Novel alkylenetris- and alkylenetetrakis-[1,2,3,4-tetrahydroisoquinoline] and -[3,4-dihydroisoquinoline] compounds, the pharmaceutically acceptable acid addition salts thereof and compositions containing such substances have been found useful for inhibiting the formation of blood clots in mammals and/or dissolving blood clots in mammals after they have been formed.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
This invention relates to new compounds useful for inhibiting the formation 
of blood clots, or dissolving blood clots after they have been formed, and 
more particularly to novel alkylenetris- and 
alkylenetetrakis-[1,2,3,4-tetrahydroisoquinoline] and 
-[3,4-dihydroisoquinoline] compounds, and the pharmaceutically acceptable 
acid addition salts thereof. 
2. Description of the Prior Art 
In the formation of a blood clot, for example a thrombus, fibrinogen, a 
soluble plasma protein, is converted to the insoluble protein fibrin. As 
the fibrin is deposited it entraps blood cells within its meshwork to form 
a coagulum. In the case of a thrombus, the coagulum usually interferes 
with the flow through the blood vessel. 
The defense of the living organism against such occurrence is the plasma 
protein called plasminogen which, under certain conditions, can be 
activated by an "activator" whereby the plasminogen is converted to the 
protein, plasmin. Plasmin possesses the property of efficiently digesting 
and destroying fibrin (fibrinolysis). The fibrinolysis results in 
dissolution of the clot, and, in the case of a thrombus, restores the 
patency of the vessel. 
Under normal conditions, the organism has low levels of "activator" in the 
blood stream. It is believed that small amounts of plasminogen are 
constantly undergoing conversion to plasmin by the action of the 
"activator". However, from a quantitative viewpoint, the amount of 
activator normally present in insufficient to produce enough plasmin to 
lyse the relatively large amount of fibrin present in a clot such as a 
thrombus. 
Fibrinolytic activity in vitro is manifested by many compounds such as the 
aromatic sulfonic acids, derivatives of salicylic acid, long chain fatty 
acids and halogenated unsaturated acids. Such compounds have not, however, 
been found to exhibit in vivo fibrinolytic or thrombolytic activity. 
Fibrinolytic activity in vivo can be induced by nicotinic acid, procaine, 
phenylbutazone, acetylcholine, epinephrine, serotonin and histamine. 
However, the effect of these compounds is of short-lived duration, i.e., 
of the order of minutes. 
Some sulphonylureas and steroids can induce an increase in fibrinolytic 
activity, but a lag period of the order of hours precedes the slow 
increase in lytic activity. Compounds of this type cannot be used when a 
substance is employed to effect thrombolytic therapy, because in such 
instance the activity must be rapidly induced to be effective in 
dissolving clots. 
Streptokinase, a streptococcal protein, has been used for thrombolysis, but 
the side effects of pyrogenicity and anaphylactic reactions have limited 
its use. 
Urokinase, a protein isolated from human urine, has also been used for 
thrombolysis but the difficulties involved in accumulating large supplies 
of the starting material, human urine, and the great cost of preparing the 
substance has proscribed its general and practical utility. 
Bacterial pyrogens have also been used to effect thrombolysis, but the 
severity and unpredictability of the pyrogenic reactions have negated 
their usefulness. 
SUMMARY OF THE INVENTION 
The present invention provides compounds which inhibit the formation of 
blood clots (by inhibiting platelet aggregation and/or fibrin formation) 
or dissolve such clots as they are formed (by fibrinolysis) or after they 
have been formed (by fibrinolysis). Such substances demonstrate activity 
in mammals in vivo, are highly potent, long-lasting, rapid in onset, 
readily prepared and suffer fron none of the difficulties associated with 
materials of natural origin. 
Various of the compounds of this invention may be used to effect 
fibrinolysis of the clot in acute thrombosis. Many possess the further 
advantage of oral activity and may be employed prophylactically to 
maintain increased fibrinolytic activity on a long term basis and thus 
diminish the incidence of new thrombotic episodes. 
Other objects and advantages of the compounds disclosed in the present 
application, methods of preparing them and compositions containing the 
same which are useful in preventing the formation of blood clots, or in 
effecting high sustained levels of fibrinolytic activity in mammals 
without toxic effect, even at substantially high dosage levels, will be 
apparent from the following detailed description of the preferred 
embodiments thereof. 
The novel compounds according to the invention are characterized by the 
following general formula: 
##STR1## 
wherein 
A and B is each hydrogen or, taken together, represent an additional carbon 
to nitrogen bond; 
R.sub.1 and R.sub.2 represent hydrogen or lower alkyl; 
R.sub.3, R.sub.4 and R.sub.5 represent hydrogen, lower alkyl, halogen, 
hydroxy, lower alkoxy, lower alkenoxy, lower alkynoxy, lower acyloxy, 
aryloxy or phenyl lower alkoxy. R.sub.3 and R.sub.4 or R.sub.4 and R.sub.5 
may be linked to form a lower alkylenedioxy. By the term "lower" alkyl, 
alkoxy, etc., is meant such groups having from 1 to about 6 carbon atoms, 
except for "lower" alkylenedioxy, which refers to alkylenedioxy having up 
to 3 carbon atoms; 
Z represents an organic radical having a valence of n, said radical being a 
hydrocarbon group that can contain up to four hetero atoms selected from 
the group consisting of oxygen, sulfur, and nitrogen, and wherein said 
radical can contain up to three substituents selected from the group 
consisting of amino, nitro, halo, hydroxy, lower alkyl, lower alkoxy, 
benzyloxy, trifluoromethyl, and a lower alkylenedioxy; 
n represents the numbers 3 or 4. 
This invention is also characterized by pharmaceutically acceptable acid 
addition salts of the compounds of the above general formula as well as 
compositions containing such substances. The term "pharmaceutically 
acceptable addition salt" includes such salts as: the mineral acid salts, 
e.g., the hydrochloride, hydrobromide, sulfate and phosphate; and organic 
acid salts such as the lactate, tartrate, citrate, succinate, benzoate, 
acetate, p-toluenesulfonate and benzenesulfonate, and others 
conventionally formed from acids conventionally used in the pharmaceutical 
art. 
The alkylenetris- or alkylenetetrakis-[1,2,3,4-tetrahydroisoquinoline] 
compounds within the above formula are useful as fibrinolytic agents in 
mammals. Such materials additionally possess the property of inhibiting 
platelet aggregation and may thus be utilized for inhibiting the formation 
of blood clots as well as for dissolving such clots as they may be formed 
or after they have been formed. The alkylenetris- or 
alkylenetetrakis-[3,4-dihydroisoquinoline] compounds within the above 
formula are intermediates in the preparation of the corresponding 
tetrahydroisoquinoline compounds and, moreover, possess the property of 
inhibiting platelet aggregation. Thus, both the tetrahydroisoquinoline and 
dihydroisoquinoline compounds within the above formula are useful for 
inhibiting the formation of blood clots. 
The compounds of the invention are prepared by permitting selected tri- and 
tetracarboxylic acids or their derivatives (esters, and chlorides and the 
like) to react with appropriately substituted phenethylamines. The tri- 
and tetraphenethylamides thus derived are cyclized through dehydration to 
the 3,4-dihydroisoquinoline compounds within the above formula, in 
accordance with the Bischler-Napieralski synthesis* with which those 
skilled in the art are familiar. The cyclization is effected by reacting 
the amides with phosphorus oxychloride (POCl.sub.3) by itself or diluted 
with an equal amount of a suitable solvent, e.g., benzene or toluene. The 
dihydroisoquinolines thus produced are thereafter converted to the 
1,2,3,4-tetrahydroisoquinoline compounds of the above formula by 
reduction. The reduction step is carried out employing, for example, 
sodium borohydride in alcoholic solution or lithium aluminum hydride in 
tetrahydrofuran. 
FNT * See, for instance, Whaley et al, Organic Reactions VI, 74 (1951); and 
Bergstrom, Chem. Revs. 35, 218 (1944). 
It will be apparent from a consideration of the chemistry involved in 
making the products of this invention that their preparation results in 
the formation of mixtures of diastereoisomers. It has been found that all 
such isomers display fibrinolytic or platelet aggregation inhibiting 
activity. The preceding formula therefore embraces all of the isomers 
arising during the synthesis of these compounds. The designation of the 
compounds of the formula, by names and by formulas throughout the 
specification and claims, shall be read to include all isomers and 
mixtures thereof. The preparation of any particular stereoisomer from a 
mixture of such isomers will be within the competence of one skilled in 
the art. A typical technique involves reacting the mixture of isomers of 
any given compound with a particular stereoisomer of an optically-active 
acid to form an isomeric mixture of acid addition salts. These salts will 
have differing physical properties and can be separated by known means. 
Oxygenated functions are generally beneficial for maximum clot-dissolving 
activity and with one preferred aspect of this invention there is included 
in R.sub.3, R.sub.4 and R.sub.5 one or more lower alkoxy functions such as 
methoxy, isopropoxy, butoxy, or a methylenedioxy. These functions are most 
effective when situated at the 6 and 7 positions of the 
tetrahydroisoquinoline rings. 
The Z variable represents, in most cases, the residue after removal of the 
carboxy groups of the tri- or tetracarboxylic acid that was used to 
produce the compound of the invention. Representative types of organic 
groups that can be the Z variable include alkanetriyl, alkanetetrayl, 
alkanetriyl having from 1 to 3 oxygen, sulfur, or nitrogen hetero atoms, 
phenylalkanetriyl, benzylalkanetriyl and substituted benzylalkanetriyl, 
alkanetetrayl having from 1 to 4 oxygen, sulfur or nitrogen atoms, 
cycloalkanediylidenetetraethylene, 
tetrahydrothiopyrandiylidenetetraethylene, 
tetrahydropyrandiylidenetetraethylene, and the like. In addition, the Z 
variable can contain substituents such as amino, nitro, halo, hydroxy, 
lower alkyl, lower alkoxy, benzyloxy, trifluoromethyl, and a lower 
alkylenedioxy. In most cases, the Z variable will contain from 5 to 18 
carbon atoms. 
Thus, the Z chain connecting the tetrahydroisoquinoline and 
dihydroisoquinoline groups in the above formula may vary within wide 
limits with retention of potency. Activity is maximized, however, when the 
individual isoquinoline moieties are separated by chains of from three to 
ten carbon atoms. The nature of Z is determined by the tri- and 
tetracarboxylic acids or their derivatives (esters, acid chlorides and the 
like) used in the synthesis of the compounds within the generic formula. 
Representative of acids which may be used in the preparation of 
biologically potent compounds of the above class are the following: 
##STR2## 
PREFERRED EMBODIMENTS OF THE INVENTION 
Within the broad claims of the fibrinolytically active 
1,2,3,4-tetrahydroisoquinoline compounds of the invention, there are 
several preferred classes of compounds. Such preferred classes include the 
following: 
I. Tris[1,2,3,4-tetrahydro-1-isoquinolinyl]alkanes, wherein the alkane 
moiety has from 5 to 18 carbon atoms and wherein the 
tetrahydroisoquinoline moieties can be unsubstituted or can be substituted 
with lower alkyl, lower alkoxy, lower alkylenedioxy, benzyloxy, or hydroxy 
groups. 
II. Tetrakis[1,2,3,4-tetrahydro-1-isoquinolinyl]alkanes, wherein the alkane 
moiety has from 7 to 18 carbon atoms and wherein the 
tetrahydroisoquinoline moieties can be unsubstituted or can contain lower 
alkyl, lower alkoxy, lower alkylenedioxy, benzyloxy or hydroxy 
substituents. 
III. 
1,1'-{1-[(1,2,3,4-Tetrahydro-1-isoquinolinylmethyl)thio]pentanemethylene}b 
is[1,2,3,4-tetrahydroisoquinolines] and 
1,1'-{1-[(1,2,3,4-tetrahydro-1-isoquinolinylmethyl)oxy]pentamethylene}bis[ 
1,2,3,4-tetrahydroisoquinolines], wherein the tetrahydroisoquinoline 
moieties can be unsubstituted or can have lower alkyl, lower alkoxy, lower 
alkylenedioxy, benzyloxy or hydroxy substituents. These compounds can be 
produced by first reacting a 3-bromo-2-oxocyclohexanecarboxylic acid ester 
with a glycolic acid ester or thioglycolic acid ester to produce a 
3-(carboxymethyl)oxy-(or thio)-2-oxocyclohexanecarboxylic acid di-ester. 
This latter compound is reacted with sodium hydroxide, water and ethanol 
to form a tri-ester of 2-(carboxymethyl)oxy-(or thio)-heptanedioic acid. 
(The reaction involved here is the known "acid" hydrolysis of a betaketo 
ester). The tricarboxylic acid ester is then reacted with an appropriate 
phenethylamine in a Bischler-Napieralski synthesis, followed by reduction 
to produce the compounds of the invention. 
IV. 
1,1'-{3-Benzyl-3-[2-(1,2,3,4-tetrahydro-1-isoquinolinyl)ethyl]pentamethyle 
ne}bis[1,2,3,4-tetrahydroisoquinolines] wherein the benzyl moiety can be 
unsubstituted or can contain up to three lower alkyl, lower alkoxy, halo 
(fluoro, chloro, bromo, or iodo), trifluoromethyl, or a lower 
alkylenedioxy substituent on the benzene ring, and wherein the 
tetrahydroisoquinoline moieties can be unsubstituted or can contain lower 
alkyl, lower alkoxy, lower alkylenedioxy, benzyloxy, or hydroxy 
substituents. These compounds are prepared by first cyanoethylating an 
appropriately substituted acetophenone (the substituents, if any, are on 
the phenyl group of the acetophenone) to produce a 
3-benzoyl-3-(2-cyanoethyl)-1,5-pentanedicarbonitrile. The trinitrile is 
hydrolyzed to produce a 4-benzoyl-4-(2-carboxyethyl)-heptanedioic acid. 
After a Wolff-Kishner reduction (to change the benzoyl group to a benzyl 
group), the triacid is esterified and then reacted with a phenethylamine, 
cyclized, and reduced to the compounds of the invention. 
V. 
1,1',1",1'"-(1,3-Cycloalkanediylidenetetraethylene)tetrakis[1,2,3,4-tetrah 
ydroisoquinolines], wherein the cycloaliphatic ring contains from 5 to 8 
carbon atoms, and wherein the tetrahydroisoquinoline moieties can be 
unsubstituted, or can contain lower alkyl, lower alkoxy, lower 
alkylenedioxy, benzyloxy, or hydroxy substituent. 
VI. 
1,1',1",1'"-(3,5-Tetrahydrothiopyrandiylidenetetraethylene)tetrakis[1,2,3, 
4-tetrahydroisoquinolines] and 1,1',1",1'"-(3,5-tetra 
hydropyrandiylidenetetraethylene)tetrakis[1,2,3,4-tetrahydroisoquinolines] 
, wherein the isoquinoline moieties can be unsubstituted or can contain 
lower alkyl, lower alkoxy, lower alkylenedioxy, benzyloxy, or hydroxy 
substituents. 
VII. 1,1',1"-(Nitrilotrialkylene)tris[1,2,3,4-tetrahydroisoquinolines], 
wherein each alkylene individually contains from 1 to 3 carbon atoms, and 
wherein the tetrahydroisoquinoline moieties can be unsubstituted or can 
contain lower alkyl, lower alkoxy, lower alkylenedioxy, benzyloxy, or 
hydroxy substituents. 
VIII. 
1,1',1",1'"-[Alkylenedinitrilotetra(alkylene')]tetrakis[1,2,3,4-tetrahydro 
isoquinolines], wherein alkylene contains from 2 to 8 carbon atoms, and 
each alkylene' individually contains 1 or 2 carbon atoms, and wherein the 
tetrahydroisoquinoline moieties can be unsubstituted or can contain lower 
alkyl, lower alkoxy, lower alkylenedioxy, benzyloxy, or hydroxy 
substituents. These would include such compounds as 
1,1',1",1"-(ethylenedinitrilotetramethylene)tetrakis[1,2,3,4-tetrahydroiso 
quinolines], 
1,1',1",1'"-(tetramethylenedinitrilotetraethylene)tetrakis[1,2,3,4-tetrahy 
droisoquinolines], and 
1,1',1",1'"-(ethylenedinitrilo-N,N'-diethylene-N,N'-dimethylene)tetrakis[1 
,2,3,4-tetrahydroisoquinolines]. 
The corresponding 3,4-dihydroisoquinoline compounds are also preferred in 
accordance with the present invention. 
From a consideration of the foregoing discussion, it is apparent that there 
are a wide variety of compounds that are within the scope of the above 
formula. In said formula, the several variables R.sub.1 - R.sub.5 and Z 
can be any of a wide variety of groups. For instance, specific 
representative R.sub.1 and R.sub.2 groups include hydrogen, methyl, ethyl, 
propyl, hexyl, and the like. Illustative R.sub.3, R.sub.4 and R.sub.5 
groups are hydrogen, methoxy, ethoxy, butoxy, hexyloxy, methyl, ethyl, 
isopropyl, butyl, pentyl, hexyl, chloro, bromo, iodo, fluoro, allyloxy, 
2-butenyloxy, 2-propynyloxy, acetoxy, phenoxy, benzyloxy, methylenedioxy, 
ethylenedioxy, trimethylenedioxy, hydroxy, and the like. 
An outstanding feature of the compounds of this invention is their relative 
lack of toxicity. Although they are active at very low dose levels, it is 
possible to exceed minimum effective levels by wide margins without 
encountering serious adverse reactions. This permits the compounds to be 
used within wide limits without concern about undesirable side effects, as 
are so frequently encountered upon inadvertent overdosage of other 
substances of great potency. For example, by intraperitoneal 
administration to rats, 
1,1'-{3-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolinyl)ethyl]heptame 
thylene}bis[1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline] trihydrochloride, 
a compound within the above generic formula, was found to be effective in 
inducing fibrinolysis at 0.01 mg./kg. and at 10 mg./kg. (a 1000-fold 
difference in dose) without producing toxicity. 
Certain representative compounds within the scope of the present invention 
have been tested for fibrinolytic activity by the whole blood clot lysis 
method, as modified from the procedure of Billimoria et al..sup.1 In this 
method, blood from rats given a fibrinolytic compound intraperitoneally is 
taken and diluted 1:10. A standard amount is clotted with thrombin, 
incubated at 37.degree. C for four hours, and the amount of clot that has 
lysed is determined. The ED.sub.50 dose of a compound is that amount, in 
mg/kg, which will cause the lysis of 50% of the clot under the above 
conditions. These ED.sub.50 values for the various compounds tested are 
set forth in the following table, each of the compounds being identified 
by name and by the number of the ensuing example in which its synthesis is 
described. As basis for comparison, the value of bisobrin (EN-1661, 
1,1'-tetramethylenebis[1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline], meso 
isomer).sup.2 in this test is shown at the end of the table. 
FNT .sup.1 Billimoria, J. D., Drysdale, J., James, D. C., Maclagan, N. F., 
Lancet II, 471 (1959) 
FNT .sup.2 Schor, J. M.: Chemical Control of Fibrinolysis-Thrombolysis. New 
York, Wiley-Interscience, 1970, pp. 113-34 (cf. fig. 4.7, p. 123) 
______________________________________ 
FIBRINOLYTIC ACTIVITY OF COMPOUNDS 
OF THE INVENTION 
Example No. 
Compound Name ED.sub.50 
______________________________________ 
1.1 1,1'-{3-[2-(1,2,3,4-tetrahydro-6,7-di- 
methoxy-1-isoquinolinyl)ethyl]hepta- 
methylene}bis[1,2,3,4-tetrahydro-6,7- 
dimethoxyisoquinoline] trihydrochloride 
0.02 
2.1 1,1',1",1'"-(1,4,8,11-undecatetrayl)- 
tetrakis[1,2,3,4-tetrahydro-6,7-di- 
methoxyisoquinoline] tetrahydrochloride 
0.03 
5.1 1,1'-{3,6-bis[2-(1,2,3,4-tetrahydro-6,7- 
dimethoxy-1-isoquinolinyl)ethyl]octa- 
methylene}bis[1,2,3,4-tetrahydro-6,7- 
dimethoxyisoquinoline] tetrahydrochloride 
0.06 
6.1 1,1'-{1-[(1,2,3,4-tetrahydro-6,7-di- 
methoxy-1-isoquinolinylmethyl)thio]- 
pentamethylene}bis[1,2,3,4-tetrahydro- 
6,7-dimethoxyisoquinoline] trihydro- 
chloride &lt;0.6 
7.1 1,1'-{2-phenyl-5-[2-(1,2,3,4-tetrahydro- 
6,7-dimethoxy-1-isoquinolinyl)ethyl]- 
heptamethylene}bis[1,2,3,4-tetrahydro- 
6,7-dimethoxyisoquinoline] trihydro- 
chloride &lt;0.1 
8.1 1,1'-{2,2-dimethyl-5-[2-(1,2,3,4-tetra- 
hydro-6,7-dimethoxy-1-isoquinolinyl)- 
ethyl]heptamethylene}bis[1,2,3,4-tetra- 
hydro-6,7-dimethoxyisoquinoline] tri- 
hydrochloride &lt;0.4 
10.1 1,1'-{3-[2-(1,2,3,4-tetrahydro-6- 
methoxy-1-isoquinolinyl)ethyl]hepta- 
methylene}bis[1,2,3,4-tetrahydro-6- 
methoxyisoquinoline] trihydrochloride 
0.5 
15.1 1,1',1",1'"-(1,5,10,14-tetradecane- 
tetrayl)tetrakis[1,2,3,4-tetrahydro- 
6,7-dimethoxyisoquinoline] tetrahydro- 
chloride 0.04 
16.1 1,1',1",1'"-(1,4,9,12-dodecanetetrayl)- 
tetrakis[1,2,3,4-tetrahydro-6,7-dimethoxy- 
isoquinoline] tetrahydrochloride 
0.03 
17.1 1,1',1"-[1,2,3-propanetriyltri(oxyethyl- 
ene)-tris[1,2,3,4-tetrahydro-6,7-di- 
methoxyisoquinoline] trihydrochloride 
0.8 
17.3 1,1',1"-(nitrilotriethylene)tris[1,2,3,4- 
tetrahydro-6,7-dimethoxyisoquinoline] 
trihydrochloride 0.7 
18.1 1,1'-{3-nitro-3-[2-(1,2,3,4-tetrahydro- 
6,7-dimethoxy-1-isoquinolinyl)ethyl]- 
pentamethylene}bis[1,2,3,4-tetrahydro- 
6,7-dimethoxyisoquinoline] trihydro- 
chloride &lt;0.6 
19.1 1,1',1"-(1,4,7-heptanetriyl)tris[1,2,3,4- 
tetrahydro-6,7-dimethoxyisoquinoline] 
trihydrochloride 0.03 
Standard bisobrin dihydrochloride 
0.5 
______________________________________ 
Another selection of representative compounds within the scope of the 
present invention, including some listed in the previous table, have been 
tested for their ability to inhibit platelet aggregation. Citrated whole 
blood from human volunteers, who had not taken any medicine for the 
previous week, was centrifuged to obtain platelet rich plasma. On addition 
of ADP (adenosine diphosphate) to this platelet rich plasma, incubated at 
37.degree. C with constant stirring, in an aggregometer, optical density 
changes can be observed which are caused by platelet aggregation. Thus, 
the extent of ADP-induced platelet aggregation is determined for each 
sample of blood used. Compounds to be tested were incubated for five 
minutes prior to the addition of ADP. The ED.sub.50 of a compound is that 
amount, in .gamma./ml, which reduces platelet aggregation by 50% under the 
above conditions. These ED.sub.50 values for the various compounds are 
listed in the table below, each of the compounds again being identified by 
name and by the number of the example in which its synthesis is described. 
As standard for comparison, the value of dipyridamole (Persantin, 
2,2',2",2'"-[(4,8-dipiperidinopyrimido[5,4-d]pyrimidine-2,6-diyl)dinitrilo 
]tetraethanol), a clinically used coronary vasodilator, generally 
recognized as being effective against ADP-induced platelet aggregation and 
experimental thrombosis.sup.3, is listed at the end of the table. 
FNT .sup.3 Didisheim, P., Bowie, E. J., Owen, C. A., Mayo Clin. Proc. 45, 51 
(1970) 
______________________________________ 
PLATELET AGGREGATION INHIBITORY ACTIVITY 
OF COMPOUNDS OF THE INVENTION 
Example No. 
Compound Name ED.sub.50 
______________________________________ 
1.1 1,1'-{3-[2-(1,2,3,4-tetrahydro-6,7- 
dimethoxy-1-isoquinolinyl)ethyl]hepta- 
methylene}bis[1,2,3,4-tetrahydro-6,7- 
dimethoxyisoquinoline] trihydrochloride 
6 
1.1a 1,1'-{3-[2-(3,4-dihydro-6,7-dimethoxy- 
1-isoquinolinyl)ethyl]heptamethylene}- 
bis[3,4-dihydro-6,7-dimethoxyisoqui- 
noline] trihydrochloride 
&lt;40 
7.1a 1,1'-{5-[2-(3,4-dihydro-6,7-dimethoxy- 
1-isoquinolinyl)ethyl]-2-phenylhepta- 
methylene}bis[3,4-dihydro-6,7-dimethoxy- 
isoquinoline] trihydrochloride 
&lt;40 
15.1a 1,1',1",1'"-(1,5,10,14-tetradecane- 
tetrayl)tetrakis[3,4-dihydro-6,7-di- 
methoxyisoquinoline] tetrahydrochloride 
27 
17.1a 1,1',1"[1,2,3-propanetriyltri(oxy- 
ethylene)]tris[3,4-dihydro-6,7-di- 
methoxyisoquinoline] trihydrochloride 
&lt;40 
18.1 1,1'-{3-nitro-3-[2-(1,2,3,4-tetrahydro- 
6,7-dimethoxy-1-isoquinolinyl)ethyl]- 
pentamethylene}bis[1,2,3,4-tetrahydro- 
6,7-dimethoxyisoquinoline] trihydro- 
chloride 9 
18.1a 1,1'-{3-[2-(3,4-dihydro-6,7-dimethoxy-1- 
isoquinolinyl)ethyl]-3-nitropentamethylene}- 
bis[3,4-dihydro-6,7-dimethoxyisoquinoline] 
trihydrochloride 6 
19.1a 1,1',1"-(1,4,7-heptanetriyl)tris[3,4- 
dihydro-6,7-dimethoxyisoquinoline] tri- 
hydrochloride &lt;40 
Standard dipyridamole 270 
______________________________________ 
The compounds of this invention are also active by intravenous, 
intramuscular, oral and rectal administration. 
The compositions of this invention contain a compound of the above formula 
or a non toxic acid addition salt thereof together with a carrier. The 
carrier may be either a solid or liquid and the dry filled capsules, 
dragees, pills, aqueous solutions, non-aqueous solutions, jellies, 
suppositories, syrups, suspensions, sprays, powders, and the like. The 
compositions can, and in many cases do, contain suitable preservatives, 
coloring and flavoring agents. Some examples of the carriers which can be 
used in the preparation of the products of the invention are gelatin 
capsules, sugars such as lactose and sucrose; cellulose, methyl cellulose 
and cellulose acetate phthalate; gelatin; talc; magnesium stearate; 
vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, 
corn oil and oil of theobroma; liquid petrolatum, polyethylene glycol; 
glycerine, sorbitol; propylene glycol; ethanol; agar; water and isotonic 
saline. 
In preparing the compositions of the invention for pharmaceutical uses, the 
conventional practices and precautions are used. The compositions intended 
for parenteral administration must be sterile and this can be accomplished 
either by using sterile ingredients and carrying out the production under 
aseptic conditions or by sterilizing the final composition by one of the 
usual procedures such as millipore filtration. Customary care should be 
exercised that no incompatible condition exists between the active 
component and the diluent preservative or flavoring agent or in the 
conditions employed in preparation of the compositions. 
The compositions of the invention can be introduced into the mammal by the 
oral, rectal, or parenteral route. This can be done by injecting the 
liquid preparations intravenously, intramuscularly, intraperitoneally, or 
subcutaneously; by swallowing, in the cases of the solid and liquid 
preparations, by local application to the mucous membranes, in the case of 
jellies, suppositories, tablets and the like; by inhalation of sprays or 
mists of the liquid preparations and the like.

The invention is illustrated by the following non-limiting examples in 
which all temperatures specified are in degrees centrigrade, and in which 
decomposition temperatures are identified by ("dec.") as appropriate. 
EXAMPLE 1 
1,1'-{3-[2-(1,2,3,4-TETRAHYDRO-6,7-DIMETHOXY-1-ISOQUINOLINYL)ETHYL]HEPTAMET 
HYLENE}BIS[1,2,3,4-TETRAHYDRO-6,7-DIMETHOXYISOQUINOLINE] TRIHYDROCHLORIDE 
TRIHYDRATE 
A mixture of 100 g. of the trimethyl ester of 4-(2-carboxyethyl)nonanedioic 
acid and 210 g. of 3,4-dimethoxyphenethylamine is stirred and heated at 
180.degree.-200.degree. for 5 hours under an atmosphere of nitrogen, 
cooled to about 50.degree. and dissolved in 1 l. of chloroform. The 
solution is washed thrice with 800 ml. portions of 1:1 hydrochloric acid, 
then with water, dried over anhydrous magnesium sulfate and filtered. The 
filtrate is stripped of the solvent under reduced pressure, the residue 
dissolved in a minimum quantity of acetone and the solution is added, with 
stirring, to an excess of anhydrous ether cooled in dry ice. The resulting 
triamide which separates is filtered and melts at 101.degree.-103.degree. 
after recrystallization from ethanol. 
A mixture of 100 g. of the amide and 400 ml. of phosphorus oxychloride 
diluted with an equal volume of anhydrous benzene is refluxed, protected 
from moisture, for 5 hours, cooled, and evaporated to dryness under 
reduced pressure. The residue is carefully hydrolyzed with water and the 
clear solution thus obtained is extracted once with 500 ml. of chloroform. 
The chloroform extract is discarded, the aqueous layer is cooled and 
neutralized with 50% aqueous sodium hydroxide, and then extracted thrice 
with 800 ml. portions of chloroform. The combined chloroform extracts are 
thoroughly washed with water, dried over anhydrous magnesium sulfate and 
filtered. The filtrate is stripped of the solvent under reduced pressure, 
the residue (1.1a) dissolved in 500 ml. of absolute ethanol and treated 
with 13.5 g. of sodium borohydride, added in small portions, with vigorous 
stirring. The mixture is then refluxed, protected from moisture, for 5 
hours, cooled, and evaporated to dryness under reduced pressure. The 
residue is treated with about a liter of water and extracted thrice with 
800 ml. portions of benzene. The combined benzene extracts are washed 
thoroughly with water, dried over anhydrous magnesium sulfate and 
filtered. The residue obtained from the filtrate after removal of the 
solvent under reduced pressure is dissolved in minimum quantity of 
anhydrous benzene and the solution added, with agitation, to 1 l. of 
absolute ether saturated with dry hydrogen chloride. The salt that 
separates is filtered rapidly, washed repeatedly with anhydrous ether, 
air-dried, dissolved in the requisite quantity of pure chloroform and 
added with stirring to an excess of anhydrous ether. The solid thus 
obtained is filtered rapidly, washed thoroughly with anhydrous ether and 
dried in a vacuum desiccator, to yield (1.1) the title compound, m.p. 
175.degree.-198.degree. (dec.). 
To purify the intermediate (1.1a), the crude residue obtained after 
stripping off the chloroform is converted to the hydrochloride, in ether, 
and the resulting salt taken up in chloroform. Precipitation with ether, 
followed by two further reprecipitations from chloroform solution by 
either yields (1.1a) 
1,1'-{3-[2-(3,4-dihydro-6,7-dimethoxy-1-isoquinolinyl)ethyl]heptamethylene 
}bis[3,4-dihydro-6,7-dimethoxyisoquinoline] trihydrochloride trihydrate, as 
a yellow solid, m.p. 130-150.degree. (dec.). 
When, in the above procedure for the preparation of 1.1, the 
3,4-dimethoxyphenethylamine is replaced by an equimolar amount of 
4-allyloxy-3-methoxyphenethylamine 
3,4,5-trimethoxyphenethylamine 
3,4-dimethoxy-.alpha.-methylphenethylamine 
3,4-dimethoxy-.beta.-methylphenethylamine 
3,4-dimethoxy-.alpha.,.beta.-dimethylphenethylamine 
3-ethoxy-2-isopropoxyphenethylamine 
4-butoxy-3-methoxy-.alpha.-methylphenethylamine 
m-methylphenethylamine 
m-chlorophenethylamine 
2,3-dimethylphenethylamine 
2,3-dimethoxyphenethylamine 
respectively, following products are obtained: 
(1.2): 
1,1'-{3-[2-(7-allyloxy-1,2,3,4-tetrahydro-6-methoxy-1-isoquinolyl)ethyl]he 
ptamethylene}bis[7-allyloxy-1,2,3,4-tetrahydro-6-methoxyisoquinoline] 
trihydrochloride trihydrate 
(1.3): 
1,1'-{3-[2-(1,2,3,4-tetrahydro-6,7,8-trimethoxy-1-isoquinolinyl)ethyl]hept 
amethylene}bis[1,2,3,4-tetrahydro-6,7,8-trimethoxyisoquinoline] 
trihydrochloride trihydrate 
(1.4): 
1,1'-{3-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-3-methyl-1-isoquinolinyl)ethy 
l]heptamethylene}bis[1,2,3,4-tetrahydro-6,7-dimethoxy-3-methylisoquinoline] 
trihydrochloride trihydrate 
(1.5): 
1,1'-{3-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-4-methyl-1-isoquinolinyl)ethy 
l]heptamethylene]bis[1,2,3,4-tetrahydro-6,7-dimethoxy-4-methylisoquinoline] 
trihydrochloride trihydrate 
(1.6): 
1,1'-{3-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-3,4-dimethyl-1-isoquinolinyl) 
ethyl]heptamethylene}bis[1,2,3,4-tetrahydro-6,7-dimethoxy-3,4-dimethylisoqu 
inoline] trihydrochloride trihydrate 
(1.7): 
1,1'-{3-[2-(6-ethoxy-1,2,3,4-tetrahydro-5-isopropoxy-1-isoquinolinyl)ethyl 
]heptamethylene}bis[6-ethoxy-1,2,3,4-tetrahydro-5-isopropoxyisoquinoline] 
trihydrochloride trihydrate 
(1.8): 
1,1'-{3-[2-(7-butoxy-1,2,3,4-tetrahydro-6-methoxy-1-isoquinolinyl)ethyl]he 
ptamethylene}bis[7-butoxy-1,2,3,4-tetrahydro-6-methoxyisoquinoline] 
trihydrochloride trihydrate 
(1.9): 
1,1'-{3-[2-(1,2,3,4-tetrahydro-6-methyl-1-isoquinolinyl)ethyl]heptamethyle 
ne}bis[1,2,3,4-tetrahydro-6-methylisoquinoline] trihydrochloride trihydrate 
(1.10): 
1,1'-{3-[2-(6-chloro-1,2,3,4-tetrahydro-1-isoquinolinyl)ethyl]heptamethyle 
ne}bis[6-chloro-1,2,3,4-tetrahydroisoquinoline] trihydrochloride trihydrate 
(1.11): 
1,1'-{3-[2-(1,2,3,4-tetrahydro-5,6-dimethyl-1-isoquinolinylethyl]heptameth 
ylene}bis[1,2,3,4-tetrahydro-5,6-dimethylisoquinoline] trihydrochloride 
trihydrate 
(1.12): 
1,1'-{3-[2-(1,2,3,4-tetrahydro-5,6-dimethoxy-1-isoquinolinylethyl]heptamet 
hylene}bis[1,2,3,4-tetrahydro-5,6-dimethoxyisoquinoline] trihydrochloride 
trihydrate 
EXAMPLE 2 
1,1',1",1'"-(1,4,8,11-UNDECANETETRAYL)TETRAKIS[1,2,3,4-TETRAHYDRO-6,7-DIMET 
HOXYISOQUINOLINE] TETRAHYDROCHLORIDE TETRAHYDRATE 
To a freshly prepared solution of 54 g. of sodium methoxide in 1 l. of 
anhydrous methanol, 156 g. of a commercially available mixture of the 
methyl and ethyl esters of 2-oxocyclopentanecarboxylic acid is added, with 
stirring, in a rapid stream, followed, after 5 minutes, by the addition of 
101 g. of 1,3-dibromopropane. The mixture is stirred and refluxed for 14 
hours, cooled and filtered, and the residue washed with ether. The 
combined filtrates are stripped of the solvents under reduced pressure, 
the residue is treated with water, and then extracted twice with ether. 
The combined ether extracts are washed with water, dried over anhydrous 
magnesium sulfate and filtered. The liquid obtained by removal of the 
solvent from the filtrate under reduced pressure is distilled under 
vacuum. Tetramethyl 1,4,5,11-undecanetetracarboxylate is collected at 
215.degree.-220.degree./0.5 mm. 
A mixture of 36.4 g. of this tetraester and 90 g. of 
3,4-dimethoxyphenethylamine is heated, with stirring, at 
180.degree.-200.degree. for 5 hours in an atmosphere of nitrogen, cooled 
to about 50.degree., and added to 500 ml. of chloroform. The resulting 
solution is washed thrice with 600 ml. portions of 1:1 hydrochloric acid, 
then with water and dried over anhydrous magnesium sulfate and filtered. 
The filtrate is stripped of the solvent under reduced pressure and the 
residue dissolved in methanol and added to a large excess of anhydrous 
ether. The product separates as a sticky solid which is filtered, washed 
with anhydrous ether and air-dried. 
Of the amorphous tetramide thus obtained, 28 g. are mixed with 110 ml. of 
phosphorous oxychloride and refluxed for 5 hours. The residue obtained by 
evaporation of the mixture to dryness under reduced pressure is treated 
carefully with water, and the resulting clear solution is extracted twice 
with 400 ml. of chloroform. The chloroform extracts are discarded and the 
aqueous layer is cooled, rendered strongly alkaline with 50% aqueous 
sodium hydroxide and extracted thrice with 300 ml. portions of chloroform. 
The combined chloroform extracts are washed thoroughly with water, dried 
over anhydrous magnesium sulfate and filtered. The filtrate is stripped of 
the solvent under reduced pressure, the residue dissolved in 100 ml. of 
absolute ethanol and treated with 5 g. of sodium borohydride, added in 
small portions, with stirring. The mixture, protected from moisture, is 
refluxed for 5 hours with stirring, and then evaporated to dryness under 
reduced pressure. The residue is treated with 500 ml. of water and 
extracted thrice with 300 ml. portions of benzene. The combined benzene 
extracts are washed thoroughly with water, dried over anhydrous magnesium 
sulfate and filtered. The residue left on removal of the solvent from the 
filtrate under reduced pressure is dissolved in minimum quantity of 
anhydrous benzene and added to 500 ml. of anhydrous ether saturated with 
anhydrous hydrogen chloride. (2.1) 
1,1',1",1'"-(1,4,8,11-Undecanetetrayl)tetrakis[1,2,3,4-tetrahydro-6,7-dime 
thoxyisoquinoline] tetrahydrochloride tetrahydrate thus obtained, after 
purification by dissolution in a minimum quantity of methanol, followed by 
reprecipitation by an excess of anhydrous ether, melts at 
180.degree.-212.degree. (dec.) (sint. at 75.degree.) 
EXAMPLE 3 
1,1',1",1'"-(3,5-TETRAHYDROTHIOPYRANDIYLIDENETETRAETHYLENE)TETRAKIS[1,2,3,4 
-TETRAHYDRO-6,7-DIMETHOXYISOQUINOLINE] TETRAHYDROCHLORIDE TETRAHYDRATE 
To a stirred solution of 23.2 g. of tetrahydro-4H-thiopyran-4-one in 250 
ml. of dioxane maintained at 50.degree., 4 ml. of a 40% methanolic 
solution of N-benzyltrimethylammonium hydroxide (Triton B) are added, 
followed, after five minutes, by rapid dropwise addition of 45 g. of 
acrylontrile. The temperature of the mixture rises to 
85.degree.-90.degree. within a few minutes and crystals start to separate. 
On completion of addition the mixture is stirred for 30 minutes, diluted 
with 250 ml. of methanol, filtered, and the solid washed with methanol and 
ether. The 4-oxothiopyrandiylidenetetrapropionitrile thus obtained melts 
at 222.degree.-225.degree., and is pure enough for the next step. 
To a solution of 76 g. of sodium hydroxide and 760 ml. of water, 133 g. of 
this oxotetrapropionitrile are added, the mixture is stirred and refluxed 
vigorously for 20 hours, and filtered to remove any undissolved 
impurities. The filtrate is cooled and acidified with conc. hydrochloric 
acid. Cooling the mixture in an icebath with vigorous scratching furnishes 
colorless crystals of the corresponding oxothiopyrantetrapropionic acid, 
which are filtered, washed thoroughly with water and air-dried. 
Recrystallization from a mixture of tetrahydrofuran and hexane yields the 
pure product, m.p. 186.degree.-188.degree.. 
A 3 l. pressure bomb is charged with 54 g. of powdered sodium hydroxide, 
dispersed in 200 ml. of absolute ethanol, 35 ml. of 100% hydrazine 
hydrate, and a solution of 83 g. of the oxothiopyrantetrapropionic acid in 
500 ml. of hot absolute ethanol, the bomb is closed and heated at 
190.degree.-210.degree. for 18 hours. It is then cooled and the nitrogen 
formed during the reaction is released carefully. The supernatant 
alcoholic solution is removed and evaporated to dryness under reduced 
pressure. The sodium salts left in the bomb are dissolved in minimum 
quantity of water and added to the residue obtained by evaporation of the 
alcoholic solution. The resulting clear solution is cooled, acidified with 
concentrated hydrochloric acid and extracted thrice with 500 ml. portions 
of chloroform. The combined chloroform extracts are dried over anhydrous 
magnesium sulfate, filtered and stripped of the solvent under reduced 
pressure. The residue is dissolved in 200 ml. of anhydrous methanol 
saturated with dry hydrogen chloride, left at room temperature overnight 
and stripped of the solvent and hydrogen chloride. The residue is 
dissolved in 800 ml. of ether and the solution is washed with saturated 
aqueous sodium bicarbonate, then with water, dried over anhydrous 
magnesium sulfate and filtered. The filtrate is stripped of the solvent 
under reduced pressure and the residual liquid distilled under vacuum. 
Tetramethyl 3,5-tetrahydrothiopyrandiylidenetetrapropionate is collected 
at 220.degree.-250.degree./0.3-0.4 ml. 
Following the procedure outlined in Example 1, the tetraester is converted 
into the tetramide by heating with 3,4-dimethoxyphenethylamine, the 
tetramide cyclized with phosphorus oxychloride, and the tetrakis 
dihydroisoquinoline thus obtained is reduced, without purification, with 
sodium borohydride to yield (3.1) 
1,1',1",1'"-(3,5-tetrahydrothiopyrandiylidenetetraethylene)tetrakis[1,2,3, 
4-tetrahydro-6,7-dimethoxyisoquinoline], isolated as its tetrahydrochloride 
tetrahydrate, m.p. 190.degree.-200.degree. (dec.) 
Pyrophoric nickel is prepared by washing commercial Raney nickel several 
times in absolute ethanol, and then refluxing the centrifuged solids for 
three hours in absolute ethanol. A mixture of 20 g. of this nickel and 2 
g. of 1,1', 
1",1'"-(3,5-tetrahydrothiopyrandiylidenetetraethylene)tetrakis[1,2,3,4-tet 
rahydro-6,7-dimethoxyisoquinoline] tetrahydrochloride is refluxed for two 
days in 70% ethanol. The mixture is centrifuged, the liquid decanted from 
the nickel, which is washed twice with hot ethanol and once with water, 
and the combined washings are evaporated to dryness under reduced 
pressure. The residue is worked up as in Example 1 to yield (3.2) 
1,1'-{3,5-dimethyl-3,5-bis[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinol 
inyl)ethyl]heptamethylene}bis[1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline] 
, isolated as its tetrahydrochloride. 
Following the same sequence of steps outlined above for 3.1, but using 
tetrahydro-4H-pyran-4-one in place of the tetrahydro-4H-thiopyran-4-one, 
(3.3) 
1,1',1",1'"-(3,5-tetrahydropyrandiyldenetetraethylene)tetrakis[1,2,3,4-tet 
rahydro-6,7-dimethoxy-1-isoquinoline] is prepared and isolated as its 
tetrahydrochloride. 
EXAMPLE 4 
1,1',1",1'"-(1,3-CYCLOPENTANEDIYLIDENETETRAETHYLENE)TETRAKIS[1,2,3,4-TETRAH 
YDRO-6,7-DIMETHOXYISOQUINOLINE] TETRAHYDROCHLORIDE TETRAHYDRATE 
A mixture of 185 g. of 2-oxo-1,3-cyclopentanediylidenetetra propionic acid, 
1 liter of absolute ethanol, 100 g. of powdered sodium hydroxide and 65 
ml. of 100% hydrazine hydrate is heated in a pressure bomb at 
190.degree.-210.degree. for 18 hours. The bomb is opened carefully to 
release the nitrogen formed during the course of the reaction, the 
supernatant solution decanted and evaporated to dryness under reduced 
pressure. The sodium salts left in the bomb are dissolved in a minimum 
quantity of water and the solution added to the residue mentioned above. 
The resulting clear solution is cooled, acidified with concentrated 
hydrochloric acid and extracted thrice with 800 ml. portions of ether. The 
combined ether extracts are dried over anhydrous magnesium sulfate and 
filtered. The filtrate on evaporation to dryness under reduced pressure 
yields a viscous liquid which solidifies on standing to give 
1,3-cyclopentanediylidenetetrapropionic acid, which is recrystallized from 
a mixture of benzene and hexane. 
A solution of 178 g. of the tetracarboxylic acid, dissolved in 600 ml. of 
anhydrous methanol, is treated carefully with 40 ml. of conc. sulfuric 
acid, with agitation, refluxed for 15 hours and then stripped of the 
solvent in vacuo. The residue is treated with crushed ice and water and 
extracted thrice with 600 ml. portions of ether. The combined ether 
extracts are washed successively with water, saturated aqueous sodium 
bicarbonate and water, dried over anhydrous magnesium sulfate and 
filtered. Removal of the solvent from the filtrate under reduced pressure 
yields a liquid which is distilled under vacuum. Tetramethyl 
1,3-cyclopentanediylidenetetrapropionate distills over at 
240.degree.-245.degree./0.8-0.9 mm. and solidifies on standing. After 
trituration with n-pentane, it melts at 50.degree.-52.degree.. 
The ester is converted through the series of reactions outlined in Example 
1 to (4.1) 
1,1',1",1"-(1,3-cyclopentanediylidenetetraethylene)tetrakis[1,2,3,4-tetrah 
ydro-6,7-dimethoxyisoquinoline] tetrahydrochloride tetrahydrate, m.p. 
223.degree.-228.degree. (dec.). 
When, in the above procedure, the 3,4-dimethoxyphenethylamine is replaced 
by an equimolar amount of 
m-methoxyphenethylamine 
4-benzyloxy-3-methoxyphenethylamine 
3,4-methylenedioxyphenethylamine 
3,4-diethoxyphenethylamine 
.beta.-methyl-3,4-methylenedioxyphenethylamine 
3,4-dimethylphenethylamine 
phenethylamine 
respectively, the following products are obtained: 
(4.2): 
1,1',1",1'"-(1,3-cyclopentanediylidenetetraethylene)tetrakis[1,2,3,4-tetra 
hydro-6-methoxyisoquinoline] tetrahydrochloride tetrahydrate 
(4.3): 
1,1',1",1'"-(1,3-cyclopentanediylidenetetraethylene)tetrakis[7-benzyloxy-1 
,2,3,4-tetrahydro-6-methoxyisoquinoline] tetrahydrochloride tetrahydrate 
(4.4): 
1,1',1",1'"-(1,3-cyclopentanediylidenetetraethylene)tetrakis[1,2,3,4-tetra 
hydro-6,7-methylenedioxyisoquinoline] tetrahydrochloride tetrahydrate 
(4.5): 
1,1',1",1'"-(1,3-cyclopentanediylidenetetraethylene)tetrakis[6,7-diethoxy- 
1,2,3,4-tetrahydroisoquinoline] tetrahydrochloride tetrahydrate 
(4.6): 
1,1',1",1'"-(1,3-cyclopentanediylidenetetraethylene)tetrakis[1,2,3,4-tetra 
hydro-4-methyl-6,7-methylenedioxyisoquinoline] tetrahydrochloride 
tetrahydrate 
(4.7): 
1,1',1",1'"-(1,3-cyclopentanediylidenetetraethylene)tetrakis[1,2,3,4-tetra 
hydro-6,7-dimethylisoquinoline] tetrahydrochloride tetrahydrate 
(4.8): 
1,1',1",1'"-(1,3-cyclopentanediylidenetetraethylene)tetrakis[1,2,3,4-tetra 
hydroisoquinoline] tetrahydrochloride tetrahydrate 
Reduction of 4.3 with hydrogen over 10% palladium on charcoal in acetic 
acid gives rise to (4.9) 
1,1',1",1'"-(1,3-cyclopentanediylidenetetraethylene)tetrakis[1,2,3,4-tetra 
hydro-6-methoxy-7-isoquinolinol], isolated as its tetrahydrochloride 
tetrahydrate. 
When a 2 g. portion of 4.1 is heated in 20 g. of 48% hydrobromic acid 
containing 0.2 g. of 50% hypophosphorus acid until no more hydrogen 
chloride or methyl bromide is evolved, the demethylated product (4.10) 
1,1',1",1'"-(1,3-cyclopentanediylidenetetraethylene)tetrakis[1,2,3,4-tetra 
hydro-6,7-isoquinolinediol], isolated as its tetrahydrobromide 
tetrahydrate, is obtained. By the same procedure, demethylation of 4.2 
yields (4.11) 
1,1',1",1'"-(1,3-cyclopentanediylidenetetraethylene)tetrakis[1,2,3,4-tetra 
hydro-6-isoquinolinol] tetrahydrobromide tetrahydrate. 
EXAMPLE 5 
1,1'-{3,6-BIS[2-(1,2,3,4-TETRAHYDRO-6,7-DIMETHOXY-1-ISOQUINOLINYL)ETHYL]OCT 
AMETHYLENE}BIS[1,2,3,4-TETRAHYDRO-6,7-DIMETHOXYISOQUINOLINE] 
TETRAHYDROCHLORIDE TETRAHYDRATE 
A mixture of 34.6 g. of 4,7-bis(2-carboxyethyl)decanedioic acid and 72.4 g. 
of 3,4-dimethoxyphenethylamine is heated at 180.degree.-200.degree. for 5 
hours in an atmosphere of nitrogen. The mixture is then cooled and 
dissolved in chloroform. The resulting solution is washed thrice with 300 
ml. portions of 1:1 hydrochloric acid, then with water and then dried over 
anhydrous magnesium sulfate. Filtration and removal of the solvent from 
the filtrate under reduced pressure yields a solid which is recrystallized 
from ethanol. The tetramide thus obtained melts at 
148.degree.-150.degree.. 
The amide is converted by the procedure described in Example 1 to (5.1) 
1,1'-{3,6-bis[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolinyl)ethyl]-o 
ctamethylene}bis[1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline] 
tetrahydrochloride tetrahydrate, m.p. 210.degree.-215.degree. (dec.), via 
(5.1a) 
1,1'-{3,6-bis[2-(3,4-dihydro-6,7-dimethoxy-1-isoquinolinyl)ethyl]octamethy 
lenebis[3,4-dihydro-6,7-dimethoxyisoquinoline], isolated as a light yellow 
tetrahydrochloride tetrahydrate, m.p. 218.degree.-220.degree. (dec.) after 
two recrystallizations from isopropanol. 
Replacing the 3,4-dimethoxyphenethylamine in the above procedure for the 
preparation of 5.1 by an equimolar amount of: 
2,5-dimethoxyphenethylamine 
4-benzyloxy-3-methoxyphenethylamine 
3-methoxy-4-phenoxyphenethylamine 
m-ethoxyphenethylamine 
3-methoxy-4-methylphenethylamine 
2-chloro-3,4-dimethoxyphenethylamine 
respectively, gives rise to the following products: 
(5.2): 
1,1'-{3,6-bis[2-(1,2,3,4-tetrahydro-5,8-dimethoxy-1-isoquinolyl)ethyl]octa 
methylene}bis[1,2,3,4-tetrahydro-5,8-dimethoxyisoquinoline] 
tetrahydrochloride tetrahydrate 
(5.3): 
1,1'-{3,6-bis[2-(7-benzyloxy-1,2,3,4-tetrahydro-6-methoxy-1-isoquinolinyl) 
ethyl]octamethylene}bis[7-benzyloxy-1,2,3,4-tetrahydro-6-methoxyisoquinolin 
e] tetrahydrochloride tetrahydrate 
(5.4): 
1,1'-{3,6-bis[2-(1,2,3,4-tetrahydro-6-methoxy-7-phenoxy-1-isoquinolinyl)et 
hyl]octamethylene}bis[1,2,3,4-tetrahydro-6-methoxy-7-phenoxyisoquinoline] 
tetrahydrochloride tetrahydrate 
(5.5): 
1,1'-{3,6-bis[2-(6-ethoxy-1,2,3,4-tetrahydro-1-isoquinolinylethyl]octameth 
ylene}bis[6-ethoxy-1,2,3,4-tetrahydroisoquinoline] tetrahydrochloride 
tetrahydrate 
(5.6): 
1,1'-{3,6-bis[2-(1,2,3,4-tetrahydro-6-methoxy-7-methyl-1-isoquinolinyl)eth 
yl]octamethylene}bis[1,2,3,4-tetrahydro-6-methoxy-7-methylisoquinoline] 
tetrahydrochloride tetrahydrate 
(5.7): 
1,1'-{3,6-bis[2-(5-chloro-1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolinyl 
)ethyl]octamethylene}bis[5-chloro-1,2,3,4-tetrahydro-6,7-dimethoxyisoqinoli 
ne] tetrahydrochloride tetrahydrate 
Debenzylation of 5.3 by the method of 4.9 gives rise to (5.8) 
1,1'-{3,6-bis[1,2,3,4-tetrahydro-7-hydroxy-6-methoxy-1-isoquinolinyl)ethyl 
]octamethylene}-bis[1,2,3,4-tetrahydro-6-methoxy-7-isoquinolinol], isolated 
as its tetrahydrochloride tetrahydrate. 
Demethylation of 5.2 and 5.6 respectively by the method of 4.11, gives rise 
to the following products: 
(5.9): 
1,1'-{3,6-bis[2-(1,2,3,4-tetrahydro-5,8-dihydroxy-1-isoquinolinyl)ethyl]oc 
tamethylene}bis[1,2,3,4-tetrahydro-5,8-isoquinolinediol] tetrahydrochloride 
tetrahydrate 
(5.10): 
1,1'-{3,6-bis[2-(1,2,3,4-tetrahydro-6-hydroxy-7-methyl-1-isoquinolinyl)eth 
yl]octamethylene}bis[1,2,3,4-tetrahydro-7-methyl-6-isoquinolinol] 
tetrahydrochloride tetrahydrate 
EXAMPLE 6 
1,1'-{1-[(1,2,3,4-TETRAHYDRO-6,7-DIMETHOXY-1-ISOQUINOLINYLMETHYL)THIO]PENTA 
METHYLENE}BIS[1,2,3,4-TETRAHYDRO-6,7-DIMETHOXYISOQUINOLINE] 
TRIHYDROCHLORIDE TRIHYDRATE 
A solution of 72 g. of ethyl thioglycolate in 30 ml. of absolute ethanol is 
added to a stirred, freshly prepared solution of 17.5 g. of sodium 
ethoxide in 200 ml. of absolute ethanol. After 10 minutes the mixture is 
cooled to -20.degree., stirred in an atmosphere of nitrogen and treated 
with 150 g. of ethyl 3-bromo-2-oxocyclohexanecarboxylate in 60 ml. of 
absolute ethanol, added dropwise. After the addition of the bromo ester is 
complete, the mixture is stirred at room temperature for 2 hours and 
filtered. The residue is washed with anhydrous ether and the combined 
filtrates are stripped of ethanol and ether under reduced pressure. The 
residue is treated with water and extracted twice with 500 ml. portions of 
ether. The combined ether extracts are washed with water, dried over 
anhydrous magnesium sulfate and filtered. Removal of the solvent from the 
filtrate under reduced pressure yields 
3-[(carboxymethyl)thio]-2-oxocyclohexanecarboxylic acid diethyl ester, 
which is collected by vacuum distillation at 190.degree.-200.degree./0.3 
mm. 
A mixture of 250 g. of sodium hydroxide, 200 ml. of water and 150 ml. of 
ethanol is heated at 50.degree. for 30 minutes in an atmosphere of 
nitrogen and then treated with a solution of 100 g. of the above ester in 
50 ml. of ethanol in the course of 30 minutes. After the addition is 
complete the mixture is heated at 50.degree., in an atmosphere of 
nitrogen, for 5 hours, and stripped of the solvent under reduced pressure. 
The residue is treated with ice and water, acidified and extracted thrice 
with 300 ml. portions of chloroform. The combined chloroform extracts are 
dried over anhydrous magnesium sulfate and filtered. The filtrate, on 
being stripped of the solvent under reduced pressure, yields a viscous 
liquid which is dissolved in 150 ml. of absolute ethanol, and the 
alcoholic solution is saturated with dry hydrogen chloride and refluxed 
for 30 minutes. Removal of the solvent and hydrogen chloride under reduced 
pressure furnishes a liquid which is distilled under vacuum. 
2-[(Carboxymethyl)thio] heptanedioic acid triethyl ester is collected at 
208.degree.-212.degree./0.3-0.4 mm. 
Following the procedure described in Example 1, 11 g. of the ester thus 
obtained on being heated with 25 g. of 3,4-dimethoxyphenethylamine, yields 
the corresponding triamide which, without purification, is cyclized with 
phosphorus oxychloride. The product is reduced with sodium borohydride to 
yield (6.1) 
1,1'-[1-[(1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolinylmethyl)thio]pent 
amethylene]bis[1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline], isolated as 
its trihydrochloride trihydrate, m.p. 125.degree.-165.degree. (dec.) 
(sint. at 100.degree.). 
EXAMPLE 7 
1,1'-[2-PHENYL-5-[2-(1,2,3,4-TETRAHYDRO-6,7-DIMETHOXY-1-ISOQUINOLINYL)ETHYL 
]HEPTAMETHYLENE}-BIS[1,2,3,4-TETRAHYDRO-6,7-DIMETHOXYISOQUINOLINE] 
TRIHYDROCHLORIDE TRIHYDRATE 
Following the procedure outlined in Example 1, 28 g. of 
6-(2-carboxyethyl)-3-phenylnonanedioic acid trimethyl ester, b.p. 
190.degree.-195.degree./0.2 mm. on being heated with 47 g. of 
3,4-dimethoxyphenethylamine yields the corresponding triamide, m.p. 
71.degree.-75.degree., which is cyclized with phosphorus oxychloride, and 
the resulting product (7.1a) reduced with sodium borohydride to yield 
(7.1) 1,1'-{2-phenyl-5-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinoliny 
l)ethyl]heptamethylene}bis[1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline], 
isolated as its trihydrochloride trihydrate, m.p. 190.degree.-210.degree. 
(dec.). 
The intermediate 7.1a is purified in a manner very similar to that used to 
purify 1.1a, to yield (7.1a) 
1,1'-{5-[2-(3,4-dihydro-6,7-dimethoxy-1-isoquinolinyl)ethyl]-2-phenylhepta 
methylene}bis[3,4-dihydro-6,7-dimethoxyisoquinoline] trihydrochloride 
trihydrate, a light yellow solid with a m.p. of 200.degree.-210.degree. 
(dec.) 
EXAMPLE 8 
1,1'-{2,2-DIMETHYL-5-[2-(1,2,3,4-TETRAHYDRO-6,7-DIMETHOXY-1-ISOQUINOLINYL)E 
THYL]HEPTAMETHYLENE}BIS[1,2,3,4-TETRAHYDRO-6,7-DIMETHOXYISOQUINOLINE] 
TRIHYDROCHLORIDE TRIHYDRATE 
Following the procedure outlined in Example 1, 49.5 g. of 
6-(2-carboxyethyl)-3,3-dimethylnonanedioic acid trimethyl ester, b.p. 
145-155/0.7-0.9 mm., on being heated with 95 g. of 
3,4-dimethoxyphenethylamine yields the corresponding triamide, m.p. 
91.degree.-93.degree., which is cyclized with phosphorus oxychloride, and 
the product obtained is reduced with sodium borohydride to yield (8.1) 
1,1'-{2,2-dimethyl-5-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolinyl) 
ethyl]heptamethylene}bis[1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline], 
isolated as its trihydrochloride trihydrate, m.p. 190.degree.-197.degree. 
(dec.). 
EXAMPLE 9 
1,1'-{3-[2-(1,2,3,4-TETRAHYDRO-1-ISOQUINOLINYL)ETHYL]HEPTAMETHYLENE}BIS[1,2 
,3,4-TETRAHYDROISOQUINOLINE] TRIHYDROCHLORIDE TRIHYDRATE 
Following the procedure outlined in Example 1, 57 g. of 
4-(2-carboxyethyl)nonanedioic acid trimethyl ester on being heated with 92 
g. of phenethylamine gives rise to the corresponding triamide, m.p. 
118.degree.-120.degree., which is cyclized with phosphorus oxychloride and 
the resulting product reduced with sodium borohydride to yield (9.1) 
1,1'-{3-[2-(1,2,3,4-tetrahydro-1-isoquinolinyl)ethyl]heptamethylene}bis[1, 
2,3,4-tetrahydroisoquinoline], isolated as its trihydrochloride trihydrate, 
m.p. 140.degree.-200.degree. (dec.). 
EXAMPLE 10 
1,1'-{3-[2-(1,2,3,4-TETRAHYDRO-6-METHOXY-1-ISOQUINOLINYL)ETHYL]HEPTAMETHYLE 
NE}BIS[1,2,3,4-TETRAHYDRO-6-METHOXYISOQUINOLINE] TRIHYDROCHLORIDE 
TRIHYDRATE 
Following the method outlined in Example 1, 30 g. of 
4-(2-carboxyethyl)nonanedioic acid trimethyl ester on being heated with 60 
g. of m-methoxyphenethylamine yields the corresponding triamide, which is 
cyclized with phosphorus oxychloride and the product obtained is reduced 
with sodium borohydride to yield (10.1) 
1,1'-{3-[2-(1,2,3,4-tetrahydro-6-methoxy-1-isoquinolinyl)ethyl]heptamethyl 
ene}bis[1,2,3,4-tetrahydro-6-methoxyisoquinoline], isolated as its 
trihydrochloride trihydrate, m.p. 130.degree.-190.degree. (dec.). 
When in the above procedure, the m-methoxyphenethylamine is replaced by an 
equimolar amount of 
m-methoxy-.beta.-methylphenethylamine 
m-methoxy-.alpha.-methylphenethylamine 
m-ethoxyphenethylamine 
respectively, the following products are obtained: 
(10.2): 
1,1-{3-[2-(1,2,3,4-tetrahydro-6-methoxy-4-methyl-1-isoquinolinyl)ethyl]hep 
tamethylene}bis[1,2,3,4-tetrahydro-6-methoxy-4-methylisoquinoline] 
trihydrochloride trihydrate 
(10.3): 
1,1'-{3-[2-(1,2,3,4-tetrahydro-6-methoxy-3-methyl-1-isoquinolinyl)ethyl]he 
ptamethylene}bis[1,2,3,4-tetrahydro-6-methoxy-3-methylisoquinoline] 
trihydrochloride trihydrate 
(10.4): 
1,1'-{3-[2-(6-ethoxy-1,2,3,4-tetrahydro-1-isoquinolinyl)ethyl]heptamethyle 
ne}bis[6-ethoxy-1,2,3,4-tetrahydroisoquinoline] trihydrochloride trihydrate 
Demethylation of the products prepared in Examples 10.1, 1.1 and 1.3 
respectively, by the method of Example 4.11, gives rise to the following 
products: 
(10.5): 
1,1'-{3-[2-(1,2,3,4-tetrahydro-6-hydroxy-1-isoquinolinyl)ethyl]heptamethyl 
ene}bis[1,2,3,4-tetrahydro-6-isoquinolinol] trihydrochloride trihydrate. 
(10.6): 
1,1'-{3-[2-(1,2,3,4-tetrahydro-6,7-dihydroxy-1-isoquinolinyl)ethyl]heptame 
thylene}bis[1,2,3,4-tetrahydro-6,7-isoquinolinediol] trihydrochloride 
trihydrate 
(10.7): 
1,1'-{3-[2-(1,2,3,4-tetrahydro-6,7,8-trihydroxy-1-isoquinolinyl)ethyl]hept 
amethylene}bis[1,2,3,4-tetrahydro-6,7,8-isoquinolinetriol] trihydrochloride 
trihydrate. 
Addition of 200 mg. of (10.5) to a mixture of 10 ml. chloroform and 20 ml. 
acetyl chloride gives rise, after the usual workup, to: 
(10.8): 
1,1'-{3-[2-(1,2,3,4-tetrahydro-6-hydroxy-1-isoquinolinyl)ethyl]heptamethyl 
ene}bis[1,2,3,4-tetrahydro-6-isoquinolinol] triacetate trihydrochloride 
trihydrate 
Similarly, when 800 mg. of (10.6) is suspended in 20 ml. glacial acetic 
acid containing 2 g. of acetyl chloride, and dry hydrogen chloride is 
bubbled through the mixture, on workup 
(10.9): 
1,1'-{3-[2-(1,2,3,4-tetrahydro-6,7-dihydroxy-isoquinolinyl)ethyl]heptameth 
ylene}bis[1,2,3,4-tetrahydro-6,7-isoquinolinediol] hexaacetate 
trihydrochloride trihydrate 
is obtained. 
EXAMPLE 11 
1,1'-{3-[2-(7-BENZYLOXY-1,2,3,4-TETRAHYDRO-6-METHOXY-1-ISOQUINOLINYL)ETHYL] 
HEPTAMETHYLENE}BIS[7-BENZYLOXY-1,2,3,4-TETRAHYDRO-6-METHOXYISOQUINOLINE] 
TRIHYDROCHLORIDE 
Following the procedure outlined in Example 1, 10 g. of 
4-(2-carboxyethyl)nonanedioic acid trimethyl ester on being heated with 26 
g. of 4-benzyloxy-3-methoxyphenethylamine yields the corresponding 
triamide, m.p. 110.degree.-114.degree., which is cyclized with phosphoric 
oxychloride (in toluene as solvent), and the resulting product is reduced 
with sodium borohydride to yield (11.1) 
1,1'{3-[2-(7-benzyloxy-1,2,3,4-tetrahydro-6-methoxy-1-isoquinolinyl)ethyl] 
heptamethylene}bis[7-benzyloxy-1,2,3,4-tetrahydro-6-methoxyisoquinoline], 
isolated as its trihydrochloride, m.p. 135.degree.-147.degree. (dec.). 
Debenzylation of this product by the method of Example 4.9 yields (11.2) 
1,1'-{3-[2-(1,2,3,4-tetrahydro-7-hydroxy-6-methoxy-1-isoquinolinyl)ethyl]h 
eptamethylene}bis[1,2,3,4-tetrahydro-6-methoxy7-isoquinolinol] 
trihydrochloride trihydrate. 
Further reaction with butyryl chloride in butyric acid by the method of 
Example 10.9, gives (11.3) 
1,1'-{3-[2-(1,2,3,4-tetrahydro-7-hydroxy-6-methoxy-1-isoquinolinyl)ethyl]h 
eptamethylene}bis[1,2,3,4-tetrahydro-6-methoxy-7-isoquinolinol] tributyrate 
trihydrochloride trihydrate. 
EXAMPLE 12 
1-{3,3-BIS[2-(1,2,3,4-TETRAHYDRO-6,7-DIMETHOXY-1-ISOQUINOLINYL)ETHYL]PENTYL 
)-1,2,3,4-TETRAHYDRO-6,7-DIMETHOXYISOQUINOLINE TRIHYDROCHLORIDE TRIHYDRATE 
4-(2-Carboxyethyl)-4-ethylheptanedioic acid trimethyl ester, b.p. 
167.degree.-175.degree. 0.5-0.8 mm., is prepared by the Wolff-Kischner 
reduction of 4-acetyl-4-(2-carboxyethyl)heptanedioic acid followed by 
esterification of the product with methanol according to the method 
described in Example 3. 
Following the procedure outlined in Example 1, 25 g. of the above triester 
on being heated with 60 g. of 3,4-dimethoxyphenethylamine yields the 
corresponding triamide, which, without purification, is cyclized with 
phosphorus oxychloride, and the product obtained is reduced with sodium 
borohydride, to yield (12.1) the title compound, m.p. 
210.degree.-255.degree. (dec.). 
Replacing the 3,4-dimethoxyphenethylamine in the above procedure by an 
equimolar amount of .beta.-methyl-3,4-methylenedioxyphenethylamine yields 
(12.2) 
1-{3,3-bis[2-(1,2,3,4-tetrahydro-4-methyl-6,7-methylenedioxy-1-isoquinolin 
yl)ethyl]pentyl}1,2,3,4-tetrahydro-4-methyl-6,7-methylenedioxyisoquinoline] 
, isolated as the trihydrochloride trihydrate. 
EXAMPLE 13 
1,1'-{3-BENZYL-3-[2-(1,2,3,4-TETRAHYDRO-6,7-DIMETHOXY-1-ISOQUINOLINYL)ETHYL 
]PENTAMETHYLENE}BIS[1,2,3,4-TETRAHYDRO-6,7-DIMETHOXYISOQUINOLINE] 
TRIHYDROCHLORIDE TRIHYDRATE 
4-Benzyl-4-(2-carboxyethyl)heptanedioic acid trimethyl ester, b.p. 
215.degree.-230.degree./0.4 mm., is prepared by the Wolff-Kishner 
reduction of 4-benzoyl-4-(2-carboxyethyl)heptanedioic acid, followed by 
esterification of the product with methanol according to the method 
described in Example 3. 
Following the procedure outlined in Example 1, 80 g. of the above ester on 
being heated with 200 g. of 3,4-dimethoxyphenethylamine, yields the 
corresponding triamide which is cyclized with phosphorus oxychloride, and 
the resulting product is reduced with sodium borohydride to yield (13.1) 
the title compound, m.p. 155.degree.-180.degree. (dec.). 
EXAMPLE 14 
1,1'-{3-(p-CHLOROBENZYL)-3-[2-(1,2,3,4-TETRAHYDRO-6,7-DIMETHOXY-1-ISOQUINOL 
INYL)ETHYL]PENTAMETHYLENE}BIS[1,2,3,4-TETRAHYDRO-6,7-DIMETHOXYISOQUINOLINE] 
TRIHYDROCHLORIDE 
4-(2-Carboxyethyl)-4-(p-chlorobenzyl)heptanedioic acid trimethyl ester, 
b.p. 270.degree.-280.degree./0.9 mm., is prepared according to the method 
outlined in Example 3, starting with 4'-chloroacetophenone, which is 
cyanoethylated to 
3-(p-chlorobenzoyl)-3-(2-cyanoethyl)-1,5-pentanedicarbonitrile, m.p. 
135.degree.-137.degree.. On hydrolysis, this trinitrile yields 
4-(2-carboxyethyl)-4-(p-chlorobenzoyl)heptanedioic acid, m.p. 
225.degree.-227.degree., which is subjected to Wolff-Kishner reduction 
followed by esterification of the product. 
Following the procedure outlined in Example 1, 18 g. of the above triester 
on being heated with 32 g. of 3,4-dimethoxyphenethylamine yields the 
corresponding triamide which, without purification is cyclized with 
phosphorus oxychloride, and the resulting product is reduced with sodium 
borohydride to yield (14.1) the title compound, m.p. 
135.degree.-185.degree. (dec.). 
By the same sequence of steps, but using in place of the 
4'-chloroacetophenone an equimolar amount of 
4'-ethoxyacetophenone 
3'-trifluoromethylacetophenone 
3',4'-methylenedioxyacetophenone 
2'-methylacetophenone 
3',4'-dimethoxyacetophenone 
respectively, the following products are obtained: 
(14.2): 
1,1'-{3-(p-ethoxybenzyl)-3-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquino 
linyl)ethyl]pentamethylene}bis[1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline 
] trihydrochloride 
(14.3): 
1,1'-{3-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolinyl)ethyl]-3-(m-t 
rifluoromethylbenzyl)pentamethylene}bis[1,2,3,4-tetrahydro-6,7-dimethoxyiso 
quinoline] trihydrochloride 
(14.4): 
1,1'-{3-(3,4-methylenedioxybenzyl)-3-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy- 
1-isoquinolinyl)ethyl]pentamethylene}bis[1,2,3,4-tetrahydro-6,7-dimethoxyis 
oquinoline] trihydrochloride 
(14.5): 
1,1'-{3-(o-methylbenzyl)-3-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquino 
linyl)ethyl]pentamethylene}bis[1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline 
] trihydrochloride 
(14.6): 
1,1'-{3-(3,4-dimethoxybenzyl)-3-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-1-iso 
quinolinyl)ethyl]pentamethylene}bis[1,2,3,4-tetrahydro-6,7-dimethoxyisoquin 
oline] trihydrochloride 
EXAMPLE 15 
1,1',1",1'"-(1,5,10,14-TETRADECANETETRAYL)TETRAKIS[1,2,3,4-TETRAHYDRO 
6,7-DIMETHOXYISOQUINOLINE] TETRAHYDROCHLORIDE TETRAHYDRATE 
To a freshly prepared solution of 13.5 g. of sodium methoxide in 500 ml. of 
methanol, 55 g. of the mixed methyl and ethyl esters of 
1,1'-tetramethylenebis[2-oxocyclohexanecarboxylic acid], b.p. 
210.degree.-215.degree./1 mm., prepared by alkylation of the commercially 
available mixture of methyl and ethyl 2-oxocyclohexanecarboxylates with 
1,4-dibromobutane, are added. The residue is treated with water and 
extracted twice with 500 ml. portions of ether. The combined ether 
extracts are washed successively with water, aqueous sodium bicarbonate 
and water, dried over anhydrous magnesium sulfate and filtered. Removal of 
the solvent from the filtrate under reduced pressure yields a liquid which 
is distilled under vacuum. Tetramethyl 
1,5,10,14-tetradecanetetracarboxylate, which distills over at 225-235/0.3 
mm., solidifies on standing. Trituration with pentane and filtration 
furnishes colorless crystals, m.p. 61.degree.-65.degree.. 
Following the procedure outlined in Example 2, 12.6 g. of the above 
tetraester on being heated with 21 g. of 3,4-dimethoxyphenethylamine, 
yields the corresponding tetramide, which is cyclized with phosphorus 
oxychloride in anhydrous benzene and the resulting product (15.1a) is 
reduced with sodium borohydride, to yield (15.1) 
1,1',1",1'"-(1,5,10,14-tetradecanetetrayl)tetrakis[1,2,3,4-tetrahydro-6,7- 
dimethoxyisoquinoline], isolated as its tetrahydrochloride tetrahydrate, 
m.p. 185.degree.-205.degree. (dec.). The pure dihydro precursor to 15.1, 
isolated as the colorless solid (15.1a) 
1,1',1",1'"-(1,5,10,14-tetradecanetetrayl)tetrakis[3,4-dihydro-6,7-dimetho 
xyisoquinoline] tetrahydrochloride tetrahydrate, has a m.p. of 
120.degree.-130.degree. (dec.). 
When, in the above procedure for the preparation of 15.1, the 
3,4-dimethoxyphenethylamine is replaced by an equimolar amount of 
m-methoxyphenethylamine 
m-methoxy-.beta.-methylphenethylamine 
4-benzyloxy-3-methoxyphenethylamine 
3-methoxy-4-phenoxyphenethylamine 
3-methoxy-2-pentyloxyphenethylamine 
3-ethoxy-2-isopentyloxy-1-methylphenthylamine 
respectively, the following products are obtained: 
(15.2): 
1,1',1",1'"-(1,5,10,14-tetradecanetetrayl)tetrakis[1,2,3,4-tetrahydro-6-me 
thoxyisoquinoline] tetrahydrochloride tetrahydrate 
(15.3): 
1,1',1",1'"-(1,5,10,14-tetradecanetetrayl)tetrakis[1,2,3,4-tetrahydro-6-me 
thoxy-4-methylisoquinoline] tetrahydrochloride tetrahydrate 
(15.4): 
1,1',1",1'"-(1,5,10,14-tetradecanetetrayl)tetrakis[7-benzyloxy-1,2,3,4-tet 
rahydro-6-methoxyisoquinoline] tetrahydrochloride tetrahydrate 
(15.5): 
1,1',1",1'"-(1,5,10,14-tetradecanetetrayl)tetrakis[1,2,3,4-tetrahydro-6-me 
thoxy-7-phenoxyisoquinoline] tetrahydrochloride tetrahydrate 
(15.6)- 
1,1',1",1'"-(1,5,10,14-tetradecanetetrayl)tetrakis[1,2,3,4-tetrahydro-6-me 
thoxy-5-pentyloxyisoquinoline] tetrahydrochloride tetrahydrate 
(15.7): 
1,1',1",1'"-(1,5,10,14-tetradecanetetrayl)tetrakis[3-ethoxy-1,2,3,4-tetrah 
ydro-5-isopentyloxy-3-methylisoquinoline] tetrahydrochloride tetrahydrate 
EXAMPLE 16 
1,1',1",1'"-(1,4,9,12-DODECANETETRAYL)TETRAKIS[1,2,3,4-TETRAHYDRO-6,7-DIMET 
HOXYISOQUINOLINE] TETRAHYDROCHLORIDE TETRAHYDRATE 
Following the procedure outlined in Example 2, 30 g. of tetramethyl 
1,4,9,12-dodecanetetracarboxylate, b.p. 200.degree.-212.degree./0.5 mm., 
on being heated with 81.5 g. of 3,4-dimethoxyphenethylamine, yields the 
corresponding tetramide, m.p. 165.degree.-170.degree., which is cyclized 
with phosphorus oxychloride in anhydrous benzene, the product (16.1a) is 
reduced with sodium borohydride and (16.1) 
1,1',1",1'"-(1,4,9,12-dodecanetetrayl)tetrakis[1,2,3,4-tetrahydro-6,7-dime 
thoxyisoquinoline] is isolated as its tetrahydrochloride tetrahydrate, m.p. 
193.degree.-215.degree. (dec.). Pure (16.1a) 
1,1',1",1'"-(1,4,9,12-dodecanetetrayl)tetrakis[3,4-dihydro-6,7-dimethoxyis 
oquinoline], isolated as the tetrahydrochloride tetrahydrate, is a light 
yellow solid which melts at 105.degree.-110.degree. (dec.) after two 
recrystallizations from isopropanol. 
Replacing the 3,4-dimethoxyphenethylamine in the above procedure for the 
preparation of 16.1, by an equimolar amount of 
4-benzyloxy-3-methoxyphenethylamine 
m-methoxy-.alpha.-methylphenethylamine 
3,4,5-trimethoxyphenethylamine 
3,4-diethoxyphenethylamine 
2-chloro-3,4-dimethoxy-.alpha.-methylphenethylamine 
respectively, yields the following products: 
(16.2): 
1,1',1",1'"-(1,4,9,12-dodecanetetrayl)tetrakis[7-benzyloxy-1,2,3,4-tetrahy 
dro-6-methoxyisoquinoline] tetrahydrochloride tetrahydrate 
(16.3): 
1,1',1",1'"-(1,4,9,12-dodecanetetrayl)tetrakis[1,2,3,4-tetrahydro-6-methox 
y-3-methylisoquinoline] tetrahydrochloride tetrahydrate 
(16.4): 
1,1',1",1'"-(1,4,9,12-dodecanetetrayl)tetrakis[1,2,3,4-tetrahydro-6,7,8-tr 
imethoxyisoquinoline] tetrahydrochloride tetrahydrate 
(16.5): 
1,1',1",1'"-(1,4,9,12-dodecanetetrayl)tetrakis[6,7-diethoxy-1,2,3,4-tetrah 
ydroisoquinoline] tetrahydrochloride tetrahydrate 
(16.6): 
1,1',1",1'"-(1,4,9,12-dodecanetetrayl)tetrakis[5-chloro-1,2,3,4-tetrahydro 
-6,7-dimethoxyisoquinoline] tetrahydrochloride tetrahydrate 
EXAMPLE 17 
1,1',1"-[1,2,3-PROPANETRIYLTRI-(OXYETHYLENE)]TRIS[1,2,3,4-TETRAHYDRO-6,7-DI 
METHOXYISOQUINOLINE] TRIHYDROCHLORIDE 
A mixture of 148 g. of 3,3',3"-(1,2,3-propanetriyltrioxy)tripropionitrile, 
obtained by the cyanoethylation of glycerol, and 850 ml. of 10% aqueous 
sodium hydroxide is refluxed overnight, cooled, acidified with conc. 
hydrochloric acid, and the resulting mixture evaporated to dryness under 
reduced pressure. Extraction with hot acetone, followed by filtration and 
removal of the solvent under reduced pressure yields 
3,3',3"-(1,2,3-propanetriyltrioxy)tripropionic acid. 
A mixture of 46.2 g. of this tripropionic acid and 89 g. of 
3,4-dimethoxyphenethylamine is heated at 180.degree.-200.degree. with 
stirring for five hours under an atmosphere of nitrogen to yield the 
corresponding triamide, which is cyclized with phosphorus oxychloride in 
anhydrous benzene to (17.1a) 
1,1',1"-[1,2,3-propanetriyltri(oxyethylene)]tris[3,4-dihydro-6,7-dimethoxy 
isoquinoline], isolated as its trihydrochloride, m.p. 
110.degree.-115.degree. (dec.). On reduction with sodium borohydride, this 
trihydrochloride yields (17.1) the title compound, isolated as its 
trihydrochloride, m.p. 205.degree.-210.degree.. 
Using the same sequence of steps outlined above for the preparation of 
17.1, but using (1,2,3-propanetriyltrioxy)triacetic acid trimethyl ester, 
obtained by the alkylation of glycerol with methyl chloroacetate, in place 
of the tripropionic acid, (17.2) 
1,1',1"-[1,2,3-propanetriyltri(oxymethylene)]tris[1,2,3,4-tetrahydro-6,7-d 
imethoxyisoquinoline] is obtained, isolated as its trihydrochloride. 
Similarly, but starting with nitrilotripropionic acid, the above sequence 
of steps yields (17.3) 
1,1',1"-(nitrilotriethylene)tris[1,2,3,4-tetrahydro-6,7-dimethoxyisoquinol 
ine], isolated as its trihydrochloride trihydrate, m.p. 
175.degree.-185.degree. (dec.). 
EXAMPLE 18 
1,1'-{3-AMINO-3-[2-(1,2,3,4-TETRAHYDRO-6,7-DIMETHOXY-1-ISOQUINOLINYL)ETHYL] 
PENTAMETHYLENE}BIS[1,2,3,4-TETRAHYDRO-6,7-DIMETHOXYISOQUINOLINE] 
A mixture of 40 g. of 4-(2-carboxyethyl)-4-nitroheptanedioic acid and 250 
ml. of pure thionyl chloride is refluxed for 16 hours, and the resulting 
clear solution is stripped of excess thionyl chloride under reduced 
pressure. The crude tripropionyl chloride thus obtained is dissolved in 
150 ml. of pure chloroform and added, dropwise, to a vigorously stirred 
mixture of 100 g. of 3,4-dimethoxyphenethylamine in 500 ml. of chloroform 
and 500 ml. of a 10% aqueous solution of sodium carbonate. On completion 
of the addition the mixture is stirred for a further 90 minutes, and the 
chloroform layer is separated. After washing once with water, twice with 6 
N hydrochloric acid, and once again with water, it is dried over anhydrous 
magnesium sulfate and filtered. On removal, under reduced pressure, of the 
solvent, the corresponding triamide is obtained, which, without 
purification, is cyclized in phosphorus oxychloride and anhydrous benzene. 
The resulting product is converted to (18.1a) 
1,1'-{3-[2-(3,4-dihydro-6,7-dimethoxy-1-isoquinolinyl)ethyl] 
-3-nitropentamethylene}bis[3,4-dihydro-6,7-dimethoxyisoquinoline] 
trihydrochloride, m.p. 180.degree.-190.degree. (dec.). Reduction of this 
trihydrochloride with sodium borohydride yields (18.1) 
1,1'-{3-nitro-3-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolinyl)ethyl 
]pentamethylene}bis[1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline], isolated 
as the trihydrochloride trihydrate, m.p. after recrystallization from 
isopropanol 210.degree.-220.degree. (dec.). 
Reduction of the crude base corresponding to 18.1a with lithium aluminum 
hydride in anhydrous tetrahydrofuran, followed by purification by 
chromatography over alumina gives rise to the title compound (18.2), m.p. 
85.degree.-115.degree., which can be converted to a hydrate of a 
hydrochloride, m.p. 215.degree.-220.degree. (dec.). 
EXAMPLE 19 
1,1',1"-(1,4,7-HEPTANETRIYL)TRIS[1,2,3,4-TETRAHYDRO-6,7-DIMETHOXYISOQUINOLI 
NE] TRIHYDROCHLORIDE TRIHYDRATE 
To a freshly prepared solution of 6.8 g. of sodium ethoxide in 500 ml. of 
absolute ethanol, 16 g. of the commercially available mixture of methyl 
and ethyl 2-oxocyclopentanecarboxylates is added with stirring, followed 
by the addition of 19.9 g. of ethyl 4-bromobutyrate and 2.0 g. of powdered 
sodium iodide. After the mixture has been refluxed with stirring for 18 
hours it is filtered, and the filtrate stripped of the solvent under 
reduced pressure. The residue is treated with water and extracted twice 
with 250 ml. portions of ether. The combined ether extracts are washed 
first with saturated aqueous sodium bicarbonate solution, then with water, 
and then dried over magnesium sulfate. Filtration and removal of solvent 
from the filtrate under reduced pressure leaves a liquid, which is 
distilled under vacuum. The desired triethyl 1,4,7-heptanetricarboxylate 
is collected at 150.degree.-155.degree./0.3-0.4 mm. 
A mixture of 9.5 g. of this triester and 19.9 g. of 
3,4-dimethoxyphenethylamine is heated at 180.degree.-200.degree. for five 
hours in an atmosphere of nitrogen to yield the corresponding triamide, 
m.p. 184.degree.-186.degree., which is cyclized with phosphorus 
oxychloride in anhydrous benzene to (19.1a) 
1,1',1"-(1,4,7-heptanetriyl)tris[3,4-dihydro-6,7-dimethoxyisoquinoline], 
isolated as its trihydrochloride by precipitation with ether from a 
chloroform solution, m.p. 120.degree.-130.degree. (dec.). This 
trihydrochloride is reduced with sodium borohydride to yield (19.1) the 
title compound, isolated as its trihydrochloride trihydrate, m.p. 
195.degree.-215.degree. (dec.). (sinters at 185.degree.) 
EXAMPLE 20 
______________________________________ 
Ingredients Mg/Tablet 
______________________________________ 
1,1'-3-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy- 
1-isoquinolinyl)ethyl]heptamethylene bis[1,2,- 
3,4-tetrahydro-6,7-dimethoxyisoquinoline] 
trihydrochloride 25 
Lactose USP (Spray dried) 
170 
Starch USP 10 
Magnesium stearate USP 1 
Stearic acid USP 5 
Flavor q.s. 
______________________________________ 
All of the above ingredients are passed through a 60 mesh sieve, blended 
for 30 minutes and compressed directly into tablets on a suitable tablet 
press at a weight of 211 mg. using a 11/32 inch biconcave, scored punch. 
EXAMPLE 21 
______________________________________ 
Ingredients Ampoule 
______________________________________ 
1,1',1",1" -(1,5,10,14-tetradecanetetrayl)- 
tetrakis[1,2,3,4-tetrahydro-6,7-dimethoxyiso- 
quinoline] tetrahydrochloride 
5 g. 
Mannitol, N.F. To make the 
solution iso- 
tonic 
Pyrogen free water for injection 
q.s. to 1 liter 
______________________________________ 
The compound is added to the water and the solution made isotonic with 
mannitol. The resulting pH is 5.5. The solution is filled into ampoules 
under sterile conditions and the sealed ampoule is autoclaved. Each 
ampoule contains 10 ml. of the 5 mg./ml. solution.