CH601288A5 - 11-Piperazino-5H-di:benzodiazepine derivs. - Google Patents

Abstract

Prodn. of new diazepine derivs. of formula (I) comprises reacting the ketones (II) with a metal-amine complex (in which the metal is of Gp. 4B or V), and a piperazine of formula (III) (where R1 is H, is not >4C alkyl or hydroxyalkyl, or is not >5C alkoxyalkyl. R2 is is not >4C alkyl or hydroxyalkyl, 2-4C alkenyl or is not >5C alkoxyalkyl).(I) are neuroleptics useful for treating psychotic disorders at a daily dose of 3-50 mg/kg. compared with commercial neuroleptics they have fewer side effects e.g. reduced circulatory activity. They also have antidepressant activity at 0.07-5 mg/kg per day.In an example 8-F-5-CH3-11-(4-CH3-piperazino)-5H-dibenzo b,e 1,4 diazepine was prepd. from (II; R2 is CH3) and (III; R1 is CH3).

Description

  

  
 



   The invention relates to a process for the preparation of organic compounds of the formula I,
EMI1.1
 where Rl stands for hydrogen, an alkyl or hydroxyalkyl group with at most 4 carbon atoms or an alkoxyalkyl group with at most 5 carbon atoms together and R2 for an alkyl or hydroxyalkyl group with at most 4 carbon atoms, an alkenyl group with 2-4 carbon atoms or an alkoxyalkyl group with at most 5 carbon atoms together stand.



   In compounds of the formula I, the alkyl groups can be straight-chain or branched and are, for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert. Butyl.



   The hydroxyalkyl groups preferably have 24 carbon atoms and are, for example, hydroxyethyl or a straight-chain or branched hydroxypropyl or hydroxybutyl group.



   The alkoxyalkyl groups are, for example, methoxy ethyl, methoxypropyl, methoxybutyl, ethoxyethyl, ethoxypropyl or propoxyethyl.



   The alkenyl group in R2 stands in particular for allyl or 2-methylallyl.



   The compounds of the formula I can be converted into their acid addition salts and vice versa.



   According to the invention, compounds of the formula I are obtained by adding compounds of the formula II,
EMI1.2
 wherein R2 has the above meaning, with a metal-amine complex consisting of a metal from group IVb of the periodic table or vanadium, and a compound of the formula III,
EMI1.3
 wherein Rl has the above meaning.



   The process according to the invention can be carried out in a manner known per se. The reaction is conveniently carried out in the presence of an acid-binding agent, for example a tert. Amine, such as triethylamine, pyridine, dimethylaniline or an excess of the compound of formula III.



   The compounds of the formula I obtained according to the invention can be isolated and purified in a manner known per se. Before isolating the compounds of the formula I, it is necessary to precipitate the metal fraction in the solution by adding water.



   The compounds of the formula II can be obtained, for example, by alkyl 2-nitro-4-fluoro-diphenylamine-2'-carboxylate in alkyl N-R2-2-nitro-4-fluoro-diphenylamine-2'-carboxylate, where R2 has the above meaning , converted, these to the N-R2-2-amino-4-fluoro-diphenylamine-2'-carboxylic acid alkyl esters, in which R2 has the above meaning, reduced and the compounds of formula II obtained therefrom by ring closure.



   The compounds of the formula I are distinguished by favorable pharmacodynamic activities. They can be used in particular as neuroleptics, for example for the treatment of psychotic disorders. This beneficial effect is shown, for example, in a test in which the inhibition of running activity in mice after p.o. Administration of 1 to 50 mg of active substance per kg of animal body weight according to the method of Caviezel and Baillod in Pharm. Acta Helv.



  (1958) 33, 469-484, given method is measured.



   The compounds of the formula I are moreover surprisingly characterized by pharmacodynamic effects that are less than side effects compared to similar neuroleptics available on the market, e.g. B. due to lower circulatory effects.



   For the above application, the dose to be administered can vary depending on the active ingredient used, the mode of administration and the therapy desired.



  In general, satisfactory results are obtained with a daily dose of 3 mg to about 50 mg per kg of animal body weight. This amount can also be administered in smaller doses 2 to 4 times a day or in sustained release form. For larger mammals, the amount to be administered daily should be from 10 to 600 mg. The form suitable for oral administration should contain from 10 to approx. 200 mg of the active ingredient together with a solid or liquid pharmacodynamically acceptable carrier or diluent.



   The compounds of the formula I also have an antidepressant effect, as can be seen from the results of the corresponding tests, for example a test in which the reversal of the tetrabenazine catalepsy and tetrabenazine ptosis [Stille, Arzneimittelforschung 1964, 14, 534] is found .



   The dose to be administered for this application depends on the compound used and the mode of administration and the mode of treatment. Satisfactory results are obtained when compounds of the formula I are administered in a daily dose of 0.07 to 5 mg / kg animal body weight. For larger mammals, a daily dose of between 5 and 300 mg is indicated. This amount to be administered daily can also be administered in smaller doses 15 times a day or in retard form. A unit dose, for example a tablet suitable for oral administration, can contain between 5 and 50 mg of the active ingredient together with suitable pharmaceutically inert excipients.



   The compounds of the formula I can also be administered in the form of their pharmaceutically acceptable acid addition salts, which have the same degree of activity as the free bases.



   A unit dose, for example a tablet suitable for oral administration, can contain between 5 and 100 mg of the active ingredient together with suitable pharmaceutically inert excipients such as lactose, corn starch, talc, magnesium stearate, etc.



   The administration of compounds of the formula I or



  the salts thereof can either be administered orally in the form of tablets, granules, capsules or dragees, or parenterally in the form of injection solutions.



   A preferably tablet preparation consists of 10 mg of 8-fluoro-5-methyl-1 1- (4-methyl-1-piperazinyl) -5H dibenzo [b, e] [1,4] diazepine, 140 mg of lactose, 5 mg of corn starch, 5 mg talc and 0.1 mg magnesium stearate.



   Compounds of formula I preferred from a pharmacodynamic point of view are those in which R1 and R2 are methyl.



   In the following examples, the temperatures are given in degrees Celsius. The room temperature is approx. 20 300C.



   Example 1 8-Fluoro-5-methyl-11- (4-methyl-1-piperazinyl) 5H-dibenzo [b, e] [1,4] diazepine. To a red solution formed from 2.2 ml of titanium tetrachloride, 4.35 ml of anisole and 40 ml of toluene, a solution of 9.0 ml of N-methylpiperazine in 5.0 ml of toluene is added dropwise with stirring and ice-water cooling over a period of 10 minutes green insoluble complex is formed. Then 4.85 g of 8-fluoro-5-methyl-10,11-dihydro-5H-dibenzo [- b, e] [1,4] diazepin-11-one and 4.5 ml of N-methylpiperazine are added, and the mixture obtained is heated to boiling (reflux) for 3 hours. After adding 3.0 ml of water, the precipitate formed is filtered off and washed with methanol.

  The filtrate is evaporated to dryness in vacuo, the residue is taken up in acetic acid, the solution is clarified with charcoal and made alkaline by adding a concentrated aqueous ammonia solution. The precipitated base is taken up in ether, the ether solution is washed with water, dried over sodium sulfate and concentrated. The residue is recrystallized from ether / petroleum ether, the 8-fluoro-5-methyl-11- (4-methyl-1-piperazinyl) -5H-dibenzo [b, ej [1, 4] diazepine of mp.



     172-1740C received.



   The 8-fluoro-5-methyl-10,11-dihydro-5H-dibenzo [b, e] [1,4] diazepin-11-one used as the starting compound can be obtained by mixing anthranilic acid with 2-bromo-5-fluoronitrobenzene in The presence of potassium carbonate and copper powder in boiling amyl alcohol (Ullmann condensation) to form 2-nitro-4-fluoro-diphenylamine-2'-carboxylic acid of melting point 236-2370C, which converts this via the acid chloride into 2-nitro-4-fluoro Diphenylamine-2'-carboxylic acid methyl ester of melting point 156-158 converted, this with methyl iodide in the presence of sodium hydride in hexamethylphosphoric triamide to form N-methyl-2-nitro-4-fluoro-diphenylamine 2'-carboxylic acid methyl ester, from this by reduction with Raney Nickel in ethyl acetate receives the N-methyl-2-amino4-fluorodiphenylamine-2'-carboxylic acid methyl ester and this a ring closure,

   for example, by heating for several hours in dioxane in the presence of sodium amide, the 8-fluoro-5-methyl-10,11 dihydro-5H-dibenzo [b, e] [1,4] diazepin-1 1-one of m.p. 209 211ob received.



   Analogously to Example 1 and using appropriate starting compounds, the following compounds of the formula I are obtained: Example R1 R2 mp.



  2 -CH3 -C2Hs 133-135 "3 -CH3 -C3H7 95-970 and 115-117 4 -CH3 n-C4H9 124-125 5 -CH3 -CH2-CH = CH2 157-159

 

Claims (1)

PATENT CLAIM Process for the preparation of new organic compounds of the formula I, EMI2.1 where Rl stands for hydrogen, an alkyl or hydroxyalkyl group with at most 4 carbon atoms or an alkoxyalkyl group with at most 5 carbon atoms together and R2 for an alkyl or hydroxyalkyl group with at most 4 carbon atoms, an alkenyl group with 2-4 carbon atoms or an alkoxyalkyl group with at most 5 carbon atoms together stand, characterized in that compounds of the formula II, EMI2.2 wherein R2 has the above meaning, with a metal-amine complex consisting of a metal from group IVb of the periodic table or vanadium, and a compound of the formula III, EMI2.3 wherein Rl has the above meaning.