Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
  • C07C205/45—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by at least one doubly—bound oxygen atom, not being part of a —CHO group
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
  • C07D211/56—Nitrogen atoms

Definitions

• R and R can each be straight or branched chain lower alkyl ternatively R and R taken together with the 7-position nitrogen atomgcan form a m-onoheterocyclic ring containing at the most one further hetero atom selected from 3,262,665 Patented Aug. Z4, 1965 p we;
• halogen included all four halogens and especially preferred are fluorine and chlorine.
• the pharmaceutically acceptable salts of said compounds form pharmaceutically acceptable acid addition salts with pharmaceutically acceptable organicand inorganic acids; such as hydrochloric acid, hydrobrornic acid, sulfuric acid, phosphoric .acid, nitric acid, tartaric acid, citric acid, camphor sulfonic acid, ethane sulfonic acid, toluene 'sulfonic acid, ascorbic acid, salicylic acid, maleic acid, succinic acid, mandelic acid, formic acid, acetic acid and the like.
• pharmaceutically acceptable organicand inorganic acids such as hydrochloric acid, hydrobrornic acid, sulfuric acid, phosphoric .acid, nitric acid, tartaric acid, citric acid, camphor sulfonic acid, ethane sulfonic acid, toluene 'sulfonic acid, ascorbic acid, salicylic acid, maleic acid, succinic acid, mandelic acid, formic acid, acetic
• compounds of Formula I above form pharmacentically acceptable quaternary ammonium salts with conventional quaternizing agents, such as lower alkyl halides, lower alkylsulf-ates, aralkyl halides'and closed herein in order that the present disclosure may be complete.
• conventional quaternizing agents such as lower alkyl halides, lower alkylsulf-ates, aralkyl halides'and closed herein in order that the present disclosure may be complete.
• R R and R have the same meaning as above;
• the acid utilized is glycine, where R; is lower alkyl a-arnin-o acids having the formula R CH(NH )COOH are used to introduce the group K; into the final compound.
• Alanine for example is exemplary of such a-amino acids.
• the reaction of the 5-substituted amino-2-aminobenzophenones with an a-amino acid is carried out with an a-amino acid ester, such as a lower alkyl ester of an u-amino acid, and is preferably effected in the presence of an inert organic solvent such as pyridine, dimet-hylformamide, or the like.
• one of the materials, or a fraction thereof, present in the form of the salt of a strong organic or inorganic acid such as glycine hydrochloride, glycine ethyl ester hydrochloride, pyridine hydrochloride, or the like.
• the 5-(N-substituted-amino)- Z-aminobenzophenone described above is reacted with an a-halo-lower .alkanoyl halide to form a S-(N-substituted-amino)-2-(a-halo lower alkanoylamino)-benzophenone which can then be reacted with ammonia to yield the final product of Formula I above wherein A is Compounds of Formula I above wherein A is -CHNH i.e., the 4,5-dihydro derivatives, can be prepared from compounds of Formula I wherein A is by reduction. For example, the latter compounds can be reduced with hydrogen in the presence of a hydrogenation catalyst such as platinum oxide to yield the former compounds.
• a hydrogenation catalyst such as platinum oxide
• Another method for preparing compounds of Formula I above comprises the reductive alkylation of a compound of the formula (III) wherein A, R and R have the same meaning as above.
• This reductive alkylation is preferably conducted using hydrogen as a reducing agent in the presence of a hydrogenation catalyst such as Raney nickel.
• a hydrogenation catalyst such as Raney nickel.
• formaldehyde is used as the alkylating agent.
• This reductive alkylation can be conducted at room temperature or elevated temperatures, and is preferably conducted-in the presence of conventional inert organic solvent such as methanol, ethanol, or the like.
• R is lower alkyl
• Compounds of Formula I above, wherein R is lower alkyl can be derived from compounds of Formula III above wherein R is lower alkyl, or via condensation of 5-substituted amino-Z-lower alkylamino-benzophenones prepared from the above described 5-substituted amino-2- aminobenzophenones.
• compounds of Formula I above wherein R is lower alkyl can be prepared from corresponding compounds of Formula I above wherein R is hydrogen, by reacting the latter in the form of an alkali metal salt with di-lower alkyl sulfate, lower alkyl halide or similar alkylating agents, in an inert organic solvent medium such as ether, benzene, alcohol, dimethylformamide, dioxane, or the like, preferably at room temperature or below.
• an inert organic solvent medium such as ether, benzene, alcohol, dimethylformamide, dioxane, or the like, preferably at room temperature or below.
• the compounds of Formula I above are useful as sedatives, muscle relaxants and anticonvulsants.
• the compounds of Formula I, their pharmaceutically acceptable acid addition salts, and their pharmaceutically acceptable quaternary ammonium salts can be administered internally, i.e. parenterally or entrally, by incorporating therapeutic dosages in conventional pharmaceutical liquid or solid vehicles to provide elixirs, suspensions, tablets, capsules, and the like according to accepted pharmaceutical practice.
• Example 1 To a solution of 10 g. of 5-chloro-2-nitrobenzopheuone in 150 ml. of ethanol was added a solution of approximately 22 g. of dimethylamine in m1. of ethanol. The mixture was heated in an autoclave under nitrogen atmosphere to for 24 hours. The alcoholic solution was concentrated in vacuo and cooled. Yellow needles of S-dimethylamino-Z-nitrobenzophenone separated which were collected on a filter and after recrystallization from alcohol melted at -132.
• reaction mixture was washed successively with two 200 cc. portions of ice water, two 200 cc. portions of cold 10% sodium carbonate and finally with 200 cc. of 10% sodium chloride solution. Emulsions were broken by filtration through a thin pad of diatomaceous earth. The methylene chloride solution was dried over magnesium sulfate and evaporated in vacuo (50) leaving a thick oily residue wihch soon crystallized exothermically yielding 2- nitro-S chlorobenzophenone which upon recrystallization from 30 cc. of methanol melted at 87-89.
• Example 2 A mixture of 6.2g. of 2-nitro-S-piperidinobenzophene, 50 ml. of morpholine was refluxed for 18hours. Excess morpholine was removed in vacuo yielding an oil which was poured into ice water. Crystals formed which werecollected on a filter and recrystallized from methanol. Yellow leaflets of 5 morpholine 2 -nitrobenzophenone melting at 152-154 were obtained,
• Example 4 A mixture of 6.2 g. of 2-nit-ro5-piperidinobenzophenone, 1500 ml. of ethanol and approximately 0.5 g. of Raney nickel was shaken at 25 and normal pressure under an atmosphere of hydrogen. The uptake was 1450 ml. of hydrogen (ca. 0.06 mole). After filtering from the catalyst the solution was concentrated in vacuo to a volume of 100 ml. and ml. of a 4 N solution of hydrogen chloride in ethanol was added.
• Example 6 To a solution of 56 g. of 7-nitro-5-phenyl-3H-1,4-benzodiazepin-2( 1H)-one in 800 ml. of methanol was added 80 ml. of a 37% aqueous solution of formaldehyde and ca. 8 g. of Raney nickel. This mixture was shaken for 22 hours and ca. atm. of hydrogen pressure. The solution was filtered from the catalyst and concentrated yielding yellow needles of 7-dimethylamino-5-phenyl-3H- .1,4-benzodiazepin-2(1H)-one, which upon recrystallization from ethyl acetate gave crystalsmelting at 245-247".
• reaction product S-phenyl-BH-1,4-benzodiazepin-2(1H)- .one, crystallized out, was filtered OE and then recrystallized from acetone in the form of colorless rhombic prisms, M.P. 182-183".
• Example 8 yielded white platelets melting at 174176.
• Example 9 A solution containing 5.6 g. of 7-dimethylamino-1- methyl-S-phenyl-3H-1,4-benzodiazepin-2(1H)-one and 10 g. of methyl bromide in 60 ml. of acetone was kept at room temperature for 24 hours. After this time brown crystals had separated which were collected on a filter.
• Example 10 To a solution of 10' g. of 5-(2-chlorophet1yl)-7-nitro- 3H-1,4-benzodiazepin-2(1H)-one in 275 ml; of methanol was added 20 ml. of a 37% aqueous solution of formaldehyde and ca. 5 g. of Raney nickel. This mixture was shaken overnight under an initial pressure of 5-6 atm. of hydrogen. The solution was filtered from the catalyst and evaporated in vacuo. The residue was recrystallized hours, cooled and poured on ice.
• Example 11 To a solution of 35 g. of 7-nitro-5-(a,a,a-trifiuoro-otolyl)-3H-1,4-benzodiazepin-2(1H)-one in 800 ml. of methanol was added 50 ml. of a 37% aqueous solution of formaldehyde and ca. 8 g. of Raney nickel. This mixture was shaken overnight under an initial pressure of ca. 20 atm. of hydrogen. The solution was filtered from the catalyst and evaporated in vacuo.
• a solution of o-trifiuoromethyl phenyl magnesium bromide was prepared in the usual manner from 50.0 g. of o-bromo-benzotrifluoride, 5.55 g. of magnesium and ml. of anhydrous ether.
• the Grignard reagent can also be prepared by reacting 39.7 g. of o-chlorobenzotrifluoride with 5 .55 g. of magnesium in tetrahydrofurane. This solution was added with stirring at 20 C. over a period of 3 hours to a solution of 33.0 g. of 2-methyl- 4H-3-l-benzoxazin-4-one in 300 ml. of methylene chloride.
• Example 12 To a solution of 6 g. of -(2-chlorophenyl)-7-dimethylamino-BH-l,4-benzodiazepin-2(lH)-one in 100 ml. of dimethylformamide 1.25 g. of solid sodium methoxide was added with stirring. The mixture was cooled to 0 and a solution of 4 g. of methyl iodide in 50 ml. of dimethylformamide was added dropwise. The temperature was maintained between 0 and The excess of methyl iodide was removed in vacuo without heating and the solution was poured into ice water. The aqueous phase was extracted with ether, the ether was washed with Water, dried and evaporated.
• Example 14 To a solution of 7.3 g. of 1-methyl-7-nitro-S-(a,cc, xtrifluoro o tolyl) 3H 1,4 benzodiazepin 2(1H)- one in 275 ml. of methanol was added 25 ml. of a 37% aqueous solution of formaldehyde and ca. 4 g. of Raney nickel. This mixture was shaken for 4 hours and at an initial pressure of 14 atm. hydrogen. The resulting solution was filtered from the catalyst and the methanol then evaporated in vacuo. The residue was dissolved in ether and dried with sodium sulfate.
• Example 15 A solution of 8.8 g. of 7-dimethylamino-l-methyl-S- phenyl-3H-l,4-benzodiazepin-2(1H)-one in 150 ml. of acetic acid was hydrogenated with 0.3 g. of platinum oxide at 25 and 1 atm. After 1 hour the uptake of hydrogen had stopped and the solution was filtered from the catalyst. 0n neutralization with sodium hydroxide white flocks separated which were extracted with dichloromethane. The organic phase was washed with water and dried over sodium sulfate.
• Example 16 To a solution of 8 g. of 2',S-dichloro-Z-nitrobenzophenone in 175 ml. of ethanol there was added a solution of app. 5 g. of dimethylamine in 25 ml. of ethanol. The mixture was heated in an autoclave under nitrogen atmosphere to for 20 hours and the resulting solution concentrated in vacuo and cooled. Yellow prisms of 2-chloro-5-dimethylamino-2-nitrobenzophenone separated and were collected on a filter and, after recrystallization from methanol, melted at 156-158.
• Example 17 and after recrystallization from a mixture of ethanol and water melted at approximately 70.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

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Citations (7)

• 1962
  • 1962-03-09 US US178566A patent/US3202665A/en not_active Expired - Lifetime
• 1963
  • 1963-02-07 CH CH149363A patent/CH440298A/de unknown
  • 1963-02-12 AT AT115064A patent/AT242157B/de active
  • 1963-03-01 GB GB8239/63A patent/GB984707A/en not_active Expired
  • 1963-03-07 CH CH1709366A patent/CH457462A/de unknown
  • 1963-03-08 SE SE2567/63A patent/SE318885B/xx unknown
  • 1963-03-08 ES ES285855A patent/ES285855A1/es not_active Expired
• 1966
  • 1966-12-16 SE SE1728266A patent/SE317681B/xx unknown

Patent Citations (7)

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