Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D273/00—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00
  • C07D273/02—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00 having two nitrogen atoms and only one oxygen atom
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/20—Hypnotics; Sedatives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
  • C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
  • C07D239/72—Quinazolines; Hydrogenated quinazolines
  • C07D239/74—Quinazolines; Hydrogenated quinazolines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to ring carbon atoms of the hetero ring
  • C07D239/76—N-oxides
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
  • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
  • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
  • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
  • C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
  • C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
  • C07D243/24—Oxygen atoms

Definitions

• the present invention relates to an improved process for making such 3-fluorobenzodiazepines, novel intermediates used in the improved process and the further use of such novel intermediates as tranquilizers, muscle relaxants and sedatives in mammals.
• the present invention relates to:
• Compounds preferred for their activity are those of formulae II and III where X is chlorine or bromine. More preferred compounds are those where X is chlorine or bromine and Y is hydrogen, chlorine or fluorine. Most preferred compounds are those compounds where X is chlorine or bromine and Y is hydrogen or fluorine.
• Fluoroacetamidobenzophenone anti-oximes of Formula II can be prepared by contacting a solution of a benzophenone anti-oxime of Formula I in an inert solvent with a fluorohaloacetyl halide in either the presence or absence of a suitable base.
• Inert solvents suitable for use include CH 2 Cl 2 , CHC1 3 , chlorobenzene, benzene, toluene, and other hydrocarbons or chlorohydrocarbons, diethyl ether, tetrahydrofuran, ethylene glycol dimethyl ether, and other ether solvents, acetonitrile, acetone, and other solvents that are inert to both of the reactants.
• Bases suitable for use include aqueous solutions of inorganic bases such as NaOH, KOH, Na 2 CO 3 , NaHCO 3 , and KHC0 3 , and organic tertiary amines such as triethylamine and pyridine, and suspensions of solid inorganic bases such as NaHCO 3 .
• the temperature at which the reaction is conducted is not critical, but it should be below about 100° to prevent isomerization of the oximes and must be above the melting point of the solid so that mixing can be accomplished.
• Fluorohaloacetyl halides suitable for use in this reaction include CHFC1COC1, CHFClCOBr, CHFBrCOCl and CHFBrCOBr.
• the product of the reaction can be isolated and purified by conventional means, such as recrystallization or column chromatography. If some isomerization does occur during the reaction, or if the starting material is composed of a mixture of syn and anti-oximes, the desired product anti-oxime of Formula II can be separated from its syn-isomer by fractional recrystallization.
• (B) 3-Fluorobenzodiazepine oxides of Formula III can be prepared by treating a solution of a fluorohaloacetamidobenzophenone anti-oxime of Formula II with an alkali metal hydroxide.
• the reaction can be accomplished by mixing a solution of II in a water-immiscible inert solvent, such as CH 2 C1 2 , CHC1 3 , chlorobenzene, benzene toluene, and other hydrocarbon or chlorohydrocarbon solvents, or diethyl ether, with an aqueous solution of NaOH or KOH.
• a solution of II in a water- miscible solvent such as ethyleneglycol dimethyl ether, dioxane, tetrahydrofuran, ethanol, or methanol can be mixed with an aqueous or alcoholic solution of NaOH or KOH.
• a water- miscible solvent such as ethyleneglycol dimethyl ether, dioxane, tetrahydrofuran, ethanol, or methanol
• aqueous or alcoholic solution of NaOH or KOH aqueous or alcoholic solution of NaOH or KOH.
• the temperature is not critical, but it is most conveniently carried out from 0° to 25°, although temperatures of up to 80° are operable.
• the product 3-fluorobenzodiazepine oxides can be isolated from the reaction mixture by conventional means.
• the 3-fluorobenzodiazepine oxides of Formula III can be prepared in one step from the reaction of benzophenone anti-oximes of Formula I with a fluorohaloacetyl halide in the presence of an alkali metal hydroxide, without isolation of the intermediate fluorohaloacetamidobenzophenone anti-oxime (III).
• (C) 3-Fluorobenzodiazepines of Formula IV can be prepared by the reduction of 3-fluorobenzodiazepine 4- oxides (III) with selected mild reducing agents.
• Suitable reducing agents include, but are not limited to, phosphines of the general formula PR'R"R'', where R', R" and R''' can be alike or different and include alkoxy, aryloxy, alkyl, aryl, and halo (some specific examples are P(OCH 3 ) 3 , P(OC 2 H 5 ) 3 , P(butyl)3, ( PC1 3 , and PC120CH3), and elemental hydrogen in the presence of a suitable catalyst such as finely divided Pt or Pd.
• the most preferred reducing agent is trimethyl phosphite, since the by-product trimethyl phosphate is water soluble and can be removed from the product 3-fluorobenzodiazepine by washing with water.
• the phosphines containing halogen bonded to phosphorous are not preferred since hard-to-remove chlorine-containing products are produced as impurities.
• An inert solvent for the reduction is usually advantageous, but is not necessary if the reducing agent itself is a liquid.
• the reduction is best accomplished at a relatively low temperature to avoid over reduction (loss of fluorine).
• Ambient temperature about 20-25°C is preferred, but temperatures from 0°C to 50° are operable.
• the product 3-fluorobenzodiazepine can be isolated from the reaction mixture by evaporation of the solvent and recrystallization of the residue.
• the glyme filtrate was concentrated to one-half its volume by evaporation under reduced pressure, and allowed to remain at room temperature for 3 days.
• reaction mixture was neutralized with 10% hydrochloric acid, and the precipitated solid was collected on a filter,, washed with water, recrystallized from methyl ethyl ketone, and dried under vacuum at 100° to give 1.43 g (75%) of 7-chloro-3-fluoro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one oxide as colorless crystals: m.p.
• a rapidly stirred solution of 7.82 g (0.03 mole) of 5-chloro-2-methylamino anti-oxime in 100 ml of methylene chloride was mixed with 40 ml of water and cooled to 5°, and (A) 36 ml of IN sodium hydroxide and (B) 4.32 g (0.033 mole) of chlorofluoroacetyl chloride made up to 36 ml with methylene chloride were added at the same rate over 15 minutes from separate dropping funnels. The mixture was stirred for 1 hour at 5°, and then 30 ml of 1N sodium hydroxide was added over 15 minutes. The reaction mixture was stirred for an additional hour, and then neutralized with IN hydrochloric acid.
• Methyl sulfate 2.2 ml (0.023 mole) was added dropwise to a stirred suspension of 6.1 g (0.02 mole) of 7-chloro-3-fluoro-1,3-dihydro-5-phenyl-2H-1,4-benzodia- zepin-2-one 4-oxide in a cooled solution prepared by dissolving 1.0 g (0.025 mole) of sodium hydroxide in 170 ml water and 34 ml ethanol. The reaction mixture was stirred at 10° for 4 hours. The solid that precipitated was collected on a filter, washed with water, and dried in vacuum over phosphorous pentoxide to give 4.1 g (64%) of product as a white crystalline powder.
• a 3-1., three-necked flask was fitted with a thermometer, a heating mantle, a mechanical stirrer, and a distillation head with a condenser and a 500 ml receiving flask backed up by a dry ice cooled trap.
• the reaction flask was charged with 500 g (3.72 mole) of crude sodium chlorofluoroacetate and 1.1 (1400 g 6.9 mole) of practical grade phthaloyl chloride.
• the stirrer was started, and the contents of the flask were heated slowly until product began to distill from the reaction mixture (pot temperature about 100-110°).
• the heating mantle was turned off until the initial reaction subsided, and then heating was resumed and continued until the pot temperature reached 245°.
• Table I shows additional fluorohaloacetamidobenzophenone anti-oximes that can be made by the process disclosed and exemplified above using the appropriate anti-oxime of formula I and an appropriate fluorohaloacetyl halide.
• Table II shows additional 3-fluorobenzodiazepin 4-oxides that can be made by the processes disclosed and exemplified above using the appropriate anti-oxime of formula II and a suitable base.
• Table III shows additional 3-fluorobenzodiazepines that can be prepared by the processes disclosed and exemplified above using an appropriate N-oxide and a suitable reducihg agent.
• the tranquilizers, muscle relaxants, and sedatives of formulae II and III can be administered to produce the desired effect by any means that produces contact of the active agent with the agent's site of action in the body of a mammal. They can be administered by any conventional means available for use in conjunction with pharmaceuticals; either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but are generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
• the dosage administered will, of course, vary depending upon know factors such as the pharmacodynamic characteristics of the particular agent, and its mode and route of administration; age, health, and weight of the recipient; nature and extent of symptoms, kind of concurrent treatment, frequency of treatment, and the effect desired.
• a daily dosage of active ingredient can be about 0.05 to 500 milligrams per kilogram of body weight.
• 0.5 to 50, and preferably 1.0 to 25 milligrams per kilogram per day given in divided doses 2 to 4 times a day or in sustained release form is effective to obtain desired results.
• the active ingredient will ordinarily be present in an amount of about 0.5 - 95% by weight based on the total weight of the composition.
• the active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions; it can also be administered parenterally, in sterile liquid dosage forms; or rectally in the form of suppositories.
• Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, sucrose, mannitol, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
• powdered carriers such as lactose, sucrose, mannitol, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the
• Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
• parenteral solutions In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions.
• Solutions for parenteral administration contain preferably a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances.
• Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid either alone or combined are suitable stabilizing agents.
• citric acid and its salts and sodium EDTA are also used.
• parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.
• Suppositories contain the active ingredient in a suitable oleaginous or water-soluble base.
• the oleaginous class includes cocoa butter and fats with similar properties; the water-soluble class includes polyethylene glycols.
• Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, E. W. Martin, a standard reference text in this field.
• Useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows:
• a large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 20.0 milligrams of powdered active ingredient, 110 milligrams of lactose, 32 milligrams of talc, and 8 milligrams magnesium stearate.
• a mixture of active ingredient in soybean oil is prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 10 milligrams of the active ingredient.
• the capsules are washed in petroleum ether and dried.
• a large number of tablets are prepared by conventional procedures so that the dosage unit is 5.0 milligrams of active-ingredient, 7 milligrams of ethyl cellulose, 0.2 milligrams of colloidal silicon dioxide, 7 milligrams of magnesium stearate, 11 milligrams of microcrystalline cellulose, 11 milligrams of cornstarch and 98.8 milligrams of lactose.
• Appropriate coatings may be applied to increase palatability or delay absorption.
• a parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution is sterilized by filtration.
• An aqueous suspension is prepared for oral administration so that each 5 milliliters contain 5.0 milligrams of finely divided active ingredient, 500 milligrams of acacia, 5 milligrams of sodium benzoate, 1.0 grams of sorbitol solution, U.S.P., 5 milligrams of sodium saccharin, and 0.025 milliliters of vanilla tincture.
• a parenteral composition suitable for administration by injection is prepared by dissolving 1% by weight of active ingredient in sodium chloride injection U.S.P. XV and adjusting the pH of the solution to between 6 and 7. The solution is sterilized by filtration.
• Standard procedures for detecting and comparing the tranquilizer, muscle-relaxant, and sedative activity of compounds in this series for which there is a correlation with human efficacy are the following: pinna reflex tests, prehensile traction reflex tests, a muscle relaxant (anti-Straub tail) test, an antipentylenetetrazole test, and a mouse activity suppression test (MAST).
• Fasted female white mice 5 per dose are intubated with drug at 4, 12, 36, 108 and 324 mg/kg in 1% Methocelo-1.25% Tween 800, at 10 ml/kg.
• the auditory and tactile pinna are tested at 0.5, 2, 5 and 24 hours.
• the mouse is placed on a horizontal bar 9 cm from a Galton whistle adjusted for 13 Kc. Failure to flatten the ears during one or two short bursts of sound constitutes loss of auditory pinna reflex.
• the mouse is held by the tail and the hairs inside the right ear are touched by the fine wire stylus from a 27 gauge needle. Failure of the mouse to twitch or move the head constitutes loss of the tactile pinna reflex.
• the mouse is gently swung by the tail toward a horizontal 12 gauge wire tautly stretched 25 cm above the bench. After the mouse grasps the wire with its forepaws, its posterior end is held directly below the wire. A normal mouse grasps the wire with its forepaws and immediately lifts its hind limbs to the wire. Failure to grasp the wire with the forepaws in one of 2 trials constitutes loss of the grip reflex; failure to lift the hind limbs to grasp the wire with at least one hind paw within 5 seconds constitutes loss of the lift reflex.
• Fasted female white mice 5 per dose are intubated with test drug. Twenty-five minutes later morphine sulfate is given subcutaneously at 53.7 mg/kg. Thirty minutes after test drug the mice are observed for presence of Straub tail. Quantal ED50 values for blockade of morphine-induced Straub tail are calculated.
• Fasted female white mice 10 per dose are intubated with drug in vehicle as above at doses such as 0, 1, 3, 9, 27 and 81 mg/kg. Thirty minutes later the mice are dosed intravenously with PTZ (Metrazole 1 ) at 40 mg/kg (ED98 for clonic convulsions). Dosed animals which remain on a 4" x 4" platform for 20 seconds are considered protected. Quantal ED50's are calculated by the moving average method. 1 Original brand of pentylenetetrazole; sterile 10% aqueous solution for parenteral injection, Knoll Pharmaceutical Company.
• the mouse activity suppression test is a model system designed to detect compounds with possible antianxiety activity in humans. The test is based upon punishment of mice for exhibiting normal exploratory locomotor behavior. The punishment, an electric shock applied through the mouse's paws, quickly extinguishes normal behavior. Pretreatment with a minor tranquilizer prevents or delays the extinction, while major tranquilizers, analgesics, stimulants, antidepressants, antihistaminics, and purely sedative drugs are inactive.
• test procedure is modified from Boissier, et al., European J. Pharm., 4, 145-151 (1968).
• Female white mice, fasted 16-22 hours, are randomly distributed to fiberglass holding boxes. Mice in groups of 10-20 are dosed orally and returned to their holding boxes until test time.
• Test drug suspensions or solutions are prepared by sonication in 1% Methocele. Typical dose ranges include 0.5, 1, 2, and 4 mg/kg or 1, 3, 9, 27, 81 mg/kg plus a vehicle control and are selected to include one dose at which an effect such as sedation, stimulation, muscle weakness or analgesia was seen.
• the test apparatus is an opaque, black plastic box with a clear lid and a stainless steel grid floor.
• the floor of the test box is marked off into four squares of equal size.
• a mouse is gently placed in one corner of the testing box and during the next minute each time the mouse makes a full crossing from one square section of the box to another, the floor is electrified with 0.2 ma current for 2.0 seconds.
• Potency in the antipentylenetetrazole (PTZ) and the MAST indicates a potent antianxiety agent.
• Great potency for blockade of the mouse auditory pinna reflex with little or no effect on tactile pinna reflex is characteristic of minor tranquilizers.
• Centrally acting skeletal muscle relaxants profoundly affect the lift reflex with little effect on the grip reflex.
• Potency in the mouse anti-Straub tail test suggests skeletal muscle relaxant activity.
• the following table includes the results of these tests conducted with the compounds of this invention; it also includes the results for diazepam and chlordiaze- poxide, two well-known benzodiazepines widely-used commercially as tranquilizers.

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• 1977
  • 1977-06-16 US US05/807,075 patent/US4182760A/en not_active Expired - Lifetime
• 1978
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