CA1038409A - Inhalation anesthetic utilizing bromofluoromethyl cyclopropanes - Google Patents
Inhalation anesthetic utilizing bromofluoromethyl cyclopropanesInfo
- Publication number
- CA1038409A CA1038409A CA226,942A CA226942A CA1038409A CA 1038409 A CA1038409 A CA 1038409A CA 226942 A CA226942 A CA 226942A CA 1038409 A CA1038409 A CA 1038409A
- Authority
- CA
- Canada
- Prior art keywords
- bromo
- fluoro
- methylcyclopropane
- compound
- dimethylcyclopropane
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C23/00—Compounds containing at least one halogen atom bound to a ring other than a six-membered aromatic ring
- C07C23/02—Monocyclic halogenated hydrocarbons
- C07C23/04—Monocyclic halogenated hydrocarbons with a three-membered ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
ABSTRACT
The following bromofluoromethylcyclopropanes have been found to possess utility as general inhalation anesthetics: 1-bromo-1-fluoro-2,2-dimethylcyclopropane, 1-bromo-1-fluoro-2,3-dimethylcyclopropane, 1-bromo-1, 2-difluoro-2-methylcyclopropane, and 1-bromo-1-fluoro-2-methylcyclopropane.
The following bromofluoromethylcyclopropanes have been found to possess utility as general inhalation anesthetics: 1-bromo-1-fluoro-2,2-dimethylcyclopropane, 1-bromo-1-fluoro-2,3-dimethylcyclopropane, 1-bromo-1, 2-difluoro-2-methylcyclopropane, and 1-bromo-1-fluoro-2-methylcyclopropane.
Description
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-
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 ~ -1- ''`,~ ~
~, , .
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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-la-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) . .~ .
., ~ . , ~
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.
' - ' ' ~ ~, ' '' ' -, . ., ,, r~
'' ` ` ' ' . 10389~09 , , " ,, ; , The olefinic start m ~ material and the product obtained in this and _. --~ other examples are listed in the following tablc.
. . ~ .
TABLE I
... . .
PREPARATIQN OF METHYLBRO~SOFLUOROCYCLOPROP~ES
.. . . .
- - ,. .
; 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
, 2 2-butene 1-Br-l-F-2,3-dimethylcyclopropane . ` 53% 16?oO4 1.3?520 110~5 r . . - ',.- . ..
. . , , ` ''
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 ~ -1- ''`,~ ~
~, , .
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)] .
. .. .
. .
~: ' ' ~' ,~''" ' ' ' ~'' .
~'.` `~ ' .
. .
' ;, -,. , '.:' ' , : :
;. ' :
.' .
..
,~
o ': . ~,:
,' "`' ~
' ' `,'." ' ~ ~ ' ' , ,' ,, ',':"- -':
:.','^ ' .
'.'~:' '~:
' : -:
-la-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) . .~ .
., ~ . , ~
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.
' - ' ' ~ ~, ' '' ' -, . ., ,, r~
'' ` ` ' ' . 10389~09 , , " ,, ; , The olefinic start m ~ material and the product obtained in this and _. --~ other examples are listed in the following tablc.
. . ~ .
TABLE I
... . .
PREPARATIQN OF METHYLBRO~SOFLUOROCYCLOPROP~ES
.. . . .
- - ,. .
; 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
, 2 2-butene 1-Br-l-F-2,3-dimethylcyclopropane . ` 53% 16?oO4 1.3?520 110~5 r . . - ',.- . ..
. . , , ` ''
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 . ' ' ,. ' ,,','':
.` . ,., ., .~ ~ . , .
`~ 20 ~These yields are calculatod on dibromofluoromethane basis.
''I' , .
j The cyclopropanes shown in Table 1 are clear liquids at room :. ! .: ~ .
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 ,~ Je~n ~rfrat~J
preceding examples were-i-cer~r~ as follows, using a standard test for , ~ .
., ~
. ~'~' : 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.
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 : ' :: ~.
` 20 *When two figures are given, the actual value lies between them. ~`
::
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 `: ~
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 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.
~ ~ .
:
' ' :
,~` :' .. ... . .
-'
29% 153.01 1.4582 85 . ' ' ,. ' ,,','':
.` . ,., ., .~ ~ . , .
`~ 20 ~These yields are calculatod on dibromofluoromethane basis.
''I' , .
j The cyclopropanes shown in Table 1 are clear liquids at room :. ! .: ~ .
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 ,~ Je~n ~rfrat~J
preceding examples were-i-cer~r~ as follows, using a standard test for , ~ .
., ~
. ~'~' : 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.
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 : ' :: ~.
` 20 *When two figures are given, the actual value lies between them. ~`
::
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 `: ~
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 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.
~ ~ .
:
' ' :
,~` :' .. ... . .
-'
5 - :
.. ' .'.
.. ' .'.
Claims (5)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. 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, 1-bromo-1-fluoro-2-methylcyclopropane and 1-bromo-1-fluoro-2,2-dimethylcyclopropane, and another inhalation anesthetic compound and/or oxygen.
2. A composition as claimed in claim 1 wherein the compound is 1-bromo-1,2-difluoro-2-methylcyclopropane.
3. A composition as claimed in claim 1 wherein the compound is 1-bromo-1-fluoro-2,3-dimethylcyclopropane.
4. A composition as claimed in claim 1 wherein the compound is 1-bromo-1-fluoro-2-methylcyclopropane.
5. A composition as claimed in claim 1 wherein the compound is 1-bromo-1-fluoro-2,2-dimethylcyclopropane.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US49976174A | 1974-08-22 | 1974-08-22 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1038409A true CA1038409A (en) | 1978-09-12 |
Family
ID=23986590
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA226,942A Expired CA1038409A (en) | 1974-08-22 | 1975-05-14 | Inhalation anesthetic utilizing bromofluoromethyl cyclopropanes |
Country Status (7)
| Country | Link |
|---|---|
| JP (1) | JPS5126846A (en) |
| AU (1) | AU7911575A (en) |
| CA (1) | CA1038409A (en) |
| DE (2) | DE2510158A1 (en) |
| FR (1) | FR2282264A1 (en) |
| SE (1) | SE7503076L (en) |
| ZA (1) | ZA751613B (en) |
-
1975
- 1975-03-08 DE DE19752510158 patent/DE2510158A1/en active Pending
- 1975-03-14 AU AU79115/75A patent/AU7911575A/en not_active Expired
- 1975-03-14 FR FR7508126A patent/FR2282264A1/en not_active Withdrawn
- 1975-03-14 DE DE19752511166 patent/DE2511166A1/en active Pending
- 1975-03-14 JP JP50030284A patent/JPS5126846A/ja active Pending
- 1975-03-18 SE SE7503076A patent/SE7503076L/en unknown
- 1975-05-14 CA CA226,942A patent/CA1038409A/en not_active Expired
-
1976
- 1976-01-20 ZA ZA00751613A patent/ZA751613B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| SE7503076L (en) | 1976-02-23 |
| DE2511166A1 (en) | 1976-03-04 |
| ZA751613B (en) | 1976-02-25 |
| JPS5126846A (en) | 1976-03-05 |
| DE2510158A1 (en) | 1976-03-04 |
| FR2282264A1 (en) | 1976-03-19 |
| AU7911575A (en) | 1976-09-16 |
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