US3157642A - 2, 3, 4, 5-tetra-hydro-1h-1, 3-benzo-diazepin-4-ones - Google Patents

2, 3, 4, 5-tetra-hydro-1h-1, 3-benzo-diazepin-4-ones Download PDF

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US3157642A
US3157642A US120179A US12017961A US3157642A US 3157642 A US3157642 A US 3157642A US 120179 A US120179 A US 120179A US 12017961 A US12017961 A US 12017961A US 3157642 A US3157642 A US 3157642A
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phenyl
phenylene
lower alkyl
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Stevens George De
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BASF Corp
Novartis Corp
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Ciba Geigy Corp
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    • 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
    • C07D243/04—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 3

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  • R represents a carbocyclic aryl or a heterocyclic aryl radical
  • R represents an aliphatic, a carboxylic aryl or a carbocyclic aryl-aliphatic radical
  • R stands for hydrogen or an aliphatic radical
  • the compounds of this invention may, therefore, be represented by the formula in which Ph represents a substituted 1,2-phenylene radical, R represents a carbocyclic aryl or a heterocyclic aryl radical, the letter it stands for one of the numbers 1, 2 or 3, R stands for an aliphatic, a carbocyclic aryl or a carbocyclic aryl-aliphatic radical, and R represents hydrogen or an aliphatic radical, salts, N-oxides or quaternary ammonium compounds thereof.
  • R-lower alkyl group which group is represented by (C H )R in the above formula, is more especially a monocyclic carbocyclic-lower alkyl group, in which the monocyclic carbocyclic aryl group stands for phenyl, as well as substituted phenyl, in which one or more than one of the same or of different substituents may be attached to any of the positions available for substitution.
  • Substituents are, for example, lower alkyl, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiary butyl and the like, etherified hydroxyl, particularly lower alkoxy, e.g.
  • Substituted phenyl groups are, therefore, (lower alkyl)-phenyl, e.g.
  • the group R in the R-lower alkyl substituent may also represent a bicyclic carbocyclic aryl group, e.g. l-naphthylor 2-naphthyl, as well as substituted naphthyl, such as (lower alkyl)-naphthyl, (etherified hydroxy)-naphthyl, particularly (lower alkoxy) -naphthyl, (lower alkenyloxy)- naphthyl or (lower alkylenedioxy)-napl1thyl and the like, (esterified hydroXy)-naphthyl, particularly (halogeno)- naphthyl and the like, (etherified mercapto) -naphthyl, particularly (lower alkyl-mercapto)-naphthyl and the like, (nitro)-naphthyl, (tertiary amino)-nap
  • the group R in an R-lower alkyl group may also represent a heterocyclic, particularly monocyclic heterocyclic, aryl radical, which may be represented by pyridyl, e.g. 2-pyridyl, 3-pyridyl or 4-pyridyl, or substituted pyridyl, such as (lower alkyl)-pyridyl, (lower alkoxy)-pyridyl, (halogeno)-pyridyl and the like, in which lower alkyl, lower alkoxy or halogeno have the previously-given meaning, thienyl, e.g. Z-thienyl and the like, furyl, e.g. 2-furyl and the like, or any other heterocyclic aryl group.
  • pyridyl e.g. 2-pyridyl, 3-pyridyl or 4-pyridyl
  • substituted pyridyl such as (lower alkyl)-pyr
  • the alkyl portion of an R-lower alkyl radical which connects the group R with the ring-nitrogen atom, and is represented by -(C,,H in the above formula, stands for lower alkylene having from one to three carbon atoms, particularly for methylene as well as 1,1-ethylene, 1,2-ethylene, 1-rnethyl-1,2-ethylene, 2-methyl-1,2- ethylene or 1,3-propylene and the like.
  • the substituent R is primarily an aliphatic radical, especially lower alkyl, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl and the like. It may also stand for a carbocyclic aryl, particularly a monocyclic carbocyclic aryl group, e.g.
  • phenyl or substituted phenyl such as (lower alkyl)-phenyl, (etherified hydroxy) -phenyl, particularly (lower alkoxy)-phenyl, (lower alkenyloxy)- phenyl, (lower alkylenedioxy)-phenyl and the like, (esterified hydroxy)-phenyl, particularly (halogeno)-phenyl and the like, (etherified mercapt0)-phenyl, particularly (lower alkyl-mercapto)-phenyl and the like, (nitro) -phenyl, (tertiary amino)-phenyl, particularly (N,N-di-lower alkylamino)-phenyl, (trifluoromethyl)-phenyl and the like, or any other suitably substituted phenyl group; in these substituted phenyl groups, the substitutents have the previously-given meaning.
  • the substituent R may also represent a carbocyclic aryl-aliphatic radical, particularly a monocyclic or bicyclic carbocyclic aryl-lower alkyl radical, such as phenyl-lower alkyl, e.g.
  • substituted phenyl is represented by (lower alkyl)-phenyl, (etherified hydr0Xy)-phenyl, particularly (lower alkoxy)-phenyl, (lower alkenyloxy)- phenyl, (lower alkylenedioxy)-phenyl and the like, (esterified hydroXy)-phenyl, particularly (halogeno)-phenyl and the like, (etherified mercapto)-phenyl, particularly (lower alkyl-mercapto-)phenyl and the like, (nitro)-phenyl, (tertiary amino)-phenyl, particularly (N,N-di-lower a1- kyl-amino)-phenyl, (trifluoromethyl)-pheny1 and the like, or any other suitably substituted
  • the substituent R is primarily hydrogen, but may also stand for an aliphatic radical, especially lower alkyl, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl and the like, or any other aliphatic radical.
  • the hexacyclic carbocyclic aromatic portion of the 2,3, 4,5-tetrahydro-1H-1,3benzodiazepin-4-one nucleus which in the above formula is represented by the substituted 1,2-phenylene radical Ph, is substituted by one or more than one of the same or of different substituents which may be attached to any of the positions available for substitution.
  • substituents are particularly aliphatic hydrocarbon, such as lower alkyl, e.g. methyl, ethyl, npropyl, isopropyl and the like, lower alkenyl, e.g. allyl, Z-methyl-allyl and the like, etherified hydroxyl, particularly lower alkoxy, e.g.
  • the substituted LZ-phenylene group Ph in the above formula may, therefore, be represented by (lower alkyl)- l,2-phenylene, e.g. 3-methyl-l,2-phenylene, 4,5-dimethyl- 1,2-phenylene, 4-ethyl-1,2-phenylene, 3 -isopropyl 1,2- phenyleneand the like, (lower alkenyl)-l,2-phenylene, e.g.
  • Salts of the compounds of this invention are particularly pharmacologically and therapeutically acceptable, nontoxic acid addition salts with an inorganic acid, e.g. hydrochloric, hydrobromic, nitric, sulfuric, phosphoric acids and the like, an organic carboxylic acid, e.g.
  • salts which are primarily used for identification purposes are particularly those with acidic organic nitro compounds, e.g. picric, picrolonic, flavianic acid and the like, or with metal complex acids, e.g. phosphotungstic, phosphomolybdic, chloroplatinic, Reinecke acid and the like.
  • N-oxides of the l-R-lower alkyl-3-R -5-R -2,3,4,5-tetrahydro-lH-1,3-ben2odiazepin-4-0nes and the pharmacologically and therapeutically acceptable, non-toxic acid addition salts of such N-oxides, particularly those with the above-mentioned acids.
  • Quaternary ammonium derivatives of the compounds of this invention are particularly those with reactive esters formed by hydroxylated compounds with strong acids, particularly those with lower alkyl halides, e.g. methyl, ethyl, n-propyl or isopropyl chloride, bromide or iodide and the like, phenyl-lower alkyl halides, e.g. benzyl or 2- phenylethyl chloride, bromide or iodide and the like, dilower alkyl sulfates, e.g.
  • lower alkyl halides e.g. methyl, ethyl, n-propyl or isopropyl chloride, bromide or iodide and the like
  • phenyl-lower alkyl halides e.g. benzyl or 2- phenylethyl chloride, bromide or iodide and the like
  • quaternary ammonium compounds are the quaternary ammonium hydroxides, and the salts obtained by reacting such quaternary ammonium hydroxides with inorganic or, particularly, with organic acids, such as with the salts described hereinbefore as being suitable for the preparation of acid addition salts.
  • Compounds of this invention may have one or more than one asymmetric center and can, therefore, be present in the form of racemates or optically active antipodes.
  • the compounds of this invention have tranquilizing and sedative properties and may be used accordingly, for example, in states of overactiveness and excitement, particularly in connection with mental disturbances and disorders, or as calming agents in the treatment of overactive and panic-proned animals.
  • Particularly useful as tranquilizing compounds are those of the formula in which R represents phenyl, (halogeno)-phenyl or (lower alkoxy)phenyl, the letter n stands for one of the numbers 1, 2 and 3, R represents lower alkyl, and Ph stands primarily for an (etherified hydroxy)-1,2-phenylene radical, particularly a (lower alkoxy)-l,2-phenylene radical, as well as a (lower alkylenedioxy)-l,2-phenylene or a (lower alkenyloxy)-1,2-phenylene radical, or a (lower alkyl)-l,2-phenylene or a (halogeno)-1,2-phenylene radical, or pharmacologically acceptable, non-toxic acid addition salts thereof.
  • the compounds of this invention may be used in the form of pharmaceutical preparations, which contain the new compounds in admixture with an organic or inorganic, solid or liquid carrier suitable for enteral or parenteral administration.
  • an organic or inorganic, solid or liquid carrier suitable for enteral or parenteral administration.
  • substances which do not react with the active ingredient such as water, gelatine, lactose, starches, stearic acid, magnesium stearate, stearyl alcohol, talc, vegetable oils, benzyl alcohols, gums, polyalkylene glycols or any other known carrier used for pharmaceutical preparations.
  • the latter may be in the solid form, for example, as capsules, tablets, dragees and the like, or in liquid form, for example, as solutions, suspensions, emulsions and the like.
  • auxiliary substances such as preserving, stabilizing, wetting, emulsifying agents and the like, salts for varying the osmotic pressure, butters, etc. They may also contain in combination, other pharmacologically useful substances.
  • the compounds of this invention may be prepared, for example by reacting an a-[2-(R-lower alkyl-amino)- phenyl]-a-R -acetic acid N-R -amide, in which the phenyl group carries additional substitutents, and R, R and R have the previously-given meaning, with formaldehyde or a formaldehyde-furnishing compound, and, if desired, converting a resulting salt into the free compound, and/or, if desired, converting a resulting free compound into a salt, an N-oxide or.a quaternary ammonium compound thereof, and, if desired, separating a mixture of isomers into the single isomers.
  • the above reaction is preferably carried out at an elevated temperature and in the presence of an inert solvent, such as, for example, diethylene glycol dimethylether, N,N-dimethylformamide and the like.
  • an inert solvent such as, for example, diethylene glycol dimethylether, N,N-dimethylformamide and the like.
  • Formaldehyde may be added in an aqueous solution; it may also be used in the form of a reactive polymer thereof, e.g. trioxymethylene, paraformaldehyde and the like, or an acetal with a lower alkanol thereof, e.g. dimethoxymethane, diethoxymethane and the like, or of any formaldehydefurnishing substances e.g. hexamethylene tetramine and the like.
  • the reaction may be performed in a closed vessel and/or in the atmosphere of an inert gas, e.g. nitrogen and the like.
  • the starting materials used in the above procedure may be prepared, for example, by converting in an a-(2-aminophenyl)-u-R -acetic acid N-R -amide, in which the phenyl radical is further substituted, the amino group into a R- lower alkyl-amino group, in which 2 has the previouslygiven meaning, and, if desired, converting a resulting salt into the free compound, and/or, if desired, converting the free compound into a salt thereof.
  • the conversion of the free amino group into the R- lower alkyl-amino group is carried out according to known methods, for example, by alkylation using a reactive ester of an R-lower alkanol with a strong acid; such reactive ester is, for example, an R-lower alkyl halide, e.g. chloride, bromide and the like, or an R-lower alkyl sulfonate, e.g. an R-lower alkyl p-toluene sulfonate and the like.
  • a reactive ester of an R-lower alkanol with a strong acid such reactive ester is, for example, an R-lower alkyl halide, e.g. chloride, bromide and the like, or an R-lower alkyl sulfonate, e.g. an R-lower alkyl p-toluene sulfonate and the like.
  • the preferred method for the conversion of the amino group of the starting material into the desired R-lower alkyl-amino group comprises reacting the u.-(2-aminophenyl)-u-R -acetic acid N-R -amide, in which phenyl carries additional substituents, and R and R have the previously-given meaning, with an R-lower alkanal, in which R has the previously-giving meanings, and removing in the resulting a-[Z-(R-Iower alkylideneamino) phenyl] a R acetic acid N-R -amide, in which phenyl carries additional substituents, and R, R
  • the reaction of the aminocompound with the R-lower alkanal is carried out by contacting the two reagents, preferably in the presence of an inert solvent, e.g. diethyleneglycol dimethylether and the like, and at an elevated temperature.
  • an inert solvent e.g. diethyleneglycol dimethylether and the like
  • removal of the Schiif-base type double bond is performed according to known reduction procedures, for example, by catalytic hydrogenation, or more especially, by treatment with a suitable light metal hydride, particularly a borohydride, e.g. sodium borohydride and the like, in the presence of a suitable inert solvent, e.g. methanol, ethanol and the like.
  • a suitable light metal hydride particularly a borohydride, e.g. sodium borohydride and the like
  • a suitable inert solvent e.g. methanol, ethanol and the like.
  • the starting material i.e. a-[Z-(R-lower alkyl-amino) in which Ph, R, R R and n have the previously-given meaning, and are more especially represented by the formulae in which Ph', R, R and n have the previously-given meaning; salts of these compounds are acid addition salts, particularly those with inorganicmineral, acids.
  • the compounds of this invention may be obtained in the form of the free bases or as the acid addition salts thereof.
  • a salt may be converted into the free base, for example, by reaction with an alkaline reagent, such as an alkali metal hydroxide, e.g. lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, an alkali metal carbonate or hydrogen carbonate, e.g. sodium carbonate, potassium hydrogen carbonate and the like, ammonia and the like,
  • an alkaline reagent such as an alkali metal hydroxide, e.g. lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, an alkali metal carbonate or hydrogen carbonate, e.g. sodium carbonate, potassium hydrogen carbonate and the like, ammonia and the like,
  • a free base may be converted into its pharmacologically useful acid addition salts by reaction with one of the acids outline hereinbefore, for example, by treating a solution of the base in an inert solvent or solvent mixture with the acid or a solution thereof.
  • the salts may also be obtained as the hemihydrates, monohydrates, sesquihydrates or polyhydrates depending on the conditions used in the formation of the salts.
  • N-oxides of the compounds of this invention may be prepared by reacting a solution of the l-R-lower alkyl-3- R -5-R -2,3,4,5 tetrahydro-lH-l,B-benzodiazepinl-one compound in an inert solvent with an N-oxidizing reagent; suitable reagents are, for example, hydrogen peroxide, persulfuric acid or, more especially, organic peracids, e.g. peracetic, perbenzoic, monoperphthalic, ptoluene persulfonic acid and the like.
  • the reaction is preferably about carried out at a low temperature, and care has to be taken that the oxidation does not proceed further than intended.
  • the quaternary ammonium derivatives of the compounds of this invention may be obtained, for example, by reacting the tertiary base with an ester formed by a hydroxylated compound and a strong inorganic or organic acid, particularly with a lower alkyl halide, e.g. methyl, ethyl, n-propyl, isopropyl' or n-butyl chloride, bromide or iodide and the like, a phenyl-lower alkyl halide, e.g. benzyl bromide, 2-phenyl-ethyl chloride and the'like, a di-lower alkyl sulfate, e.g.
  • a lower alkyl halide e.g. methyl, ethyl, n-propyl, isopropyl' or n-butyl chloride, bromide or iodide and the like
  • the quaternizing reaction is performed in the absence or presence of a solvent, if necessary, while cooling or at an elevated temperature, in a closed vessel under pressure, and/or in the atmosphere of an inert gas, e.g. nitrogen.
  • Quaternary ammonium compounds obtained may be converted into the corresponding quaternary ammonium hydroxides, for example, by reacting a quaternary ammonium halide with silver oxide, or a quaternary ammonium sulfate with barium hydroxide, by treating a quaternary ammonium salt with an anion exchanger, or by electrodialysis. From a resulting quaternary ammonium hydroxide there may be prepared quaternary ammonium salts by reacting it with acids, for example, with those outlined hereinbefore for the preparation of the acid addition salts, or with mono-lower alkyl sulfates, e.g.
  • a quaternary ammonium compound may also be converted directly into another quaternary ammonium salt without the formation of the quaternary ammonium hydroxide; for example, a quaternary ammonium iodide may be treated with freshly prepared silver chloride to yield the quaternary ammonium chloride, or a quaternary ammonium iodide may be converte into the corresponding chloride by treatment with hydrochloric acid in anhydrous methanol. Quaternary ammonium compounds may also crystallize as the hydrates.
  • the invention also comprises any modification of the process wherein a compound obtainable as an intermediate at any stage of the process is used as starting material and the remaining step(s) of the precess is(are) carried out, as well as any new intermediates.
  • Example 1 A solution of 6.5 g. of a-(2-benzylamino-4,5-dimethoxyphenyl)-acetic acid N-methyl-amide and 2 ml. of a 37 percent aqueous formaldehyde solution in 60 ml. of diethyleneglycol dimethylether is allowed to stand at room temperature for one hour and is then refluxed for three hours. The solution is evaporated to dryness and the solid residue is recrystallized twice to yield the l-benzyl-7,8- dimethoxy-3-methyl-2,3,4,5-tetrahydro-1H 1,3 benzodiazepin-4-one of the formula CH2- H: C O
  • the starting material may be prepared as follows: Methyl amine is bubbled through a solution of 30 g. of ethyl a-(4,5-dimethoxy-2-nitro-phenyl)-acetate in 1100 ml. of ethanol for six hours. The reaction vessel is then closed and allowed to stand for four days. 20 g. of the crystalline a-(4,5-dimethoXy-2-nitro-phenyl) acetic acid N-methyl-amide is filtered olf, M.P. 175-l80; another 4.0 g. is recovered from the filtrate.
  • a suspension of 6.0 g. of a-(4,5-dimethoxy-2-nitrophenyl)-acetic acid N-methyl-amide and 0.5 g. of palladium on charcoal percent) in 250 ml. of ethanol is treated with hydrogen under about three atmospheres which is dissolved in methanol and treated with a 2.28 g. of sodium borohydride given to the solution in portions.
  • the reaction mixture is allowed to stand overnight and is then diluted with water.
  • Example 2 A solution of 5.6 g. of a[2-(4-chlorobenzylamino)-4,5- dirnethoxy-phenylJ-acetic acid N-methyl-amide and 1.5 ml. of a 37 percent aqueous solution of formaldehyde in 50 ml. of diethyleneglycol dimethylether is allowed to stand at room temperature and is then refluxed for 2 /2 hours. The solvent is evaporated, and the remaining solid is recrystallized from ethanol to 3.3 g. of l-(4-chlorobenzyl-7,8-dimethoxy-3-methyl 2,3,4,5 tetrahydro 1H- 1,3-benzodiazepin-4-one of the formula N-CH;
  • the starting material may be prepared according to the procedure shown in Example 1 by treating the Ell-(2- amino-4,5-dimethoxy)-acetic acid N-methyl-amide with 4-chloro-benzaldehyde and reducing in the resulting a-[Z- (4-chloro-benzalamino)-4,5 dimethoxy phenyl] acetic acid N-methyl-amide of the formula NCH llaQa the Schiif basetype double bond by treatment with sodi- 9 um borohydride; the desired a-[2-(4-chloro-benzylamino)- 4,5-dimethoXy-phenyl] -acetic acid N-methyl-amide of the formula Example 3 A solution of 5.7 g.
  • N--CH3 H300 which melts at ISO-132.
  • the starting material may be prepared accordinging to the procedure shown in Example 1 by treating the a-(2- amino-4,5-dimethoxy)-acetic acid N-methyl-amide with 4-methoxy-benzaldehyde and reducing in the resulting a.[-2-(4-methoxy-benzalamino)-4,5 dimethoxy phenylJ- acetic acid N-methyl-amide of the formula the Schiff base-type double bond by treatment with sodium borohydride; the desired a-[2-(4-methoxybenzylamin0)- 4,5-dimethoxy-phenyl]-acetic acid N-methyl-amide of the formula I CHr-GCOHI which melts at l04106.
  • R' is (halogeno)-pheny1, the letter it stands for '1, R stands for lower alkyl, and P11 stands for (lower alkoxy -1,2-phenylene.

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Description

United States Patent 3,157,642 2,3,4,5-TETRA-HYDRO-'1H-'1,3-BENZO- DIAZEPIN-4-ONES George de Stevens, New Providence, N.J., assignor to Ciba Corporation, a corporation of Delaware No Drawing. Filed June 28, 1961, Ser. No. 120,179 7 Claims. (Cl. 260-2393) The present invention concerns certain 2,3,4,5-tetrahydro-lH-1,3-benzodiaZepin-4-ones. More especially, it relates to l-R-lower alkyl 3-R --R -2,3,4,5-tetrahydrolH-1,3-benzodiazepin-4-ones, in which R represents a carbocyclic aryl or a heterocyclic aryl radical, R represents an aliphatic, a carboxylic aryl or a carbocyclic aryl-aliphatic radical, and R stands for hydrogen or an aliphatic radical, and in which the benzonucleus is substituted, salts, N-oxides or quaternary ammonium compounds thereof. The compounds of this invention may, therefore, be represented by the formula in which Ph represents a substituted 1,2-phenylene radical, R represents a carbocyclic aryl or a heterocyclic aryl radical, the letter it stands for one of the numbers 1, 2 or 3, R stands for an aliphatic, a carbocyclic aryl or a carbocyclic aryl-aliphatic radical, and R represents hydrogen or an aliphatic radical, salts, N-oxides or quaternary ammonium compounds thereof.
An R-lower alkyl group, which group is represented by (C H )R in the above formula, is more especially a monocyclic carbocyclic-lower alkyl group, in which the monocyclic carbocyclic aryl group stands for phenyl, as well as substituted phenyl, in which one or more than one of the same or of different substituents may be attached to any of the positions available for substitution. Substituents are, for example, lower alkyl, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiary butyl and the like, etherified hydroxyl, particularly lower alkoxy, e.g. methoxy, ethoXy, n-propyloxy, isopropyloxy, n-butyloxy and the like, lower alkenyloxy, e.g. allyloxy and the like, lower alkylenedioxy, e.g. methylenedioxy and the like, or any other etherified hydroxyl group, esterified hydroxyl, particularly halogeno, e.g. fluoro, chloro, bromo and the like, or other esteritied hydroxyl, etherified mercapto, particularly lower alkyl-mercapto, e.g. methylmercapto, ethylmercapto and the like, or any other etherified mercapto group, nitro, tertiary amino, particularly N,N-di-lower alkyl-amino, e.g. N,N-dirnethylamino, N,N-diethylamino and the like, or any other amino group, trifluoromethyl or any other suitable substituent. Substituted phenyl groups are, therefore, (lower alkyl)-phenyl, e.g. 3-methylphenyl, 4-methyl-phenyl, 2,4,5-trimethyl-phenyl, 4-ethylphenyl, 4-isopropyl-phenyl and the like, (etherified hydr0Xy)-phenyl, particularly (lower alkoxy)-phenyl, e.g. 4-methoXy-pheny1, 3,4 dimethoxy phenyl, 3,4,5 trimethoxy-phenyl, 4-ethoxy-phenyl and the like, (lower alkenyloXy)-phenyl, e.g. 2-allyloXy-phenyl and the like, (lower alkylenedioxy)-phenyl, e.g. 3,4-methylenedioxyphenyl and the like, or any other (etherified hydroxy)- phenyl group, (esterified hydroxy)-phenyl, particularly (halogen)-phenyl, e.g. 4-fluoro-phenyl, 4-ch1oro-phenyl 3,4-dichloro-phenyl, 2-bromo-phenyl and the like, or any other (esterified hydroXy)-phenyl, (etherified mercapto)- phenyl, particularly (lower alkyl-mercapto)-phenyl, e.g. 4-methylmercapto-phenyl, 4 ethylmercapto phenyl and the like, or any other (etherified mercapto)-phenyl, (nitro)-phenyl, e.g. 4-nitro-phenyl and the like, (tertiary Patented Nov. 17, 1964 amino)-phenyl, particularly (N,N-di-lower alkylamino)- phenyl, e.g. 4-N,N-dimethylamino-phenyl and the like, or any other (amino)-phenyl, (trifluoromethyl)-phenyl, e.g. 4-itrifluoromethylphenyl and the like, or any other suitably substituted phenyl group.
The group R in the R-lower alkyl substituent may also represent a bicyclic carbocyclic aryl group, e.g. l-naphthylor 2-naphthyl, as well as substituted naphthyl, such as (lower alkyl)-naphthyl, (etherified hydroxy)-naphthyl, particularly (lower alkoxy) -naphthyl, (lower alkenyloxy)- naphthyl or (lower alkylenedioxy)-napl1thyl and the like, (esterified hydroXy)-naphthyl, particularly (halogeno)- naphthyl and the like, (etherified mercapto) -naphthyl, particularly (lower alkyl-mercapto)-naphthyl and the like, (nitro)-naphthyl, (tertiary amino)-naphthyl, particularly (N,N-di-lower alkyl-amino)-naphthy1 and the like, (trifluoromethyl)-naphthyl and the like, or any other substituted naphthyl group; in the above-mentioned substituted naphthyl radicals, substituents are analogous to those in the substituted phenyl groups.
The group R in an R-lower alkyl group may also represent a heterocyclic, particularly monocyclic heterocyclic, aryl radical, which may be represented by pyridyl, e.g. 2-pyridyl, 3-pyridyl or 4-pyridyl, or substituted pyridyl, such as (lower alkyl)-pyridyl, (lower alkoxy)-pyridyl, (halogeno)-pyridyl and the like, in which lower alkyl, lower alkoxy or halogeno have the previously-given meaning, thienyl, e.g. Z-thienyl and the like, furyl, e.g. 2-furyl and the like, or any other heterocyclic aryl group.
The alkyl portion of an R-lower alkyl radical, which connects the group R with the ring-nitrogen atom, and is represented by -(C,,H in the above formula, stands for lower alkylene having from one to three carbon atoms, particularly for methylene as well as 1,1-ethylene, 1,2-ethylene, 1-rnethyl-1,2-ethylene, 2-methyl-1,2- ethylene or 1,3-propylene and the like.
The substituent R is primarily an aliphatic radical, especially lower alkyl, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl and the like. It may also stand for a carbocyclic aryl, particularly a monocyclic carbocyclic aryl group, e.g. phenyl or substituted phenyl, such as (lower alkyl)-phenyl, (etherified hydroxy) -phenyl, particularly (lower alkoxy)-phenyl, (lower alkenyloxy)- phenyl, (lower alkylenedioxy)-phenyl and the like, (esterified hydroxy)-phenyl, particularly (halogeno)-phenyl and the like, (etherified mercapt0)-phenyl, particularly (lower alkyl-mercapto)-phenyl and the like, (nitro) -phenyl, (tertiary amino)-phenyl, particularly (N,N-di-lower alkylamino)-phenyl, (trifluoromethyl)-phenyl and the like, or any other suitably substituted phenyl group; in these substituted phenyl groups, the substitutents have the previously-given meaning. The substituent R may also represent a carbocyclic aryl-aliphatic radical, particularly a monocyclic or bicyclic carbocyclic aryl-lower alkyl radical, such as phenyl-lower alkyl, e.g. benzyl, l-phenylethyl, Z-phenylethyl and the like, as well as substituted phenyllower alkyl, in which substituted phenyl is represented by (lower alkyl)-phenyl, (etherified hydr0Xy)-phenyl, particularly (lower alkoxy)-phenyl, (lower alkenyloxy)- phenyl, (lower alkylenedioxy)-phenyl and the like, (esterified hydroXy)-phenyl, particularly (halogeno)-phenyl and the like, (etherified mercapto)-phenyl, particularly (lower alkyl-mercapto-)phenyl and the like, (nitro)-phenyl, (tertiary amino)-phenyl, particularly (N,N-di-lower a1- kyl-amino)-phenyl, (trifluoromethyl)-pheny1 and the like, or any other suitably substituted phenyl group; in these substituted phenyl groups, the substituents have the previously-given meaning.
The substituent R is primarily hydrogen, but may also stand for an aliphatic radical, especially lower alkyl, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl and the like, or any other aliphatic radical.
The hexacyclic carbocyclic aromatic portion of the 2,3, 4,5-tetrahydro-1H-1,3benzodiazepin-4-one nucleus, which in the above formula is represented by the substituted 1,2-phenylene radical Ph, is substituted by one or more than one of the same or of different substituents which may be attached to any of the positions available for substitution. These substituents are particularly aliphatic hydrocarbon, such as lower alkyl, e.g. methyl, ethyl, npropyl, isopropyl and the like, lower alkenyl, e.g. allyl, Z-methyl-allyl and the like, etherified hydroxyl, particularly lower alkoxy, e.g. methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy and the like, lower alkenyloxy, e.g. vinyloxy, allyloxy and the like, or lower alkylenedioxy, e.g. methylenedioxy and the like, esterified hydroxyl, particularly halogeno, e.g. fluoro, chloro, bromo and the like, etherified mercapto, particularly lower alkyl-mercapto, e.g. methylmercapto, ethylmercapto and the like, nitro, tertiary amino, particularly N,N-di-lower alkylamino, e.g. N,N-dimethylamino, N,N-diethylamino and the like, tritluoromethyl or any other suitable substituent. The substituted LZ-phenylene group Ph in the above formula may, therefore, be represented by (lower alkyl)- l,2-phenylene, e.g. 3-methyl-l,2-phenylene, 4,5-dimethyl- 1,2-phenylene, 4-ethyl-1,2-phenylene, 3 -isopropyl 1,2- phenyleneand the like, (lower alkenyl)-l,2-phenylene, e.g. 3allyl-1,2-phenylene and the like, (etherified hydroxy)-1,2-pheny1ene, such as (lower alkoxy)-1,2-phenylene, e.g. 3-methoxy-1,2-phenylene, 4,5-dimethoxy-1,2- phenylene, 3,6-dimethoxy-1,2-phenylene, 4,5-diethoxy-1,2- phenylene, 3-n-propyloxy-1,Z-phenylene, 4-isopropyloxy- 1,2-phenylene and the like, (lower alkenyloxy)-l,2-phenylene, e.g. 3-vinyloxy-1,2-phenylene, 3-allyloxy-1,2-phenylene, 4-allyloxy-l,2-phenylene and the like, (lower alkylenedioXy)-l,2-phenylene, e.g. 4,5-methylenedioxy- 1,2- phenylene and the like, (esterified hydroxy)-1,2-phenylene, particularly (halogeno)-l,2-phenylene, e.g. 3-fluoro- 1,2-phenylene, 3-chloro-l,2-phenylene, 4-chloro-l,2-phenylene, 4,5-dichloro-1,2-phenylene, 3,6-dichloro-l,2-phenylene, 3-bromo-l,2-phenylene, 4,5-dibromo-l,2-phenylene and the like, (etherified mercapto)-1,2-phenylene, particularly (lower alkyl-mercapto)-1,2-phenylene, e.g. 3-methylmereapto-1,2-phenylene, 4-ethylmercapto-1,2-phenylene and the like, (nitro)-l,2-phenylene, e.g. 3-nitro-1,2-phenylene, 4-nitro-l,2-phenylene and the like, (tertiary amino) 1,2-phenylene, particularly (N,N-di-lower alkyl-amino)- 1,2-phenylene, e.g. 3-N,N-dimethylamino-1,2-phenylene, 4-N,N-diethylamino-1,2-phenylene and the like, (trifluoromethyl)-1,2-pheny1ene, e.g. 4-trifluoromethyl-l,2-phenylone and the like, or any other suitably substituted 1,2- phenylene radical.
Salts of the compounds of this invention are particularly pharmacologically and therapeutically acceptable, nontoxic acid addition salts with an inorganic acid, e.g. hydrochloric, hydrobromic, nitric, sulfuric, phosphoric acids and the like, an organic carboxylic acid, e.g. acetic, propionic, glycolic, lactic, pyruvic, oxalic, malonic, succinic, maleic, hydroxymaleic, dihydroxymaleic, fumaric, malic, tartaric, D-tartaric, citric, benzoic, cinnamic, mandelic, salicylic, 4-aminosalicylic, Z-phenoxybenzoic, Z-acetoxybenzoic acid and the like, or an organic sulfonic acid, e.g.
methane sulfonic, ethane sulfonic, 2-hydroxyethane sultonic, ethane 1,2-disulfonic, p-toluene sulfonic acid and the like. Salts which are primarily used for identification purposes are particularly those with acidic organic nitro compounds, e.g. picric, picrolonic, flavianic acid and the like, or with metal complex acids, e.g. phosphotungstic, phosphomolybdic, chloroplatinic, Reinecke acid and the like.
Also included within the scope of this invention are the N-oxides of the l-R-lower alkyl-3-R -5-R -2,3,4,5-tetrahydro-lH-1,3-ben2odiazepin-4-0nes and the pharmacologically and therapeutically acceptable, non-toxic acid addition salts of such N-oxides, particularly those with the above-mentioned acids.
Quaternary ammonium derivatives of the compounds of this invention are particularly those with reactive esters formed by hydroxylated compounds with strong acids, particularly those with lower alkyl halides, e.g. methyl, ethyl, n-propyl or isopropyl chloride, bromide or iodide and the like, phenyl-lower alkyl halides, e.g. benzyl or 2- phenylethyl chloride, bromide or iodide and the like, dilower alkyl sulfates, e.g. dirnethyl sulfate, diethyl sulfate and the like, lower alkyl lower alkane sulfonates, e.g. methyl or ethyl methane sulfonate or ethane sulfonate and the like, or lower alkyl aryl sulfonates, e.g. methyl ptoluene sulfonate and the like. Also included as quaternary ammonium compounds are the quaternary ammonium hydroxides, and the salts obtained by reacting such quaternary ammonium hydroxides with inorganic or, particularly, with organic acids, such as with the salts described hereinbefore as being suitable for the preparation of acid addition salts.
Compounds of this invention may have one or more than one asymmetric center and can, therefore, be present in the form of racemates or optically active antipodes.
The compounds of this invention have tranquilizing and sedative properties and may be used accordingly, for example, in states of overactiveness and excitement, particularly in connection with mental disturbances and disorders, or as calming agents in the treatment of overactive and panic-proned animals.
Particularly useful as tranquilizing compounds are those of the formula in which R represents phenyl, (halogeno)-phenyl or (lower alkoxy)phenyl, the letter n stands for one of the numbers 1, 2 and 3, R represents lower alkyl, and Ph stands primarily for an (etherified hydroxy)-1,2-phenylene radical, particularly a (lower alkoxy)-l,2-phenylene radical, as well as a (lower alkylenedioxy)-l,2-phenylene or a (lower alkenyloxy)-1,2-phenylene radical, or a (lower alkyl)-l,2-phenylene or a (halogeno)-1,2-phenylene radical, or pharmacologically acceptable, non-toxic acid addition salts thereof.
The compounds of this invention may be used in the form of pharmaceutical preparations, which contain the new compounds in admixture with an organic or inorganic, solid or liquid carrier suitable for enteral or parenteral administration. For making up the preparations there can be employed substances which do not react with the active ingredient, such as water, gelatine, lactose, starches, stearic acid, magnesium stearate, stearyl alcohol, talc, vegetable oils, benzyl alcohols, gums, polyalkylene glycols or any other known carrier used for pharmaceutical preparations. The latter may be in the solid form, for example, as capsules, tablets, dragees and the like, or in liquid form, for example, as solutions, suspensions, emulsions and the like. If desired, they may contain auxiliary substances, such as preserving, stabilizing, wetting, emulsifying agents and the like, salts for varying the osmotic pressure, butters, etc. They may also contain in combination, other pharmacologically useful substances.
The compounds of this invention may be prepared, for example by reacting an a-[2-(R-lower alkyl-amino)- phenyl]-a-R -acetic acid N-R -amide, in which the phenyl group carries additional substitutents, and R, R and R have the previously-given meaning, with formaldehyde or a formaldehyde-furnishing compound, and, if desired, converting a resulting salt into the free compound, and/or, if desired, converting a resulting free compound into a salt, an N-oxide or.a quaternary ammonium compound thereof, and, if desired, separating a mixture of isomers into the single isomers.
The above reaction is preferably carried out at an elevated temperature and in the presence of an inert solvent, such as, for example, diethylene glycol dimethylether, N,N-dimethylformamide and the like. Formaldehyde may be added in an aqueous solution; it may also be used in the form of a reactive polymer thereof, e.g. trioxymethylene, paraformaldehyde and the like, or an acetal with a lower alkanol thereof, e.g. dimethoxymethane, diethoxymethane and the like, or of any formaldehydefurnishing substances e.g. hexamethylene tetramine and the like. If necessary, the reaction may be performed in a closed vessel and/or in the atmosphere of an inert gas, e.g. nitrogen and the like.
The starting materials used in the above procedure may be prepared, for example, by converting in an a-(2-aminophenyl)-u-R -acetic acid N-R -amide, in which the phenyl radical is further substituted, the amino group into a R- lower alkyl-amino group, in which 2 has the previouslygiven meaning, and, if desired, converting a resulting salt into the free compound, and/or, if desired, converting the free compound into a salt thereof.
The conversion of the free amino group into the R- lower alkyl-amino group is carried out according to known methods, for example, by alkylation using a reactive ester of an R-lower alkanol with a strong acid; such reactive ester is, for example, an R-lower alkyl halide, e.g. chloride, bromide and the like, or an R-lower alkyl sulfonate, e.g. an R-lower alkyl p-toluene sulfonate and the like.
The preferred method for the conversion of the amino group of the starting material into the desired R-lower alkyl-amino group comprises reacting the u.-(2-aminophenyl)-u-R -acetic acid N-R -amide, in which phenyl carries additional substituents, and R and R have the previously-given meaning, with an R-lower alkanal, in which R has the previously-giving meanings, and removing in the resulting a-[Z-(R-Iower alkylideneamino) phenyl] a R acetic acid N-R -amide, in which phenyl carries additional substituents, and R, R
and R have the previously-given meaning, the Schiifbase C=N-double bond. The reaction of the aminocompound with the R-lower alkanal (for example, benzaldehyde, phenylacetaldehyde and the like) is carried out by contacting the two reagents, preferably in the presence of an inert solvent, e.g. diethyleneglycol dimethylether and the like, and at an elevated temperature. The
removal of the Schiif-base type double bond is performed according to known reduction procedures, for example, by catalytic hydrogenation, or more especially, by treatment with a suitable light metal hydride, particularly a borohydride, e.g. sodium borohydride and the like, in the presence of a suitable inert solvent, e.g. methanol, ethanol and the like.
The starting material, i.e. a-[Z-(R-lower alkyl-amino) in which Ph, R, R R and n have the previously-given meaning, and are more especially represented by the formulae in which Ph', R, R and n have the previously-given meaning; salts of these compounds are acid addition salts, particularly those with inorganicmineral, acids.
The compounds of this invention (including the N- oxides) may be obtained in the form of the free bases or as the acid addition salts thereof. A salt may be converted into the free base, for example, by reaction with an alkaline reagent, such as an alkali metal hydroxide, e.g. lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, an alkali metal carbonate or hydrogen carbonate, e.g. sodium carbonate, potassium hydrogen carbonate and the like, ammonia and the like,
or an anion exchanger, etc. A free base may be converted into its pharmacologically useful acid addition salts by reaction with one of the acids outline hereinbefore, for example, by treating a solution of the base in an inert solvent or solvent mixture with the acid or a solution thereof. The salts may also be obtained as the hemihydrates, monohydrates, sesquihydrates or polyhydrates depending on the conditions used in the formation of the salts.
N-oxides of the compounds of this invention may be prepared by reacting a solution of the l-R-lower alkyl-3- R -5-R -2,3,4,5 tetrahydro-lH-l,B-benzodiazepinl-one compound in an inert solvent with an N-oxidizing reagent; suitable reagents are, for example, hydrogen peroxide, persulfuric acid or, more especially, organic peracids, e.g. peracetic, perbenzoic, monoperphthalic, ptoluene persulfonic acid and the like. The reaction is preferably about carried out at a low temperature, and care has to be taken that the oxidation does not proceed further than intended.
The quaternary ammonium derivatives of the compounds of this invention may be obtained, for example, by reacting the tertiary base with an ester formed by a hydroxylated compound and a strong inorganic or organic acid, particularly with a lower alkyl halide, e.g. methyl, ethyl, n-propyl, isopropyl' or n-butyl chloride, bromide or iodide and the like, a phenyl-lower alkyl halide, e.g. benzyl bromide, 2-phenyl-ethyl chloride and the'like, a di-lower alkyl sulfate, e.g. dimethyl sulfate, diethyl sulfate and the like, a lower alkyl lower alkane sulfonate, e.g. methyl methane sulfonate and the like, or a lower alkyl aryl sulfonate, e.g. methyl p-toluene sulfonate and the like. The quaternizing reaction is performed in the absence or presence of a solvent, if necessary, while cooling or at an elevated temperature, in a closed vessel under pressure, and/or in the atmosphere of an inert gas, e.g. nitrogen.
Quaternary ammonium compounds obtained may be converted into the corresponding quaternary ammonium hydroxides, for example, by reacting a quaternary ammonium halide with silver oxide, or a quaternary ammonium sulfate with barium hydroxide, by treating a quaternary ammonium salt with an anion exchanger, or by electrodialysis. From a resulting quaternary ammonium hydroxide there may be prepared quaternary ammonium salts by reacting it with acids, for example, with those outlined hereinbefore for the preparation of the acid addition salts, or with mono-lower alkyl sulfates, e.g. methyl sulfate, ethyl sulfate and the like. A quaternary ammonium compound may also be converted directly into another quaternary ammonium salt without the formation of the quaternary ammonium hydroxide; for example, a quaternary ammonium iodide may be treated with freshly prepared silver chloride to yield the quaternary ammonium chloride, or a quaternary ammonium iodide may be converte into the corresponding chloride by treatment with hydrochloric acid in anhydrous methanol. Quaternary ammonium compounds may also crystallize as the hydrates.
The invention also comprises any modification of the process wherein a compound obtainable as an intermediate at any stage of the process is used as starting material and the remaining step(s) of the precess is(are) carried out, as well as any new intermediates.
In the process of this invention such starting materials are preferably used which lead to final products mentioned in the beginning as preferred embodiments of the invention.
The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees centigrade.
Example 1 A solution of 6.5 g. of a-(2-benzylamino-4,5-dimethoxyphenyl)-acetic acid N-methyl-amide and 2 ml. of a 37 percent aqueous formaldehyde solution in 60 ml. of diethyleneglycol dimethylether is allowed to stand at room temperature for one hour and is then refluxed for three hours. The solution is evaporated to dryness and the solid residue is recrystallized twice to yield the l-benzyl-7,8- dimethoxy-3-methyl-2,3,4,5-tetrahydro-1H 1,3 benzodiazepin-4-one of the formula CH2- H: C O
which melts at 154-155"; yield: 5.0 g.
The starting material may be prepared as follows: Methyl amine is bubbled through a solution of 30 g. of ethyl a-(4,5-dimethoxy-2-nitro-phenyl)-acetate in 1100 ml. of ethanol for six hours. The reaction vessel is then closed and allowed to stand for four days. 20 g. of the crystalline a-(4,5-dimethoXy-2-nitro-phenyl) acetic acid N-methyl-amide is filtered olf, M.P. 175-l80; another 4.0 g. is recovered from the filtrate.
A suspension of 6.0 g. of a-(4,5-dimethoxy-2-nitrophenyl)-acetic acid N-methyl-amide and 0.5 g. of palladium on charcoal percent) in 250 ml. of ethanol is treated with hydrogen under about three atmospheres which is dissolved in methanol and treated with a 2.28 g. of sodium borohydride given to the solution in portions. The reaction mixture is allowed to stand overnight and is then diluted with water. The desired a-(Z-benzylaminm 4,5-dimethoxy-phenyl)-acetic acid N-methyl-amide of the formula i CHg-CNH-CH3 E 00 precipitates, is filtered off and recrystallized from a mixture of benzene and hexane and then from a mixture of ethanol and water M.P. 82-84"; yield: 8.5 g.
Example 2 A solution of 5.6 g. of a[2-(4-chlorobenzylamino)-4,5- dirnethoxy-phenylJ-acetic acid N-methyl-amide and 1.5 ml. of a 37 percent aqueous solution of formaldehyde in 50 ml. of diethyleneglycol dimethylether is allowed to stand at room temperature and is then refluxed for 2 /2 hours. The solvent is evaporated, and the remaining solid is recrystallized from ethanol to 3.3 g. of l-(4-chlorobenzyl-7,8-dimethoxy-3-methyl 2,3,4,5 tetrahydro 1H- 1,3-benzodiazepin-4-one of the formula N-CH;
which melts at -142.
The starting material may be prepared according to the procedure shown in Example 1 by treating the Ell-(2- amino-4,5-dimethoxy)-acetic acid N-methyl-amide with 4-chloro-benzaldehyde and reducing in the resulting a-[Z- (4-chloro-benzalamino)-4,5 dimethoxy phenyl] acetic acid N-methyl-amide of the formula NCH llaQa the Schiif basetype double bond by treatment with sodi- 9 um borohydride; the desired a-[2-(4-chloro-benzylamino)- 4,5-dimethoXy-phenyl] -acetic acid N-methyl-amide of the formula Example 3 A solution of 5.7 g. of a[2-(4-methoxybenzylamino)- 4,5-dimethoxy-phenyl]-acetic acid N-methyl-amide and 1.5 ml. of a 37 percent aqueous formaldehyde solution in 50 ml. of diethyleneglycol dimethylether is treated as shown in Example 2 to yield 4.4 g. of l-(4-methoxybenzyl)-7,8-dimethoxy-3-methyl-2,3,4,S tetrahydro 1H- 1,3-benzodiazepin-4-one of the formula melts at 109-110".
N--CH3 H300 which melts at ISO-132.
The starting material may be prepared acording to the procedure shown in Example 1 by treating the a-(2- amino-4,5-dimethoxy)-acetic acid N-methyl-amide with 4-methoxy-benzaldehyde and reducing in the resulting a.[-2-(4-methoxy-benzalamino)-4,5 dimethoxy phenylJ- acetic acid N-methyl-amide of the formula the Schiff base-type double bond by treatment with sodium borohydride; the desired a-[2-(4-methoxybenzylamin0)- 4,5-dimethoxy-phenyl]-acetic acid N-methyl-amide of the formula I CHr-GCOHI which melts at l04106.
Other compounds, such as, for example, 1-benzyl-7,8- methylenedioxy-3-ethyl-2,3,4,5-tetrahydro-III-1,3 benzodiazepin-4-one, 1-benzyl-7-ethoxy-3-methyl-2,3,4,5 tetrahydro-lH-l,3-benzodiazepin-4-one, 1-benzyl-7,8-dichloro- 3-methyl-2,3,4,S-tetrahydro-IH-1,3-benzodiazepin-4 one, 1-benzyl-3,S-dimethyl-Z,3,4,5-tetrahydro-1H 1,3 benzodiazepin-4-one, 1-benzyl-3-methyl-8-nitro 2,3,4,5 tetrahydro-lH-1,3-benzodiazepin-4-one, l benzyl 7,8 dimein which Ph is a member selected from the group consisting of (lower alkyl)-1,2-phenylene, (lower alkoxy)-1,2- phenylene, (lower alkenyloxy)-1,2 phenylene, (lower alkylenedioxy)-l,2-phenylene, (halogeno)-1,2-phenylene, (nitro)-phenylene and (trifluoromethyl)-1,2-phenylene, R is a member selected from the group consisting of phenyl, (lower alkyl)-pl1enyl, (lower alkoxy)-phenyl, (halogeno)- phenyl, naphthyl and pyridyl, the letter n stands for a member selected from the group consisting of the numbers 1, 2 and 3, R stands for a member selected from the group consisting of lower alkyl and phenyl, and R stands for a member selected from the group consisting of hydrogen and lower alkyl, and a pharmacologically acceptable I acid addition salt thereof.
2. A compound of the formula in which R is (lower alk0xy)-phenyl, the letter n stands for 1, R stands for lower alkyl, and Ph' stands for (lower alkoxy) 1 ,Z-phenylene.
3. A compound of the formula Pl N-Rr NCH2 ( n 2n) R' in which R is phenyl, the letter n stands for 1, R stands for lower alkyl, and Ph stands for (lower alkoxy)-1,2 phenylene.
4. A compound of the formula in which R' is (halogeno)-pheny1, the letter it stands for '1, R stands for lower alkyl, and P11 stands for (lower alkoxy -1,2-phenylene.
5. 1-benzyl-7,8-dimethoxy-3-methyl-2,3,4,5-tetrahydr0- 1H-1,3-benzodiazepin-4-one.
6. 1-(4-chloro-benzyl)-7,8-dimethoxy-3-methyl-2,3,4,5- tetrahydro-lI-I-1,3-benzodiazepin-4-one.
7. 1-(4-rnethoxy benzy1)7,8 dimethoxy 3 methyl- 2,3,4,5-tetrahydro-1H-l,3=benzodiazepin-4-one.
UNITED STATES PATENTS Hoffman et a1 Sept. 16, 1958 Sternbach July 7, 1959 Weinstock Apr. 5, 1960 Eden May 10, 1960 Fuller May 17, 1960 Harris et a1. May 17, 1960 Werner Oct. 25, 1960

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US2936323A (en) * 1957-10-16 1960-05-10 Diamond Alkali Co Chemical composition and process
US2937204A (en) * 1957-11-25 1960-05-17 Dow Chemical Co Nu-alkanoyl dinitrobenzamides
US2937203A (en) * 1957-09-27 1960-05-17 Du Pont Nu-tertiary-alkyl amides of terephthalic, isophthalic, and trimesic acids
US2957867A (en) * 1958-06-23 1960-10-25 Ciba Pharm Prod Inc 1, 5-benzodiazepin-4-ones and process of producing same

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US2852510A (en) * 1954-03-03 1958-09-16 Ciba Pharm Prod Inc Heterocyclic compounds and process for producing same
US2937203A (en) * 1957-09-27 1960-05-17 Du Pont Nu-tertiary-alkyl amides of terephthalic, isophthalic, and trimesic acids
US2936323A (en) * 1957-10-16 1960-05-10 Diamond Alkali Co Chemical composition and process
US2937204A (en) * 1957-11-25 1960-05-17 Dow Chemical Co Nu-alkanoyl dinitrobenzamides
US2957867A (en) * 1958-06-23 1960-10-25 Ciba Pharm Prod Inc 1, 5-benzodiazepin-4-ones and process of producing same
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