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United States Patent (19) (11) 4,109,016 Moilliet 45 Aug. 22, 1978

54 ANAESTHETIC COMPOSITION 56) References Cited 75 Inventor: John Stewart Moilliet, Runcorn, U.S. PATENT DOCUMENTS England 3,469,011 9/1969 Terrel ...... 424/342 73 Assignee: Imperial Chemical Industries Limited, London, England OTHER PUBLICATIONS Terrell et al., J. of Med. Chem., vol. 14, No. 6, (1971), (21) Appl. No.: 847,026 pp. 517-519. 22 Filed: Oct. 31, 1977 Primary Examiner-Jerome D. Goldberg Related U.S. Application Data Attorney, Agent, or Firm-Cushman, Darby & Cushman 62 Division of Ser. No. 637,680, Dec. 4, 1975, Pat. No. 57 ABSTRACT 4,080,389. The compound 2-chloro-1,2,2-trifluoroethyl di 30 Foreign Application Priority Data fluoromethyl ether, processes for its manufacture, com Dec. 6, 1974 GB United Kingdom ...... 52834/74 positions containing it and its use as an inhalation anaes 51) Int. Cl...... A61K 31/08 thetic. 52 U.S. Cl...... 424/342 58 Field of Search...... 424/342 3 Claims, No Drawings 4,109,016 1. 2 the composition is administered by inhalation to a ANAESTHETIC COMPOSITION warm-blooded animal anaesthesia is produced and/or maintained, and the proportion of oxygen in the compo This is a division of application Ser. No. 637,680, filed sition being such that when the composition is adminis Dec. 4, 1975, now U.S. Pat. No. 4,080,389. 5 tered by inhalation to a warm-blooded animal respira This invention relates to a novel tion is maintained. which possesses anaesthetic activity and which is sub It is to be understood that the 2-chloro-1,2,2-tri stantially free from undesirable side-effects when ad fluoroethyl difluoromethyl ether must be free of toxic ministered to warm-blooded animals by inhalation. According to the present invention there is provided impurities when it is used in the composition of the the novel compound 2-chloro-1,2,2-trifluoroethyl di 10 invention. fluoromethyl ether having the formula The oxygen present in the composition of the inven CHFOCHFCCIF. tion may be pure oxygen, or it may be in the form of air, The structure of the compound is confirmed by the that is in a mixture with and smaller quantities following physical data: of other gases. 15 The other physiologically-acceptable material(s) that may optionally be present in the composition of the Mass spectrum: principal ions invention may be, for example, one or more substances nae % intensity ion selected from other inhalant anaesthetics, for example 49 2 CHFOCHFCF, 117A19 3A4 F6 20 , , , , O O CFO trifluoroethyl vinyl ether, , trichloroethy 99 10 CFHO 85/87 4/1 cal lene, , , , , 71 8 CF.H. and 1-chloro-2,2,2-trifluoroethyl di 67A69 13/4 5. 5 OO CHF, fluoromethyl ether; pharmaceutically-inert gases, for 29 78 CHO example nitrogen, chemically inert gases such as are 25 present in air, for example neon and argon, and carbon dioxide and water vapour; and pharmaceutically acceptable stabilisers which may be present to protect Proton magnetic resonance spectrum (in carbon tetrachloride using tetramethylsilane as internal one or more of the other components of the composi reference) 30 tion from the effect of light, oxidation and/or attack by acid or base. As a suitable stabiliser there may be used, 5.83 doublet of triplets -CHF for example, a volatile stabilising agent which is physio 6.4 triplet -CHF logically tolerable, for example ethanol, or a non volatile stabilising agent which is not carried over sub 35 stantially during vaporisation, for example . The composition of the invention will usually contain F'magnetic resonance spectrum (in CFCI) between 0.25% and 3.5% volume by volume of the 140.7 ppm doublet of multiplets -CHF 86.2 ppm doublet AB system -CHF 2-chloro-1,2,2-trifluoroethyl difluoromethyl ether. 72.0 ppm doublet of doublets CFd The composition of the invention may be adminis tered to warm-blooded animals, including man, for the The compound has a boiling point of 56' C. at normal production of anaesthesia by conventional techniques. atmospheric pressure. The composition may be preformed and administered as According to a further feature of the invention there such, or alternatively the 2-chloro-1,2,2-trifluoroethyl is provided a process for the manufacture of 2-chloro difluoromethyl ether and oxygen, either of which may 1,2,2-trifluoroethyl difluoromethyl ether which com 45 have other physiologically-acceptable materials present prises either the chlorination of difluoromethyl 1,2,2-tri with it, may be administered separately, the composi fluoroethyl ether (CHFOCHFCHF) or the fluorina tion of the invention being formed either immediately tion of methyl 2,2,2-trichloroethyl ether prior to, or during, the course of administration. For (CHOCHCCl). example, the composition may be used in apparatus or The chlorination process may conveniently be car 50 machines adapted for the vaporisation of liquid anaes ried out at a laboratory temperature using gaseous chlo thetics and the admixture thereof with oxygen or with rine under the influence of ultraviolet radiation. The air or other gaseous mixtures containing oxygen in fluorination process may conveniently be carried out amount capable of supporting respiration. using a high-valency metal fluorinating agent, for exam According to a further feature of the invention there ple cobaltic fluoride, at an elevated temperature, for 55 is provided an inhalation anaesthetic apparatus charged example at 60° C. with 2-chloro-1,2,2-trifluoroethyl difluoromethyl ether. The CHFOCHFCHF used as starting material is a According to a further feature of the invention there known compound (Tetrahedron, 1971, 27, 4533 to is provided a method for producing anaesthesia in a 4551), The CHOCHCCls used as starting material is a warm-blooded animal which comprises administering known compound (Bulletin de la Société Chimique de to said animal an anaesthetically-effective amount of France 1967, 1520-1532). 2-chloro-1,2,2-trifluoroethyl difluoromethyl ether to According to a further feature of the invention there gether with sufficient oxygen to maintain respiration. is provided an inhalation anaesthetic composition The invention is illustrated but not limited by the which comprises as anaesthetic agent 2-chloro-1,2,2-tri following Examples: fluoroethyl difluoromethyl ether together with oxygen 65 and optionally together with one or more other physio EXAMPLE logically-acceptable material(s), the proportion of an Chlorine gas was bubbled during 4 hours at a rate of aesthetic agent in the composition being such that when 40 ml/minute through 40 ml. (57g) of difluoromethyl 4,109,016 3 4. 1,2,2-trifluoroethyl ether (CHFOCHFCHF) under ether which anaesthetises 3 mice out of 6 after 30 min ultraviolet irradiation. Unreacted chlorine passed from utes exposure, is found to be 0.9%. The LCso, that is the the reaction vessel through a vertical air condenser and concentration by volume of 2-chloro-1,2,2-trifluoro a dephleg, maintained at -78 C. with trichloroe ethyl difluoromethyl ether which kills 3 mice out of 6 thylene/solid carbon dioxide, which condensed any after 30 minutes exposure, is found to be 4.2%. The organic components of the exit gases. The reaction therapeutic ratio of the compound is therefore 4.2/0.9, mixture was then distilled into a cold trap, dried over a that is 4.7. Under similar conditions the ACso, LCso and molecular sieve and finally separated into its compo therapeutic ratio for halothane are respectively 0.85%, nents on a preparative gas-liquid chromatogram using a 3.4% and 4.0. 30 ft. column containing 20% by weight of diethyl 10 hexyl sebacate supported on “Celite' (Registered Trade EXAMPLE 4 Mark). 2-Chloro-1,2,2-trifluoroethyl difluoromethyl ether A mixture of 2-chloro-1,2,2-trifluoroethyl di was obtained in about 6% yield based on di fluoromethyl ether (3% w/v) and air (97% w/v) was fluoromethyl 1,2,2-trifluoroethyl ether. administered to a cat for a period of 10 minutes. Induc 15 tion of anaesthesia and subsequent recovery from anaes EXAMPLE 2 thesia were smooth, and rapid. Methyl 2,2,2-trichloroethyl ether (56 ml.) was added EXAMPLE 5 during 5 hours to a reactor containing cobalt (III) fluo ride (2000 g) which was stirred and maintained at 60 20 A cat was anaesthetised by injection of a 2.5% w/v C. Nitrogen was then blown through the stirred reactor solution of thiopentone sodium in water into a cephalic contents for 1 hour, the material entrained by the nitro vein at a dose equivalent to 20 mg/kg. bodyweight. gen being condensed and collected in a trap maintained Anaesthesia was subsequently maintained by adminis at -75° C. The contents of the trap were washed with tration of a mixture of 2-chloro-1,2,2-trifluoroethyl di water and dried over molecular sieve, 45 g. of material 25 fluoromethyl ether (1% w/v) and oxygen (99% v/v) being produced. contained in a large nylon reservoir bag. Aanesthesia The combined product from ten such reactions was was maintained in this way for 40 minutes. Mean arte fractionally distilled and the desired fraction further rial pressure and heart rate during this period were both purified by gas chromatography using a 30 ft. X 0.5 substantially higher than under comparable anaesthesia inch column containing 20% by weight of a polyethyl 30 with halothane. ene glycol ("Carbowax' M; Registered Trade Mark) What we claim is: supported on “Celite'. There was thus obtained 2 1. An inhalation anaesthetic composition which com chloro-1,2,2-trifluoroethyl difluoromethyl ether (120 prises as anaesthetic agent an anaesthetically effective g). amount of 2-chloro-1,2,2-trifluoroethyl difluoromethyl 35 ether together with oxygen, the proportion of anaes EXAMPLE 3 thetic agent in the composition being such that when A group of 6 mice is placed in a chamber of 10 liters the composition is administered by inhalation to a capacity which contains solid soda lime, and a mixture warm-blooded animal anaesthesia is produced or main of 2-chloro-1,2,2-trifluoroethyl difluoromethyl ether tained, and the proportion of oxygen in the composition and oxygen, of known percentage, is released into the being such that when the composition is administered chamber. A reservoir bag containing the known per by inhalation to a warm-blooded animal respiration is centage mixture is used to maintain atmospheric pres maintained. sure as the mixture is inhaled by the mice and as exhaled 2. A composition as claimed in claim 1 which con carbon dioxide is absorbed by the soda lime. After 30 tains between 0.25% and 3.5% volume by volume of the minutes the concentration of 2-chloro-1,2,2-trifluoro 45 2-chloro-1,2,2-trifluoroethyl difluoromethyl ether. ethyl difluoromethyl ether in the chamber is determined 3. A method for producing anaesthesia in a warm by gas chromatography. blooded animal which comprises administering by inha The experiment is repeated using different mixtures lation to said animal an anaesthetically-effective amount of 2-chloro-1,2,2-trifluoroethyl difluoromethyl ether of 2-chloro-1,2,2-trifluoroethyl difluoromethyl ether and oxygen, and the ACso, that is the concentration by 50 together with sufficient oxygen to maintain respiration. volume of 2-chloro-1,2,2-trifluoroethyl difluoromethyl k k k sk ak

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