DE2327901A1 - HALOCYCLOPROPANE - Google Patents

Description

W. R. Grace & Co. (Prio: June 2, 1972

US 259 253 and US 258 957

62 Whittemore Avenue ^{A 21l8rL} " ^1O 363)

Cambridge, Mass./V.St.A. Hamburg, May 28, 1973

Halocyclopropanes

The present invention relates to certain halocyclopropanes ₉ suitable as anesthetics, a process for preparing the same, anesthetic mixtures containing these compounds and a process for anesthetizing mammals and humans using these compounds.

Although some halogenated hydrocarbons are considered suitable Anesthetics have become known, so is their mechanism of action in physiological terms and the context the toxic and therapeutic properties in relation to the differences in the relatively similarly structured compounds Hardly researched »Because of this situation, it is necessary to find further substances with a desired combination of properties for anesthetic purposes outside of any routine work ο

30th

It has now been found that new halocyclopropanes of the following general formula I

X
- Y

in which X is a fluorine atom or a trifluoromethyl radical and Y is a chlorine atom or a methyl radical, where X is a fluorine atom when Y is a chlorine atom, such as, for example, 1-methyll-trifluoromethyl-2,2-difluorocyclopropane, 1-methy1-1 , 2 ₉ 2-trifluorocyclopropane and 1-chloro-1,2,2-trifluorocyclopropane, have excellent effectiveness as a general anesthetic for humans and mammals and can be used as inhalation anesthetics.

The present invention accordingly relates to a method of anesthesia for animals and humans, which is characterized by the fact that the living being is connected to the general Formula I administered.

The compounds can be prepared by reacting a CFp carbene with an olefin by the method of Sargent (J. Org. Cher _{; s} 1970, 35 (3), 678-82). The CF ₂ ~ carbene is obtained by thermal cleavage from kexafluoropropylene oxide; this compound can be relatively easily synthesized as., J. Org Chen, 1966, 3I ₃ 2312 _s is described. The implementation proceeds according to the following scheme:

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CF ₃ CF-CF ₂ O 185 ° C. : CF ₃ + CF ₃ C (O) F

\ / r— 1

: CF ₀ + C = C-> CC-CF ₅

. / AA ²

It must noted v / _s ground that this synthesis does not always yield the desired compound, presumably because in some cases the cyclization does not occur either or are unstable at a cyclization, the obtained cyclic compounds at the carbenerzeugenden temperatures.

The present invention further relates to a process for the preparation of the compound of general formula I by Reacts difluorocarbene with a compound of the general formula II:

CH ₂ = CXY,
in which X and Y have the meaning given above.

The compounds according to the invention are liquid at room temperature; they can be stored in containers that too are used for conventional anesthetics with a comparable boiling point, such as bromochlorotrifluoroethane (Halothanes); these compounds can be administered using conventional anesthetic devices, including liquid ones Anesthetics vaporized and exposed to air, oxygen or others

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Gases that aid the respiration are mixed. The compounds according to the invention can also be used in mixtures with pharmaceutically acceptable diluents or stabilizers such as thymol or in combination used with one or more known inhalation anesthetics such as nitrous oxide, ether, halothane, chloroform and 2 ^ -Dichlor-ljl-difluoroethyl methyl ether (methoxyfluorane).

The invention also relates to an anesthetic mixture, which is characterized in that it is a compound of the general Formula I and another anesthetic compound and / or oxygen in an amount that will stimulate respiration supports. The anesthetic mixture can contain 1 to 25 vol% of the Compound of general formula I contain. With quantities in the lower concentration range, a light one quickly becomes Generates anesthesia, while deep anesthesia is achieved very quickly at higher concentrations.

Other related halocyclopropanes that can be used as anesthetics are in our German patent application .... (file 10362) of May 28, 1973.

In the following, the invention is to be explained in more detail by means of examples, all quantitative data being based on weight relate.

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example 1

45 parts by weight of 2-Pluorpropen and * l6,9 parts by weight of hexafluoropropylene oxide were added in an evacuated autoclave, which had been cooled to -78 ⁰ C. The mixture was heated for 6 hours at 185 ⁰ C »After cooling to room temperature, the autoclave contents were brought to a cold trap of -196 C ^O. The components boiling below room temperature were driven off and. the remainder was purified by preparative vapor phase chromatography. There was obtained 1-methyl-ltrifluoromethy.l ~ 2 _s 2-difluorocyclopropane with a molecular weight of 111, a boiling point of 34 ° C. and a density of djj ° = 1.106 g / ml

Example 2

88.8 parts by weight of 2-trifluoromethylpropene and 7 ^ _s 0 parts by weight of hexafluoropropylene oxide were placed in an evacuated autoclave previously cooled to -78 ° C. and ^{heated in this for 5 »75 hours at 185 °} C. After cooling to room temperature, the autoclave contents were placed in a cold trap -196 ⁰ C brought ο The constituents boiling below room temperature were driven off and the remainder was purified by preparative vapor phase chromatography. It was l-methyl-l _a 2 ₉ 2-trifluorcy.clopropane with a molecular weight of 160 _{s and} a boiling point of 51 ° C

20th
and a density of d ,. - 1 _S 268 g / ml received «

Example 5

1 part by weight of 4-t-butyl-pyrocatechol was placed in a stainless steel autoclave, which was sealed, evacuated, and cooled to -78 ⁰ C. The autoclave was then charged with 80.5 parts by weight of 1-chloro-1-fluoroethylene and 40.3 parts by weight of hexafluoropropylene oxide. The mixture was heated at 185 ° C. for 8 hours. After cooling to room temperature, the autoclave contents were brought to a cold trap of -196 ^0C. The constituents boiling below room temperature were driven off and the remainder was purified by preparative vapor phase chromatography. 1-chloro-lj2 ₃ 2-trifluorocyclopropane with a molecular weight of 130, a boiling point of 31 ° C. and a density of cL = 1 * 358 g / ml was obtained.

Example 4

The physiological effects of these two cyclopropanes were determined as follows using a standard procedure worked for the evaluation of inhalation anesthetics, as it was analogous to Robbins in. J. Pharmacology and Experimental Therapeutica, 19 ^ 6, 86, 197, is described.

In a rotating drum, mice were given the anesthetic for 10 minutes exposed «, Then the reflexes were the Corneal reflexes and the return of the erect reflex were observed.

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At least four set doses were used to determine the minimum concentration to anesthetize 50% of the test animals - the so-called ΑΟ, -Q value - and also to kill the minimum concentration by 50% of the mice - the LD.- value . The anesthesia index (AI) was then calculated from these minimum concentrations. The results of these experiments are summarized in Table I below.

Cyclopropane

Table I.

AC

50 (in Vol5S)

LD ₁

50

AI

I 1-methyl-1-trifluoromethyl-2,2-difluoro-5-10

II 1-Methy1-1,2,2-tri-

fluorine- 3-7.5

III 1-chloro-1,2,2-trifluoro-4

15-20

> 8

1.5-2

> 2

> 2

If two numbers are given, the actual value of the parameter is between these two numbers.

For comparison, a common anesthetic was used, namely the l, l, l-trifluoro-2-bromo-2-chloroethane known under the name halothane used, which had an AI value of 3.2 under the same test conditions. This clearly shows

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that the compounds of the invention are excellent anesthetics of low potency, also as analgesics can be used.

Example 5

The concentration of the compounds was determined in tests, which are practical in mixtures; the fourth are given in Table II below:

Table II concentration
in V0I5S Cyclopropane
link 5-25
5-25
1-10 I.
II
III

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Claims (3)

Expectations / l. / A compound of the general formula I. in which X is a fluorine atom or a tr i fluorine thy Ir es t and Y are a chlorine atom or a methyl radical, where X is a fluorine atom is when .Y is a chlorine atom. 2. Process for the preparation of a compound according to claim characterized in that one has a difluorocarbene with a Compound of the general formula II CH ₂ = CXY
converts, where X and Y have the meaning given above. 3. An anesthetic mixture, characterized in that it comprises a compound according to claim 1 and another anesthetic and / or contains oxygen. ue: kö 309851/1165