Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
  • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
  • C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines

Definitions

• dibenzo[c,e]azepin-5-ones disclosed herein are potent anti-inflammatory, anti-pyretic and analgesic agents. Also included herein are pharmaceutical compositions containing said dibenzo[c,e]azepin-5-one compounds as an active ingredient, and methods of treating inflammation, fever and pain in patients by administering said compounds. Further encompassed is 6,7- dihydro-S H-dibenzo[c,e ]azepin-5-one possessing novel anti-inflammatory, anti-pyretic and analgesic activities.
• novel dibenzo[-c,e]azepin-5-ones which are highly effective in the treatment of inflammation, pain and fever.
• the novel dibenzo[c,e]azepin-5-ones are of value in the treatment of arthritic and dermatological disorders of like conditions responsive to anti-inflammatory drugs. In general they are indicated for a wide variety of conditions where one or more of the symptoms of inflammation, fever and pain are manifested. Included within this category are diseases such as rheumatoid arthritis, osteo-arthritis, gout, infectious arthritis and wherein n, R2, R and R are eac hydrogen, halogen, such as fluorine,
• alkoxy such as methoxy
• dialkylamino such as dimethylamino, diethylamino, methylethylamino and the like
• dialkenylamino such as I dibutenylamino, dipentenylamino, dipropenylamino and the like
• alkylamino such as methylamino, ethylamino, butylamino and the like
• arylamino such as anilino, o,m or p-tolylamino, anisidino and the like
• aralkylamino such as benzylamino, phenethylamino, o,m or p-methoxybenzylamino, o,m or p-halobenzylamino, alkenylamino, such as butenylamino, propenylamino and the like
• alkenylsulfoxide such as allylsulfoxide and the like
• arylsulfoxide such as phenylsulfoxide
• aralkylsulfoxide such as benzylsulfoxide
• alkylsulfone such as methylsulfone
• alkenylsulfone such as butenylsulfone
• arylsulfone such as phenylsulfone
• aralkylsulfone such as benzylsulfone
• arylcarbamoyl such as phenylcarbamoyl
• dipropenylcarbamoyl and the like amidino, ureido, carbamoyloxy N-alkylcarbamoyloxy, such as N-methylcarbamoyloxy N-ethylcarbamyloxy N-isopropylc'arbamyloxy N-butylcarbamyloxy and the like, N-dialkylcarbamoyloxy, such as N-dimethylcarbamoyloxy,
• alkylsulfamyl such as methylsulfamyl, ethylsulfamyl, isopropylsulfamyl
• dialkylsulfamyl such as dimethylsulfamyl, diethylsulfamyl, methylethylsulfamyl, di-isopropylsulfamyl and the like
• haloalkoxy such as trifluoromethoxy, difluoromethoxy, dibromoethoxy, dichloromethoxy, trifluoroethoxy, fluoromethoxy and the like
• haloalkylthio such as trifluoromethylthio, difluoromethylthio, fluoromethylthio, bromomethylthio, dichloroethylthio, trifluoroethylthio and the like
• alkenyloxy such as propenyloxy, ethenyloxy and the like
• aryloxy such as phenoxy, o,m or p-halophenoxy, o,m or p-tolyloxy
• a-carboxyethyl and the like carboxyalkenyl, such as a-c arboxy( ethylidenyl a-carboxy(butenyl) and the like;
• R is hydrogen, alkyl, such as methyl, ethyl, propyl and the like, acyl, such as acetyl, propionyl, butyryl and the like, aroyl, such as o,m or p-halobenzoyl, benzoyl and the like, alkoxyalkyl, such as nethoxymethyl, methoxyethyl, propyloxymethyl and the like, aminoalkyl, such as aminoethyl, aminopropyl, aminobutyl and the, like, carboxyalkyl, such as carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl and the like, hydroxyalkyl, such as hydroxymethyl, hydroxyethyl,
• alkenyl such as propenyl, v butenyl and the like
• alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, isopropyloxycarbonyl and the like
• carbamoyl, carboxyalkoxy such as carboxymethoxy, carboxyethoxy, carboxyis'opropyloxy and the like
• mercaptoalkyl such as mercaptomethyl, mercaptoethyl, I mercaptoisopropyl, mercaptobutyl and the like
• 'alkylthioalkyl such as methylthiomethyl, methylthiomethyl, methylthioethyl, ethylthiomethyl, ethylthioethyl, isopropylthioethyl and the like
• aralkylthioalkyl such as benzylthioethyl, o,m or
• R is hydrogen, acylimido, or acetylimido; with the proviso that when R is hydrogen or alkyl at least one of R R and R is other than hydrogen.
• novel compounds of the invention are prepared by employing 6,7-dihydro-5H-dibenzo[c,e]azepin- 5-one (A) as the starting material wherein R is hydrogen.
• said starting material (A) is treated with a nitrating reagent whereby there is obtained a mono-nitro derivative in the ring containing position 8,9,10 and ll (B) or a dinitro derivative where the other ring containing position 1,2,3 and 4 is nitrated (L).
• the nitro substituent of the compound thus obtained is reduced to obtain monoor di-amino-6,7- dihydro-5Hdibenzo[c,elazepin-S-one (C).
• This amino compound is then diazotized and converted to the corresponding monoor di-haloazepin-S-one (D). Treating the compound thus obtained with a cyano forming reagent yields the corresponding monoor di-cyanoazepin-S-one (E). This compound is then hydrolyzed to obtain the corresponding monoor di-carbamoylazepin-S-one (F). Said carbamoyl compound is further hydrolyzed to obtain the corresponding acid (G). This compound is then treated with a trihalo forming reagent to yield the corresponding monoor ditrihalomethyl compound (V).
• Said monoor di-trihalo compound (V) is then treated with an R forming reagent thereby obtaining the corresponding N-substituted compound (W).
• the carboxy compound (G) is then treated with an acid halide forming reagent to obtain the corresponding monoor di-acid halide (H). Reacting this compound with an amino reagent gives the corresponding monoor di-substituted-carbamoyl (I).
• Said Monoor di-substituted carbamoyl compound (I) is then treated with an R forming reagent whereby there is obtained the corresponding N-substituted compound (J).
• compound (E) is treated with an alkoxyamidino forming reagent to obtain the corresponding monoor di-(alkoxyamidino)azepin 5-one (Q). Said monoor di-(alkoxyamidino) compound (0') is then converted to the corresponding monoor di-(amidino)- 6,7-dihydro-azepin-5-one (R).
• Monoor di-nitro-6,7- dihydro-SH-dibenzo[c,e]azepin-5-one (B) is treated with an R reagent to obtain monoor dinitro-N-R -,-6,7- dihydro-5l-l-dibenzo[c,e]azepin-5-one.
• S Compound (S) is then reduced to obtain the corresponding monoor di-amino-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one (Y).
• the compound (Y) thus obtained is then treated with a diazotizing reagent in the presence of an acid to obtain the corresponding monoor di-hydroxy-dibenzo[c,e]azepin-S-one (B').
• Compound (A) is then nitrated to obtain the corresponding nitro-, monoor di-(alkoxy or aralkoxy)- azepin-S-one (J compound (B') is treated with an alkylcarbamyloxy forming reagent whereby there is obtained the corresponding monoor di-alkyl-carbamyloxy-azepin-S-one (L).
• said compound (B') can be treated with a haloalkoxy forming reagent to obtain the corresponding monoor di-(haloalkoxy)- azepin-S-one (K).
• Treating compound (Y), N-substituted-monoor di-amino-6,7-dihydro-5H-dibenzo[c- ,e]-azepin-5-one with a mercapto forming reagent gives the corresponding mono-or di-mercapto-azepin-5-one (M').
• SAid mono or di-mercapto compound (M') is then converted to the corresponding monoor di- (haloethylthio)-azepin-5-one (0').
• compound (Y) is treated with a ureido forming reagent to obtain the corresponding monoor di-(ureido)-6,7-dihydroazepin-S-one N
• Compound (C) monoor di-amino-6,7- dihydrodibenzo[c,e]azepin-5-one, is treated with an acyl, aroyl or aralkyloyl forming reagent whereby there is obtained the corresponding monoor di-acyl, aroyl or aralkyloyl-6-acetyl, aroyl or aralkylOyl-azepin-S-one (T).
• compound (T) is then nitrated to obtain the corresponding nitro-monoor di-(acetylamino, aroylamino or aralkoyl-amino)-6,7-dihydro-azepin- 5-one (P').
• compound (C) is treated with a diazotizing reagent in the presence of an acid to obtain monoor di-hydroxy- 6,7-dihydro-dibenzo[c,e]azepin 5-one (M).
• novel monoor di-sulfur derivatives of the invention are obtained by employing compound (D), monoor di-halo-6,7-dihydro-dibenzo[c,e]azepin-5-one as the starting material.
• Compound (D) is treated with an R forming substituent to obtain the corresponding monoor di-halo-N-substituted-azepin-S-one (N).
• Compound (N) is treated with an alkyl, aryl or alkyl-sulfide forming reagent to yield the corresponding monoor dialkyl, aryl or aralkylthio-azepin-S-one (U).
• the monoor di-alkyl, aryl or aralkylthio substituent may be converted to the mercapto substituent.
• the compound (U) thus obtained is then treated with an oxidizing reagent to yield the corresponding monoor di-alkyl, aryl or aralkyl-sulfinyl-azepin-S-one (X). Further oxidation of this sulfinyl compound gives the corresponding monoor di-alkyl, aryl or aralkylsulfoneazepin-S-one (C').
• Said starting material (E) is treated with an R forming substituent whereby there is obtained monoor di-cyano-N-R -6,7-dihydro-dibenzo[c,e]azepin- 3O 8 5-one (O)
• This compound is then hydrolyzed to obtain the corresponding monoor dicarbamoyl-azepin-S-one (P).
• Said carbamoyl compound (P) is further hydroylzed to yield the corresponding monoor di-carboxyazepin-S-one (Q).
• compound (A) is treated with an alkylthioalkyl forming reagent to obtain 6- (methylthiomethyl)-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one (F).
• the compound thus obtained is then oxidized to yield the corresponding 6- (methylsulfinylmethyl)-6,7-dihydro-azepin-S-one (G)
• the novel monoordi-sulfamyl derivatives of the invention are obtained by employing compound (R) as the starting material, wherein R is as previously defined.
• N-substituted-6,7- dihydro-5H-dibenzo[c,e]azepin-5-one is treated with a sulfamyl forming reagent whereby there can be obtained the corresponding N substitute'dmonoor disulfonyl halide-azepin-5-one (H) intermediate, and the corresponding N-substituted-mono-or di-sulfamylazepin-5-one (l).
• Flow Sheet 1 represents the general sequence for the preparation of the novel compounds of the invention (c Y, L,
• aralkyl such as benzyl, phenethyl, 0, m or pmethylbenzyl, o, m or p-methoxybenzyl and the like; 55
• R is alkyl such as methyl, ethyl, isopropyl and the like; Y is halogen such as fluorine, bromine and the like; X is an integer ranging from 1 4; and N is an integer equal to 0 to 1.
• Step 1.2 bination of sulfuric acid and potassium nitrate at room temperature until the reaction is complete.
• the reaction is performed by hydrogenation over a catalyst such as palladium-on-carbon, platinum, Raney nickel, and the like, in the presence of an inert solvent such as ethanol, propanol, butanol, benzene, toluene, tetrahydrofuran, ether and the like, at temperatures ranging from C. to near reflux.
• a catalyst such as palladium-on-carbon, platinum, Raney nickel, and the like
• an inert solvent such as ethanol, propanol, butanol, benzene, toluene, tetrahydrofuran, ether and the like, at temperatures ranging from C. to near reflux.
• an inert solvent such as ethanol, propanol, butanol, benzene, toluene, tetrahydrofuran, ether and the like
• the reaction is performed in a water-acid solvent such as water-sulfuric acid, water-fluoroboric acid, water-hydrochloric acid, water-p-toluenesulfonic acid and the like, in the presence of a diazotizing agent such as sodium nitrite, nitrous acid and the like, with a halogenating reagent such as cuprous halide (cuprous chloride, cuprous bromide, cuprous fluoride and the like), at temperatures ranging from 0C. to reflux.
• a water-acid solvent such as water-sulfuric acid, water-fluoroboric acid, water-hydrochloric acid, water-p-toluenesulfonic acid and the like
• a diazotizing agent such as sodium nitrite, nitrous acid and the like
• a halogenating reagent such as cuprous halide (cuprous chloride, cuprous bromide, cuprous fluoride and the like)
• the reaction is performed in an inert solvent such as dimethyl formamide, benzene, toluene, ethanol, dimethylsulfoxide, dimethoxyethane, and the like, with a cyano forming reagent such as cuprous cyanide, alkali cyanide (potassium, lithium and the like), at temperatures ranging from room temperature to reflux.
• a cyano forming reagent such as cuprous cyanide, alkali cyanide (potassium, lithium and the like)
• the reaction is performed in an acid such as sulfuric, phosphoric, methanesulfonic and the like, at temperatures ranging from 0C. to 50C.
• an acid such as sulfuric, phosphoric, methanesulfonic and the like, at temperatures ranging from 0C. to 50C.
• sulfuric acid at room temperature until the reaction is complete.
• the reaction is performed in an inert solvent such as chloroform, benzene, toluene, dimethylsulfoxide, ether and the like, with a N-halo-acylimide such as N- bromosuccinimide, N-chlorosuccinimide, and the like, at temperatures ranging from near reflux to reflux.
• an inert solvent such as chloroform, benzene, toluene, dimethylsulfoxide, ether and the like
• a N-halo-acylimide such as N- bromosuccinimide, N-chlorosuccinimide, and the like
• the reaction is performed in an inert solvent such as ether, dimethylsulfoxide, tetrahydrofuran, benzene, toluene and the like, in the presence of a base such as sodium hydride, sodium amide, potassium hydroxide and the like with an alkyl halide such as methyl iodide, propyl bromide, butyl iodide and the like, or an alkenyl halide such as allyl bromide, vinyl iodide, propenyl chloride and the like, at temperatures ranging from 0C. to 60C.
• a base such as sodium hydride, sodium amide, potassium hydroxide and the like
• an alkyl halide such as methyl iodide, propyl bromide, butyl iodide and the like
• an alkenyl halide such as allyl bromide, vinyl iodide, propenyl chloride and the like
• the reaction is performed with an acyl, aroyl or aralkoyl forming reagent such as acetic anhydride, propionic anhydride, benzoic anhydride, benzoyl chloride, phenyl propionyl chloride and the like, at temperatures ranging from 60C. to near reflux.
• an acyl, aroyl or aralkoyl forming reagent such as acetic anhydride, propionic anhydride, benzoic anhydride, benzoyl chloride, phenyl propionyl chloride and the like, at temperatures ranging from 60C. to near reflux.
• acetic anhydride at 90C.-95C. until the reaction is complete.
• the reaction is performed by diazotizing the amine in an aqueous acid solution such as sulfuric acid, hydrochloric acid, and the like, with sodium nitrite, and raising the temperature from 0C. to 100C. until the reaction is complete.
• reaction is performed in an inert solvent such as dimethylformamide, benzene, tetrahydrofuran, ether, toluene, and the like, in the presence of a base such as sodium methoxide, ammonium hydroxide, potassium hydroxide and the like, with alkyl halide, aryl halide or aralkyl halide such as methyl iodide, propyl iodide,
• the reaction is performed with copper, lutidine and dialkyldisulfide such as dimethyldisulfide, diethyldisulfide, diphenyldisulfide, benzyldisulfide and the likecomplex at temperatures ranging from C. to 175C. Of particular preference is dimethyldisulfide complex at 155C. until the reaction is complete.
• the reaction is performed in a combination of inert v solvents such as acetone-methanol, water-acetone, methanol-water, benzene-ethanol and the like, with an oxidizing agent such as sodium periodate, oxygen, hydrogen peroxide and the like, at temperatures ranging from 20C. to 50C.
• inert v solvents such as acetone-methanol, water-acetone, methanol-water, benzene-ethanol and the like
• an oxidizing agent such as sodium periodate, oxygen, hydrogen peroxide and the like
• the reaction is performed in an acid such as acetic acid, propionic acid, N-butyric acid and the like, with an oxidizing agent such as hydrogen peroxide, sodium periodate, oxygen and the like, in the presence of the acid employed as the solvent, at temperatures ranging from 0C. to 60C.
• an oxidizing agent such as hydrogen peroxide, sodium periodate, oxygen and the like
• the acid employed as the solvent at temperatures ranging from 0C. to 60C.
• acetic acid and hydrogen peroxide-acetic acid at room temperature until the reaction is complete.
• the reaction is performed with an acid such as sulfuric acid, hydrochloric acid, p-toluenesulfonic acid, methanesulfonic acid and the like, in the presence of a diazotizing reagent such as sodium nitrite, nitrous acid and the like, at temperatures ranging from 40C. to C.
• a diazotizing reagent such as sodium nitrite, nitrous acid and the like, at temperatures ranging from 40C. to C.
• sulfuric acid and sodium nitrite at 75C. until the reaction is complete.
• the reaction is performed with or without an inert solvent such as ether, benzene, and the like, and an acid halide forming reagent such as phosphorus trichloride, phosphorus pentachloride, thionyl chloride, phosphorus tribromide and the like, at temperatures ranging from room' temperature to reflux. Of particular preference is thionyl chloride at reflux until the reaction is complete.
• the reaction is performed with an aqueous monoor di-alkylamine such as methylamine, dimethylamine, propylamine; monoor di-arylamine or monoor diaralkylamine such as aniline, diphenylamine, benzylamine, dibenzylamine, B-phenethylamine and the like,
• an aqueous monoor di-alkylamine such as methylamine, dimethylamine, propylamine
• monoor di-arylamine or monoor diaralkylamine such as aniline, diphenylamine, benzylamine, dibenzylamine, B-phenethylamine and the like
• the reaction is performed in the presence of a hydrohalic acid such as hydrochloric acid, hydrobromic acid, hydrofluoric acid and the like, with a halogenating reagent such as sulfur tetrafluoride, sulfur tetrachloride, sulfur tetrabromide and the like, in a stainless steel container at temperatures ranging from 50C. to 175C.
• a hydrohalic acid such as hydrochloric acid, hydrobromic acid, hydrofluoric acid and the like
• a halogenating reagent such as sulfur tetrafluoride, sulfur tetrachloride, sulfur tetrabromide and the like
• the reaction is performed in an inert solvent such as dimethylforrnamide, tetrahydrofuran, dioxane and the like, with an alkyl halocarbonate such as ethyl chlorocarbonate, methyl chlorocarbonate and the like, at temperatures ranging from C. to room temperature.
• an inert solvent such as dimethylforrnamide, tetrahydrofuran, dioxane and the like
• an alkyl halocarbonate such as ethyl chlorocarbonate, methyl chlorocarbonate and the like
• the reaction is performed in a base such as ammonium hydroxide, methylamine, methylethylamine, dimethylamine, and the like, at temperatures ranging from 10C. to 50C. Of particular preference is ammonium hydroxide at 35C. until the reaction is complete.
• a base such as ammonium hydroxide, methylamine, methylethylamine, dimethylamine, and the like.
• ammonium hydroxide at 35C. until the reaction is complete.
• the reaction is performed in an inert solvent such as dimethylfonnamide, tetrahydrofuran, dioxane, benzene and the like, in thepresence of a base such as NaH, LiH and the like, with a haloalkyl alkyl sulfide such as chloromethyl methyl sulfide, chloroethyl ethyl sulfide and the like, at temperatures ranging from 0C. to room temperature.
• a base such as NaH, LiH and the like
• a haloalkyl alkyl sulfide such as chloromethyl methyl sulfide, chloroethyl ethyl sulfide and the like
• the reaction is performed in a solvent such as ace-' tone, acetic acid, dimethylforrnamide and the like, with an oxidizing agent such as sodium periodate, potassium periodate and the like at temperatures ranging from 10C. to 40C.
• a solvent such as ace-' tone, acetic acid, dimethylforrnamide and the like
• an oxidizing agent such as sodium periodate, potassium periodate and the like at temperatures ranging from 10C. to 40C.
• a solvent such as ace-' tone, acetic acid, dimethylforrnamide and the like
• the reaction is performed in a halosulfonic acid such as chlorosulfonic acid.
• This intermediate is added to a base such as ammonium hydroxide, methylamine, dimethylamine and the like, attemperatures below 30C. until the reaction is complete.
• the reaction is performed in an inert solvent such as dimethylforrnamide, tetrahydrofuran, dioxane and the like, with a haloalkene at temperatures ranging from 60C. to 120C. in a sealed container.
• an inert solvent such as dimethylforrnamide, tetrahydrofuran, dioxane and the like
• a haloalkene at temperatures ranging from 60C. to 120C.
• a sealed container is the combination of dimethylforrnamide and fluoro-chloro ethylene at 100C. until the reaction is complete.
• the reaction is performed in an inert solvent such as tetrahydrofuran, methylene chloride, dioxane, dimeth ylformamide and the like, with an alkyl isocyanate such as ethyl isocyanate, methyl isocyanate and the like, at temperatures ranging from 10C. to C
• an inert solvent such as tetrahydrofuran, methylene chloride, dioxane, dimeth ylformamide and the like
• an alkyl isocyanate such as ethyl isocyanate, methyl isocyanate and the like
• the reaction is performed in an acid such as acetic, propionic, hydrochloric and the like, with an alkali isocyanate such as potassium isocyanate, sodium isocyanate and the like at temperatures ranging between 10C and 40C.
• an alkali isocyanate such as potassium isocyanate, sodium isocyanate and the like at temperatures ranging between 10C and 40C.
• acetic acid and potassium isocyanate at room temperature until the reaction is complete.
• the reaction is performed with a diazotizing agent, treated with an alkali alkyl xanthate such as potassium xanthate, sodium xanthate and the like, and hydrolyzed.
• a diazotizing agent such as potassium xanthate, sodium xanthate and the like
• the reaction is performed in an alkanol solvent such as methanol, ethanol, propanol and the like and a reagent such as hydrochloride, hydrobromide and the like.
• This intermediate is added to a base such as ammonia, methylamine, dimethylamine and the like, at temperatures ranging between 0C. and room temperature.
• a base such as ammonia, methylamine, dimethylamine and the like, at temperatures ranging between 0C. and room temperature.
• a base such as ammonia, methylamine, dimethylamine and the like
• Representative compounds of the invention are:
• the oral form ranging from 10 to 2,000 mg./kg. of body weight per day. Of preference is 50-500 mg./kg. of body weight per day for varying periods of treatment as required. Comparable amounts of the compounds may be administered in topical or parenteral forms.
• the compounds of the invention may be administered orally, topically and parenterally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
• parenteral as used herein includes intravenous or intramuscular.
• the compounds of the invention are effective in the treatment of humans.
• compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs.
• Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide a pharmaceutically elegant and palatable prepareation. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for manufacture of tablets.
• excipients may be, for example, inert dilu ents such as calcium carbonate, sodium carbonate, lac-' tose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, maize starch or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example, magnesium stearate, stearic acid or talc.
• the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastro-intestinal tract and thereby provide a sustained action over a longer period.
• a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
• Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example arachis oil, peanut oil, liquid paraffin or olive oil.
• an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
• water or an oil medium for example arachis oil, peanut oil, liquid paraffin or olive oil.
• Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
• excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example, polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example, polyoxyethylene sorb
• the said aqueous suspensions may also contain one or more preservatives, for example, ethyl or npropyl p-hydroxy benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.
• preservatives for example, ethyl or npropyl p-hydroxy benzoate
• coloring agents for example, ethyl or npropyl p-hydroxy benzoate
• flavoring agents such as sucrose or saccharin.
• sweetening agents such as sucrose or saccharin.
• Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example, arachis oil, olive oil, sesame oil, or coconutoil, or in a mineral oil such as liquid paraffin'
• the oil suspensions may contain a thickening agent, for example, beeswax, hard paraffin or cetyl alcohol.
• Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
• These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
• Dispersible powders and granules suitable for preparation of an aqueous suspension by the additionof water provide the active ingredient in admixture with v a dispersing or wetting agent, suspending agent and one or more preservatives.
• Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, flavoring and coloring agents, may also be present.
• the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
• the oily phase may be a vegetable oil, for example, olive oil or arachis oils, or a mineral 01, for example, liquid paraffin or mixtures of these.
• Suitable emulsifying agents may be naturally-occurring gums, for example, gum acacia or gum tragacanth, naturally-occurring phosphatides, for example, soya bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example, sorbitan mono-oleate, and condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate.
• the emulsions may also contain sweetening and flavoring agents.
• Syrups and elixirs may be formulated with sweetening agents, for example, glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
• the pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleagenous suspension.
• This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
• the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in a 1,3-butane diol.
• acceptable vehicles and solvents that may be employed are water, Ringers solution, and isotonic sodium chloride solution.
• sterile, fixed oils are conventionally employed as a solvent or suspending medium.
• any bland fixed oil may be employed including synthetic monoor di-glycerides.
• fatty acids such as oleic acid find use in the preparation of injectables.
• the amount of active ingredient that may be com- I bined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
• a formulation intended for the oral administration of humans may contain from 5 mg. to 10 grams of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition.
• Dosage unit forms will generally contain between from about 175 mg. to about 1.75 g. of active ingredient. Comparable amounts of the compounds may be administered in topical or parenteral forms.
• the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
• the starting material employed in the invention is represented by compound (A) which is shown in Flow Sheet I.
• Said starting material is known and processes for its preparation can be found in the literature. For example, see U.S.S.R. Patent 261,390 and US. Pat. No. 3,551,414.
• the mixture is extracted with 3 X 250 ml. of ethyl acetate.
• the compound extracts are washed with water and then with aqueous sodium bicarbonate.
• the ethyl acetate is evaporated and the residue is purified by crystallization from dimethylformamide-ether to obtain the product, 9-cyano-6,7-dihydro- 5H-dibenzo[c,e]azepin-5-one, mp. 272-274C.
• 6-acetyl, benzoyl, methyl or allyl-9-cyano-6,7- dihyro-5H-dibenzo[c,e]azepin-5-one is substitutedfor 9-cyano-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one, there is obtained 6-acetyl, benzoyl, methyl or a1lyl-9- carbamoyl-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one.
• EXAMPLE 7 9-( N ,N-Dimethylcarbamyl )-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one
• One gram (.004 mole) of 9-carboxy-6,7-dihydro-5H- dibenzo[c,e]azepin-S-one is refluxed in ml. of thionyl chloride for 3 hours. The excess reactant is removed in vacuo and the residue is dissolved in acetone. The resulting solution is added to a cooled and stirred solution of 20 ml. of 40% aqueous dimethylamine over a 15 minute period. The crude product, 9-(N,N- dimethylcarbamoyl)-6,7-dihydro-5H-dibenzo[c,elazepin-S-one, is filtered and recrystallized from dimethylformamide-ether.
• EXAMPLE l0 9-Nitro-6-acetyl-6,7-dihydro-5H-dibenzo[c,e]azepin- 5-one
• the procedure of Example 9 is repeated, except that the starting material is 9-nitro-6,7-dihydro-dibenzo[c- ,e]azepin-5-one.
• the product '9-nitro- 6-acetyl-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one.
• dibenzo[c,e]azepin-S-one is substituted for'9-carboxy- 6,7-dihydro-5H-dibenzo[c,e ]azepin-5-one, tthere is obtained 6-methyl or allyl-9-(N,N'- dimethylcarbamoyl )-6,7-dihydro-5H-dibenzo- [c,e]azepin-5-one.
• EXAMPLE 13 The procedure of Example 2 is repeated, except that the starting material is 6-acetyl, benzoyl, methyl or allyl-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one. Using the same reaction conditions and techniques, there is obtained the product, 6-acetyl, benzoyl, methyl or allyl-9- nitro-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one.
• EXAMPLE 15 9-Nitro-6-methyl-6,7-dihydro-5H-dibenzo[c,e]azepin- -one
• the procedure of Example 14 is repeated, except that the starting material is 9-nitro-6,7-dihydro-5H- dibenzo[c,elazepin-S-one.
• the product 9-nitro-6-methyl-6,7-dihydro-5H-dibenzo[c.e]azepin-S-one.
• EXAMPLE l6 o-Acetyl-9-acetylamino-fiJ-dihydro-SH-dibenzo[c- .e lazepin-S-one 1.1 Grams (.005 mole) of 9-amino-6,7-dihydro-5H- dibenzo[c,e]azepin-5-one is heated in 20 ml. of acetic anhydride on the steam-bath at 9095C. for 18 hours. Most of the excess anhydride is removed in vacuo and the residue is tritrated with water until solidification. The product, 6-acetyl-9-acetylamino-6,7-dihydro-5H- dibenzo[c,e]azepin-5-one, is purified by crystallization from benzene.
• EXAMPLE 17 9-Methylthio-6,7 dihydro-5H-dibenzo[c,e]azepin- 5-one'
• a mixture containing 380 mg. of copper powder, ml. of 2,4-lutidine and 660 mg. of dimethyl disulfide is heated at 125C. for 4 hours.
• the mixture is cooled and 1.5 g. of 9-bromo-6,7-dihydro-5H-dibenzo[c,e]azepin- 5-one is added.
• This mixture is heated at 155C. for 18 hours.
• the solvent is evaporated and the product, 9- methylthio-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one, is isolated from the residue by column chromatography.
• EXAMPLE 1 9-Methylsulfinyl-6,7-dihydro-5H-dibenzo[c,e]azepin- 5-one
• a solution of 2.4 g. of 9-methylthio-6,7- dihydro-5H-dibenzo[c,e]azepin-5-one in 50 ml. of acetone and 50 ml. of methanol is added a solution of 2.1 g. of sodium periodate in 30 ml. of water over one hour. The reaction mixture is stirred overnight. Most of the organic solvent is evaporated and the crude product, 9-methylsulfinyl-6,7-dihydro-5H-dibenzo[c,elazepin- 5-one, can be recrystallized or purified by column chromatography.
• reaction mixture is maintained at room temperature with slight agitation for 1.6 hours, then poured into ice and filtered to obtain the product, 9-methylsulfony1-6,7-dihydro-5H-dibenzo[c- ,elazepin-S-one.
• EXAMPLE 20 9-Mercapto-6.7-dihydro-5 H-dibenzo[c,e ]azepin-5-one
• a mixture of 1.2 g. of 9-methylthio-6,7-dihydro-5H- dibenzo[c,e]azepin-5-one and 5 g. (.04 mole of pyridine hydrochloride under a nitrogen atmosphere is placed in an oil-bath at 230C. The mixture is heated for 10 minutes, cooled and extracted with hot ethyl acetate. The ethyl acetate extracts are evaporated to obtain the product, 9-mercapto-6,7-dihydro-5H dibenzo[c,e]azepin-5-one.
• EXAMPLE 21 9-Trifluoromethyl-6,7-dihydro-5H-dibenzo[c,elazepin-5-one
• a mixture containing 2.5 g. of 9-carboxy-6,7- dihydro-5H-dibenzo[c,e]azepin-5-one, hydrogen fluoride, and about 0.05 mole of sulfur tetrafluoride in a stainless steel lined shaker is heated at C. for 8 hours. The reaction mixture is cooled, vented, and then concentrated.
• the crude product, 9-trifluoromethyl- 6,7-dihydro-5H-dibenzo[c,e]azepin-5-one can be purified by crystallization or column chromatography.
• EXAMPLE 22 9-Trifluoromethyl-6-acetyl-6,7-dihydro-5H-dibenzo[c- ,e]azepin-5-one
• the procedure of Example 9 is repeated, except that the starting material is 9-trifluoromethyl-6,7-dihydro- 5H-dibenzo[c,e]azepin-5-one.
• the product 9-trifluoromethyl-6-acetyl-6,7-dihydro-5l-l-dibenzo[c,e]azepin-5-one.
• the reaction mixture is stirred in ice an additional minutes and then at room temperature for an hour.
• the reaction is warmed on the steam-bath for minutes, filtered and the filtrate is diluted with 0.5 N sodium hydroxide solution until the product crystallizes.
• the product, 9-methoxy-6,7-dihydro-5H-dibenzo[c,e]azepin-S-one, is purified from benzene-petroleum ether, mp. 183C.
• EXAMPLE 26 9-Amidino-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one
• Into a cold suspension of equal molar quantities of 9-cyano-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one and ethanol is passed dry hydrogen chloride until the mixture is saturated. After standing 24 hours, the excess hydrogen chloride is removed and an excess of aqueous ammonia added. The resulting compound is 9-amidino-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one.
• EXAMPLE 29 9-( Ethylcarbamyloxy )-6-methyl-6,7-dihydro-5 H- dibenzo[c,e lazepin-S-one To a mixture of 9-hydroxy-6-methyl-6,7-dihydro-5H- A dibenzo[c,e]azepin-5-one in dioxane is added ethyl isocyanate to yield the title compound.
• EXAMPLE 31 9-( l ,1,2-Trifluoro-2-chloroethoxy)-6,7-dihydro-5H- dibenzo[c,e]azepin-5-one Into a solution of 5 grams of 9-hydroxy-6,7-dihydro- SH-dibenzo[c,e]azepin-5-one in 150 ml. of dimethylformamide is added 500 mg. of sodium methoxide and an excess of trifluorochloro ethylene. This solution is heated in a bomb at C. for 6 hours. The addition of water precipitates the product.
• EXAMPLE 32 EXAMPLE 33 9-Carbamyl-6,7-dihydro-5 H-dibenzo[c,e]azepin-5-one
• the above compound (9-carbethoxy-6,7-dihydro- 5H-dibenzo[c,e]azepin-5-one) is warmed in ammonium hydroxide for one hour to give the title compound.
• R is hydrogen, alkyl of up to three carbon atoms, al-
• kanoyl of up to four carbon atoms benzoyl, carbalkoxy of up to four carbon atoms, alkenyl of up to four carbon atoms, alkylthioalkyl of up to four carbon atoms, or methylsulfinylmethyl;
• R isv hydrogen, succinimido, acetylimido or phthalimido
• R is hydrogen, nitro, amino, halo. alkoxy of up to four carbon atoms, hydroxy, cyano, carbamyl, carboxy, dialkylcarbamyl of up to four carbon atoms, alkanoylamino of up to four carbon atoms, benzoylamino, alkylthio of up to four carbon atoms, phcnylthio, benzylthio, alkylsulfinyl of up to three carbon atoms, alkylsulfonyl of up to three carbon atoms, phenysulfinyl, benzylsulfinyl, mercapto, trifluoromethyl, amidino, ureido, alkylcarbamyloxy of up to four carbon atoms or sulfamyl; and R is hydrogen;
• R is hydrogen or methyl at least one of R R, or R is other then hydrogen.
• R is hydrogen, nitro, amino, fluro, bromo, chloro,
• dimethylcarbamyl acetylamino, benzoylamino, allyl propionylamino, methylthio, phenylthio, benzylthio, methylsulfinyl, methylsulfonyl, phenylsulfinyl, benzylsulfinyl, mercapto, trifluoromethyl, amidino, ureido, ethylcarbamyloxy, or sulfamyl; and
• R is hydrogen
• R is hydrogen, or methyl at least one of R R or R is other than hydrogen.
• R is alkanoyl of up tofour carbon atoms
• R is hydrogen, nitro, amino, halo, alkoxy of up to four carbon atoms, hydroxy, cyano, carbamyl, carboxy, dialkylcarbamyl of up to four carbon atoms, alkanoylamino of up to four carbon atoms, benzoylamino, alkylthio of up to four carbon atoms, phenylthio, benzylthio, alkylsulfinyl of up to three carbon atoms, alkylsulfonyl of up to three carbon atoms, phenysulfinyl, benzylsulfinyl, mercapto, trifluoromethyl, amidino, ureido, alkylcarbamyloxy of up to four carbon atoms or sulfamyl.
• R is butyryl. 8. A compound of the formula:
• R R10 l0 R 0 i N wherein Y R, R; R, and R,,, are each hydrogen, R is alkenyl of up to four carbon atoms, and
• R is hydrogen, nitro, amino, halo, alkoxy of up to four carbon atoms, hydroxy, cyano, carbamyl, carboxy, dialkylcarbamyl of up to four carbon atoms, alkanoylamino of up to four carbon atoms, phenylthio, benzylthio, alkylsulfinyl of up to three carbon atoms, alkylsulfonyl of up to three carbon atoms, phenysulfinyl, benzylsulfinyl, mercapto, trifluoromethyl, amidino, ureido, alkylcarbamyloxy ofup to four carbon atoms or sulfamyl.
• R is allyl.
• R R, R, and R,, are each hydrogen, R, is amino, and R is hydrogen, nitro, amino, halo, alkoxy of up to four carbon atoms, hydroxy, cyano, carbamyl, carboxy, dialkylcarbamyl of up to four carbon atoms,
• alkanoylamino of up to four carbon atoms phenylthio, benzylthio, alkylsulfinyl of up to three carbon atoms, alkylsulfonyl of up to three carbon atoms, phenysulfinyl, benzylsulfinyl, mercapto, trifluoromethyl, amidino, ureido, alkylcarbamyloxy of up to four carbon atoms or sulfamyl. 11.
• R9 Rm R1 R2 i f wherein R; R, R, and R,,, are each hydrogen, R, is halogen, and R is hydrogen, nitro, amino, halo, alkoxy of up to four carbon atoms, hydroxy, cyano, carbamyl, car- 12.
• R is fluoro and R is hydrogen.
• R is chloro and R is hydrogen.

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• 1971
  • 1971-08-09 US US00170384A patent/US3821201A/en not_active Expired - Lifetime
• 1972
  • 1972-07-27 NL NL7210374A patent/NL7210374A/xx not_active Application Discontinuation
  • 1972-07-28 SE SE7209885A patent/SE399426B/xx unknown
  • 1972-08-03 GB GB3633872A patent/GB1393600A/en not_active Expired
  • 1972-08-07 CH CH1164772A patent/CH582155A5/xx not_active IP Right Cessation
  • 1972-08-08 FR FR7228634A patent/FR2150748B1/fr not_active Expired
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