Note: Descriptions are shown in the official language in which they were submitted.
409
This invention relates to anesthetic compositions containing
certain bromofluoromethylcyclopropanes.
Although a certain number of hslogenated hydrocarbon compounds,
including some bromocyclopropanes and methylcyclopropanes, have ~oined the
; ranks of useful anesthetics in the recent past, little has been added to the
understanding of the mode of action of chemicals in this physiological role,
so that the relationships of the structural differences between fairly similar
compounds with either their deleterious, inert or therapeutic properties
remain substantially unidentified. At this stage in the art, therefore, the
discovery of additional substances possessing a desirable combination of
physical, chemical and physiological properties for anesthetic purposes still
lies beyond the scope of routine expertise. -
It has now been discovered that four newly synthesized bromo-
fluoremethylcyclopropanes possess high potency as general anesthetics when
administered to inhalation-anesthetic-susceptible organisms. They are:
l-bromo-l-fluoro-2,2-dimethylcyclopropane, 1-bromo-1-fluoro-2,3-dimethyl-
cyclopropane, l-bromo-1,2-difluoro-2-methylcyclopropane and l-bromo-l-fluoro-
2-methylcyclopropane.
Accordingly, the invention provides an anesthetic composition
comprising a compound selected from the group consisting of 1-bromo-1,2-
difluoro-2-methylcyclopropane, 1-bromo-1-fluoro-2,3-dimethylcyclopropane,
l-bromo-l-fluoro-2-methylcyclopropane and 1-bromo-1-fluoro-2,2-dimethylcyclo-
propane, and another inhalation anesthetic compound andtor oxygen.
The compounds which constitute the basis of this invention may be
prepared by any of several methods depending on the availability of starting
materials and on the yield considered acceptable under the circumstances.
These methods ultimately involve a catalyzed cyclization reaction between a
suitable halocarbene (:CYZ) and an appropriate olefinic compound:
:CYZ +>C_C~ > YZ <~
The halocarbene is generated by the decomposition of the appropriate phenyl
- (trihalomethyl) mercury compound, according to the method of D. Seyferth et
,~ s al ~J. Am. Chem. Soc. 87, 4259-70 (1965)~ . However, the actual method
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10;~09
employed in the present instance, as described in the following example, is :an adaptation of a known procedure for the general synthesis of gem~
dihalocyclopropane ~Synthesis 2, 112 (1973)] .
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1038409
Examples 1 to 4
The methylbromocyclopropanes of the invention were prcpared by the
cycli~ation of the carbene :CFBr with an appropriate olefin. The carbene was
prepared in concentrated sodium hydroxide solution from dibromofluoromethane
with the assistance of an ionic salt such as triethylben~ylammonium bromide.
The reactions involved are:
R4NX + OH -~R4NOH + X (1)
CHFBr2 + R4NoH-~cFBr2R4N + H20 (2)
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CFBr2R4N ~ CFBr + R4NBr (3)
The quaternary ammonium hydroxide formed (1), being insoluble in the reaction
mixture, migrates to the boundary between the aqueous and the organic phases
~ where it reacts with the trihalomethane to yield the quaternary ammonium
derivative of the trihalomethyl anion (2), After diffusion into the organic
phase, the der1vative is transformed (3) into the carbene :CFBr and the
catalyst halide. The carbene then reacts with the olefin to yield a cyclo-
propane. The olefins used in these examples and the products obtained are
listed in Table 1.
In a typical preparation, for instance that of Example 1, 50%
aqueous sodium hydroxide, 125 ml, is placed into a 300 ml stainless steel
autoclave with triethylbenzylammonium bromide, 1.0 g, dibromofluoromethane,
; 0,53 mole, and isobutylene, 0.98 mole. The contents of the autoclave are
stirred at ambient temperature until all the halogenated methane has been
consumed, in this case a period of about 24 hours. The reaction mixture
is then vacuum distilled to collect the organic phase and the distillate
is further refined by redistillation after separation of entrained water
Clear colorless liquid l-bromo-l-fluoro-2,2-dimethylcyclopropane is obtained,
as identified by specific gravity and boiling point (Table 2), in yield of
64% based on the methane.
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; , The olefinic start m ~ material and the product obtained in this and
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~ other examples are listed in the following tablc.
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TABLE I
... . .
PREPARATIQN OF METHYLBRO~SOFLUOROCYCLOPROP~ES
.. . . .
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; Lxo Olef~n Product
Spec~ ~oiling
Yiold* Mol. Wt. Gravity Point
1 Isobutylene 1-nr-l F-2,2-dim~thylcyclopropane
64% 167.0i 1.3~020 C 102C
19
, 2 2-butene 1-Br-l-F-2,3-dimethylcyclopropane
. ` 53% 16?oO4 1.3?520 110~5
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3 Z_fluoro propene 1-Br-1,2-diF-2-methylcyclopropane
- 34% 17~.00 1.S682 90
4 Propylene l-Br-1-F-2-methylcyclopropane ;~
29% 153.01 1.4582 85
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`~ 20 ~These yields are calculatod on dibromofluoromethane basis.
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j The cyclopropanes shown in Table 1 are clear liquids at room
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temperature They can be stored in containers of the type commonly used
for conventional anesthetics of comparable boiling point, e.g. halothane, and
. . ~ .
they can be administered by means of apparatus or machines designed to
~aporize liquid anesthetics and mix them with air, oxygen or other gaseous ~ ;
combinations in proportions capable of supporting respiration.
Examples 5 to 8
The physiological effects of the cyclopropanes prepared in the
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preceding examples were-i-cer~r~ as follows, using a standard test for
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: 1~384~1~9 `
- evaluation of inhalation anesthetics similar to that described in Robbins
[J. Pharmacology and Experimental Therapeutics 86, 197 (1946)].
Mice were exposed to the anesthetics for a period of 10 minutes
in a rotating drum. Observations were then made of the pinch reflex, the
- corneal reflex and the return of the righting reflex. At least four graded
- doses were employed to determine the minimum concentration required to
anesthetize 50% of the mice used (AC50) and the minimum concentration required
to kill 50% of the mice (LC50). The anesthetic lndex (AI) was then calculated
from these minimum concentrations. The results of these tests are summarized
.`'
in the following table.
TABLE 2
ANESTHETIC PROPERTIES OF METHYLBROMOFLUOROCYCLOPROPANES
Ex. Cyclopropane AC50 ` LC50 AI
(% volume)(LC50/AC50)
1-Br-l-F-2,2-dimethyl <1% ~4% ~ 4
. . :
6 1-Br-l-F-2,3-dimethyl '0.53% 2.1-4.2%* 4-8
.. ..
: ~ 7 1-Br-1-2-diF-2-methyl 0.5% 5% lO
8 1-Br-l-F-2-methyl <2% 4 - 6% >2
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` 20 *When two figures are given, the actual value lies between them. ~`
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As these results indicate J four effective anesthetic agents have
been contributed to the art. It is contemplated that the compounds may be
used in admixture with pharmaceutically acceptable diluents and stabilizers
~ such as thymol, or in combination with one or more of the known inhalation
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anesthetics, e.g. nitrous oxide, ether, halothane, chloroform, methoxyflorane
and the like. Other variations can be carried out in either the preparation
or the administration of the compounds to accommodate factors such as, for
instance, economic considerat1ons, level and duration of anesthesia desired
the nature and quantity of auxiliary medication employed, and the subject
treated. Such variations fall within the scope of the present invention. In
103841D9
general, the concentrations to be employed for induction of anesthesia will
: be higher than those necessary to maintain anesthesia. With these considera-
: tions in mind anesthetic compositions containing approximately the following
concentrations of the compounds of general formula (1) are suitable for prac-
tical use.
. .
. Compound I (Ex. 1): 0.4 to 9 percent volume
Compound II (Ex. 2): 0.5 to 5 percent volume
Compound III ~Ex. 3): 0.3 to 10 percent volume
Compound IV (Ex~ 4): 0.4 to 10 percent volume.
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