NL8105804A - METHOD FOR PREPARING A THERAPEUTIC PREPARATION AND METHOD FOR PREPARING A COMPOUND SUITABLE FOR THAT PREPARATION - Google Patents

Description

·. - 1 -

Process for "preparation of a therapeutic preparation as well as process for" preparation of a compound suitable for that preparation.

The invention relates to a process for the preparation of a therapeutic preparation, in which a 1-substituted 6-phenyl-ta-s-triazolo / U, 3-a / - / T, 1 »7-benzodiazepine, of which the 6- phenyl group and the phenyl ring 5 of the benzodiazepine ring system may be substituted, or bring a pharmaceutically acceptable acid addition salt thereof into a form suitable for therapeutic use.

Such a method is known from Dutch patent application 70.03750.

According to this patent application, the compounds used can be substituted in the 1-position, inter alia, by an alkyl group with 1 to 3 carbon atoms. However, there is no mention of a possible substitution of such an alkyl group.

According to the invention, in such a process, a compound of the formula (3) is used, in which E1 is an alkyl group with 1 to 3 carbon atoms, R is a cyano, hydroxy or nitro group or a dialkylamino or alkoxy -group, wherein the alkyl group contains 1 to 3 carbon atoms, or an alkylthio-20 group having 1 to 3 carbon atoms or a -C00R "group, wherein R" represents an alkyl group having 1 to 3 carbon atoms, and Eg, R ^, R ^ and R ^ each a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, halogen, a nitro, cyano, trifluoromethyl or alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoylamino- or 25 dialkylamino group, in which the carbon contains residues and 1 to 3 carbon atoms.

Namely, it has been found that also the compounds having an alkyl in the 1-position, the methyl group of which is substituted in the 1-position with one of the indicated substituents, are of use because of their soothing, calming and 4 w - * - * '- 1a - muscle tensioning effect in mammals and birds.

8105804 * - 2 -

The sedative effect of compounds can be determined in the following experiments on mice.

Chimney Test: (Med. Exp. 4, II (1961)).

The test determines the ability of mice to emerge from a vertical glass cylinder within 30 seconds. EDQ indicates the dose of a sedative to be administered to mice so that 30% of the mice fail. 8-chloro-1- (dimethylamino) methyl-4-methyl-6-phenyl-4H-s-triazolo / 4,3-a / 1,4-benzodiazepine 10 shows an ED ^ q of 38 in this test mg / kg.

Dish test;

Mice in Petri shells (10 cm diameter, 5 cm high, partially embedded in wood shavings) quickly climb out when not treated. Mice that remain in the shell for more than 15 minutes have calmed down. ED, -q is the dose of test compound to be administered to mice so that 50% of the mice remain in the dish. Of 1- (dimethylamino) -methyl-4-methyl-6-phenyl-8-chloro-4H-s-triazolo / 4,3-a 1 1,4-benzodiazepine m the ED ^ q by intraperitoneal administration 20 45 mg / kg.

Pedestal test:

The untreated mouse leaves the pedestal in less than 1 minute to climb back to the floor of the standard mouse box. ED ^ q indicates the dose of test compound to be administered to mice so that 50% of them remain on the pedestal for more than 1 minute. Of the compound 1- (dimethylamino) -methyl-4-methyl-6-phenyl-8-chloro-4H-s-triazolo / 4,3-a-7 / 1,4 / benzodiazepine, the ED ^ q is intraperitoneal administration 63 mg / kg.

30 Nicotine Antagonism Test:

Mice are injected in a group of six with the test compound. 30 minutes later, these mice as well as untreated control mice are injected with nicotine salicyhat (2 mg / kg). ED ^ q indicates the dose of test compound which prevents 50% of the treated mice from dying of cramps. From l- (dimethyl- 8105804 Λ · ί X - - 3 - $ amino) -methyl-4-methyl-6-phenyl-8-chloro-4H-s-triazoΙο / 4,3-a / - / 1,4_benzodiazepine the ED in this test is 6.3 mg / kg.

The invention relates to the preparation of pharmaceutical preparations suitable for oral, parenteral and rectal use, for example tablets, powders, cachets, dragees, capsules, solutions, suspensions, sterile injectable forms, suppositories, probes and the like. Suitable diluents or carriers, such as carbohydrates, (lactose), proteins, lipids, calcium phosphate, corn starch, stearic acid, methyl cellulose and the like can be used as carriers or for coating purposes. Oils, for example, coconut oil, sesame oil, safflower oil, cottonseed oil, groundnut oil can be used for the preparation of solutions or suspensions of the active drug. Sweeteners, colors and flavors can be added.

For mammals and birds, feed premixes with starch, oatmeal, dried fish meat, fish meal flour and the like can be prepared.

All this shows that the expression therapeutic preparation as used in the present application is to be understood in a broad sense.

The invention also relates to a process for the preparation of a compound of the formula 3, wherein a compound of the formula 1, wherein R 1, R 1, R 1, R 1, R 1 and R 1 25 have the same meaning as indicated above, in an inert organic solvent heated to a temperature between 60 and 120 ° C with a hydrazide of the formula 2, in which R has the same meaning as indicated above, after which if R is a cyano group and it is desired to prepare a compound of the formula 3, in which R is a C00R "group, wherein R" represents an alkyl group having 1 to 3 carbon atoms, hydrolyzes the resulting compound in the presence of R'OH. The preparation of the compounds used according to the invention thus takes place in a manner similar to that of the compounds according to patent application 70.03750 Ned. be prepared.

The preparation of compounds used according to the invention 8 1 0 5 8 0 4 • s - 4 - is illustrated in the following example:

A stirred solution of 7-chloro-1,3-dihydro-3-methyl-5-phenyl-2H-1,4-benzodiazepine-2-thione 5 (3.00 g, 0.01 mol) and n butanol (100 ml) was treated with 3.51 g (0.03 mol) of dimethylaminoacetic acid hydrazide. The mixture was refluxed for 18 hours while bubbling nitrogen through it. The solution was then concentrated in vacuo, the residue was mixed with water and extracted with dichloromethane. The extract was washed with brine and dried with sodium sulfate, then concentrated in vacuo. The residue was chromatographed on silica gel (350 g) using trichloromethane containing 5% methanol. The product thus obtained was crystallized from a mixture of ethyl acetate and Skellysolve B and recrystallized from a mixture of dichloromethane, methyl acetate and Skellysolve B. Thus, 1.10 g of 8-chloro-1- (dimethylamino) methyl-4 -methyl-6-phenyl-4H-s-triazolo / 4,3-alpha / 1,4-benzodiazepine 20. Melting point 2-4-215 ° C after initial melting occurred at 204-205 ° C followed by re-solidification. 0.625 g of said compound with a melting point of 202-206 ° C and 0.23 g with a melting point of 201-210 ° C were also obtained. The total yield was therefore 53%. An analytical sample melted at 202-205 ° C and then solidified and melted again at 214-215 ° C. In ethanol, the compound exhibited ultraviolet absorption at 221 τψ. (ε * 39,700); ^ max (shoulder at 17,350), 265 (shoulder at 6,950), 285 (shoulder at 3,350). The infrared and nmr spectra supported the supposed structure.

Analysis: Calculated for ^ 0 ^ 20 ^ ¾: C 65.66%, H 5.51%, Cl 9.69%, N 19.14% Found: C 65.23%, H 5.46%, Cl 9 , 76%, N 19.10%.

8105804

Claims (2)

A process for the preparation of a therapeutic composition, comprising a 1-substituted 6-phenyl-4'-s-triazolo / 4,3-a / / 1,4_ / benzodiazepine, of which the 6-phenyl group and the phenyl ring of the benzodiazepine system can be substituted or bring a pharmaceutically acceptable acid addition salt thereof into a form suitable for therapeutic use, characterized in that a compound of the formula 3, wherein R 1 is an alkyl group having 1 to 3 carbon atoms , R is a cyano, hydroxy or nitro group, or a dialkylamino or alkoxy group, in which the alkyl group contains 1 to 3 carbon atoms, or an alkylthio group, having 1 to 3 carbon atoms, or a -C00R "group in which R": an alkyl group having 15 to 3 carbon atoms, and R2, Rg, R4 and Rg each represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, halogen, a nitro, cyano, trifluoromethyl or alkoxy , alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoylamino or dialkylamino group, wherein the k hydrocarbon residues 1 to 3 contain carbon atoms, respectively represents a pharmacologically acceptable acid addition salt thereof in a form suitable for therapeutic use. 2. Process for preparing a compound suitable for use in the process according to claim 1 by using a 1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-thione with a hydrazide at a temperature between 60 and 120 ° C, characterized in that a compound of the formula 1 in which R 1, R 2, Rg, R 1 and Rg have the same meaning as in claim 1 is heated with a compound of the formula 2, wherein R has the same meaning as in claim 1, where if R is a cyano group and it is desired to prepare a compound of formula 3 wherein R is a C00R "group, wherein R" is an alkyl group having 1 to 3 carbon atoms represents, the resulting compound hydrolyses in the presence of R "0H. 8105804