidino, 4-ethylpiperidino, 
2,4-dimethylpiperidino, 4-methyl-1-piperazinyl, 4-ethyl-1-piperazinyl, 
4-propyl-1-piperazinyl, 3-carbamoyl-1-pyrrolidinyl, 3-carbamoylpiperidino, 
4-carbamoylpiperidino. 
The preferred 
##STR18## 
groups are 1-pyrrolidinyl, piperidino and C.sub.5 -C.sub.7 
4-alkyl-1-piperazinyl, each of which is unsubstituted or substituted with 
one or two groups selected from C.sub.1 -C.sub.3 alkyl and carbamoyl. 
In the above formula (I), the 3-aminopropoxy group may be located at any of 
the 2- to 4-position of the benzene nucleus; preferably, it is located at 
either the 2- or 4-position, and more preferably it is located at the 
2-position. 
In the above formula (I), the substituent positions of R.sup.1 and R.sup.2 
on the benzene nucleuses are not limited, preferably any of the 2'- to 
4'-position and any of the 4- to 6-position, respectively. 
Representative of the compounds of this invention are the following: 
2-[(3-dimethylamino-2-hydroxy)propoxy]bibenzyl; 
2-[(3-dimethylamino-2-carboxymethoxy)propoxy]bibenzyl; 
2-[[3-dimethylamino-2-(2-carboxyethoxy)]propoxy]bibenzyl; 
2-[[3-dimethylamino-2-(3-carboxypropoxy)]propoxy]bibenzyl; 
2-[[3-dimethylamino-2-(3-carboxypropionyloxy)]propoxy]bibenzyl; 
2-[[3-dimethylamino-2-(4-carboxybutyryloxy)]propoxy]bibenzyl; 
2-[[3-dimethylamino-2-(2-carboxycyclobutylcarbonyloxy)]propoxy]bibenzyl; 
2-[[3-dimethylamino-2-(2-carboxycyclopentylcarbonyloxy)]propoxy]bibenzyl; 
2-[[3-dimethylamino-2-(2-carboxycyclohexylcarbonyloxy)]propoxy]bibenzyl; 
2-[[3-dimethylamino-2-(2-carboxy-4-cyclohexenylcarbonyloxy)]propoxy]bibenzy 
l; 
2-[[3-dimethylamino-2-(2-carboxy-1-cyclohexenylcarbonyloxy)]propoxy]bibenzy 
l; 
2-[(3-diethylamino-2-hydroxy)propoxy]bibenzyl; 
2-[(3-diethylamino-2-carboxymethoxy)propoxy]bibenzyl; 
2-[[3-diethylamino-2-(2-carboxyethoxy)]propoxy]bibenzyl; 
2-[[3-diethylamino-2-(3-carboxypropoxy)]propoxy]bibenzyl; 
2-[[3-diethylamino-2-(3-carboxypropionyloxy)]propoxy]bibenzyl; 
2-[[3-diethylamino-2-(4-carboxybutyryloxy)]propoxy]bibenzyl; 
2-[[3-diethylamino-2-(2-carboxycyclobutylcarbonyloxy)]propoxy]bibenzyl; 
2-[[3-diethylamino-2-(2-carboxycyclopentylcarbonyloxy)]propoxy]bibenzyl; 
2-[[3-diethylamino-2-(2-carboxyhexylcarbonyloxy)]propoxy]bibenzyl; 
2-[[3-diethylamino-2-(2-carboxy-4-cyclohexenylcarbonyloxy)]propoxy]bibenzyl 
; 
2-[[3-diethylamino-2-(2-carboxy-1-cyclohexenylcarbonyloxy)]propoxy]bibenzyl 
; 
2-[[3-(1-pyrrolidinyl)-2-hydroxy]propoxy]bibenzyl; 
2-[[3-(1-pyrrolidinyl)-2-carboxymethoxy]propoxy]bibenzyl; 
2-[[3-(1-pyrrolidinyl)-2-(2-carboxyethoxy)]propoxy]bibenzyl; 
2-[[3-(1-pyrrolidinyl)-2-(3-carboxypropoxy)]propoxy]bibenzyl; 
2-[[3-(1-pyrrolidinyl)-2-(3-carboxypropionyloxy)]propoxy]bibenzyl; 
2-[[3-(1-pyrrolidinyl)-2-(4-carboxybutyryloxy)]propoxy]bibenzyl; 
2-[[3-(1-pyrrolidinyl)-2-(2-carboxycyclobutylcarbonyloxy)]propoxy]bibenzyl; 
2-[[3-(1-pyrrolidinyl)-2-(2-carboxycyclopentylcarbonyloxy)]propoxy]bibenzyl 
; 
2-[[3-(1-pyrrolidinyl)-2-(2-carboxycyclohexylcarbonyloxy)]propoxy]bibenzyl; 
2-[[3-(1-pyrrolidinyl)-2-(2-carboxy-4-cyclohexenylcarbonyloxy)]propoxy]bibe 
nzyl; 
2-[[3-(1-pyrrolidinyl)-2-(2-carboxy-1-cyclohexenylcarbonyloxy)]propoxy]bibe 
nzyl. 
2-[(3-piperidino-2-hydroxy)propoxy]bibenzyl; 
2-[(3-piperidino-2-carboxymethoxy)propoxy]bibenzyl; 
2-[[3-piperidino-2-(2-carboxyethoxy)]propoxy]bibenzyl; 
2-[[3-piperidino-2-(3-carboxypropoxy)]propoxy]bibenzyl; 
2-[[3-piperidino-2-(3-carboxypropionyloxy)]propoxy]bibenzyl; 
2-[[3-piperidino-2-(4-carboxybutyryloxy)]propoxy]bibenzyl; 
2-[[3-piperidino-2-(2-carboxycyclobutylcarbonyloxy)]propoxy]bibenzyl; 
2-[[3-piperidino-2-(2-carboxycyclopentylcarbonyloxy)]propoxy]bibenzyl; 
2-[[3-piperidino-2-(2-carboxycyclohexylcarbonyloxy)]propoxy]bibenzyl; 
2-[[3-piperidino-2-(2-carboxy-4-cyclohexenylcarbonyloxy)]propoxy]bibenzyl; 
2-[[3-piperidino-2-(2-carboxy-1-cyclohexenylcarbonyloxy)]propoxy]bibenzyl. 
2-[[3-(4-methylpiperidino)-2-hydroxy]propoxy]bibenzyl; 
2-[[3-(4-methylpiperidino)-2-carboxymethoxy]propoxy]bibenzyl; 
2-[[3-(4-methylpiperidino)-2-(2-carboxyethoxy)]propoxy]bibenzyl; 
2-[[3-(4-methylpiperidino)-2-(3-carboxypropoxy)]propoxy]bibenzyl; 
2-[[3-(4-methylpiperidino)-2-(3-carboxypropionyloxy)]propoxy]bibenzyl; 
2-[[3-(4-methylpiperidino)-2-(4-carboxybutyryloxy)]propoxy]bibenzyl; 
2-[[3-(4-methylpiperidino)-2-(2-carboxycyclobutylcarbonyloxy)]propoxy]biben 
zyl; 
2-[[3-(4-methylpiperidino)-2-(2-carboxycyclopentylcarbonyloxy)]propoxy]bibe 
nzyl; 
2-[[3-(4-methylpiperidino)-2-(2-carboxycyclohexylcarbonyloxy)]propoxy]biben 
zyl; 
2-[[3-(4-methylpiperidino)-2-(2-carboxy-4-cyclohexenylcarbonyloxy)]propoxy] 
bibenzyl; 
2-[[3-(4-methylpiperidino)-2-(2-carboxy-1-cyclohexenylcarbonyloxy)]propoxy] 
bibenzyl. 
2-[[3-(4-methyl-1-piperazinyl)-2-hydroxy]propoxy]bibenzyl; 
2-[[3-(4-methyl-1-piperazinyl)-2-carboxymethoxy]propoxy]bibenzyl; 
2-[[3-(4-methyl-1-piperazinyl)-2-(2-carboxyethoxy)]propoxy]bibenzyl; 
2-[[3-(4-methyl-1-piperazinyl)-2-(3-carboxypropoxy)]propoxy]bibenzyl; 
2-[[3-(4-methyl-1-piperazinyl)-2-(3-carboxypropionyloxy)]propoxy]bibenzyl; 
2-[[3-(4-methyl-1-piperazinyl)-2-(4-carboxybutyryloxy)]propoxy]bibenzyl; 
2-[[3-(4-methyl-1-piperazinyl)-2-(2-carboxycyclobutylcarbonyloxy)]propoxy]b 
ibenzyl; 
2-[[3-(4-methyl-1-piperazinyl)-2-(2-carboxycyclohexylcarbonyloxy)]propoxy]b 
ibenzyl; 
2-[[3-(4-methyl-1-piperazinyl)-2-(2-carboxy-4-cyclohexenylcarbonyloxy)]prop 
oxy]bibenzyl; 
2-[[3-(4-methyl-1-piperazinyl)-2-(2-carboxy-1-cyclohexenylcarbonyloxy)]prop 
oxy]bibenzyl; 
2-[[3-(4-carbamoylpiperidino)-2-hydroxy]propoxy]bibenzyl; 
2-[[3-(4-carbamoylpiperidino)-2-carboxymethoxy]propoxy]bibenzyl; 
2-[[3-(4-carbamoylpiperidino)-2-(2-carboxyethoxy)]propoxy]bibenzyl; 
2-[[3-(4-carbamoylpiperidino)-2-(3-carboxypropoxy)]propoxy]bibenzyl; 
2-[[3-(4-carbamoylpiperidino)-2-(3-carboxypropionyloxy)]propoxy]bibenzyl; 
2-[[3-(4-carbamoylpiperidino)-2-(4-carboxybutyryloxy)]propoxy]bibenzyl; 
2-[[3-(4-carbamoylpiperidino)-2-(2-carboxycyclobutylcarbonyloxy)]propoxy]bi 
benzyl; 
2-[[3-(4-carbamoylpiperidino)-2-(2-carboxycyclopentylcarbonyloxy)]propoxy]b 
ibenzyl; 
2-[[3-(4-carbamoylpiperidino)-2-(2-carboxycyclohexylcarbonyloxy)]propoxy]bi 
benzyl; 
2-[[3-(4-carbamoylpiperidino)-2-(2-carboxy-4-cyclohexenylcarbonyloxy)]propo 
xy]bibenzyl; 
2-[[3-(4-carbamoylpiperidino)-2-(2-carboxy-1-cyclohexenylcarbonyloxy)]propo 
xy]bibenzyl. 
The above examples are exemplary of those compounds of Formula (I) wherein 
R.sup.1 and R.sup.2 are hydrogen and R.sup.4 is dimethylamino, 
diethylamino, 1-pyrrolidinyl, piperidino, 4-methylpiperidino, 
4-methyl-1-piperazinyl or 4-carbamoylpiperidino. 
Similarly, these respective corresponding compounds in which R.sup.2 is 
hydrogen and R.sup.1 is fluoro, chloro, methoxy, methyl or dimethylamino 
or R.sup.1 is hydrogen and R.sup.2 is fluoro, chloro or methoxy are also 
illustrative of the compounds of this invention. 
The pharmaceutically acceptable acid addition salts of the above compounds 
are, of course, also included within the scope of this invention. 
It will be understood that the term "pharmaceutically acceptable acid 
addition salts" as used herein is intended to include non-toxic salts of 
the compounds of this invention with an anion. 
Representative of such salts are hydrochlorides, hydrobromides, sulfates, 
phosphates, nitrates, acetates, succinates, adipates, propionates, 
tartrates, maleates, oxalates, citrates, benzoates, toluenesulfonates and 
methanesulfonates. 
Of the compounds of this invention, it will be understood that the 
following compounds are most preferred due to their high level of ability 
to inhibit the platelet aggregation. 
2-[(3-dimethylamino-2-hydroxy)propoxy]bibenzyl hydrochloride 
2-[(3-dimethylamino-2-hydroxy)propoxy]-3'-methoxybibenzyl hydrochloride 
2-[[3-dimethylamino-2-(3-carboxypropionyloxy)]propoxy]bibenzyl 
hydrochloride 
2-[[3-dimethylamino-2-(3-carboxypropionyloxy)]propoxy]-3'-methoxybibenzyl 
hydrochloride 
2-[(3-dimethylamino-2-carboxymethoxy)propoxy]bibenzyl hydrochloride 
2-[[3-dimethylamino-2-(2-carboxyethoxy)]propoxy]bibenzyl hydrochloride 
2-[[3-dimethylamino-2-(2-carboxyethoxy)]propoxy]-3'-methoxybibenzyl 
hydrochloride. 
The above compounds are intended only to illustrate the typical compounds 
of this invention, and the above listing is not to be construed as 
limiting the scope of the invention. 
The method for preparing the compounds according to this invention will be 
described below. 
The compound of the formula (I) wherein R.sup.3 is hydrogen, that is, 
(3-aminopropoxy)bibenzyl derivative of the formula (V); 
##STR19## 
wherein R.sup.1, R.sup.2 and R.sup.4 are as defined in Formula (I), can be 
prepared by reacting an epoxy derivatives of the formula (III): 
##STR20## 
wherein R.sup.1 and R.sup.2 are as defined in Formula (I), with an amine 
of the formula (IV); 
EQU R.sup.4 H (IV) 
wherein R.sup.4 is as defined in Formula (I) in a suitable solvent such as 
water, alcohol, tetrahydrofuran, acetone and the like at a temperature of 
from room temperature to the boiling point of the solvent. The epoxy 
derivatives of the formula (III) above can be prepared by reacting a 
hydroxybibenzyl of the formula (II): 
##STR21## 
wherein R.sup.1 and R.sup.2 are as defined in Formula (I), with 
epichlorhydrin in an aprotic solvent such as dimethyl formamide, 
tetrahydrofuran and benzene in the presence of a metal hydride such as 
sodium hydride or in a alcohol such as methanol and ethanol in the 
presence of a metal alcoholate. 
The reaction temperature may vary from room temperature to the boiling 
point of the solvent. 
The compound of the formula (I) wherein R.sup.3 is 
##STR22## 
that is, (3-aminopropoxy)bibenzyl derivative of the formula (VII): 
##STR23## 
wherein R.sup.1, R.sup.2, R.sup.4 and Y are as defined in Formula (I), can 
be prepared by reacting the (3-aminopropoxy)bibenzyl derivative of the 
formula (V) with an acid anhydride of the formula (VI): 
##STR24## 
wherein Y is as defined in Formula (I), the reaction can be carried out by 
heating the mixture in an aprotic solvent such as tetrahydrofuran. 
The compound of the formula (I) wherein R.sup.3 is --(CH.sub.2).sub.n 
--COOH, that is (3-aminopropoxy)bibenzyl derivative of the formula (X): 
##STR25## 
wherein R.sup.1, R.sup.2, R.sup.4 and n are as defined in Formula (I), can 
be prepared by the alkaline hydrolysis of a (3-aminopropoxy)bibenzyl 
derivative of the formula (IX): 
##STR26## 
wherein R.sup.1, R.sup.2, R.sup.4 and n are as defined in Formula (I) and 
R.sup.9 is lower alkyl. 
The (3-aminopropoxy)bibenzyl derivatives (IX) above can be prepared either 
by reacting the (3-aminopropoxy)bibenzyl derivative (V) with an 
.omega.-halogenoalkanoic acid ester of the formula (VIII): 
EQU X(CH.sub.2).sub.n CO.sub.2 R.sup.9 (VIII) 
wherein n is as defined in Formula (I), X is halogen and R.sup.9 is lower 
alkyl, in a tertiary alcohol in the presence of a metal salt of the 
tertiary alcohol, or by reacting the compound (V) with methyl acrylate 
without solvents or in an aprotic solvent such as dimethylformamide in the 
presence of a metal hydride. 
Pharmacological testing of the (3-aminopropoxy)bibenzyl derivatives of this 
invention has demonstrated that they possess anticoagulant activity, 
especially activity against blood platelet aggregation, and are suitable 
for use in the cure and prevention of thrombosis. Their activity against 
blood platelet aggregation can be demonstrated by an increase or decrease 
in platelet aggregation value caused by the administration of the 
compounds of this invention to rabbits. 
Evaluation of the compounds of this invention for their activity against 
platelet aggregation was carried out according to a turbidometric method 
described by G. V. R. Born, Nature, 194, 927 (1962). Platelet aggregation 
was measured using platelet-rich plasma prepared from citrated blood which 
was collected from a carotid artery of male white rabbits of Japanese 
native kind. A suspension of collagen (bovine Achilles tendon collagen, 
Sigma) in saline was used to cause platelet aggregation. The aggregation 
of rabbit blood platelet was induced by adding the suspension of collagen 
to give 10 to 15 .mu.g collagen per milliliter. At this time, the tests 
were conducted at 37.degree. C. at levels of 4.times.10.sup.5 
platelet/mm.sup.3. A solution of compounds of this invention in saline was 
added to the platelet-rich plasma. After three minutes of preincubation 
with the platelet-rich plasma, collagen was added to cause platelet 
aggregation. Percent inhibition was calculated by comparison with 
controls. 
The concentration of the compound in micromoles inhibiting platelet 
aggregation by 50 percent (I.sub.50) are shown in Table 1. 
LD.sub.50 was determined by Litchfield-Wilcoxon method. The LD.sub.50 
values of the compounds of this invention are in the range of 2,000 to 
5,000 mg/kg (in mice p.o.), for example, the LD.sub.50 of 
2-[[3-dimethylamino-2-(3-carboxyethoxy)]propoxy]bibenzyl is above 3,000 
mg/kg (p.o.). 
The compounds of this invention can be administered by any means that 
effects inhibiting blood platelet aggregation in warm-blooded animals. 
For example, administration can be parenterally, subcutaneously, 
intravenously, intramuscularly, or intraperitoneally. Alternatively or 
concurrently, administration can be by the oral route. The dosage 
administered will be dependent upon the age, health and weight of the 
recipient, kind of concurrent treatment if any, frequency of treatment, 
and the nature of the effect desired. Generally, a daily dosage of active 
ingredient compound will be from about 0.5 to 50 mg per kg of body weight. 
Normally, from 1 to 30 mg per kg per day, in one or more applications per 
day is effective to obtain the desired result. 
The compound of this invention can be employed in dosage forms such as 
tablets, capsules, powder packets, or liquid solutions, or elixirs, for 
oral administration, or sterile liquid formulations such as solutions or 
suspensions for parenteral use. In such compositions, besides the active 
ingredient of this invention, the composition will contain a solid or 
liquid non-toxic pharmaceutical carrier for the active ingredient. In one 
embodiment of a composition, the solid carrier can be a capsule of the 
ordinary gelatin type. In another embodiment, the active ingredient can be 
tableted with or without adjuvants, or put into powder packets. These 
capsules, tablets and powders will generally constitute from about 5% to 
about 95% and preferably from 25% to 90% by weight of active ingredient. 
These dosage forms preferably contain from about 5 to about 500 mg of 
active ingredient, with from about 25 to about 250 mg being most 
preferred. 
The pharmaceutical carrier can be a sterile liquid such as water and oils, 
including those of petroleum, animal, vegetable or synthetic origin, such 
as peanut oil, soybean oil, mineral oil, sesame oil, and the like. 
In general, water saline, aqueous dextrose and related sugar solutions, and 
glycols such as propylene glycol and polyethylene glycol are preferred 
liquid carriers, particularly for injectible solutions such as saline will 
ordinarily contain from about 0.5% to 20% and preferably about 1 to 10% by 
weight of the active ingredient. 
As mentioned above, oral administration can be in a suitable suspension or 
syrup, in which the active ingredient normally will constitute from about 
0.5 to 10% by weight. The pharmaceutical carrier in such composition can 
be a watery vehicle such as an aromatic water, a syrup or a pharmaceutical 
mucilage.

Having generally described the invention, a more complete understanding can 
be obtained by reference to certain specific examples, which are included 
for purposes of illustration only and are not intended to be limiting 
unless otherwise specified. 
EXAMPLE 1 
2-[(3-dimethylamino-2-hydroxy)propoxy]bibenzyl hydrochloride 
To a suspension of 2.2 g of 60% sodium hydride in 30 ml of 
N,N-dimethylformamide was added dropwise a solution of 10 g of 
2-hydroxybenzyl in 30 ml of N,N-dimethylformamide under stirring and 
ice-cooling. After completion of the dropwise addition, 23.4 g of 
epichlorhydrin was added in one portion. The ice bath was removed and the 
mixture was stirred for 3 to 4 hours at room temperature. The reaction 
solvent was then distilled off in vacuo and 40 ml of benzene and 20 ml of 
water were added to the residue. After the aqueous layer was separated, 
the benzene layer was washed with water and the benzene was distilled off 
in vacuo to give an oily epoxide. 
To the epoxide obtained above were added 40 ml of tetrahydrofuran and 53 ml 
of aqueous 50% dimethylamine and the mixture was stirred for 4 to 5 hours 
at room temperature. After the tetrahydrofuran and dimethylamine were 
distilled off in vacuo, 50 ml of isopropyl ether and 10 ml of water were 
added and the aqueous layer was separated. The isopropyl ether layer was 
washed with water and dried over anhydrous sodium sulfate followed by 
addition of 9.7 ml of 20% hydrogen chloride in ethyl acetate under 
stirring and ice-cooling. The resulting crystals were collected by 
filtration and recrystallized from ethyl acetate to give 14.4 g (85% 
yield) of 2-[(3-dimethylamino-2-hydroxy)propoxy]bibenzyl hydrochloride. 
The properties of this compound are shown in Table 1 as Compound 1. 
Likewise, Compounds 2 and 3 were prepared in the same way and their 
properties are also shown in Table 1. 
EXAMPLE 2 
2-[[3-dimethylamino-2-(3-carboxypropionyloxy)]propoxy]bibenzyl 
hydrochloride 
To a solution of 5 g of 2-[(3-dimethylamino-2-hydroxy)propoxy]bibenzyl in 
25 ml of tetrahydrofuran was added 1.9 g of succinic anhydride and the 
mixture was stirred for 3 hours under heating at reflux. After completion 
of the reaction, the reaction solvent was distilled off in vacuo and the 
residue was dissolved in 20 ml of chloroform. 
To the solution was added 3.2 ml of 20% hydrogen chloride in ethyl acetate 
under stirring and ice-cooling followed by addition of 80 ml of ether. The 
resulting crystals were collected by filtration and recrystallized from 
acetone to give 6.6 g (91% yield) of 
2-[[3-dimethylamino-2-(3-carboxypropionyloxy)]propoxy]bibenzyl 
hydrochloride. The properties of this compound are shown in Table 1 as 
Compound 4. 
Likewise, Compounds 5 to 11, 15 and 16 were prepared in the same way and 
their properties are also shown in Table 1. 
EXAMPLE 3 
2-[(3-dimethylamino-2-carboxymethoxy)propoxy]bibenzyl hydrochloride 
To a solution of 8.1 g of 2-[(3-dimethylamino-2-hydroxy)propoxy]bibenzyl in 
60 ml of tert-butanol was added 6.2 g of potassium tert-butoxide and the 
mixture was stirred at 70.degree. C. for 20 minutes. After cooling to room 
temperature, 4.9 g of tert-butyl chloroacetate was added dropwise under 
stirring. After completion of the dropwise addition, the reaction mixture 
was allowed to stand for 1 hour and then 1.6 g of tert-butyl chloroacetate 
was further added dropwise. After stirring for 2 hours, 40 ml of 2N sodium 
hydroxide solution was added and the mixture was stirred at 50.degree. C. 
for 2 hours. After completion of the reaction, ether was added and the 
aqueous layer was removed to extract the unreaction mixture. The ether 
layer was extracted twice with 0.5N sodium hydroxide solution and then the 
extract was combined with the original aqueous layer. The solution was 
adjusted to pH 3 with hydrochloric acid and extracted with chloroform. The 
extract was dried over anhydrous sodium sulfate and the solvent was 
distilled off. The residue was dissolved in acetone and 20% hydrogen 
chloride in ethyl acetate was added under cooling. The resulting crystals 
were collected by filtration and recrystallized from acetone to give 6.6 g 
(62% yield) of 2-[(3-dimethylamino-2-carboxymethoxy)propoxy]bibenzyl 
hydrochloride. 
The properties of this compound are shown in Table 1 as Compound 12. 
EXAMPLE 4 
2-[[3-dimethylamino-2-(2-carboxyethoxy)]propoxy]bibenzyl hydrochloride 
To 10 g of 2-[(3-dimethylamino-2-hydroxy)propoxy]bibenzyl was added 0.1 g 
of 60% sodium hydride and the mixture was stirred for 15 minutes at room 
temperature. Thereafter, 14.4 g of methyl acrylate was added in one 
portion and the mixture was stirred for 3 hours at room temperature. After 
completion of the reaction, 100 ml of ether and 50 ml of water were added 
and the aqueous layer was removed. The ether layer was washed with water 
and subjected to vacuum distillation. The resulting residue was dissolved 
in 30 ml of methanol and 33 ml of 2N sodium hydroxide solution was added. 
The mixture was stirred for 3 hours at room temperature. After completion 
of the reaction, ether was added and the aqueous layer was removed to 
extract the unreaction mixture. The ether layer was extracted twice with 
0.5N sodium hydroxide solution and then the extract was combined with the 
original aqueous layer. The solution was adjusted to pH 3 with 
hydrochloric acid and extracted with chloroform. The extract was dried 
over anhydrous sodium sulfate and the solvent was distilled off. The 
residue was dissolved in acetone and 20% hydrogen chloride in ethyl 
acetate was added under stirring and ice-cooling. The resulting crystals 
were collected by filtration and recrystallized from acetone to give 9.8 g 
(72% yield) of 2-[[3-dimethylamino-2-(2-carboxyethoxy)]propoxy]bibenzyl 
hydrochloride. 
The properties of this compound are shown in Table 1 as Compound 13. 
Likewise, Compounds 14 and 17 were prepared in the same way and their 
properties are also shown in Table 1. 
TABLE 1 
__________________________________________________________________________ 
##STR27## 
Addition 
No. 
R.sup.1 
R.sup.2 
R.sup.3 R.sup.4 salt 
__________________________________________________________________________ 
1 H H H N(CH.sub.3).sub.2 
HCl 
2 4'-N(CH.sub.3).sub.2 
H H N(CH.sub.3).sub.2 
2HCl 
3 3'-OCH.sub.3 
H H N(CH.sub.3).sub.2 
HCl 
4 H H CO(CH.sub.2).sub.2 CO.sub.2 H 
N(CH.sub.3).sub.2 
HCl 
5 4'-N(CH.sub.3).sub.2 
H CO(CH.sub.2).sub.2 CO.sub.2 H 
N(CH.sub.3).sub.2 
2HCl 
6 3'-OCH.sub.3 
H CO(CH.sub.2).sub.2 CO.sub.2 H 
N(CH.sub.3).sub.2 
HCl 
7 3'-F H CO(CH.sub.2).sub.2 CO.sub.2 H 
N(CH.sub.3).sub.2 
HCl 
8 3'-Cl H CO(CH.sub.2).sub.2 CO.sub.2 H 
N(CH.sub.3).sub.2 
HCl 
9 H 5-Cl 
CO(CH.sub.2).sub.2 CO.sub.2 H 
N(CH.sub.3).sub.2 
HCl 
10 
H H 
##STR28## 
N(CH.sub.3).sub.2 
HCl 
11 
H H 
##STR29## 
N(CH.sub.3).sub.2 
HCl 
12 
H H CH.sub.2 CO.sub.2 H 
N(CH.sub.3).sub.2 
HCl 
13 H H (CH.sub.2).sub.2 CO.sub.2 H 
N(CH.sub.3).sub.2 
HCl 
14 3'-OCH.sub.3 
H (CH.sub.2).sub.2 CO.sub.2 H 
N(CH.sub.3).sub.2 
HCl 
15 
H H CO(CH.sub.2).sub.2 CO.sub.2 H 
##STR30## HCl 
16 
H H CO(CH.sub.2).sub.2 CO.sub.2 H 
##STR31## HCl 
17 
2'-CH.sub.3 
H (CH.sub.2).sub.2 CO.sub.2 H 
##STR32## HCl 
__________________________________________________________________________ 
Elementary analysis 
Upper: Calcd. (%) 
m.p. Molecular Lower: Found (%) 
I.sub.50 
No. (.degree.C.) 
formula C H N (.mu.M) 
__________________________________________________________________________ 
1 101-3 
C.sub.19 H.sub.25 NO.sub.2.HCl 
67.94 
7.80 4.17 
1.5 
68.38 
7.72 3.97 
2 146-8 
C.sub.21 H.sub.30 N.sub.2 O.sub.2.2HCl 
60.72 
7.76 6.74 
0.75 
60.60 
7.65 6.80 
3 120-1 
C.sub.20 H.sub.27 NO.sub.3.HCl 
65.65 
7.71 3.83 
0.8 
65.55 
7.65 3.80 
4 146-9 
C.sub.23 H.sub.29 NO.sub.5.HCl 
63.37 
6.94 3.21 
2 
63.39 
6.87 3.07 
5 powder 
C.sub.25 H.sub.34 N.sub.2 O.sub.5.2HCl 
58.25 
7.04 5.43 
1.5 
58.05 
7.00 5.60 
6 139-42 
C.sub.24 H.sub.31 NO.sub.6.HCl 
61.86 
6.92 3.01 
1.5 
61.84 
6.89 2.98 
7 142-4 
C.sub.23 H.sub.28 FNO.sub.5.HCl 
60.86 
6.44 3.09 
1.2 
60.80 
6.39 2.96 
8 158-61 
C.sub.23 H.sub.28 ClNO.sub.5.HCl 
58.73 
6.21 2.98 
0.8 
58.53 
6.15 2.86 
9 160-1 
C.sub.23 H.sub.28 ClNO.sub.5.HCl 
58.73 
6.21 2.98 
4 
58.58 
6.19 2.96 
10 160-3 
C.sub.27 H.sub.33 NO.sub.5.HCl 
66.45 
7.02 2.87 
8.0 
66.28 
6.97 2.92 
11 107-10 
C.sub.25 H.sub.32 NO.sub.5.HCl 
64.85 
7.18 3.03 
5.5 
64.80 
7.13 3.29 
12 107-10 
C.sub.21 H.sub.27 NO.sub.4.HCl 
64.03 
7.16 3.56 
4.5 
64.00 
7.05 3.49 
13 109-10 
C.sub.22 H.sub.29 NO.sub.4.HCl 
64.78 
7.41 3.43 
3.0 
64.60 
7.31 3.40 
14 140-2 
C.sub.23 H.sub.31 NO.sub.5.HCl 
63.08 
7.36 3.20 
3.0 
62.90 
7.25 3.30 
15 158-61 
C.sub.26 H.sub.33 NO.sub.5.HCl 
65.60 
7.20 2.94 
2.5 
65.51 
7.10 2.83 
16 86-90 
C.sub.27 H.sub.34 N.sub.2 O.sub.6.HCl 
62.48 
6.80 5.40 
3 
62.29 
6.63 5.52 
17 176-8 
C.sub. 25 H.sub.35 NO.sub.4.HCl 
66.72 
8.06 3.11 
-- 
66.42 
7.99 3.13 
__________________________________________________________________________ 
The following compounds can be prepared in the same manner as disclosed in 
the above examples: 
2-[[3-(1-pyrrolidinyl)-2-(2-carboxyethoxy)]propoxy]-3'-methoxybibenzyl 
hydrochloride 
2-[[3-(4-methyl-1-piperazinyl)-2-(3-carboxypropionyloxy)]propoxy]bibenzyl 
hydrochloride 
2-[[3-(4-methylpiperidino)-2-carboxymethoxy)]propoxy]-3'-fluorobibenzyl 
hydrochloride 
2-[[3-dimethylamino-2-(2-carboxy-1-cyclohexenylcarbonyloxy)]propoxy]bibenzy 
l hydrochloride 
2-[[3-dimethylamino-2-(3-carboxypropionyloxy)]propoxy]-3'-methoxy-5-chlorob 
ibenzyl hydrochloride. 
Having now fully described the invention, it will be apparent to one of 
ordinary skill in the art that many changes and modifications can be made 
thereto without departing from the spirit of the invention as set forth 
herein.