Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
  • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
  • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
  • C07D243/12—1,5-Benzodiazepines; Hydrogenated 1,5-benzodiazepines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients

Definitions

• R1 0 91kt CH2 CI is hydroxy-alkyl of two to four carbon atoms; haloalkyl of two to four carbon atoms; di(alkyl of two to four carbon atoms)amino-alkyl of two to four carbon atoms; 'y-piperidino-propyl; alkoxy of one to two carbon atoms alkyl of one to four carbon atoms; (alkoxy of one to two carbon atoms)carbonyl-alkyl of one to four carbon atoms; (alkyl of one to two carbon atoms) mercapto-alkyl of one to four carbon atoms; straight or branched alkenyl of three to five carbon atoms; (alkoxy of one to two carbon atoms)carbonyl-alkenyl of two to four carbon atom
• R is hydroxy-alkyl of two to four carbon atoms; haloalkyl of two tofour carbon atoms; di(alkyl of two to four carbon atoms)arnino-alkyl of two to four carbon atoms; y-piperidinopropyl; alkoxy of one to two carbon atoms-alkyl of one to four carbon atoms; (alkoxy of one to two carbon' atoms )carbonyl-alkyl of one to four carbon atoms; (alkyl of one to two carbon atoms)mercapto-alkyl of one to four carbon atoms; straight or branched alkenyl of three to five carbon atoms; (alkoxy of one to two carbon atoms)carbonyl-alkenyl of two to four carbon atoms; or haIo-alkenyl of two to four carbon atoms.
• the compounds according to the present invention may be prepared by a number of different methods involving well known chemical principles, among which the following have proved to be particularly convenient and efiicient:
• the hydrolysis and ring closure proceed smoothly and with good yields in an acid as well as an alkaline medium, preferably in the presence of an alcoholic or aqueous alcoholic solvent; however, other inert solvents such as tetrahydrofuran or dioxan, are also suitable; for-acid cyclization, .acetonitrile may also be used as the solvent.
• Mineral acids, and particularly hydrohalic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphonic acid and perchloric acid are preferably used as acid cyclization agents.
• alkaline cyclization agents are sodium alcoholates and alkali metal hydroxides.
• reaction periods depend upon the quantity of acid or alkali employed and upon the type of solvent used; they vary between several hours and several days.
• the preferred reaction temperatures are preferably between +20 C. and the boiling point of the solvent which is used.
• an end product of the formula I, wherein R is unsubstituted or substituted alkyl may be carried out in various ways.
• One may, for instance, start from a compound of formula I wherein R is hydrogen and exchange the same for an alkyl group with the aid of a customary alkylating agent, such as an alkyl halide or an alkyl sulfate, such as a dialkylsulfate.
• a customary alkylating agent such as an alkyl halide or an alkyl sulfate, such as a dialkylsulfate.
• an alkali metal salt of a compound of formula I is dissolved or suspended in a suitable solvent, the a] kylating agent is added to the solution or suspension, and the reaction mixture is heated.
• a compound of the formula I wherein R is hydrogenrnay be reacted with an alkyleneoxide in the presence of a strong base, such as Triton-B.
• a strong base such as Triton-B.
• the alkylation of the l-position may also be effected after the cyclization is finished, without prior isolation of the l-unsubstituted benzodiazepine-2,4-dione cyclization product.
• the alkylating agent is added to the cyclization reaction solution containing the cyclization product, and the mixture heated.
• the reaction is preferably carried out in the presence of a suitable inert organic solvent, such as benzene, toluene, xylene, tetrahydrofuran, dioxan or dimethylformamide, at room temperature or, more advantageously, at the boiling point of the particular solvent which is used.
• a suitable inert organic solvent such as benzene, toluene, xylene, tetrahydrofuran, dioxan or dimethylformamide
• a suitable inert organic solvent such as benzene, toluene, xylene, tetrahydrofuran, dioxan or dimethylformamide
• a tertiary organic base such as pyridine
• R is hydroxyalkyl
• the hydroxyl group may subsequently be replaced by a halogen atom by treatment with a thionyl halide in the presence of dimethylformamide, or converted into an alkoxy group by treatment with a diazoalkane in the presence of borontrifluoride etherate.
• R in a compound of the formula I is dialkylaminoalkyl, it is possible to introduce a double bond into the alkyl moiety by quaternization and splitting off trialkylarnine.
• this substituent may be partially or completely hydrogenated by known methods.
• N-phenyl-N-( 2-amino-5-chloro-phenyl)- malonic acid lower alkyl ester amides of the formula 11 used as starting materials for method A are also novel. They may be prepared by reacting a correspondingly substituted N-phenyl-N-( 2-nitro 5-chloro-phenyl amine with a malonic acid monoalkyl ester halide to obtain an N-phenyl-N-(2-nitro-5-chloro-phenyl)- malonic acid alkyl ester amide, and subsequently reducing the nitro group according to the following reaction sequence:
• N-phenyl-N-(2-nitro-5- chloro-phenyD-malonic acid alkyl ester amide of the formula IV is carried out, for example, by heating a solution of N-phenyl-N-(2-nitro-5-chloro-phenyl)- amine in a suitable solvent, such as benzene, toluene or xylene, with a malonic acid ester halide, whereby the nitro compound IV is always obtained with good yields (80 percent) and in crystalline form.
• a suitable solvent such as benzene, toluene or xylene
• the subsequent reduction of compound IV may be effected by nascent or catalytic hydrogenation, for example, by hydrogenation with Raney-nickel or with a mixture of iron and glacial acetic acid.
• the starting compounds of the formula III may be prepared by conventional methods, for example, by catalytic reduction of the corresponding 2-nitrodiphenylamine, or analogous to the method described in Chem. Berichte, Volume 34, page 4204 1902), and Volume 37, page 552 (1904), that is, by cyclizing a 2- aminodiphenyl-amine with formic acid, alkylating at the nitrogen atom in the cyclization product by means of an alkyl iodide, and subsequently splitting the ring with an alkali.
• EXAMPLEl 1-( BJ-Iydroxy-ethyl )-5-phenyl-7-chlorol H- l ,5- benzodiazepine-2,4-(3H,5H)-dione by method A A mixture consisting of 28.6 gm (0.1 mol) of 5-phenyl-7-chloro-lH-l,5-benzodiazepine-2,4-( 3H,5H)- dione, 500 ml of methanol, 25 ml of water, 10-15 ml of ethyleneoxide and 1 ml of TritonBtmethanolic 35percent solution of benzyltri'methylammonium hydroxide) was stirred at room temperature for about 8 hours.
• EXAMPLE 2 1-(B-Methoxy-ethyl)-5phenyl-7-chloro- 1 H- 1 ,5 benzodiazepine-2,4-(3H,5H)-dione by method A 28.6 gm (0.1 mol) of 5-phenyl-7-chloro-1H-l,5- benzodiazepine-2,4-(3H,5H)-dione were suspended in 750 ml of absolute tetrahydrofuran, 5 gm of a 50 percent dispersion of sodium hydride in tetrahydrofuran were added to the suspension and the mixture was stirred for 2 hours at room temperature, whereby everything went into solution.
• EXAMPLE 3 was prepared from 7-chloro-5-pheny1-lH-l,5- benzodiazepine-2,4-( 3H,5H)-dione and allyl bromide.
• EXAMPLE8 Using a procedure analogous to that described in Example 2, l-(/3-methoxy-ethyl)-7-chloro-5-phenyl-1H- l,5-benzodiazepine-2,4-( 3H,5I-l)-dione, m.p. 175-178 C., of the formula ts 5555a 513;; ll 7 'h15i5 s" 5iiI i-in i ,s benzodiazepine-2,4-(3H,5H)-dione and B-methoxyethyl bromide.
• EXAMPLE 9 EXAMPLE 10 Using a procedure analogous to that described in Example 2, 1-(,B-ethoxyethyl)-7-chloro-5-phenyl-1H-l,5- benzodiazepine-2,4-(3H,5H)-dione, m.p. -l37 C., was prepared from 7-chloro-5-phenyl-1H-l,5- benzodiazepine-2,4-(3H,5H)-dione and B-ethoxyethyl bromide.
• EXAMPLE 12 Using a procedure analogous to that described in Example 2, 1-(/3-diethylamino-ethyl)-7-chloro-5-phenyl- EXAMPLE 13 Using a procedure analogous to that described in Example 2, l-(ethoxycarbonylmethyl)-7-chloro-5-phenyll H-l ,5-benzOdiazepine-2,4( 3H,5H)-dione, m.p. 159-l 60 C., of the formula was prepared from 7-chloro-5-Phenyl-1H-l ,5- benzodiazepine-2,4-(3H,5H)-dione and ethoxycarbonylmethylbromide.
• EXAMPLE 14 Using a procedure analogous to that described in Example 2, l-('y -chloro-n propyl)-7-chloro-5-phenyl)- lI-ll,5-benzodiazepine-2,4-(3H,5H)-dione,m.p. l56l 58 C., of the formula dlCHzCH-2CH2 o M CH1 o1 flHfl g was prepared fF6 fi*IEii1Z5- 11E1T 1-1H-1,5- benzodiazepine-2,4-(3H,5H)-dione an 1,3-dichloropropane.
• EXAMPLE 15 Using a procedure analogous to that described in Example 2, l-(methoxycarbonyl-allyl)-7chloro-5-phenylll-l-l ,5-benzodiazepine-2,4-( 3H,5H)-dione, m.p. l 72174 C., of the formula benzodiazepine-2,4-(3H,5H)-dione and methoxycarbonyl-allyl bromide.
• Example 16 Using a procedure analogous to that described in Example 2, l-(B-ethylmercapto-ethyl)-7-chloro-5-phenyl l H- 1 ,5-benzodiazepine-2,4-( 3H,5H)-dione, m.p. 129-131 C., ofthe formula EEK was prepared from 7-chloro-5-phenyl-1l-1-1,5- b enzodiaiepine 2,4-(3H,5H)-Dione and B-ethylmercapto-ethyl bromide.
• EXAMPLE 17 Using a procedure analogous to that described in Example 2, 1-('y-hydroxy-n-propyl)-5-phenyl-7-chloro- 11-1-1,5-benzodiazepine-2,4-(3H,5H)-dione, mp. 21 1-2l3 C., was prepared from 5-phenyl-7-chloro-1 H-l,5-benzodiazepine-2,4-(3H,5H)-dione and 3- chloro-propanol.
• EXAMPLE 18 Using a procedure analogous to that described in Example 2, l-('y-piperidino-n-propyl)-5-phenyl-7-chlorolH-1,5-benzodiazepine-2,4-(3H,5H)-dione, m.p. 42- 459 .q lrqf mu au was prepared from 5-phenyl-7-chloro-lH-l ,5- benzodiazepine-2,4-(3H,5H)-dione and piperidino-npropyl bromide.
• the compounds according to the present invention that is, those embraced by formula 1 above, have useful phannacodynamic properties. More particularly, they exhibit very efl'ective psychosedative (tranquilizing) and anticon-vulsive activities in warm-blooded animals, such as mice, rats and dogs, coupled with low toxicity.
• Particularly efiective are compounds of the formula 1 wherein R is w-hydroxy-alkyl, w-alkoxy-alkyl or dialkylarnino-alkyl, and especially l-(B-hydroxy-ethyl)-5- phenyl-7-chl0ro-lH-1,5-benzodiazepine-2,4-(3 H,5H dione, 1-( methoxy--methyl)-5-phenyl-7-chlorol H- 1,5-benzodiazepine-2,4-(3H,5H)-dione and 1(3- methoxy-ethyl )-5-phenyl7-chlorol H,- 1 ,5 benzodiazepine-2,4-(3H,5H)-dione.
• the compounds according to the present invention are administered to warm-blooded animals perorally or parenterally as active ingredients in customary dosage unit compositions, that is, compositions in dosage unit form consisting essentially of an inert pharmaceutical carrier and one effective dosage unit of the active ingredient, such as tablets, coated pills, capsules, wafers, powders, solutions, suspensions, emulsions, syrups, suppositories and the like.
• One effective dosage unit of the compounds according to the present invention is from 0.0166 to 0.833 mgm/kg body weight, preferably 0.0833 to 0.42 mgrn/kg, and the daily dose rate is from 0.166 to 2.5 mgm/kg.
• the benzodiazepinedione compound was intimately admixed with the lactose and the corn starch, the mixture was moistened with an aqueous percent solution of the gelatin, the moist mass was forced through a 1 mm-mesh screen, and the granulate obtained thereby was dried at 40 C. and again passed through the screen.
• the dry granulate was admixed with the magnesium stearate, and the mixture was pressed into 55 mgm-pill cores, which were subsequently coated with a thin shell with the aid of an aqueous suspension of sugar,talcum, titanium dioxide and arabic, and the coated pills were polished with beeswax.
• One coated pill contained 10 mgm of the benzodiazepinedione compound and, when administered to a warm-blooded animal of about 60 kg body weight in need of such treatment, produced very good tranquilizing and anticonvulsive effects.
• EXAMPLE 20 Suppositories The suppository composition was compounded from the following ingredients: 1-(-y-l-lydroxy-n propyl)-5-phenyl-7-chlorolH-l,5-benmdiazepine-2,4-(3H,5H)-dione 10.0 parts Cocoa butter 1690.0 pans Total 1700.0 parts poured into cooled suppository molds, each holding 1,700 mgm of the mixture.
• One suppository contained 10 mgm of the ,benzodiazepinedione compound and, when administered by the rectal route to a warmblooded animal of about 60 kg body weight in need of such treatment, produced very good tranquilizing and anticonvulsive efi'ects.
• R1 0 l l wherein R is hydroxy-alkyl of two to four carbon atoms; haloalkyl of two to four carbon atoms; di(alkyl of two to four carbon atoms)amino-a1kyl of two to four carbon atoms; y-piperidino'propyl; alkoxy of one .to two carbon atoms-alkyl of one to four carbon atoms; (alkoxy of one to two carbon atoms)carbonyl-alkyl of one to four carbon atoms; (alkyl of one to two carbon atoms)mercapto-alkyl of one to four carbon atoms; straight or branched alkenyl of three to five carbon atoms; (alkoxy of one to two carbon atoms)carbonyl-alkeny1 of two to four carbon atoms; or halo-alkenyl of two to four carbon atoms.
• R is w-hydroxy-alkyl of two to three carbon atoms, 7- chloro-n-propyl, ,B-di( alkyl of one to two carbon atoms)amino-ethyl, -piperidino-n-propyl, w-alkoxy of one to two carbon atoms-alkyl of one to two carbon atoms, ethoxycarbonyl-methyl, B-ethylmercapto-ethyl, alkenyl of three to five carbon atoms, y-methoxycarbonyl-allyl or 'y-chloro-allyl.
• R is w-hydroxy-alkyl of two to three carbon atoms, w-alkoxy of one to two carbon atoms-alkyl of one to two carbon atoms or B-di(alkyl of one to two carbon atoms)amino-ethyl.
• a compound according to claim 1 which is l-(B- hydroxy-ethyl-iphenyl-7-chloro-1H- 1 ,5- benzodiazepine-2,4-( 3I-1,5H)-dione.
• a compound according to claim 1 which is 1-( B- methoxy-ethyl)-5-phenyl-7-chlorol H- 1 ,5- benzodiazepine-2,4-(3H,5H)-dione.
• a compound according to claim 1 which is lbenzodiazepixze-ZA-(BHISl-lidione. methoxymethyl-S-phenyl-7-chloro-lH-l ,5- 8.

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