US3689659A - Pharmaceutical composition comprising certain {60 {62 -unsaturated ketones - Google Patents
Pharmaceutical composition comprising certain {60 {62 -unsaturated ketones Download PDFInfo
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- US3689659A US3689659A US551843A US3689659DA US3689659A US 3689659 A US3689659 A US 3689659A US 551843 A US551843 A US 551843A US 3689659D A US3689659D A US 3689659DA US 3689659 A US3689659 A US 3689659A
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- trifluoromethyl
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- 150000002576 ketones Chemical class 0.000 title abstract description 7
- 239000008194 pharmaceutical composition Substances 0.000 title abstract description 6
- 241001465754 Metazoa Species 0.000 claims abstract description 15
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 7
- 238000000034 method Methods 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 29
- -1 methyl- Chemical group 0.000 claims description 25
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 125000004775 chlorodifluoromethyl group Chemical group FC(F)(Cl)* 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 4
- OMJAUAQKUSAPIJ-UHFFFAOYSA-N 6-nitro-1,2,3,4-tetrahydronaphthalene Chemical compound C1CCCC2=CC([N+](=O)[O-])=CC=C21 OMJAUAQKUSAPIJ-UHFFFAOYSA-N 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 125000002541 furyl group Chemical group 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 125000001544 thienyl group Chemical group 0.000 claims description 3
- 230000000202 analgesic effect Effects 0.000 claims description 2
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 9
- 239000003085 diluting agent Substances 0.000 abstract description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 241000699694 Gerbillinae Species 0.000 description 5
- 238000009835 boiling Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- VBZWSGALLODQNC-UHFFFAOYSA-N hexafluoroacetone Chemical compound FC(F)(F)C(=O)C(F)(F)F VBZWSGALLODQNC-UHFFFAOYSA-N 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 239000002085 irritant Substances 0.000 description 4
- 231100000021 irritant Toxicity 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 3
- 239000000443 aerosol Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 3
- 229910052753 mercury Inorganic materials 0.000 description 3
- XHLHPRDBBAGVEG-UHFFFAOYSA-N 1-tetralone Chemical compound C1=CC=C2C(=O)CCCC2=C1 XHLHPRDBBAGVEG-UHFFFAOYSA-N 0.000 description 2
- RZPFVRFSYMUDJO-UHFFFAOYSA-N 2h-naphthalen-1-one Chemical compound C1=CC=C2C(=O)CC=CC2=C1 RZPFVRFSYMUDJO-UHFFFAOYSA-N 0.000 description 2
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 241000282693 Cercopithecidae Species 0.000 description 2
- 208000000059 Dyspnea Diseases 0.000 description 2
- 206010013975 Dyspnoeas Diseases 0.000 description 2
- 206010015995 Eyelid ptosis Diseases 0.000 description 2
- 206010039424 Salivary hypersecretion Diseases 0.000 description 2
- WAIPAZQMEIHHTJ-UHFFFAOYSA-N [Cr].[Co] Chemical compound [Cr].[Co] WAIPAZQMEIHHTJ-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 239000006199 nebulizer Substances 0.000 description 2
- 201000003004 ptosis Diseases 0.000 description 2
- 208000026451 salivation Diseases 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000009987 spinning Methods 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- ARKIFHPFTHVKDT-UHFFFAOYSA-N 1-(3-nitrophenyl)ethanone Chemical compound CC(=O)C1=CC=CC([N+]([O-])=O)=C1 ARKIFHPFTHVKDT-UHFFFAOYSA-N 0.000 description 1
- VRLJBWKYHRJXGK-UHFFFAOYSA-N 4,4,4-trifluoro-3-hydroxy-1-phenyl-3-(trifluoromethyl)butan-1-one Chemical compound FC(F)(F)C(C(F)(F)F)(O)CC(=O)C1=CC=CC=C1 VRLJBWKYHRJXGK-UHFFFAOYSA-N 0.000 description 1
- GWAQYWSNCVEJMW-UHFFFAOYSA-N 7-nitro-3,4-dihydro-2h-naphthalen-1-one Chemical compound C1CCC(=O)C2=CC([N+](=O)[O-])=CC=C21 GWAQYWSNCVEJMW-UHFFFAOYSA-N 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 206010017577 Gait disturbance Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 206010023644 Lacrimation increased Diseases 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 206010035039 Piloerection Diseases 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 241000282695 Saimiri Species 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000004397 blinking Effects 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 210000005069 ears Anatomy 0.000 description 1
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 238000004508 fractional distillation Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 208000013403 hyperactivity Diseases 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 230000004317 lacrimation Effects 0.000 description 1
- 230000006742 locomotor activity Effects 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- UMRZSTCPUPJPOJ-KNVOCYPGSA-N norbornane Chemical compound C1C[C@H]2CC[C@@H]1C2 UMRZSTCPUPJPOJ-KNVOCYPGSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000005371 pilomotor reflex Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 1
- 238000013022 venting Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
Definitions
- the invention relates to a pharmaceutical composition [51] Int. Cl. ..A0ln 9/00, A01n 9/12, A0ln 9/20 comprising a diluent and an effective amount of cer- [58] Field of Search ..l67/46 A, 47, 22 K, 22 M; tain Bfi-bisflrifluoromethyl or chlorodifluoromethyD- a,B-Unsaturated ketones and a method of applying these compositions to animals for the purpose of causing disability.
- this invention refers to B, B- bis(trifluoromethyl)-a, B-unsaturated ketones, compositions employing them and a process of applying these compounds to animals for the purpose of causing disability.
- R is t-butyl, phenyl, methyl-, cyano-, fluoro-, chloro-, bromo-, methoxyor nitro-substituted phenyl, naphthyl, chloronaphthyl, furyl, thienyl, B-phenylethenyl;
- R is hydrogen or alkyl of one through eight carbon atoms
- R and R can be combined to form cyclopentyl, a tetrahydronaphthalene, 7-nitrotetrahydronaphthalene or norbornane;
- X and Z are separately either chlorodifluoromethyl or trifluoromethyl.
- the compounds of formula (2) are treated with thionyl chloride in di-methylformamide or are dehydrated by heating with acetic anhydride.
- Compositions of this invention can be administered alone but are generally contained in a composition with a pharmaceutical carrier or diluent selected on the basis of the chosen route of administration and standard pharmaceutical practice. If the chosen route of administration is orally, the compounds can be administered in the form of tablets or capsules containing such excipients as starch, milk, sugar, clays and the like. Compounds can also be administered orally in the form of elixirs or oral suspensions containing coloring and flavoring agents.
- compositions of the compound of this invention can be prepared in an oil base such as peanut or sesame oil.
- compositions will contain some acceptable liquid such as water, acetone or alcohol.
- the amount of active ingredient in the compositions will vary from 0.005 to 95 percent by weight or even higher. Exact concentration of active ingredient will depend on the mechanism used for administration and will be easily understood by one knowledgeable in pharmaceutical application rates.
- the effective pharmaceutical dose of an intraveinous treatment is 0.5 to 5 milligrams of active compound per kilogram of body weight of the animal recipient. Rates of over 56 milligrams per kilogram of body weight will kill percent of the animal recipients.
- An effective pharmaceutical dose of an inhalation treatment is 0.5 to 2 milligrams per liter of air at exposure of one minute. More than 100 milligrams per liter of air at exposure of 1 minute is required to kill 50 percent of the animal recipients.
- EXAMPLE 1 A Hastelloy C autoclave with a 200 ml. capacity is charged with 60 parts of acetophenone, then evacuated and cooled in a liquid nitrogen bath and charged with parts of hexafluoroacetone. The autoclave is sealed, heated at for 8 hours and then cooled and opened.
- mice are treated by aerosol exposure to the test compound in the following manner:
- the compound is administered as an aerosol into a 2.8 liter chamber.
- the exposure chamber consists of a 2.8 liter bell jar over a nebulizer inserted through the floor of the chamber.
- mice are exposed for five minutes to 200 micrograms (1,000 Ct). The compound is dissolved in acetone and, during a span of twenty seconds, the compound is sprayed up into the chamber. No further air is transferred into or out of the chamber during the 5 minute exposure.
- Irritant activity can be described as the presence of one or more of the following reactive signs:
- Gerbils are treated to the test compound by exposure in a 16 liter static chamber in the following manner: The compound is dissolved in methylene chloride. The resulting colorless solution is sprayed into the chamber through a port in the bottom, animals being maintained around the entrance port. The spray impinges on the top of the chamber, then slowly settles down on the gerbils in the form of a vapor. The exposure time is one minute. A concentration which shows irritant activity is 2,000 micrograms. The gerbils are removed from the chamber at the end of one minute exposure. Characteristic symptoms in the gerbil after exposure to irritants are the following:
- Squirrel monkeys are exposed to the test compound in the following manner: The compound is dissolved in methylene chloride, forming a colorless solution. The solution is forced through a nebulizer, and thence to a turbulence bulb, where the compound forms particles distinct from the vapor of the solvent. Both solute and solvent vapors are blown into a 50 liter chamber containing two monkeys. The animals are exposed to a concentration of 2,000 micrograms for one minute, with constant flow of compound maintaining this concentration (dynamic chamber).
- the product compounds are formulated and applied to animals in like manner to provide like results.
- EXAMPLE 36 anal. calcd. for C H, Cl F O: C, 41.2; H, 2.8;
- EXAMPLE 37 a-Tetralone and hexafluoroacetone as intermediates substituted in like amount by weight for the intermediates of Example 35 give 2-(2,2,2-trifluoro-lhydroxyl-trifluoromethyl )ethyl-3 ,4-dihydro-1(2H)- naphthalenone, melting point 7475 C. which on dehydration gives 2-(hexafluoroisopropylidene)-3,4- dihydro-l(2H)-naphthalenone, boiling point 68C. at 0.1 mm. Hg. and refractive index n l .4826.
- a pharmaceutical composition comprising a pharmaceutically acceptable diluent and an effective pharmaceutical dose of a compound of the formula:
- R is selected from the group consisting of t-butyl, phenyl, methyl-, cyano-', fluoro-, chloro-, bromo-, methoxy, nitro-substituted phenyl, naphthyl, chloronaphthyl, furyl, thienyl, B-phenylethenyl;
- R' is selected from the group consisting of hydrogen and alkyl of one through eight carbon atoms
- R and R are joined to form a radical selected from the group consisting of cyclopentyl, atetrahydronaphthalene, 7- nitrotetrahydronaphthalene and norbornyl;
- X is selected from the group consisting chlorodifluoromethyl and trifluoromethyl
- Z is selected from the group consisting chlorodifluoromethyl and trifluoromethyl.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a pharmaceutical composition comprising a diluent and an effective amount of certain Beta , Beta bis(trifluoromethyl or chlorodifluoromethyl)- Alpha , Beta Unsaturated ketones and a method of applying these compositions to animals for the purpose of causing disability.
Description
United States Patent Langkammerer 1 Sept-5, 1972 [54] PHARMACEUTICAL COMPOSITION [56] References Cited COMPRISING CERTAIN 043- UNSATURATED KETONES UNITED STATES PATENTS 2,889,246 6/1959 Harker .......l67/46 A [72] Invent gf g' Langkammm" 3,068,274 12/1962 McCall ..-..;167/46 A 3,076,015 1/1963 McCall et al ..l67/46 A X [73] Assignee: E. l. du Pont de Nemours and Com- 3,238,090 3/1966 Szabo ..l67/22' M pany, Wilmington, Del. Primary Examiner-Leland A. Sebastian [22] Filed. May 17, 1966 Attorney Herbert w Larson [21] Appl. No.: 551,843
' ABSTRACT [5 2] U.S. Cl. ..424/275, 424/285, 424/331 The invention relates to a pharmaceutical composition [51] Int. Cl. ..A0ln 9/00, A01n 9/12, A0ln 9/20 comprising a diluent and an effective amount of cer- [58] Field of Search ..l67/46 A, 47, 22 K, 22 M; tain Bfi-bisflrifluoromethyl or chlorodifluoromethyD- a,B-Unsaturated ketones and a method of applying these compositions to animals for the purpose of causing disability.
2 Claims, No Drawings PHARMACEUTICAL COMPOSITION COMPRISING CERTAIN aB-UNSATURATED KETONES This invention relates to a, B-unsaturated ketones.
More specifically, this invention refers to B, B- bis(trifluoromethyl)-a, B-unsaturated ketones, compositions employing them and a process of applying these compounds to animals for the purpose of causing disability.
The compounds of this invention possess the following structural formula:
wherein R is t-butyl, phenyl, methyl-, cyano-, fluoro-, chloro-, bromo-, methoxyor nitro-substituted phenyl, naphthyl, chloronaphthyl, furyl, thienyl, B-phenylethenyl;
R is hydrogen or alkyl of one through eight carbon atoms;
R and R can be combined to form cyclopentyl, a tetrahydronaphthalene, 7-nitrotetrahydronaphthalene or norbornane; and
X and Z are separately either chlorodifluoromethyl or trifluoromethyl.
The compounds of formula (1) wherein R is hydrogen are preferred because of high incidence of animal disability at low dose rates.
Use
The compounds of formula (1) cause irritation to animals, affecting the eyes and upper respiratory tract. in aerosols the compounds could be used in riot control, rodent control or burglar alarm systems. Preparation Compounds of the present invention are made by starting with wherein R, R, X and Z have the same meaning as above.
The compounds of formula (2) are treated with thionyl chloride in di-methylformamide or are dehydrated by heating with acetic anhydride.
Composition Compounds of this invention can be administered alone but are generally contained in a composition with a pharmaceutical carrier or diluent selected on the basis of the chosen route of administration and standard pharmaceutical practice. If the chosen route of administration is orally, the compounds can be administered in the form of tablets or capsules containing such excipients as starch, milk, sugar, clays and the like. Compounds can also be administered orally in the form of elixirs or oral suspensions containing coloring and flavoring agents.
If administered parenterally, the composition can take the form of sterile aqueous solutions containing solutes such as saline, or glucose in sufficient quantity to make the solution isotonic. For intramuscular administration, compositions of the compound of this invention can be prepared in an oil base such as peanut or sesame oil.
If administered as a vapor or spray application through the mouth or nasal passages a composition will contain some acceptable liquid such as water, acetone or alcohol.
Dosage The amount of active ingredient in the compositions will vary from 0.005 to 95 percent by weight or even higher. Exact concentration of active ingredient will depend on the mechanism used for administration and will be easily understood by one knowledgeable in pharmaceutical application rates. The effective pharmaceutical dose of an intraveinous treatment is 0.5 to 5 milligrams of active compound per kilogram of body weight of the animal recipient. Rates of over 56 milligrams per kilogram of body weight will kill percent of the animal recipients.
An effective pharmaceutical dose of an inhalation treatment is 0.5 to 2 milligrams per liter of air at exposure of one minute. More than 100 milligrams per liter of air at exposure of 1 minute is required to kill 50 percent of the animal recipients.
The following additional examples are provided to more clearly set forth the invention. All parts are by weight unless otherwise indicated.
EXAMPLE 1 A Hastelloy C autoclave with a 200 ml. capacity is charged with 60 parts of acetophenone, then evacuated and cooled in a liquid nitrogen bath and charged with parts of hexafluoroacetone. The autoclave is sealed, heated at for 8 hours and then cooled and opened.
- The 141 g. of liquid remaining is distilled in a spinning band fractionating column to give 133.4 parts 93 percent yield) of 3-hydroxy-l-phenyl-4,4,4-trifluoro-3- trifluoromethyl-l-butanone boiling at 6l64C. at 0.08 mm. of mercury and with a refractive index of n l.44l0.
anal. calcd. for C H F O found:
anal. calcd. for C I-I F O: found:
Mice are treated by aerosol exposure to the test compound in the following manner: The compound is administered as an aerosol into a 2.8 liter chamber. The exposure chamber consists of a 2.8 liter bell jar over a nebulizer inserted through the floor of the chamber.
Mice are exposed for five minutes to 200 micrograms (1,000 Ct). The compound is dissolved in acetone and, during a span of twenty seconds, the compound is sprayed up into the chamber. No further air is transferred into or out of the chamber during the 5 minute exposure.
After this exposure, irritant activity is observed in all mice exposed, but not in controls exposed to acetone alone. Irritant activity can be described as the presence of one or more of the following reactive signs:
l-lyperemia of the nose, ears, and tail Salivation Ptosis Dyspnea Decreased locomotor activity Blinking Hunched posture Face pawing.
Gerbils are treated to the test compound by exposure in a 16 liter static chamber in the following manner: The compound is dissolved in methylene chloride. The resulting colorless solution is sprayed into the chamber through a port in the bottom, animals being maintained around the entrance port. The spray impinges on the top of the chamber, then slowly settles down on the gerbils in the form of a vapor. The exposure time is one minute. A concentration which shows irritant activity is 2,000 micrograms. The gerbils are removed from the chamber at the end of one minute exposure. Characteristic symptoms in the gerbil after exposure to irritants are the following:
Abnormal gait, consisting of rubbing the nose on the floor while walking about (shovelnosing) Ptosis F ace pawing Dyspnea Rats are treated in a manner similar to gerbils, and show the following symptoms in addition to the above:
Salivation Lacrimation Piloerection Hyperactivity EXAMPLE 2 The Hastelloy C autoclave used in Example 1 is charged in the same way with- 82.5 parts of 3- nitroacetophenone and 90 parts of hexafluoroacetone, sealed, and heated at 160 C. for 8 hours. After cooling and venting the 155 parts of liquid remaining is distilled in a spinning band fractionating column to give 124.2 parts (75 percent yield) of 3-hydroxy-l-(3-nitrophenyl)-4,4,4-trifluoromethyl-l-butanone boiling at 1 17 C.
at 0.17 mm. of mercury and with a refractive index of n 1.4735.
anal. calcd. for C H F NO found:
A flask attached to a reflux condenser with a calcium chloride tube at the top and a magnetic stirrer is charged with 15 parts of the 3-hydroxy-1-(3-nitrophenyl)-4,4,4-trifluoromethyl-l-butanone prepared above and with 40 parts of acetic anhydride and refluxed for 16 hours with stirring. Fractional distillation of the liquid gives 10.7 parts of l-(3-nitrophenyl)-4,4,4- trifluoro-3-trifluoromethylbutene-2-one-l with a boiling point of 94-95 at 0.3 mm. of mercury with a refractive index of n 'l .4757.
anal. calcd. for C H F NO C, 42.1; H, 1.6;
found: C, 41.7; H, 1.7;
Squirrel monkeys are exposed to the test compound in the following manner: The compound is dissolved in methylene chloride, forming a colorless solution. The solution is forced through a nebulizer, and thence to a turbulence bulb, where the compound forms particles distinct from the vapor of the solvent. Both solute and solvent vapors are blown into a 50 liter chamber containing two monkeys. The animals are exposed to a concentration of 2,000 micrograms for one minute, with constant flow of compound maintaining this concentration (dynamic chamber).
At the end of the exposure, the monkeys are removed from the chamber and caged in well ventilated quarters. Characteristic reactive signs seen in the The following compounds are made in the manner of the compounds of Examples 1 and 2 by substituting the appropriate starting materials to form compounds of the formula:
The meaning of R, R, X and Z is found in the Table.
The product compounds are formulated and applied to animals in like manner to provide like results.
TABLE Ex. No. R R X Z Product Properties 3 (CH hC H CF: CF 5,5dimethyl- 1,1,l-trifluoro EXAMPLE 35 anal. calcd. for C H F O 4 Found: 4
c, 3.1;H,3.6; C, 2.6; 1-1, 3.6
3-[( l-Hydroxy-2,2,2-trifluorol -trifluoromethyl)- ethyl1-2-norbornanone (27.6 parts), parts of dry xylene, 23.2 parts of thionyl chloride and 0.4 parts of dimethylformamide are refluxed for three days with stirring and protected from atmospheric moisture. Distillation gives 15.3 parts (60 percent yield) of 3- [2,2,2-trifluorol -trifluoromethyl)ethylidene]- bicyclo(2.2.l)-heptane-2-one with a boiling point of 9497 at 12 mm. Hg. and a refractive index of n l.4203.
anal. calc'd. for C H F O:
Found:
EXAMPLE 36 anal. calcd. for C H, Cl F O: C, 41.2; H, 2.8;
Cl, 2.44 found: C, 41.3; H, 3.4;
EXAMPLE 37 a-Tetralone and hexafluoroacetone as intermediates substituted in like amount by weight for the intermediates of Example 35 give 2-(2,2,2-trifluoro-lhydroxyl-trifluoromethyl )ethyl-3 ,4-dihydro-1(2H)- naphthalenone, melting point 7475 C. which on dehydration gives 2-(hexafluoroisopropylidene)-3,4- dihydro-l(2H)-naphthalenone, boiling point 68C. at 0.1 mm. Hg. and refractive index n l .4826.
anal. calc'd. for C H F O: C, 53.0; H, 2.7 C, 52.8;1-1 2.7
EXAMPLE 3:;
7-Nitro-l-tetralone and hexafluoroacetone as intermediates substituted in like amount by weight for the intermediates fExam le 35 ive 2- -h -3,3,3- tri-fluQrO-Z-trifluorome thyl)efi'iyl]-7 ii%ro y dihydro-l(2H)-naphthalenone, melting point I40-2 C. (Analysis calculated for C, H F NO,: C, 43.7; H, 2.5; N, 3.9. Found: C, 44.2; H, 2.8; N, 4.3), which on dehydration gave 7-nitro-2-hexafluoroisopropylidene- 3 ,4-dihydro- 1 (2H )-naphthalenone, melting point l28l 30 C.
anal. calcd. for C,;,H F,,NO;,: C, 46.0; H, 2.1;
N, 4.1 found: C, 46.1; H, 2.2;
I claim:
l. A pharmaceutical composition comprising a pharmaceutically acceptable diluent and an effective pharmaceutical dose of a compound of the formula:
wherein R is selected from the group consisting of t-butyl, phenyl, methyl-, cyano-', fluoro-, chloro-, bromo-, methoxy, nitro-substituted phenyl, naphthyl, chloronaphthyl, furyl, thienyl, B-phenylethenyl;
R' is selected from the group consisting of hydrogen and alkyl of one through eight carbon atoms;
R and R are joined to form a radical selected from the group consisting of cyclopentyl, atetrahydronaphthalene, 7- nitrotetrahydronaphthalene and norbornyl;
X is selected from the group consisting chlorodifluoromethyl and trifluoromethyl; and
Z is selected from the group consisting chlorodifluoromethyl and trifluoromethyl.
2. A method of producing analgesic effects in animals comprising applying to a warm-blooded animal an effective pharmaceutical dose of a compound of the formula:
X of
Claims (1)
- 2. A method of producing analgesic effects in animals comprising applying to a warm-blooded animal an effective pharmaceutical dose of a compound of the formula: wherein R is selected from the group consisting of t-butyl, phenyl, methyl-, cyano-, fluoro-, chloro-, bromo-, methoxy-, nitro-substituted phenyl, naphthyl, chloronaphthyl, furyl, thienyl, Beta -phenylethenyl; R'' is selected from the group consisting of hydrogen and alkyl of one through eight carbon atoms; R and R'' are joined to form a radical selected from the group consisting of cyclopentyl, Alpha -tetrahydronaphthalene, 7-nitrotetrahydronaphthalene and norbornyl; X is selected from the group consisting of chlorodifluoromethyl and trifluoromethyl; and Z is selected from the group consisting of chlorodifluoromethyl and trifluoromethyl.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US55184366A | 1966-05-17 | 1966-05-17 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US3689659A true US3689659A (en) | 1972-09-05 |
Family
ID=24202916
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US551843A Expired - Lifetime US3689659A (en) | 1966-05-17 | 1966-05-17 | Pharmaceutical composition comprising certain {60 {62 -unsaturated ketones |
Country Status (1)
| Country | Link |
|---|---|
| US (1) | US3689659A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4562292A (en) * | 1983-08-18 | 1985-12-31 | The Regents Of The University Of California | Trifluoromethylketone sulfides and reversible enzyme inhibition therewith |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2889246A (en) * | 1957-03-13 | 1959-06-02 | Commercial Solvents Corp | Method of repelling rodents by treating with a composition comprising an aryl nitroolefin |
| US3068274A (en) * | 1960-08-18 | 1962-12-11 | Eastman Kodak Co | (2-cyano-3-amino)thio-2-alkenamides |
| US3076015A (en) * | 1960-08-18 | 1963-01-29 | Eastman Kodak Co | Preparation of [2-cyano-3-alkoxy (or hydroxy)] thio-2-alke)namides |
| US3238090A (en) * | 1964-01-20 | 1966-03-01 | Stauffer Chemical Co | Inhibiting the growth of fungi with adducts of sym-dichlorotetrafluoroacetone with selected mercaptans |
-
1966
- 1966-05-17 US US551843A patent/US3689659A/en not_active Expired - Lifetime
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2889246A (en) * | 1957-03-13 | 1959-06-02 | Commercial Solvents Corp | Method of repelling rodents by treating with a composition comprising an aryl nitroolefin |
| US3068274A (en) * | 1960-08-18 | 1962-12-11 | Eastman Kodak Co | (2-cyano-3-amino)thio-2-alkenamides |
| US3076015A (en) * | 1960-08-18 | 1963-01-29 | Eastman Kodak Co | Preparation of [2-cyano-3-alkoxy (or hydroxy)] thio-2-alke)namides |
| US3238090A (en) * | 1964-01-20 | 1966-03-01 | Stauffer Chemical Co | Inhibiting the growth of fungi with adducts of sym-dichlorotetrafluoroacetone with selected mercaptans |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4562292A (en) * | 1983-08-18 | 1985-12-31 | The Regents Of The University Of California | Trifluoromethylketone sulfides and reversible enzyme inhibition therewith |
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