Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D215/20—Oxygen atoms
  • C07D215/22—Oxygen atoms attached in position 2 or 4

Definitions

• R is methyl or ethoxy prepared by treating 3- phenyl-4-hydrocarbostyril with an acylating agent, which is useful as a minor tranquilizer with less side eifect and low toxicity.
• the present invention relates to 3-phenyl-4-acyloxycarbostyrils, and their production and use.
• the said 3-phenyl-4-acyloxycarbostyrils are representable by the formula:
• R is methyl or ethoxy and include specifically 3- phenyl-4-acetoxycarbostyril and 3 phenyl-4-ethoxycarbonyloxycarbostyril.
• 3-phenyl-4-acyloxycarbostyrils [I] exert a taming effect in fighting mice.
• mice of dd strain weighing 18 to 20 g. each were used and divided into 5 groups each consisting of a pair. Two mice were put on an electrical stimulator and a 200 ml. beaker was placed upside down over the mice. Electric stimulation was given at the intervals of 7 sec. (540 v., 3 ma.). The time until two mice began to fight was measured with a timer at various times after administration of the test compound and calculated in terms of the score of 1 to 9 respectively for 0 to 5 sec., 6 to 10 sec., 11 to 15 sec., 16 to 20 sec., 21 to 25 sec., 26 to 30 sec., 31 to 35 sec., 36 to 40 sec. and more than 40 sec. The dosage showing an average mark of 5 was taken as ED Results ED (mg/kg,
• Test compound per os) 3phenyl-4-acetoxycarbostyril 11.5 3-phenyl-4-ethoxycarbonyloxycarbostyril 10.5 3-phenyl-4-hydroxycarbostyril 100 3-phenyl-4-propionyloxycarbostyril 96.0 3-phenyl-4-phenacetyloxycarbostyril 100 3-phenyl-4-benzoyloxycarbostyril 100 3-phenyl-4-propoxycarbonyloxycarbostyril 96.0 3-phenyl-4-phenyloxycarbonyloxycarbostyril 100 1-ethyl-3-phenyl-4-acetoxycarbostyril 100 1-ethyl-3-phenyl-4-ethoxycarbonyloxycarbostyril 100 1-methyl-3-phenyl-4-hydroxycarbostyril 100 1-ethyl-3-phenyl-4-hydroxycarbostyril 100 chlordiazepoxide 18.0
• the 3-phenyl-4- acyloxycarbostyrils [I] are less effective in muscle relaxation, which is considered as an unfavorable side action for the use of tanquilizers.
• the ED values of 3-phenyl-4-acetoxycarbostyril and 3-phenyl-4-ethoxycarbonyloxycarbostyril are respectively 113.0 and 117.0 mg./kg. whereas the ED value of chlordiazepoxide is 45.3 mg./kg.
• the toxicity of the 3-phenyl- 4-acyloxycarbostyrils [I] is extremely low.
• the LD values of 3-phenyl-4-acetoxycarbostyril and 3-phenyl-4-ethoxycarbonyloxycarbostyril are both more than 3,000 mg./kg.
• the LD value of chlordiazepoxide is 1,325 mg./kg.
• 3-phenyl-4-acyloxycarbostyrils [I] of the present invention are useful as minor tranquilizers with less side effect and low toxicity.
• a clinical dosage of the 3-phenyl-4-acyloxycarbostyrils [I] depends on disease syndrome, body weight, age and administration mode, but it is generally in the range of 0.05 to 500 mg./day, preferably of 0.5 to 200 mg./day. They can be used in a unit dosage form as tablets or capsules for oral administration or optionally in combination with suitable adjuvants such as calcium carbonate, starch, lactose, talc, magnesium stearate, carboxymethyl cellulose and gum acacia. Further, they can be formulated into aqueous alcohol, glycol, oil solutions or oil-water emulsions for oral administration in the same manner as conventional medical substances are formulated.
• the 3-phenyllacyloxycarbostyril [I] is prepared by subjecting 3-phenyl- 4-hydroxycarbostyril of the formula:
• the acylation may be accomplished in one or two steps.
• the 3-phenyl-4-hydroxycarbostyril [II] or its monoalkali metal salt is treated with the reactive derivative of acetic acid or of carbonic acid ethyl ester in the presence or absence of a basic catalyst such as organic tertiary amine (e.g. pyridine, triethylamine, dimethylaniline) at a temperature from to 200 C., preferably from to 120 C.
• a basic catalyst such as organic tertiary amine (e.g. pyridine, triethylamine, dimethylaniline)
• the reactive derivative may be acid halide, acid anhydride, nitrophenyl ester, thiocyanate, dithiocarbamate, trithiophosphonate or the like.
• an inert organic solvent e.g. benzene, toluene, dioxane, carbon tetrachloride.
• the 3-phenyl-4-hydroxycarbostyril [II] or its monoalkali metal salt e.g. sodium salt, potassium salt
• phosgene or nitro-substituted phenoxycarbonyl chloride e.g. p-nitrophenoxycarbonyl chloride
• an inert organic solvent e.g. dichloromethane, chloroform, dioxane, tetrahydrofuran
• the above materials are mixed together, granulated and tableted in accordance with a conventional method to give 2,000 tablets, each weighing 50 mg.
• R is methyl or ethoxy

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Quinoline Compounds (AREA)

Applications Claiming Priority (1)

Publications (1)

Family

ID=11667424

Family Applications (1)

Country Status (7)

Cited By (3)

• 1970
  • 1970-01-27 US US6316A patent/US3635985A/en not_active Expired - Lifetime
  • 1970-01-28 DE DE19702003840 patent/DE2003840A1/de active Granted
  • 1970-01-29 GB GB1252861D patent/GB1252861A/en not_active Expired
  • 1970-01-30 BE BE745289D patent/BE745289A/fr unknown
  • 1970-01-30 DK DK44270AA patent/DK122127B/da unknown
  • 1970-01-30 FR FR707003333A patent/FR2030240B1/fr not_active Expired
  • 1970-02-02 CH CH145370A patent/CH529760A/de not_active IP Right Cessation

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