DE2157399A1 - ANAESTHETICA - Google Patents

Description

2157339

VY. R. Grace & Co. 62, Whittemore Avenue Cambridge, Massachusetts V. St. Ä.

Hamburg, November 15, 1971

Anesthesia a

The invention relates to substituted cyclobutanes which are suitable as anesthetics, and also to a method for making the same and such connections containing anesthetic mixtures.

As inhalation anesthetics and anesthetics are not available Chloroform only surprisingly few compounds available ;, which is partly due to the fact that the offerings Compounds, such as lower haloalkals, have unpredictable chemical and physiological properties and effects, and that on the other hand the V / ir-

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The mechanism of anesthesia has not yet been finally clarified is. Albeit a few superficial parameters for determining individual necessary properties for good inhalation anesthetics have been established, such as a certain oil / water partition coefficient or the negative influence of fluorine atoms on chlorine, the development of suitable anesthetics goes far beyond routine assessment by chemists and physiologists. For example, cyclopropane is a good non-flammable anesthetic, while one of the higher, water-insoluble homologues, namely cyclopentane, medicinal cannot be used. One up with cyclobutanes The reviewing report in "Larsen Fluorine Chemistry", 1969, 3.J 1 and 34, does not provide any clarification either Respect, because three closely related fluorocyclobutanes are mentioned, of which the 1,2 dihydrohexafluoro compound anesthetic properties, the other, namely the 1,2 dichlorohexafluorocompound toxic and the Octafluorocompound is inactive.

It has now been found that cyclobutanes of the following general formula (I) excellent properties for use as an inhalation anesthetic or inhalation anesthetic and do not lead to convulsions when administered in the usual concentrations and are not fatal:

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- "3ζ".

2157393

in which X is a chlorine atom or a methyl radical and Y is a fluorine or chlorine atom, where X is a methyl radical when Y is a fluorine atom.

The process according to the invention relates to the preparation of cyclobutanes in which a compound of the general formula H ₂ C = CFZ, in which Z Ca) is a fluorine atom or Cb) is a chlorine atom or a methyl radical, with a compound of the general formula Z FC = CFY in which Z Ca) is a chlorine atom or a methyl radical or (b) is a fluorine atom and Y has the meaning given above.

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The reaction can be carried out by the method of Coffman et al., J. Am. Chem. Soc, 19 ^ 9, 7_1, ^ 90. The Kthylenverbindungen be suitably heated in an autoclave to the appropriate temperature of about 200 ⁰ C for about 7 hours under autogenous pressure. After the reaction has ended, the autoclave is cooled and the gaseous substances are evacuated using a cold trap. The residue is distilled and purified by gas phase chromatography on a preparative scale or in another suitable manner. In this way, compounds can be obtained in a high enough purity for anesthetic purposes.

The ethylenically unsaturated compounds suitable for this process are shown in the table below I, along with the physical properties of the final products. The cyclical structure and the number and kind of the substituents on the ring were confirmed by NMR spectrum examination.

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The anesthetic compounds shown in Table I are at room temperature clear liquids that can be stored in the usual containers as they are for Narcotics with a comparable boiling point, for example bromochlorotrifluoroethane (halothane), can be used. she are delivered to the patient with the usual devices with which liquid narcotics evaporate and mixed with air, oxygen or other gas mixtures in amounts necessary to aid respiration. Furthermore, the connections in Mixture with pharmaceutically acceptable diluents or stabilizers, such as thymol, or used in combination with one or more of the known inhalation anesthetics, such as with laughing gas, ether, halothanes, chloroform and 2,2-dichloro-1,1-difluoroethyl methyl ether (Methoxyfluorane).

The invention also relates to an anesthetic mixture which comprises a compound of the general formula I and another anesthetic compound and / or oxygen in an amount suitable to aid respiration

contains. The anesthetic mixture may be from 0.5 - contained 20% by volume of the compound of general formula I, such as 0.5 -. 20 or 0.5 - Ί and 0.5, - 10 VOX. % of the compound I or TI or * III; with lower accounts tions one gets a fleeting and with a higher concentrate i- «n '? n emo deeper anesthesia.

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The physiological effects of the compounds were
investigated on mice, using a standard method of determination for inhalation anesthesia analogous to that of
Robbins in "Pharmacology and Experimental Therapeutics", 19 ^ 6, ^ 6, 197 »methods described. In this determination method, mice were exposed to the compounds in a rotating drum for 10 minutes. Then there were the pinch reflex, the corneal reflex and the
Return to proper reflexes observed.
At least four metered doses were used to provide the minimum concentration to anesthetize 50% of the mice (ACj- ,,) and the minimum concentration

TO

intended to kill 50 % of the mice (LC, -q). The anesthesia width coefficient (AI) was then calculated from these minimum concentrations. As a result, the following results, which are shown in Table II, were obtained
are.

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Table ^ i

End product reaction density boiling part participants, t point ⁰ C

1-chloro-1,2,2, - CP ₂ = CP ₂ 1,568 ²⁰ 55 3,3-pentafluoro- _{+ CFC1 = CH}
cyclobutane 2

II 1,14-DiChIOr-I ^ r ClPC = CP ₂ 1.5 ^ 7 ²⁰ 90.5 2,1-tetrafluor- _r

cyclobutane ^{+ C1FC} - ^CH 2.

III 1-methyl-1,2,2, - P ₂ C = CP ₂ 1.3O3 ²⁴ * ⁵ 67 3,3-pen-tafluoro- _{+ CFCH}

cyclobutane ^d 3

The!, M-dichloro-l ^^^ - tetrafluorocyclobutane can also be prepared by converting ClFC = CP ₂ with vinylidene chloride to! , for example by Pluorierung with Dichlorantimontrifluorid at 150-200 ⁰ C is replaced in a closed vessel.

Table II

Connection AC ₅₀ LC ₅₀ AI

Vol.! "

I 2 % 10 5

II O, 43 ^ 2i? 2-3 1+

III 3 % 6-8 2+

If two percentages are given, the actual gas concentration is between the two Values.

The above data indicate that the compounds are effective narcotics with different security widths. They can all induce an anesthetic state in living things that breathe air, from which the animals recovered readily., provided that the lethal concentration of anesthetic vapors (LC, -q) does not reach will.

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example 1

There were 35.8 g and 0.2 mol of antimony trifluoride, 14.4 g and 0.072 mol of antimony pentachloride and 32.11 g and 0.15 mol of 1,4,4-trichloro-1,2,2-trifluorocyclobutane in a stainless steel cylinder with a capacity of 150 ml ^{heated for 24 hours at 200 0} C under autogenous pressure. After cooling and venting, the volatile liquids were removed by vacuum distillation; the residue was then distilled, 33.6 g of a distillate being obtained which was worked up by gas chromatography in a 1.83 m long column with an external diameter of 0.64 cm. There were 3 ^, 9 % corresponding to 8.17 gl ^ -Dichlor-l ^^^ - tetrafluorocyclobutane corresponding to a conversion of 7 ^ _S 5 % and a yield of 44.8 % . The final purification was carried out by gas chromatography on a preparative scale with a 1.83 m long dinonyl phthalate column with an outer diameter of 1.9 cm, whereby 2.90 g of the end product were obtained with a purity of 99 % .

Example 2

192 g of tetrafluoroethylene and 157 g of 1-chloro-l-fluoroethylene were 35/5 hours at 182 ° C. in an autoclave under autogenous pressure heated in the presence of 1 g of 4-t-butylpyrocatechol, whereby 1-chloro-1,2,2,3,3-pentafluorocyclobutane was obtained.

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Example 3

91 g of 2-fluoro propylene and 58 g of tetrafluoroethylene were g 11.25 hours at 171 ⁰ C in an autoclave under autogenous pressure in the presence of 1 JJ-t-butyl pyrocatechol heated with 1-methyl-1,2,2,3j3 ~ pentafluorcyclotmtan in a yield of 19, ^ % was obtained.

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Claims (3)

Expectations A compound of the general formula I. X Y HP in which X is a chlorine atom or a methyl radical and Y is a fluorine or chlorine atom, where X is a methyl radical and Y is a fluorine atom. 2. Process for the preparation of a compound according to claim 1, characterized in that either (1) a compound of the general formula H ₂ C = CFZ, in, of which Z (a) Fluorine atom or (b) a chlorine atom or a methyl radical is ^{reacted with a compound of the general formula Z 2} FC = CFY, in which Z (a) a chlorine atom or a methyl radical or (b) a fluorine atom and Y has the meaning given above or (2) that 1,4, Jj-trichloro-l ^, 2-trifluorocyclobutane is fluorinated to l, i} -dichloro-1,2,2, i} -tetrafluorocyclobutane. 3. Anesthetic mixture, characterized in that they are together with another anesthetic compound and / or oxygen of a compound according to claim 1 contains. ue: gü 309808/1306