NEUROMUSCULAR BLOCKING AGENTS

AGENTS DE BLOCAGE NEUROMUSCULAIRE

English Abstract

ABSTRACT OF THE DISCLOSURE
Short acting reversible neuromuscular blocking agents
of the formula (I)
<IMG> (I)
where B and C is preferably meta or maybe para
<IMG>
where m is 2, 3 or 4, and is preferably 2, R1, R2, R3, R4, R5,
R6 and R7 are the same or different and are hydrogen or lower
alkoxy of 1 to 4 carbon atoms, Y is lower alkyl of 1 to 4 carbon
atoms, n is 2, 3 or 4, most preferably 3, provided that at least
one of 3 to R4 and one of R5 to R7 is lower alkoxy and X is
a pharmaceutically acceptable anion. These neuromuscular
blocking agents of formula I are useful upon administration.
to a patient in providing muscular relaxation in the patient
during surgery and are normally intravenously administered in
a pharmaceutically acceptable carrier.

Claims

The embodiments of the invention in which an
exclusive property or privilege is claimed are defined
as follows:
1. A method of preparing a compound of formula (I)
<IMG> (I)
where B and C are the same or different, B is para or meta to
C, and each is
<IMG>
where m is 2, 3, or 4; n is 2, 3 or 4, R1, R2, R3, R4, R5, R6
and R7 are the same or different and each is hydrogen or lower
alkoxy of 1 to 4 carbon atoms; Y is lower alkyl of 1 to 4 carbon
atoms, and X is a pharmacuetically acceptable anion; provided
that at least one of R1, R2, R3 and R4 is lower alkoxy and at least
one of R5, R6 and R7 is lower alkoxy; characterised in that one:
a) reacts a species of formula
57

<IMG>
with a species of formula
<IMG>
where n, m, Y and each of R1 to R7 have the same meaning as in
formula (I) and Q and Q' are functional atoms or groups which
react together to form an ester linkage or
b) quaternises a compound of formula
<IMG>
58

where Y and each of R1 to R7 have the same meaning as in formula
(I), with a compound of formula
<IMG>
where J is halo and forms said anion X- and m and n have the
same meaning as in formula (I); or
c) alkylates the corresponding ditertiary base of
formula:
<IMG>
wherein n, m and each of R1 to R7 have the same meaning as in
formula (I), or the corresponding monotertiary base where a
group Y as defined in formula (I) is attached to one of the
isoquinolium nitrogen atoms, with an appropriate alkylating
agent for introducing one or two Y groups, as appropriate, and
said anion X-.
2. A method according to claim 1 a), which comprises
rearrangement of a salt of formula
59

<IMG>
wherein each of m, n, Y and R1 to R7 have the same meaning as in
formula (I) as defined in claim 1, and Q is halo.
3. A method according to claim 2, wherein Q is chloro,
bromo or iodo.
4. A method according to claim 2, wherein Q is chloro.
5. A method according to claim 2, wherein the salt is
heated.
6. A method according to claim 5, wherein one uses a
temperature of from 90° to 140°C.
7. A method according to claim 2, wherein the salt is
prepared by reacting the silver salt of the anion with a halide
of the cation.
8. A method according to claim 7, wherein the halide is
the bromide.
9. A method according to claim 1 a), wherein Q is

hydroxy and Q' is carboxyl or a reactive derivative thereof.
10. A method according to claim 9, wherein the reactive
derivative is an acid halide.
11. A method according to claim 9, wherein the reactive
derivative is the acid chloride.
12. A method according to claim 9, 10 or 11, wherein
an inert solvent is used.
13. A method according to claim 1 b), wherein J is iodo.
14. A method according to claim 1 a) wherein an inert
solvent is used.
15. A method according to claim 1 b), wherein the
reactants are heated up to the reflux temperature of the
reaction medium.
16. A method according to claim 1 c), wherein the
alkylating agent is a reactive ester derivative of an alcohol
YOH.
17. A method according to claim 16, wherein the alkylating
agent is an alkyl halide.
18. A method according to claim 16 or 17, wherein the
alkylating agent is an alkyl bromide, alkyl chloride or alkyl
iodide.
19. A method according to claim 1 c), wherein an inert
solvent is used.
20. A method according to claim 1 c), wherein the
reactants are heated up to the reflux temperature of the
reaction mixture.
61

21. A method according to claim 1 wherein in the compound
of formula (I) C is para to B.
22. A method according to claim 1, wherein in the compound
of formula (I) C is meta to B.
23. A method according to claim 1, wherein in the compound
of formula (I) X is iodide, mesylate, tosylate, bromide, chloride,
sulphate, phosphate, hydrogen phosphate, acetate or propionate.
24. A method according to claim 1, wherein in the compound
of formula (I) m = 2, n = 3, y is methyl, one or two of R1 to R4
are hydrogen and the others are methoxy and two or three of R5
to R7 are methoxy and when two are methoxy the other is hydrogen.
25. A method according to claim 1, wherein in the compound
of formula (I) m = 2, n = 3, Y is methyl, R1 and R4 are
hydrogen, R2 and R3 are methoxy and R5 and R6 and R7 are methoxy
at the 3, 4, 5 position of the phenyl ring.
26. A method according to claim 1, wherein in the compound
of formula (I) m = 2, n = 3, Y is methyl, R1 and R4 are hydrogen,
R2 and R3 are methoxy, R5 and R6 are methoxy and R7 is hydrogen.
27. A method according to claim 1, wherein is the compound
of formula (I) m =2, n = 3, Y is methyl, R1 is hydrogen R4 is
hydrogen, R5 and R6 are methoxy and R7 is hydrogen or methoxy.
28. A method according to claim 25, wherein C is para to B.
29. A method according to claim 25, wherein C is meta to B.
30. A method according to claim 26, wherein C is para to B.
31. A method according to claim 26, wherein C is meta to B.
62

32. A method according to claim 27, wherein C is para to B.
33. A method according to claim 27, wherein C is meta to B.
34. A compound of the formula (I), as defined in claim 1,
whenever prepared by the method of claim 1, or by an obvious
chemical equivalent.
35. A compound of formula (I), as defined in claim 1,
wherein C is para to B, whenever prepared by the method of
claim 21 or by an obvious chemical equivalent.
36. A compound of formula (I), as defined in claim 1,
wherein C is meta to B, whenever prepared by the method of
claim 22 or by an obvious chemical equivalent.
37. A compound of formula (I), as defined in claim 1,
wherein m = 2, n = 3, Y is methyl, one or two of R1 to R4 are
hydrogen and the others are methoxy and two or three of R5
to R7 are methoxy and when two are methoxy the other is hydrogen,
whenever prepared by the method of claim 24 or by an obvious
chemical equivalent.
38. A compound of formula (I), as defined in claim 1,
wherein m = 2, n = 3, Y is methyl, R1 and R4 are hydrogen, R
and R3 are methoxy, R5 and R6 and R7 are methoxy at the 3, 4
and 5 position of the phenyl ring whenever prepared by the
method of claim 25 or by an obvious chemical equivalent.
39. A compound of formula (I), as defined in claim 1,
wherein Y is methyl, R1 and R4 are hydrogen, R2 and R3 are
methoxy, R5 and R6 are methoxy and R7 is hydrogen, whenever
prepared by the method of claim 26 or by an obvious chemical
equivalent.
63

40. A compound of formula (I), as defined in claim 1,
wherein m = 2, n = 3, Y is methyl, R1 is hydrogen, R4 is
hydrogen, R5 and R6 are methoxy, R7 is hydrogen or methoxy,
whenever prepared by the method of claim 27 or by an obvious
chemical equivalent.
41. A compound of formula (I), as defined in claim 1,
wherein C is para to B, whenever prepared by the method of
claim 28 or by an obvious chemical equivalent.
42. A compound of formula (I), as defined in claim 1,
wherein C is meta to B, whenever prepared by the method of
claim 29 or by an obvious chemical equivalent.
43. A compound of formula (I), as defined in claim 1,
wherein C is para to B, whenever prepared by the method of
claim 30 or by an obvious chemical equivalent.
44. A compound of formula (I), as defined in claim 1,
wherein C is meta to B, whenever prepared by the method of
claim 31 or by an obvious chemical equivalent.
45. A compound of formula (I), as defined in claim 1,
wherein C is para to B, whenever prepared by the method of
claim 32 or by an obvious chemical equivalent.
46. A compound of formula (I), as defined in claim 1,
wherein C is meta to B, whenever prepared by the method of
claim 33 or by an obvious chemical equivalent.
47. A compound of formula (I), as defined in claim 1,
wherein X is iodide, mesylate, tosylate, bromide, chloride,
sulfate, phosphate, hydrogen phosphate, acetate or propionate,
whenever prepared by the method of claim 23 or by an obvious
chemical equivalent.
64

48. A method according to claim 1, for preparing
bis-3[N-methyl-1-(3,4,5-trimethoxybenzyl)6,7-dimethoxy-
1,2,3,4-tetrahydroisoquinolinium]propyl-m-phenylene-3,3'-
dipropionate dichloride which comprises reacting N-(3-
chloropropyl)5'-methoxy laudanosinium bromide with silver
m-phenylene dipropionate with subsequent rearrangement
of the ester.
49. Bis-3-[N-methyl-1-(3,4,5-trimethoxybenzyl)6,7-
dimethoxy-1,2,3,4-tetrahydroisoquinolinium]propyl-m-
phenylene-3,3'-dipropionate chloride, whenever prepared by
the method of claim 48, or by an obvious chemical equivalent.
50. A method according to claim 1, wherein in the
compound of formula (I), m = 2, n = 3, Y is methyl, R1,
R2 and R3 are each methoxy and R4 is hydrogen, R7 is
hydrogen and R5 is hydrogen and R6 and R7 are methoxy at
the 3 and 4 position of the phenyl ring.
51. A method according to claim 1, wherein in the
compound of formula (I), m = 2, n = 3, Y is methyl, R1,
R2 and R3 are each methoxy and R4 is hydrogen, R5, R6 and
R7 are methoxy at the 3, 4 and 5 position of the phenyl
ring.
52. A method according to claim 28, in which X is
iodide, mesylate, tosylate, bromide, chloride, sulfate,
phosphate, hydrogen phosphate, acetate or propionate.
53. A method according to claim 29, in which X is
iodide, mesylate, tosylate, bromide, chloride, sulfate,
phosphate, hydrogen phosphate, acetate or propionate.

54. A method according to claim 30, in which X is
iodide, mesylate, tosylate, bromide, chloride, sulfate,
phosphate, hydrogen phosphate, acetate or propionate.
55. A method according to claim 31, in which X is
iodide, mesylate, tosylate, bromide, chloride, sulfate,
phosphate, hydrogen phosphate, acetate or propionate.
56. A method according to claim 1, including a
step of converting a salt of formula (I) obtained having
a first anion X- to a salt of formula (I) of a second
anion X- by an ion exchange reaction with a silver salt
having the second anion X-.
57. A method according to claim 56, for preparing
bis-3-[N-methyl-1-(3,4,5-trimethoxybenzyl)-6,7-dimethoxy-
1,2,3,4-tetrahydroisoquinolinium]-propyl m-phenylene-3,3'-
dipropionate dimesylate comprising reacting bis-3-[N-methyl-1-
(3,4,5-trimethoxybenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-
isoquinolinium]propyl m-phenylene-3,3'-dipropionate
dichloride with silver mesylate.
58, A method according to claim 1 a), for preparing
bis-3-[N-methyl-1-(3,4,5-trimethoxybenzyl)-6,7-dimethoxy-
1,2,3,4-tetrahydroisoquinolinium]propyl-p-phenylene-3,3'-
dipropionate dichloride which comprises reacting N-(3-
chloropropyl)5'-methoxylaudanosinium bromide with silver
p-phenylene dipropionate with subsequent rearrangement
of the ester.
59. A method according to claim 1 a), for preparing
bis-3-[N-methyl-1-(3,4-dimethoxybenzyl)6,7-dimethoxy-
1,2,3,4-tetrahydroisoquinolinium]propyl p-phenylene-3,3'-
66

dipropionate dichloride which comprises reacting N-(3-
chloropropyl)laudanosinium bromide with silver p-phenylene
dipropionate with subsequent rearrangement of the ester.
60. A method according to claim 1 a), for preparing
bis-3-[N-methyl-1-(3,4-dimethoxybenzyl)6,7-dimethoxy-
1,2,3,4-tetrahydroisoquinolinium]propyl m-phenylene-3,3'-
dipropionate dichloride which comprises reacting N-(3-
chloropropyl)laudanosinium bromide with silver m-phenylene
dipropionate with subsequent rearrangement of the ester.
61. A method according to claim 1 a), for preparing
bis-3-[N-methyl-1-(3,4-dimethoxybenzyl)5,6,7-trimethoxy-
1,2,3,4-tetrahydroisoquinolinium]propyl p-phenylene-3,3'-
dipropionate dichloride comprising reacting N-(3-chloro-
propyl)5-methoxy laudanosinium bromide with silver
p-phenylene dipropionate with subsequent rearrangement
of the ester.
62. A method according to claim 1 a) for preparing
bis-3-NN-methyl-1-(3,4,5-trimethoxybenzyl)5,6,7-trimethoxy
1,2,3,4-tetrahydroisoquinolinium]propyl p-phenylene-3,3'-
dipropionate dichloride which comprises reacting N-(3-
chloropropyl)5,5'-dimethoxylaudanosinium bromide with
silver p-phenylene dipropionate with subsequent re-
arrangement of the ester.
63. A compound of the formula (I), as defined in
claim 1, wherein m = 2, n = 3, Y is methyl, R1 and R4
are hydrogen, R2 and R3 are methoxy and R6 and R7
are methoxy at the 3, 4 or 5 position of the phenyl ring,
C is para to B and X is iodide, mesylate, tosylate, bromide,
chloride, sulfate, phosphate, hydrogen phosphate, acetate
or propionate.
67

64. A compound of formula (I), as defined in claim 1,
wherein m = 2, n = 3, Y is methyl, R1 and R4 are hydrogen,
R2 and R3 are methoxy and R6 and R7 are methoxy at the
3,4 or 5 position of the phenyl ring, C is meta to 3
and X is iodide, mesylate, tosylate, bromide, chloride,
sulfate, phosphate, hydrogen phosphate, acetate or
propionate, whenever prepared by the method of claim
53, or by an obvious chemical equivalent.
65. A compound of formula (I), as defined in claim
1, wherein m = 2, n = 3, Y is methyl, R1 is hydrogen,
R4 is hydrogen, R5 and R6 are methoxy and R7 is hydrogen
or methoxy, C is para to B and X is iodide, mesylate,
tosylate, bromide, chloride, sulfate, phosphate, hydrogen
phosphate, acetate or propionate, whenever prepared by
the method of claim 54, or by an obvious chemical equiva-
lent.
66. A compound of formula (I), as defined in claim
1, wherein m = 2, n = 3, Y is methyl, R1 is hydrogen, R4
is hydrogen, R5 and R6 are methoxy and R7 is hydrogen
or methoxy, C is meta to B and X -is iodide, mesylate,
tosylate, bromide, chloride, sulfate, phosphate, hydrogen
phosphate, acetate or propionate, whenever prepared by
the method of claim 55, or by an obvious chemical equiva-
lent.
67. Bis-3-[N-methyl-1-(3,4,5-trimethoxybenzyl)-6,7-
dimethoxy-1,2,3,4-tetrahydrosioquinolinium]propyl m-
phenylene-3,3'-dipropionate dimesylate, whenever prepared
by the method of claim 57, or by an obvious chemical
equivalent.
68

68. Bis-3-[N-methyl-1-(3,4,5-trimethoxybenzyl)-6,7-
dimethoxy-1,2,3,4-tetrahydroisoquinolinium]propyl p-
phenylene-3,3'-dipropionate dichloride, whenever prepared
by the method of claim 58, or by an obvious chemical
equivalent.
69. Bis-3-[N-methyl-1-(3,4-dimethoxybenzyl)6,7-
dimethoxy-1,2,3,4-tetrahydroisoquinolinium]propyl p-
phenylene-3,3'-dipropionate dichloride, whenever prepared
by the method of claim 59, or by an obvious chemical
equivalent.
70. Bis-3-[N-methyl-1-(3,4-dimethoxybenzyl)6,7-
dimethoxy-1,2,3,4-tetrahydroisoquinolinium]propyl m-
phenylene-3,3'-dipropionate dichloride, whenever prepared
by the method of claim 60, or by an obvious chemical
equivalent.
71. Bis-3-[N-methyl-1-(3,4-dimetlhoxybenzyl)5,6,7-
trimethoxy-1,2,3,4-tetrahydroisoquinolinium]propyl p-
phenylene-3,3'-dipropionate dichloride, whenever prepared
by the method of claim 61, or by an obvious chemical
equivalent.
72. Bis-3-[N-methyl-1-(3,4,5-trimethoxybenzyl)5,6,7-
trimethoxy-l,2,3,4-tetrahydroisoquinolinium]propyl p-
phenylene-3,3'-dipropionate dichloride, whenever prepared
by the method of claim 62, or by an obvious chemical
equivalent.
69

Description

3~
In anesthesia, neuromuscular blocking agents are used
to provide skeletal muscular relaxation during surgery and dur-
ing intubation of the trachae.
In general there are two types of neuromuscular
blocking agents in use, nondepolarizing and depolarizing.
The nondepolarizing agents include d-tubocurarine,
pancuronuim gallamine, diallyltoxiferine and toxiferine.
The depolarizing agents include succinylcholine and
decamethonium. A11 of the conventional nondepolarizing agents
when used for producing skeletal muscle relaxation in surgery
have a long duration of action e.g., 60 to 180 minutes in man.
The depolarizing agents on the other hand provide
muscle relaxation at dosages normally used for surgery which is
less than the duration of action of nondepolarizing agents.
For example, succinylcholine providas a short duration
of action of about 5 to 15 minutes whereas decamethonium provides
about 20 to 40 minutes duration of muscle relaxation.
To the best of applicants' knowledge, there are no non-
depolarizing agents currently available for approved clinical use
which have a short duration of action.
As used herein a short duration of action is defined
as less than about 10 minutes in the monkey.
The long duration of action of nondepolarizing agents
is unacceptable in many surgical procedures which take less than
one hour because the patient is not generally fully recovered
from their effects e.g., the patient may be unable to breathe
adequately on his or her own.
Each nondepolarizing agent has inherent side-effects.
For example, gallamine and pancuronium may cause tachycardia,
and d-tubocurarine and diallyltoxiferine may cause hypotension.
' .:. : . . . . .

~ L3~6 1 `
While such drugs can be pharmacologically antagonized
with anticholinesterase agents, this obviously necessitates the
administration of a second drug which itself may have its own 1-:
side effects e.g., bradycardia, gut spasm and bronchorrhea.
Thus, to overcome the aforementioned side effects of the anti-
cholinesterase agents, a third drug, an anticholinergic drug
e.g., atropine must also be given.
The depolarizing agents to the best of applicant's
knowledge have no pharmacologic antagonists. While in most
10 cases there is no need to reverse the effects of the depolarizing
agents, in certain patients the effects of succinylcholine are
much prolonged because of abnormal metabolism of the agent by
the patient.
The depolarizing agents due to that mode of action
which initially causes skeletal muscle contraction and
stimulation of smooth muscles are also known to cause the follow-
ing side effects in certain instances: increased intraocular,
and intragastric tension, cardiac arrhythmias, potassium
release, and muscle pain.
These side effects caused by the depolarizing agents
are not caused by the nondepolarizing agents. It is therefore
clearly evident that a new neuromuscular blocking agent is I -
needed which would combine the short duration of action of the
depolarizing agents with the relatively few side effects and
the reversibility of the nondepolarizing agents.
It should be understood that while nondepolarizing
agents generally have few side effects, gallamine and pan-
curonium may cause tachycardia and d-tubocurarine and diallyl-
toxiferine may cause hypotension.
Surprisingly, the compounds of the present invention
also appear to be free of these side effects at the dosages anti-
t~ -: -
. . . ' -, . " '

cipated being used clinically in tests made to date. Reference
may be had to the text of: `
The Pharmacological Basis of Therapeutics - Fifth
Edition, edited by Louis S. Goodman and Alfred Gilman published
by The McMillia Co., copyright 1975, Chapter 28, author George
B. Koelle, for further description of neuromuscular blocking
agents.
Reference should also be had to the following article:
Neuromuscular Blocking Activity of a New Series of
Quaternary N-Substituted Choline Esters - British Journal of
Pharmacology, September 1971, vol. 43, No. 1, p. 107;
The Pharmacology of New Short Acting ~ondepolarizing
Ester Neuromuscular ~locking Agents: Clinical Implications -
published in Anesthesia and Analgesia ... Current Researches,
Vol. 52, ~o. 6, p. 982, Nov.-Dec., 1973,
Potential Clinical Uses of Short-Acting Nondepolariz-
in~ ~euromuscular-Blocking Agents as Predicted from Animal
Experiments - published in Anesthesia and ~nalgesia ... Current
Researches, Vol. S4,- ~o. 5, p. 669, Sept. - Oct. 1974 and
U.S. Patent No. 3,491,099, for a further description
of neuromuscular blocking agents. l ;
The present invention provides new and improved neuro-
.. ~:
muscular bIocking agents sometimes called muscle relaxants which
combine a nondepolarizing mode o action with the short duration
of action and reversibility needed to meet ideal clinical
requirements for use during surgery.
The neuromuscular blocking agents of this invention
are represented by the formula (I)
..
. .

B ~ . 2X (I)
C
where C is most preferably meta to B as in formula ~II)
B . 2X (II)
C
or C is para to B as in formula (III)
B - ~ C . 2X (III)
and w~ere B and C are
-(CH2 m-C-O-(CH2) ~ 3
~J--R5
i R6
~ ' -
.'
~3 .
.
`

where m is 2, 3 or 4 and is preferably 2, Rl, R2, R3, R4, R5, R6
and R7 are the same or different and are hydrogen or alkoxy of 1
to 4 carbon atoms, (methoxy~ ethoxy, propoxy or butoxy). Y is
alkyl of 1 to ~ carbon atoms (methyl, ethyl, propyl or butyl),
n i9 2, 3 or 4, most preferably 3 and X is a pharmaceutically
acceptable anion, provided that at least one of Rl to R4 is
always lower alkoxy and at least one of R5 to R7 is always lower
alkoxy. The preferred compounds of this invention are those in
which R5 to R7 are each lower alkoxy.
Of the compounds of the invention, the most preferred
are the compounds of formula II or III where Y is methyl, m is -
2, n is 3, R5, R6 and R7 are methoxy at the 3, 4 and 5 positions
of the phenyl portion of the benzyl group, Rl and R4 are
hydrogen and R2 and R3 are methoxy since these compounds appear
to be less quickly hydrolyzed than the dimethoxy benzyl com-
pounds and the meta compound (formula II) is even more preferred
than the corresponding para compound because it is significantly
shorter acting. The most preferred compounds also exhibit
minlmal side effects and high potency.
of the anions of the invention, the following are
examples of those which are suitable: iodide, mesylate,
tosylate, bromide, chloride, sul~ate, phosphate, hydrogen phos-
phate, acetate, benzene sulfonate, nitrobenzene sulfone,
naphthylene sulfonate, and propionate. The mesylate and chloride ,~
cations are most preferred because of the solubility of the salt
made therefrom in water. Since the activity is in the cation
portion of the compound, the nature of the anion is unimportant
as long as it is pharmaceutically acceptable.
The compounds of formula I, II or III are used as
nèuromuscular blocking agents in conjunction with surgery or for
intubation of the trachea by conventional parenteral ¦-
administration e.g., intramuscular or intravenous administration
- 5 - `
.

6i
in solution. The compounds of the present invention shown in
formulas I, II or III are administered to patients such as
monkeys and man (humans) and other mammals to achieve a neuro-
muscular block. The dosage for each type of patient will vary
because of the peculiarities of the species, howe~er, a suit-
able intravenous amount or dosage of the compounds of formula
I, II or III for monkey would be 1.0 to 4.0 mg~kg of body
weight, and for a man 0.2 to 3.0 mg~kg of body weight, and
most preferably 0.5 to 1.5 mg~kg of body weight, the above
being based on the weight of the cation which is the active
ingredient.
The dosage for intramuscular administration is two
to four times the intravenous dose. The compounds of this
invention would normally be readministered every 5 to 20
minutes preferably 5 to 15 minutes after initial adminstration
or given as a continuous infusion depending upon the length of
time a muscular block is desired, and as determined by the
anesthetists and surgeon in charge of the patient. The com-
pounds of this invention are reversible using conventional
anticholinesterase agents such as neostigmine and edrophonium
and appear to avoid the side effects associated with the de-
polarizing agents~
The compounds of formula I, II or III are therefore
useful for producing a short duration neuromuscular blockade,
and the present~invention provides a method of producing such
blockade in mammals e.g., man or monkeys, by intravenously
injecting a dose of 0.05 to 4.0 mg~kg to the mammal.
The compounds may be presented in a pharmaceutical
formulation for parenteral administration. The formulation
may be an aqueous or non-aqueous solution or emulsion in a
pharmaceutically acceptable liquid or mixture of liquids, which
~D

may contain bacteriostatic agents, antioxidants, buffers,
thickening agents, suspending agents or other pharmaceutically
acceptable additives. Such formulations are normally pre-
sented in unit dosage forms such as ampoules or disposable
injection devices, or in multidose forms such as a bottle from
which the appropriate dose may be withdrawn. All such
formulations should be rendered sterile.
The compounds of this invention may be presented
as a powder e.g., as a unit dose in a sealed vial to which
sterile water or other pharmaceutically acceptable sterile
liquid vehicle may be added by a needle.
A suitable unit dose to obtain a neuromuscular
block for mammals e.g., humans or monkeys is about 10 mg to
~00 mg and most preferably 50 to 300 mg.
The compounds of this invention if desired may be
administered in conjunction with other non-depolarizing agents
such as listed above.
Thus a suitable pharmaceutical parenteral pre-
paration will preferably contain 10 to 400 mg of the compounds '~
of formulas I, II or III of this invention in solution.
A simple and preferred ~ormulation is a solution of
the compound of formula I, II or III in water which may be pre- !`
pared by simply dissolving the compound into previously
sterilized pure water i.e., pyrogon free water ~nder aseptic
conditions and sterilizing the solution.
The compound of formula I, II or III may also be
administered as an infusion of a dextrose solution or a
saline solution e.g., Ringers' solution.
The compounds may also be administered in other
solvents such as alcohol, polyethyleneglycol and dimethyl-
sulfoxide. They may also be administered intramuscularly
as a suspension. The compounds (formulas I, II or III) of
. ,

thi~ invention may be prepared by the fo11owing ~ethods: ¦
Method 1
Benzyltetrahydroisoquinolines are prepared in the
customary fashion from appropriately substituted phenylethyl-
amines and phenylacetic acids by the Bischler-~apieralski
reaction. The tertiary benzylisoquinoline is quaterni~ed with ¦ :
an appropriate ~-bromo-~-chloroalkane, ~-iodo-~-chloroalkane, ¦~
or ~-iodo-~-bromoalkane. The resulting ~-methyl, ~ halo-
alkyl)-l-benzyltetrahydroisoquinolinium halide is boiled in ~:
water with the silver salt of the appropriate dicarboxylic acid, ¦ -
yielding silver bromide and the benzylisoquinolinium salt of
the acid. This sAlt rearranges to the corresponding ester
on heating: for example the generalized reaction is
illustrated using ~-bromo-~-chloroalkane as follows:
COO Ag .
2 [cl(cH2)n _~ ~ Br ~ 2 AcJ Br
_ ~ CH2 R4 1 1
COO Ag

N
-:
--N ~ ~ o
, ~ I ,
D ~:
: `
~a~ ~>~N~
. ~ _ I` ' .
_, I ~
Ug ~ U ' '-
~j _ g _

3~i
where Z is (CH2)m and Rl to R7 are as defined above.
Other salts are prepared by conventionally reacting
the dichlorosalt in an ion exchange reaction with an a~propriate
salt of the desired anion e.g., silver mesylate. The
temperature for rearrangement is preferably ~0 to 140.
Method 2.
The bis-acid chloride of an appropriate phenylene di-
carboxylic acid is prepared in the usual fashion by treatment
of the acid with thionyl chloride. The acid chloride is
esterified with an appropriate ~-hydroxy-~-iodoalkane, yielding
the desired phenylene diacyl bis-~-iodoalkyl ester:
fOCl COO(CH2)n I
+ 2 H(CH2)n I ~ + 2 N Cl
z. 1'.
COCl COO~CH2)n I
The diiodoester is refluxed with an excess of e.g.,
two moles of an appropriate 1-benzyltetrahydroisoquinoline
prepared in standard fashion by the Bischler-Napieralski
reaction as described in Method 1. The desired bis-benzyl-
~ isoquinolinium dliodide (disalt) is obtained: I
-- 10 --
;~

::
~ N~
N N
O ~ ~ _0 `'~' '
1~ ,
I
i ~ ~'; ~',' ' "'.
+ ~ ,
~ H H ;
~ ; ~
,~ ~
', ' ' ~'''
-- 11
~ . ' . ': .
.. . .. . . . .. . .. .. ... . ~ . . .. . ` . .. - .

where Z is (CH2)m and Rl to R7 are defined as above, The
desired salts are then prepared in a conventional ion exchange
reaction as described in Method
Bromine or chlorine may be substituted for iodine in
the ~-hydroxy-~-iodoalkane if desired and the reaction run as
above.
METHOD 3
me appropriate l-benzyltetra hydroisoquinoline pre-
pared as described in Method 1 is quaternized with the -
appropriate ~-halogeno-~-hydroxyalkane.
mis process may be carried out in a variety of
solvents (e.g., acetonitrile, lower alcohols, DMF, aromatic
hydro-carbons, etc.) over temperatures ranging from ambient
to reflux.
2 ;n
R5 ~ R5
R7 R7
6 R6
The bis acid chloride of an appropriate meta or para
phenylene dicarboxylic acid is prepared in the usual fashion
by treatment with a reagent such as thionyl chloride.
m e bis acid chloride is then esterified wnth e.g.,
two moles of the appropriate ~uaternary salt containing an ~-
hydroxyalkyl chain. The desired salts are then prepared by ion
exchange using conventional methods such as metathesis with a
- 12 -
`

~ ~3~
silver salt, an anion exchange resin, etc.
Method 4
By an alternate method, the product of the Bischler- 1 -
Napieralski reaction is quaternized with 3-bromo-l-propanol in
acetone at room temperature. On ~eduction with Zn a tetra- ~ -
hydroisoquinoline is obtained containing a 2-hydroxypropyl sub-
stitution. This amino alcohol is acylated with the desired
acid chloride in chloroform at room temperature and then
refluxed for 30 minutes. Chloroform is then evaporated in
vacuo, the residue is slurried in water; made alkaline by
adding excess K2CO3, and extracted with ether. Ether is
evaporated and the tertiary ester is dissolved in acetone. ;~
Excess methyl iodide is added and the solution is left to
stand overnight. Excess ether is added to precipitate the
quaterAary ester. The latter is filtered and dried.
,
~ - 13 -

3~
Example ~laudanosine)
OCH3
OCH3 Br
IH2 OHCH2CH2CH2BR HocH2cH2cH2-N
~OCH3 ~ 3
OCH3
~ OCH3
HOCH2CH2CH2-N ~ OCH3
OCH3
3 ; :
I . tertiary "Amino Alcohol'`
: (Tetrahydroisoquinoline, tertia
m e tertiary amino alcohol is then conjugated with the
appr~priate acid chloride (obtained~as described in Methods 2
and 3)~under conditions described in Method 3 to yield the
desired tertiary ester. This product may then be treated with
~J - 14 -

an alkyl halide to yield the desired bis quaternary ester as
set forth above.
m & p-phenylene diacetic acids were commercially -
available (Aldrich). m and p-phenylene diacrylic acids were
prepared through Knoevenagel-Doebner condensation of iso-
phthalic and terephthalic aldehydes with malonic acid. Tere-
phthalic aldehyde (150 mM) and malonic acid (180 mM) were `
mixed with pyridine (45 ml) and piperidine (1.5 ml). me
mixture was heated on a steam bath (85-95) for 3 hours.
The solution was then cooled at room temperature and dis-
tilled in vacuum to remove pyridine. The solid residue was
washed in hot isopropanol (70) to remove residual pyridine.
~le product, p~phenylene diacrylic acid, was filtered and
dried. (m.p. > 275)
m-phenylene diacrylic acid was prepared from iso-
phthalaldehyde in exactly the same way. (m.p. ~275)
m & p-phenylene dipropionic acids may be prepared
using conventional processes by catalytic reduction e.g., by
reacting the corresponding phenylene cliacrylic acid with
hydrogen at 40 to 45 psi gage pressure in the presence of 5
palladium on charcoal in dilute methanol or dimethyl formamide
at room temperature to 55C. For another method also see
Wagner ~ Zook, Synthetic Organic Chemistry ~ 1973, see page
431 for method 26.
The compounds of this invention may sometimes include
water of hydration in various amounts e.g., 1 to 5 molecules
or more of water per ~uaternary grouping and it is intended
that this invention include such compounds containing water
of hydration.
m e following examples illustrate the invention.
Temperatures are in degrees centigrade.
~ - 15 -

3~
EX~IPLE 1
Preparation of Bis-3-(H-methyl-l-t3,4,5-trimethoxybenzyl) 6,7-
dimethoxy-1,2,3,4-tetrahydroisoquinolinium) propyl
m-phenylene-3~3l-dipropionate dichloride ( HH 110 )
1. Preparation of silver m-phenylene dipropionate
m-phenylene dipropionic acid 4.4 gm = 40 meq
H20 60 ml
KOH lN 40 ml
The mixture i9 heated to boiling, and, if necessary,
the pH is adjusted to 7.0 with the same acid. Ag~O3 6.8 gm =
40 n M is added to the yellow hot solution. Immediately a
heavy precipitate forms. The mixture is cooled and filtered -
and the filter cake is washed with water, refiltered and
dried. Yield = quantitative. The product is an amorphous,
slightly colored powder. It is pulverised for use in the
next step.
2. Preparation of 5'-Methoxylaudanosine
CH30
CH30 ~ CH3
CH90/¢~CH3
3,4-dimethoxyphenylethylamine and 3,4,5-trimethoxy-
phenylacetic acid are heated together at 165 190 in a flash
until bubbling of water subsides. The product ~-(3,4,5-tri-
methoxyphenylacetyl) homoveratrylamine, is recrystallized from
methanol. Yield = 80~o. m.p. = 94.
- 16 -

3.9 gm (10 mM) N-(3,4,5-trimethoxyphenylacetyl) homo-
veratrylamine is refluxed in 15 ml toluene together with 5 ml
POC13 for 2 hours. The settled semisolids are carefully
separated (POC13 excess') and the free base liberated by adding
excess of NaOH and extracted with benzene. The product, 6,7-
dimethoxy-l-t3',4',5'-trimethoxybenzyl) 3,4-dihydroisoquinoline
is refluxed in acetone or benzene with an excess of methyl
iodide. The quaternary salt, 6,7-dimethoxyl-1-(3',4',5'- -
trimethoxybenzyl)-2-methyl 3,4-dihydroisoquinolinium iodide,
precipitates out. m.p. = 224.
1 gm ~10 mM) 6,7-dimethoxy-1-(3',4',5'-trimethoxy-
benzyl)2-methyl 3,4-dihydroisoquinolinium iodide is dissolved
in 80 ml H20 and 16 ml concentrated HCl. Zinc dust (1.1 gm)
is added in small portions to the boiling stirred solution.
The yellow color disappears (reaction time 15-20 minutes).
The mixtur~e is filtered hot from some unreacted zinc and
rendered alkaline with concentrated NaOH. It is impractical to
filter the partly precipitated zinc hydroxide, so to avoid
emulsions, the whole mixture is carefully shaken with chloroform.
The residue of the chloroform solution is redissolved in ether
and the ether insolubles are filtered off. The ether residue
does not crystallize on standiny. This amine is a gummy mate-
rial which hardens on standing. The crude amine is used in
the next step.
3. Preparation of ~-(3-chloropropyl)5'-methoxylaudanosinium
bromide
5'-Methoxylaudanosine 1.4 gm = 4 mM is dissolved in
8 ml dimethylformamide by warming slightly. 1-bromo-3-chloro-
propane 1.2 gm (about 100% excess) is added and the mixture
is lef~ at room temperature for 5 days. (Sometimes part of
the unreacted 5'-methoxylaudanosine crystallizes out, but
eventually it redissolves).
- 17 - -
' .
' ~ .

3~
The reddish-orange solution is treated with a large
amount of ether and the precipitated gummy quaternary salt is
decanted and slurried in fresh ether. After standing in ether
for one day, low melting solids are obtained. Yield = 1.6 gm,
about 80% of theory. -
4. Preparation of m-phenylene dipropionic diester of N-propyl
5'-methoxylaudanosine (HH 110 )
(Horenstein - Pahlicke Ester Formation)
- 18 -
~' .

~ . ~ `
:
.
:
o ~ ~ :
~ ~ ~: :
~ : ~ :
10, m~ m~ ;
c) ~ 1; :'-
o=Oy
.
.
.,
m
" o oD , I
N ~ O
m ~ .
O O , "~ ~ -
: :~ . ~ o ~ t: . .
--~ ~ o~ I
m~ e~
. ~ o ~
~<0
o ,~ ~, . ..
o --~ o . .
~ ~ .
,
- 19 -
: '

~31~6
The mixture i5 boiled in an open beaker for about
10-15 minutes, stirring by hand from time to time. At the
boiling temperature the silver salt is slightly soluble and
reacts with the quaternary bromide. ~le mixture is cooled -
to room temperature, filtered straight and the aqueous
solution is evaporated to dryness in ~ large dish on a steam
bath. Continued heating of the residue is don~ for about 2
hours on a steam bath (90C), after which rearrangement to
the ester is complete:
- 20 -
~'

- $~
~ ~ . .
.
o
~ o
~'' ~
~ ~ . I
'' '8 sq~ 8 ~ `
1` , -,'
¦ O m
a~ '
O ' ''
--( ,
o o
~ ~ .
;'':
,~, , .
'+~ + +~
18 18
~ .
I I
O ~ .
_ 21--
,
.
'' ''`

The amorphous residue is boiled with isopropanol
(about 40 ml) and filtered hot from some trace mechanical im-
purities. Gums precipitated from the filtrate at room
temperature and the precipitation is completed at about -3
overnight. The supernatant is decanted and the material is
slurried in ethyl acetate twice. By now the gum is semisolid
and can be filtered off. After careful drying at 75 the gums
become solids. At this stage they still probably retain
water in varying degrees. Yield = 1.0 gm ~about 40%).
Yields vary from batch to batch. M.P. = 80-90 (decomposes).
Analysis %Calculated %Found %
.
C 52.99 5~.22
H 6.46 5.94
N 1.99 2.00
I 18.06 19.38
calculations assume 2H20 per quaternary group.
EXhMPLE 2
Preparation of ~is-3-[N-methyl-1-(3,4,5-trimethoxybenzyl)-
6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolinium)-
propyl p-phenylene-3,3'-dipropionate dichloride
(HH 177)
1. Preparation of silver p-phenylene dipropionate
p-phenylene dipropionic acid 4.4 gm = 40 meq.
purchased from Aldrich
H20 60 ml
KOH lN 40 ml
The mixture is heated to boiling, and, if necessary,
the pH is adjusted to 7.0 with the same acid. AgNO3 6.8 gm =
40 mM is added to the yellow hot solution. Immediately a
heavy precipitate forms. The mixture is cooled and filtered
and the filter cake is washed with water, refiltered and
dried. Yield = quantitative. The product is an amorphous,
~ - 22 -

3q:~6 ~ `
slightly colored powder. It is pulverized for use in the next
step.
2. Preparation of 5'-methoxylaudanosine
'
CH30
' CH30~N
CH2
CH30 3
3,4-dimethoxyphenylethylamine and 3,4,5-trimethoxy-
phenylacetic acid are heated together at 165-190 in a flask
until bubbling of water sub9ides. The product, ~-(3,4,S-
trimethoxylphenylacetyl)homoveratrylamine, is recrystal7;ized
from methanol. Yield - 80%. m.p. 94.
103.9 gm (10 mM N-3,4,S-trimethoxyphenylacetyl)homo-
veratrylamine is-re1uxed ln 15 ml toluQne together with 5 ml
POC13 for 2 hours. qhe settled semisolids are carefully
separated (POC13 excess') and the free base liberated by add-
ing excess of ~aoH and extracted with benzene. ~he product,
6,7-dimethoxy-1-(3',4',5'-trimethoxybenzyl) 3,4-dihydroiso~
quinoline is refluxed in acetone or ~enzene with an excess of
methyl iodide. The quaternary salt, 6,7-dimethox~1-(3',4',S'-
trlmethoxybenzyl)2-methyl 3,4-dihydroisoquinolinium iodide,
precipitates out. m.p. = 224.
1 ym (10 mM) 6,7-dimethoxy-1-(3',4',5'-trimethoxy-
benzyl)2-methyl 3,4-dihydroisoquinolinium iodide is dissolved
in 80 ml H20 and 16 ml concentrated HCl. Zinc dust (1.1 gm)
is added in small portions to the boiling stirred solution.
- 23 -
,~ ' , ' .

~113`~6
The yellow color disappears (reaction time 15-20 minutes).
The mixture is filtered hot from some unreacted zinc and
rendered alkaline with concentrated NaOH. It is impractical
to filter the partly precipitated zinc hydroxide, so to avoid
emulsions, the whole mixture is carefully shaken with chloro-
form. The residue of the chloroform solution is redissolved
in ether and the ether insolubles are filtered off. The ether
residues does not crystallize on standing. This amine is a
yummy material which hardens on standing. The crude amine is
used for the next step.
3. Preparation of N-~3-chloropropyl)5'-methoxylaudanosinium
bromide
CU30 ~ CH2C~2CH2C1 1 ~r~
. CH30/¢ ~; \ CH3
OCH3
5'-Methoxylaudanosine 1.4 gm = 4 mM is dissolved in
8 ml dimethylformamide by warming slightly. 1-bromo-3-chloro
propane 1.2 gm ~about 100% excess) is added and the mixture
is left at room temperature for 5 days. (Sometimes part of
the unreacted laudanosine crystallizes out, but eventually it
redissolves).
The reddish-orange solution is treated with a large
amount of ether and the precipitated ~ummy quaternary salt is
- decanted and slurried in fresh ether. After standing in ether
for one day, low melting solids are obtained. Yield = 1.6 gm,
about 80% of theory.
- 24 ~
,~.'`~ ' , .

4. Preparation of p-phenylene dipropionic diester of N-propyl
5'-methoxylaudanosine ( HH 177) -
(Horenstein - Pahlicke Ester Formation)
`
-
- 25 -
', '

3~6
o~
o~ ~ ~
(~ ~ E
+ ~\ ~ -I ~ Q
C~
o
~ o
`
? ~1 ~
~ o
o=~ ~ o~
o~
~U~ o~
o~ ~ ~ o
;.~
o o
~ ~ ..
C) ` ;~
. .
26- `
. . .
- - ` . - . , ` .. .; . `- - . . ` ~, - . . :-

The mixture is boiled in an open beaker for about
10-15 minutes, stirring by hand from time to time. At the
boiling temperature the silver salt is slightly soluble and
reacts with the quaternary bromide. The mixture is cooled
to r~om temperature, filtered straight and the aqueous
solution is evaporated to dryness in a large dish on a steam
bath. Continued heating of the residue on a steam bath `
(90C) is done for about 2 hours, after which rearrangement
of the ester is complete.
~ - 27 -
: . . . .
,:

P~ m
o o ~ ~ ~
~ mN ~ m~
mN o_ $ ~ $U - C~ \ .
\
+~ ~
oq
l~
s~ ~3
m
~)
c)
m~
- \/U~mr'
$ . .,:
o o
. '~
~, . . .
+ ~.... ..
+~
~ ~ N O
8 m $ ~ ~ m o
u- u~ ~
- 28- :~.
~' :: ' .' , ''.- ' ' .,.; .. ~ - . ' ~ '.'': ' ': '' ': '

L3~
The amorphous residue is boiled with isopropanol
(about 40 ml) and filtered hot from some trace mechanical
impurities. Gums precipitate from the filtxate at room
temperature and the precipitation is completed at a~out -3
overnight~ The supernatant is decanted and the material
is slurried in ethyl acetate twice. By now the gum is semi-
solid and can be filtered off. After careful drying at 75
the gums become solids. At this stage they still probably
retain water in varying degrees. Yield = 1.0 gm (about
40%). Yields vary from batch to batch. M.P. = 80-90%
(decomposes).
EXAMPLE 3
Preparation of Bi s-3-[~-methyl-1-(3,4-dimethoxybenzyl)6,7-
dimethoxy-1,2,3,4-tetrahydroisoquinolinium)
propyl p-phenylene-3,3'-dipropionate dichloride.
( HH 121)
1. Preparation of silver p-phenylene dipropionate
p-phenylene dipropionic acid 4.4 gm = 40 meg.
purchased f~om Aldrich
H20 60 ml
KOH lN 40 ml
The mixture is heated to boiling, and, if necessary,
the pH is adjusted to 7.0 with the same acid. Ag~O3 6.8 gm =
40 mM is added to the yellow hot solution. Immediately a heavy
precipitate forms. ~he mixture is cooled and filtered and the
filter cake is washed with water, refiltared and dried. Yleld =
quantitative. The product is an amorphous, slightly colored
powder. It is pulverized for use in the next step.
2. Preparation of N-~3-chloropxopyl)(laudanosinium bromide):
~ - 29 -

~L3~
~'H30
CH2CH2CH2Cl B~
. fH2
¢~ OCH3
OCH3
Laudanosine tAldrich) 1.4 gm = 4 mM is dissolved in
8 ml dimethylformamide by warmlng slightly. l-bromo-3-chloro-
propane 1.2 gm tabout 100% excess) is added and the mixture is
left at room temperature for S days. (Sometimes part of the
unreacted laudanosine crystallizes out, but eventually it
redissolves).
The reddish-orange solution is treated with a large
amount of ether and the precipitated gummy ~uaternary salt is
decanted and slurried in fresh ether. After standing in ether
for one day, low melting so1ids are obtained. Yield = 1.6 gm,
about 80% of theory.
3. Preparation of p-phenylene dipropionic diester of ~
propyllaudanosine (HH121) ~ ;;
(Horenstein - Pahlicke Ester Formation)
'. ' ' `, :
'~';~,' '" '
'
- 30-

r-t t~
. .
~ ~ .
O O
(~ O
mN
~ .
O=U
~ .
U ~ CO O
~ t ~1 0 ~t
ml
~ ~rt
=[~
_ _ o
rt
O O
~1 - 31 -

The mixture is boiled in an open beaker for about
10-15 minutes stirring by hand from time to time At the ! -
boiling temperature the silver salt is slightly soluble and
reacts with the quaternary bromide. The mixture is cooled
to room temperature, filtered straight and the aqueous ~ -
solution is evaporated to dryness in a large dish on a
steam bath. Continued heating of the residue is done for
about 2 hours, after which the rearrangement to the ester
iB complete.
:. '
,
:.....
`,' '' ''`
~ - 32 -
- ' , ' . ~ . , ' , ~
.. .. ~ .

o o ~ ~
~/ \) u o o
u ~ :
lo ",N N~ N ~N o ~
+,~
a~ ..
~ ~ ' " .
U ~ ::
.
,.
~ X '
\ / / ~ ~ ~
~
' '
O O
+
:', ' '
o ~ ~ ~ ~ ~ lo :.
g~ '''~'~
_ 33 -- :
' . ~ : : ' ' '

The amorphous residue is boiled to isopropanol
(about 40 ml) and filtered hot from some trace mechanical
impurities. Gums precipitate from the filtrate at room -
temperature and the precipitation is completed at about -3 -
overnight. The supernatant is decanted and the material
is slurried in ethyl acetate twice. By now the gum is semi- `
solid and can be filtered off. After careful drying at 75
the gums become solids. At this stage they still probably
retain water in varying degrees. Yield = 1~0 gm (a~out
40%)~ Yields vary from batch to batch. M.P. = 80-90
(decomposes)
ANALYSIS: CALCULATED % FOUND Q/O
C 53.57 53.62
H 6.44 6.06
N 2.08 2.10
I 18.87 18.87
Calculations assume 2H20 per quaternary group
EXAMPLE 4
Preparation of sis-3-(N-methyl-1-(3,4-dimethoxybenzyl)
6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolinium)
propyl m-phenylene-3,3'-dipropionate dichloride.
(HH35)
1. Preparation of silver m-phenylene dipropionate
m-phenylene dipropionic acid 4.4 gm = 40 meq.
purchased from Aldrich
H20 60 ml
KOH lN 40 ml
The mixture is heated to boiling, and, if necessary,
the pH is adjusted to 7.0 with the sam~ acid. A~NO3 6.8 gm =
40 mM is added to the yellow hot solution. Immediately a
heavy precipitate forms. m e mixture is cooled and filtered
and the filter cake is washed with water, refiltered and dried.
~ 34
- ~ `~ . . ,

Yield = quantitative. The product is an amorphous, slightly
colored powder. It is pulverized for use in the next step.
2. Preparation of 3-chloropropyl laudanosinium bromide:
~ 2CH2CH2Cl ~ ;
OCH3
OCH3 , ;
. .
Laudanosine (Aldrich ) 1.4 gm = 4 mM is dissolved in
8 ml dimethylformamide by warming slightly. l-bromo-3-chloro-
propane 1.2 gm tabout 100% excess) is added and the mixture
i~ left at room temperature for 5 day~. tSometimes part of
the unreacted laudanosine crystallizes out, but eventually
it redissolves).
The reddish-orange solution is treated with a large
amount of ether and the precipitated qummy quaternary salt lS
decanted and slurried in fresh ether. After standing in ether
for one day, low melting solids are obtained. Yield = 1.6
gm, about 80% of theory~
3. Preparation of m-phenylene dipropionic diester of N-propyl
laudanosine tHH35)
Horenstein - Pahlicke Ester Formation)
~:
- 35 -
!
,

`: :
o
~{~
~ ~ : :
o=o
o ~ ~

'a O
o~
(~U{~O 1'~7PION
~< ,
o~ ~
-- 36 -- :

:: :
$~
The mixture is boiled in an open beaker for about
10-15 minutes, stirring by hand from time to time. At the
boiling temperature the silver salt is slightly soluble and
reacts with the quaternary bromide. The mixture is cooled
to room temperature, filtered straight and the aqueous
solution is evaporated to dryness in a large dish on a steam
bath. Continued heating of the residue is done for about 2
hours on a steam bath at 90C, after which the rearrangement ~ --
to the ester is complete:
-- .
~ - 37 -

J--o
~ ~ .
.
- 10 ~ X~_OO \ ~ `
\ ~
+ ~,~ -. .-`
, ~ ~ ; .
+~
~ U~ ` ~ .,
.
`
.
\ / : -
~$
o o
C) ~ ,
I
+ . "
oO ~ , : .
_ 38- ~:
.
~: : , :. : `
`` , . . ': '

3~
The amorphous residue is boiled with isopropanol
(about 40 ml) and filtered hot from some trace mechanical
impurities. Gums precipitate from the filtrate at room
temperature and the precipitation is completed at about -3
overnight. The supernatant is decanted and the material is
slurried in ethyl acetate twice. By now the gum is semi-
solid and can be filteréd off. After careful drying at 75
the gums become solids. At this stage they still probably
retain water in varying degrees. Yield = 1.0 gm (about
40%). Yields vary from batch to batch. M.P. = 80-90
(decomposes).
EXAMPLE 5
Preparation of Bis-3-[N-methyl-1-(3,4-dimethoxybenzyl)5,6,7-
trimethoxy-1,2,3,4-tetrahydroisoquinolinium]
propyl p-phenylene-3,3'-dipropionate dichloride
(LL37)
1. Preparation of silver p-phenylene dipropionate
p-phenylene dipropionic acid 4.4 gm = 40 mEq
H20 60 ml
KOH lN 40 ml
The mixture is heated to boiling, and, if necessary,
the pH is adjus`ted to 7.0 with the same acid. AgNO3 6.8 gm =
40 mM is added to the yellow hot solution. Immediately a
heavy precipitate forms. The mixture is cooled and filtered
and the filter cakeCis cooled and filtered and the filter cak~
is washed with water, refiltered and dried. Yield =
quantitative. The product is an amorphous, slightly colored
powder. It is pulverized for use in the next step.
2. Preparation of S-Methoxylaudanosine (N-methyl-1-(3,4-
dimethoxybenzyl)S,6,7-trimethoxy-1,2,3,4-
tetrahydroisoquinoline)
- 39 -

$~
. .
CH O
C~30~
C 3
C 2
''.
~ .. ,'. '
C 3
OCH3
2,3,4-trimethoxyphenylethylamine and 3,4-dimethoxy-
phenylacetic acid are heated together at 165-190 in a flask
until bubbling of water subsides. The~product, ~-(3,4-di-
methoxyphenylacetyl)-2,3,4-trimethoxyphenylethylamine, is
recrystallized from methanol. Yield = 80%. m.p. = 101.
3.9 gm (10 mM) N-~3,4-dimethoxyphenylacetyl~-2,3,4-
trimethoxyphenylethylamine is refluxed in 15 ml toluene
together with S ml POC13 for 2 hours. ~The settled semisolids
are carefully separated (POC13 excess!) and the free base
llberated by adding excess of ~aOH and extracted with benzene.
The product, 5,6,7-trimethoxy-1-(3',4'-dimethoxybenzyl)3,4-
;~ dihydrolsoquinoline,~is refluxed in acetone or benzene with an
excess of methyl iodide; The quaternary salt, 5,6,7-tri-
methoxy-1-(3',4'-dimethoxybenzylj2-methyl 3,4-dihydroiso-
quinolinium iodide, precipitates out~ m.p. = 165.
1 gm (10 mM) !5,6,7-trimethoxy-1-(3',4'-dimethoxy-
benzyl)2-methyl 3,4-dihydroisoquinolinium iodide is dissolved ~-
,
in 80 ml H20 and 16 ml concentrated HCl. Zinc dust (1.1 gm)
20 is added in small portions to the boiling stirred solution.
The yellow color disappears (reaction time 15-20 minutes).
~ - 40 -
.

,~6 , .
The mixture is filtered hot from some unreacted zinc and
rendered alkaline with concentrated NaOH. It is impractical to
filter the partly precipitated zinc hydroxide, so to avoid
emulsions, the whole mixture is carefully shaken with chloro-
form. The residue of the chloroform solution is redissolved t
in ether and the ether insolubles are filtered off. The ether
residue does not crystallize on standing. This amine is a
gummy material which hardens on standing. The crude amine is
used in the next step.
3. Preparation of ~-(3-chloropropyl)5-methoxylaudanosinium
bromide
5-methoxylaudanosine 1~4 gm = 4 mM is dissolved in
8 ml dimethylformamide by warming slightly. 1-bromo-3-chloro-
propane 1.2 gm (about 100% excess) is added and the mixture
is left at room temperature for 5 days. (Sometimes part of
the unreacted 5-methoxylaudanosine crystallizes out, but
eventually it redissolves).
The reddish-orange solution is treated wlth a large
amount of ether and the precipitated gummy quaternary salt
is decanted and slurried in fresh ether. After standing in
ether for one day, low melting solids are obtainèd. Yield =
1.6 gm, about 80% of theory.
4. Preparation of p-phenylene dipropionic diester of ~-propyl
5-methoxylaudanosine (LL37)
(Horenstein-Pahlicke Ester Formation)
- 41 -
~1

.':``.
O
N
m
oo ~ :
U ~
N C.) N
U ~ , . !,
O Y C) O
N~ O
mN ~ O
o OU ' ~ : .''
~ ~, a,
D~
o $~ o~ ~ ~ mN
~<
o o
- 42 -

3~
The mixture is boiled in an open beaker for about 10-
15 minutes, stirring by hand from time to time. At the boiling
temperature the silver salt is slightly soluble and reacts with
the quaternary bromide. me mixture is cooled to room
temperature, filtered straight and the aqueous solution is
evaporated to dryness in a large dish on a steam bath. Con-
tinued heating of the residue is done for about 2 hours on a
steam bath (90C), after which rearrangement to the ester is
complete.
- 43 -
.

~3~
1 ' `
.
N ~m~
v ~ ~
10 N N~3 N N O \
m ~ 7
N O
\/ Q) I
tm~
N
+,~, + +,~
I t~ I ' I
O~m
-- 44 -- .
.

The amorphous residue is boiled with isopropanol
(about 40 ml) and filtered hot from some trace mechanical
impurities. Gums precipitate from the filtrate at room
temperature and the precipitation is completed at about
-3 overnight. The supernatant is decanted and the mate-
rial is slurried in ethyl acetate twice. By now the gum
is semisolid and can be filtered off. After careful drying
at 75 the gums become solids. At this stage, they still
probably retain water in varying degrees. Yield = 1.0 gm
~about 40%). Yields vary from batch to batch. m.p. =
80-90 (decomposes).
EXAMPLE 6
Preparation of Bis-3-[N-methyl-1-(3,4,5-trimethoxybenzyl)5,6,7-
trimethoxy-1,2,3,4-tetrahydroisoquinolinium]propyl
p-phenylene-3,3'-dipropionate dichloride (KK194)
1. Preparation of silver p-phenylene dipropionatê
p-phenylene dipropionic acid 4.4 gm = 40 mEq
H20 60 ml
KOH lN 40 ml
The mixture is heated to boiling, and, if necessary,
the pH is adjusted to 7.0 with the same acid. AgNo3 6.8 gm = ~-~
40 mM is added to the hot solution. Immediately a heavy
precipitate forms. The mixture is cooled and filtered, and
the filter cake is washed with water, refiltered and dried. `
Yield = quantitative. The product is an amorphous, slightly
colored powder. It is pulverized for use in the next step.
2. Preparation of 5,5'-dimethoxylaudanosine
- 45 -
'.
.
' ." : , :

3L~IL~3~6
OCH3
CH30 ~ CH3
CH2
CH30 ~ OCH3
2,3,4-dimethoxyphenylethylamine and 3,4,5-tri-
methoxyphenylacetic acid are heated together at I65-190 in
a flask until bubbling of water subsides. The product, N-~3,- ;;
4,5-trimethoxyphenylacetyl)-2,3,4-trimethoxyphenylethylamine,
is recrystallized from methanol. Yield = 80%. m.p~ = 85.
3.9 gm (10 mM) N-(3,4,5-trimethoxyphenylacetyl)-
2,3,4-trimethoxyphenylethylamine is refluxed in 15 ml toluene
together with 5 ml POC13 for two hours. The settled semi-
solids are careEully separated tPocl3 excess') and the free
base liberated by adding excess of NaOH and extracted with
benzene. The product, 5,6,7-trimethoxy-1-(3',4',5'-tri-
methoxybenzyl)-3,4-dihydroisoquinoline, is refluxed in
acetone or benzene with an excess of methyl iodide. m e
quaternary salt, 5,6,7-trimethoxy-1-(3',4',5'-trimethoxybenzyl)-
~2-methyl-3,4-dihydroisoquinolinium iodide, precipitates out.
m.p. = 181
1 gm (10 mM) 5,6,7-trimethoxy-1-(3',4',5'-trimethoxy-
benzyl)-2-methyl-3,4-dihydroisoquinolinium iodide is dissolved
in 80 ml H20 and 16 ml concentrated HCl. Zinc dust tl-1 gm) is
added in small portions to the boiling stirred solution. The
yellow color disappears (reaction time 15-20 minutes~. The
- 46 -
,

3~
mixture is filtered hot from some unreacted zinc and rendered
alkaline with concentrated NaoH. It is impractical to filter
the partly precipitated zinc hydroxide, so to avoid emulsions,
the wholemixture is carefully shaken with chloroform. The
residue of the chloroform solution is redissolved in ether and
the ether insolubles are filtered off. The ether residue does
not crystallize on standing. This amine is a gummy material -
which hardens on standing. The crude amine is used in the ~-
next step.
3. Preparation of ~-(3-chloropropyl)5,5'-dimethoxylaudano- -
sinium bromide `~
5,5'-dimethoxylaudanosine 1.4 gm = 4 mM is dissolved
in 8 ml dimethylformamide by warming slightly. 1-bromo-3-
chloropropane 1.2 gm (about 100% excess) is added and the
mixture is left at room temperature for 5 days. (Sometimes
part of the unreacted S,5'-dimethoxylaudanosine crystallizes
out, but eventually it redissolves).
The reddish-orange solutio~ is treated with a large
; amount of ether and the precipitated gummy quaternary salt is
decanted and slurried in fresh ether. After standing in ether
for one day, low melting solids are obtained. Yield = 1.6
gm, about 80% of theory.
4. Preparation of p-phenylene dipropionic diester of ~-
propyl 5'-methoxylaudanosine (KK194)
(Horenstein-Pahlicke Ester Formation~
_ 47 _ -

o ~ :,
'~' ~ o~
~$~
_ t~ p O
O ~,
o = ~ ~
'
,~
C~ o
u a ~,
O ~O n~ .QI
U~ ~
N
O r~
~I :
- 48 -
,~ ~
. . . .
' ~ ' " ' '

L3~
The mixture is boiled in an open beaker for about
10-15 minutes, stirring by hand from time to time. At the
boiling temperature the silver salt is slightly soluble and
reacts with the quaternary bromide. The mixture is cooled
to room temperature, filtered straight and the aqueous
solution is evaporated to dryness in a large dish on a
steam bath. Continued heating of the residue is done for
about 2 hours on a steam bath (90C), after which rearrange- ~ -
ment to the ester is complete.
- 49 -
~i
~ . '

~:IL~6
+~ . :
. ~ .
a~ o O
m
to, ~_~, m~ 8 '~
, I
,,
~N m
~ ~ ~, ` o
m~ ~ ~
~) o a~
m~ ~
o o
c
I _ ~ u
+ : : ~
+
8 Ig ~;
m~ D
-- 50 --
`

EXAMPLE 7
Pharmaceutical formulation (HH 110) is dissolved in
water for injection to a concentration of 10 mg/ml. The
solution is then poured into 20 ml vials which are then
sealed.
EXAMPLE 8
Sterile (HH 110) powder (100 mg) is aseptically
packaged in 20 ml vials sealed with a rubber-stopper. Ten ml
sterile water for injection is added to the vials in order to
produce a 1 per cent (10 mg/ml) solution of (HH 110).
EXAMPLE 9 ;;
The compounds HH 110, HH 177, HH 121, and HH 35 were
each separately dissolved in 0.9 per cent saline at a con-
centration of 2 mg/ml. Cynomolgue monkeys are anesthetized ~`
with halothane, nitrous oxide and oxygen. The maintenance
concentration of halothane was 1.0%. ~rterial and venous
catheters were placed in the femoral vessels for drug
administration and recording of the arterial pressure.
Controlled ventilation was accomplished via an endotrachael
tube. Twitch and tetanic contractions of the tibialisarterior muscle were elicited indirectly via the sciatic
nerve. Recordings of arterial pressure electrocardiogram
(lead I), heart rate, and muscle function were made
simultaneously.
EX~MPLE 10
Bis-3-[~-methyl-1-(3,4,5-trimethoxybenzyl)-6,7-
dimethoxy-1,2,3,4-tetrahydroisoquinolinium]propyl m-phenylene-
3,3'-dipropionate dimesylate is prepared in an ion exchange
reaction by reacting HH 110 with silver mesylate. The di-
chloride HHllO is dissolved in acetonitrile as is the silvermesylate. The reaction mixture is stirred at room temperature
for 30 minutes to form the silver chloride precipitate. ~he
- 51 -

q~ ~
mixture i9 filtered through filter paper to remove the silver
chloride thereby leaving the mesylate salt in solution. m e
acetonitrile is then evaporated.
The product is then dissolved in ethanol and
filtered to remove residual silver mesylate. The ethanol is
then evaporated.
EXAMPLE 11
Preparation of bis-3-[~-methyl-1-(3,4,5-trimethoxybenzyl)-
6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolinium]propyl-m-
phenylene-3,3'-dipropionate diiodide tetrahydrate.
N-(3-hydroxypropyl)-5'-methoxylaudanosinium iodide,
3.2 g, was dissolved in dry acetonitrile and 4 g of molecular
sieve 14, was added. After stirring for 24 hours at room
temperature m-phenylene dipropionyl dichloride rprepared by
action of thionyl chloride on the known m-phenylene dipro-
pionic acid, F. S. Kipping, J. Chem. Soc., 53, 21 (1888)~,
0.78 g, was added followed by another 4 g of molecular sieve
14'. The mixture w`as s~irred for 24-48 hours at room
temperature, filtered and evaporated to dryness giving a
dark brown oil which was dissolved in hot ethanol and re-
precipitated as a light brown oil by cooling. m e oil
solidified to a light brown amorphous solid after drying.
60% yield was obtained.
This procedure was also used to prepare reIated com-
pounds by substituting para-phenylene dipropionyl dichloride
for the meta isomer and N-(3-hydroxyprolaudanosinium iodide
for the 5'-methoxylaudanosinium iodide.
EXAMPLE 12
Preparation of ~-(3-hydroxypropyl)-5'-methoxylaudanosinium
iodide
One gram of 5'-methoxylaudanosine [J. Russell Flack,
L. L. Miller and F. R. Stermitz - Tetrahedron, 30, 931 (1974)]
~ - 52 -

~3~9~
in 20 ml. of dry acetonitrile was refluxed with `1.2 g of 1-
iodo-3-propanol [S. Wawzonek, J. Org~ Chem., 25, 2068
(1960)] for 24 hours. The mixture was filtered; solvent
was evaporated under vacuum and ether was added to pre-
cipitate a yellow oily solid. After decanting the ether
and drying at 60 a yellow powder was obtained in
quantitative yield.
The same procedure was used to prepare N-(3-
hydroxypropyl)laudanosinium iodide. -
EXAMPLE 13
1,2,3,4-tetrahydroisoquinolines
m ese compounds were prepared by cyclodehydration
of ~-phenylethylamides to 3,4-dihydroisoquinolines which were
quaternized with CH3 and then reduced by Zn in hot HCl to the
corresponding 1,2,3,4-tetrahydroisoquinolines.
For example, laudanosine [1-(3,4-dimethoxybenzyl)-
2~methyl-1,2,3,4-tetrahydroisoquinoline] was prepared in the
following manner: 3,4-dimethoxyphenylethylamine (Aldrich)
(100 mM) was mixed with 3,4-dimethoxyphenylacetic acid
(Aldrich)(100 mM) and heated at 190-200 until bubbling
stops (20 minutes). The product (homoveratroylhomoveratryl-
amine) is cooled and recrystallized from methanol. Yield =
85%. m.p. = 122. Homoveratroylhomoveratrylamine (100 mM)
was mixed with 250 ml toluene and 50 ml POC13 and heated to
boiling for 2 hours, then cooled to room temperature. The
crystalloid precipitate was filtered, rinsed with petroleum
ether, dissolved in water, rendered alkaline with excess of
~H3 and extracted with benzene. The solution was then dried
with sodium sulfate, filtered, and excess methyl iodide was
added. The solution was refluxed for 15 minutes, and then
left to stand at room temperature for twelve hours. The
~ - 53 -

a~
quaternary salt, dihydropapaveris methiodide, precipitates
out. 100 mM of this quaternary salt is then reduced by boil-
ing with 12 gm zinc dust in 600 ml water and 120 ml con-
centrated hydrochloric acid for one hour, and filtered hot
to remove unreacted zinc. Excess ammonia is then added and
the product is extracted with chloroform. The chloroform is
then evaporated and the product (laudanosine) is extracted
with petroleum ether, from which it crystallizes on cooling.
m.p. = 114-115.
By an analogous procedure to that described above
for the synthesis of landanosine, the corresponding benzyl-
isoquinoline may be prepared from the analogous starting
materials. For example:
3,4-dimethoxyphenylethylamine and 3,4,5-tri-
methoxyphenylacetic acid (to yield 5'-
methoxylaudanosine);
2,3,4-trimethoxyphenylethylamine and 3,4-
dimethoxyphenylacetic acid (to yield 5-
methoxylaudanosine,
3,4,5-trimethoxyphenylethylamine (mescaline)
and 3,4 dimethoxyphenylacetic acid (to yield
8-methoxylaudanosine),
2,3,4-trimathoxyphenylethylamine and 3,4,5-
trimethoxyphenylacetic acid (to yield 5,5'-
dimethoxylaudanosine);
3,4,5-trimethoxyphenylethylamine and 3,4,5-
trimethoxyphenylacetic acid (to yield 8,5'- -
dimethoxylaudanosine).
The above compounds are then reacted as in Methods
1 to 4 to prepare the compounds of this invention.
- 54 -

~ L3~
As shown in Table 1, four to six animals received
each compound. Four additional animals received succinyl-
choline chloride or d-tubocurarine chloride as controls. The
chart shows the dose range required to produce 95 per cent
block of the twitch response of the tibiolis anterior muscle
under above anesthetic conditions in each series of animals
receiving each drug. Also listed in the chart is the range
of the duration of action of each compound in each series of
animals. Duration of action is defined as the time span from
drug injection to full recovery of the twitch response of
the tibialis anterior muscle.
The duration of action of these compounds in monkeys
is more indicative of the possible duration of action of
the compounds in man than studies done in other species, such
as the cat and dog, for the following reason: the compounds
are believed to be broken down (hydrolyzed) by an enzyme
(plasma cholinesterase) present in man, monkey, cat and dog.
The rate of breakdown of any compound by this enzyme is
believed to be the principal determinant of its duration
of action in the body. The plasma cholinesterase activity
of the monkey is known to be most similar to that of man
((c.f. Hobbiger and Peck, British Journal of Pharmacology
37: 258-271, 1969).
.
~ - 55 -
. : . . .. ,:

3~
TABLE 1
-
NEUROMUSCULAR BLOCKr~G POTENCY OF SELECTED
COMPOUNDS I~ THE CYNOMOLGUS MONKEY
. _ . .
COMPOUND NUMBER OF HD95* RANGE OF DURATION
ANIMALS (MG/KG OF ACTION (MINUTE
TESTED CATION) FROM INJECTIO~ TO
FULL RECOVERY)
_
HH 110 6 0.5 - 1.0 5 - 8
HH 177 4 0.5 - 1.0 8 - 12
HH 121 6 2.0 - 4.0 4 - 6
HH 35 4 2.0 - 4.0 3 - 5
Succinyl-
choline 4 1.0 - 2.0 4 - 6
d-Tubo-
curarine 4 0.2 - 0.4 30 - 50
l ~
*HD95 means the dose necessary to produce 95 per cent block
of the twitch response of the t:ibialis anterior muscle
stimulated indirectly at 0.15 HZ via the sciatic nerve.
- 56 -
~a :
. ~, .
" ' '