Neuromuscular relaxants

Details Neuromuscular relaxants Neuromuscular relaxants

1999-10-25

2001-08-14

Davis, Zinna Northington (Department: 1612)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

C514S530000, C514S531000, C514S532000, C514S533000, C514S534000, C514S546000, C514S547000, C560S088000

Reexamination Certificate

active

06274623

ABSTRACT:

FIELD OF INVENTION
This invention relates to compounds useful as muscle relaxants. In one of its more particular aspects, the invention relates to a series of alkoxy- and acyloxy-substituted aralkyl and aralkenyl bis quaternary ammonium derivatives of cyclic alkanol diesters. This invention also relates to methods for the preparation and use of such compounds as muscle relaxants and to pharmaceutical compositions containing such compounds.
BACKGROUND OF THE INVENTION
During surgery it is preferred that the muscles of the patient be as relaxed as possible. Although general anesthesia renders the patient unconscious, it only rarely provides sufficient skeletal muscle relaxation. A variety of muscle relaxant agents, also known as neuromuscular blocking agents, are used for muscle relaxation during surgery. One muscle relaxant used frequently in the past is succinylcholine, which has a very rapid onset and short duration of clinical action. However, succinylcholine elicits muscle membrane “depolarization” which makes this compound less desirable. Furthermore, it may produce serious side effects.
Several other so called “non-depolarizing” muscle relaxants are known and used in anesthesia and surgery. These chemically diverse non-depolarizing muscle relaxants include, among others: tubocurarine, pancuronium, atacurium, cisatacurium, vecuronium, mivacurium and rocuronium. The common structural feature of these compounds is one or usually two quaternary nitrogen atoms. They are all clinically acceptable because they produce only milk or no side effects. However, their onset of action is too slow and their duration of action is too long. Thus, these agents, without exception, fall short of the requirements of an “ideal” surgical muscle relaxant.
Hungarian Patent No. 142,597 issued on Sep. 15, 1955, discloses a series of compounds having a pair of tropine moieties bound by an ester linkage to an aliphatic or aromatic diacid. The nitrogens on both tropines are quaternized with alkyl or unsubstituted or monosubstituted benzyl groups.
Certain naturally occurring alkaloids consist of dicarboxylic acid esters of azabicyclo alkanols, such as belladonnine, which is a bis tropinester, and thesine, which is a bis oxymethyl pyrrolizidine ester. Only the ethyl quaternary derivative of belladonnine and the methyl quaternary derivative of thesine have been reported as muscle relaxants.
Some other neuromuscular blocking agents that include pairs of quaternary nitrogens as part of a tropane ring system have been reported in the literature. In these compounds tropinyl moieties are joined by bridging the two quaternary nitrogens. U.S. Pat. No. 2,746,964 (1953) discloses dicarboxylic acid esters of 3-piperidinol and their alkyl quaternary derivatives.
It is an object of the present invention to provide new and improved muscle relaxants which are characterized by very rapid onset and short duration of neuromuscular blocking action.
SUMMARY OF THE INVENTION
In our research for the “ideal” muscle relaxant we have discovered that in general, di- or poly- alkoxy- or acyloxy-substituted aralkyl and aralkenyl quaternary ammonium derivatives of cyclic aminoalkanol diesters either exhibited less side effects such as decreased blood pressure and increased heart rate or greater potencies than other agents with alkyl, unsubstituted aralkyl, or monosubstituted aralkyl quaternary groups. In particular, such alkoxy- and acyloxy-substituted aralkyl and aralkenyl quaternary derivatives of cyclic aminoalkanol diesters were much more rapidly and shorter acting than any “nondepolarizing” muscle relaxant compound hitherto known. This discovery was entirely unexpected and unpredicted and thus forms the basis of this invention.
This invention consists of a series of di- or poly-alkoxy- or acyloxy-substituted aralkyl and aralkenyl bis-quaternary ammonium derivatives of cyclic alkanol esters of dicarboxylic acids as neuromuscular relaxants, methods of making and using them, and pharmaceutical compositions containing them.
The first aspect of this invention is a group of compounds 1/a, having the general formula illustrated below:
A second aspect of this invention is a group of compounds 1/b, having the general formula illustrated below:
A third aspect of this invention is a group of compounds 1/c, having the general formula illustrated below:
where A is alkanedicarbonyl, alkenedicarbonyl, alkynedicarbonyl, cycloalkanedicarbonyl, cycloalkenedicarbonyl, bicycloalkanedicarbonyl, bicycloalkenedicarbonyl, polycycloalkanedicarbonyl, polycycloalkenedicarbonyl, aromatic dicarbonyl, substituted alkanedicarbonyl, substituted alkenedicarbonyl, substituted alkynedicarbonyl, substituted bicycloalkanedicarbonyl, substituted bicycloalkenedicarbonyl, or substituted aromatic dicarbonyl; R
1
and R
2
′ are di- or polysubstituted aralkyl or aralkenyl in which at least one of the substituents is alkoxy or acyloxy; R
2
and R
2
′ are alkyl or alkenyl; n is 0, 1, or 2; m is 0, 1, or 2; p is 0, 1, or 2; R
3
and R
3
′ are H, CH
3
, or lower alkyl; R
4
and R
4
′ are H, CH
3
,or lower alkyl; R
3
and R
4
can also be -(CH
2
)
8
-, -CH=CH-, -CH
2
)
h
-O-(CH
2
)
k
-, -epoxy-, or -(CH
2
)
h
-S-(CH
2
)
k
-, where g is 2, 3, 4, or 5, h is 1 or 2, and k is 1 or 2; and R
3
′ and R
4
′ can also be -CH
2
)
g
0
, -CH=CH-, -(CH
2
)
h
-O-(CH
2
)
k
-,
or -(CH
2
)
h
-S-(CH
2
)
k
-, where g is 2, 3, 4, or 5, h is 1 or 2, and k is 1 or 2; X is a pharmaceutically acceptable anion; R
1
and R
1
′ can be the same or different; likewise R
2
and R
2
′, R
3
and R
3
′, and R
4
and R
4
′ can be the same or different.
A fourth aspect of this invention is the method of use of the compounds of the general folmulae 1/a-1/b as neuromuscular relaxants.
A fifth aspect of this invention is a pharmaceutical composition, including the compounds of general formulae 1/a-1/c and a pharmaceutically acceptable excipient.


REFERENCES:
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patent: 3275679 (1966-09-01), Brotherton et al.
patent: 5494898 (1996-02-01), Cheng et al.
patent: 5990124 (1999-11-01), Gyermek et al.
patent: 3727915 (1958-03-01), None
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patent: 1287588 (1969-01-01), None
patent: 1933478 (1971-01-01), None
patent: 1770183 (1971-09-01), None
patent: 886183 (1962-01-01), None
patent: 1398050 (1975-06-01), None
patent: 142597 (1951-12-01), None
patent: WO81/01710 (1981-06-01), None
patent: WO96/97410 (1996-03-01), None
Gyermek et al., “The Pharmacology of Tropane Compounds in Relation to their Steric Structure,”The Journal of Pharmacy and Pharmacology9:209-229 (1957).
Haining et al., “The Neuromuscular Blocking Properties of a Serial of Bis-Quaternary Tropeines,”Brit. J. Pharmacol., 15:71-81 (1960).
Nador et al., Attempts to Find New Compounds with Curare-Like Effects, Part III. Quaternary Derivatives of Dicarboxylic Tropine Esters,Acta Chimica Hung, pp. 369-374 (1952).

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