IL28036A - 6-basic substituted morphanthridines and process for the preparation thereof - Google Patents

Description

•nilUl |Π3 ΤϊΙΠΙ"! ·π PATE NT ATTO R N EYS · 0 1 13 J ID D ' D T I U PATENTS AND DESIGNS ORDINANCE SPECIFICATION 6-Basic substituted morphanthridines and process for the preparation thereof onaaaV n*o»oa DR.A. WANDER Π.Α.-, incorporated under the laws of Switzerland, of Bobijoustrasse 115, 3001 Berne,Switzerland do hereby declare the nature of this invention and in what manner the same is to be performed, to particularly described and ascertained in and by t following statement :- Shis invention is generally concerned with heterocyclic falling within the ra ge of this invention are 6-(4- ethyl-l-piperasinyl)*-8-methyl-morphanthridine and the physiologically acceptable acid addition salts thereo .

The compounds of this invention are obtained by reacting a reaction mixture containing nitrilium or imonium cations of the formulae: (ID wherein R, is lower alkyl* with a piperazine of the general formula wherein-S—¾»&■ R^ has the meaning indicated above.

Nitrilium or imonium cations of formulae (II) can be regarded as dissociation products of compounds of the formulas , the sulfhydryl tivated, if compounds (IV) are obtained, for instance, by conversion of lactams of the ormul : wherein ^ is lower alkyl, into the thiolactams, if required with subsequent allcylation of the latter, or by reacting the lactams (V) with a halogenating agent like phosphoroxychloride or phosphorus pen aciuoride, preferably in the presence of catalytic amounts of dimethylaniline or dimethylformamide. The lactams (V) can be obtained, for example, by ring closure of suitable o«* isocyanato-diphenylmethanes with aluminium chloride. Depending upon the chemical nature of the residue X, the compounds (IV) 28036/2 or lower degree into the nitrilium or imonium cations, so' that the reaction mixtures can be used directly for reacting with the amine of formula (III). In part the compounds of formula (IV) produced in this or in another manner can be isolated in undissociated form and then yield the desired nitrilium or imonium cations (II) upon dissolution i a suitable, preferably polar solvent, if required by heating and in the presence of the amine of formula (III), which can also serve as a solvent. Re- action mixtures containing cations of formulae (II) can also be produced, for example, by intramolecular Ritter's reaction (action of a nitrile group on a phenyl cation) in o-cyano- diphenylmethanes, by Beckmann's transformation of anthron- oximes, or by Schmidt's reaction of anthrones with hydrazoic acid. Both the last-named reactions may lead to isomeric pro- ducts which, if necessary, must be subsequently separated. In the said reaction mixtures the- anionoid components which may appear are - besides those derived from the substituent X of . formula (IV) -, depending upon the mode of preparation of the cations (II), for example also anions of sulphurio, toluene sulphonic, phosphoric, hydrofluoric, or hydrofluoboric acids, etc, Compounds in accordance with this invention are also ob- tained by dehydration of urea derivatives of the formula: wherein R, R, and R, have the meaning indicated above, 28036/2 for instance through several hours ' action by dehydratin . agents like zinc dichloride, aluminium chloride, tin tetra- chloride, phosphoric acid and the like, but preferably phos- phoroxychloride, if required in the presence of an inert sol- vent with; a suitable boiling point, such as benzene, toluene, etc.

Compounds according to this invention are also obtained by ring closure, through intramolecular condensation, of acid amides or thioamides of the formula: wherein R, R^ and R^ have the above-mentioned meaning, and Y represents an oxygen OJJ, sulphur atom. A purely thermal conden- sation cannot usually be successfully carried out with the acid amides, which, in turn, are produced, for example, by reduction of suitable nitro compounds, but it can rather in the case of the thioamides, which are obtained, for example, by treating the acid amides with phosphoric pentasulphide and do not require' to be isolated prior to the subsequent condensation. Especially in "the case of the acid amides it is useful to work in the presence of condensing agents, such as phosphoric pentachloride, phosphor- oxychloride, phosgene, polyphosphoric acid, and the like. It is to be supposed that the ring closure involved goes, partly through intermediate stages, like i ide chlorides, amide chlorides, 23036/2 imidophosphates, amidophosphates or salt-like derivatives thereof, which can not generally be isolated. Condensation of the thio amides may be aided by the presence of mercury salts or by intermediate formation of (if desired activated) imido thio ethers. Heating and, if required, the use of an inert diluent are useful when working with, phosphoroxychloride and phosphoric penta- chloride, as also the addition of catalytic amounts of dimethyl- formamide Or dimethylaniline.

Compounds in accordance with this invention can further be prepared by reacting primary amines of the formula: wherein R^ denotes lower alkyl, with reactive esters of alcohols having the formula: I OH ■ HO ' wherein R and R have the meaning identified above, for instance with hydrohalic, carbonic, sul honic, or p^toluene sulphonic acid esters, if desired under prior or simultaneous action by a basic catalyst or metallizing agent like sodium amide, .lithium amide, sodium hydride, butyl lithium, phenyl sodium, sodium ethylate or potassium-t-butylate. The primary amines of formula (VIII) are obtained by treating a reaction mixture containing nitriliura or imonium cations of formulae (II) 28036/2 In so far as by one of these processes compounds are ..ob- tained, wherein R^ denotes hydrogen, substituents R^ other than hydrogen may subsequently be introduced by reaction of the se- condary amines with reactive esters of alcohols of the formula R^-OH, using the same methods as described above.

The bases (I) obtained in the manner just described are in most cases crystallizable, otherwise they can be distilled under high vacuum without decomposition, and they form with in- organic and organic acids, e.g. hydrochloric, hydrobromic, sul- phuric, nitric, phosphoric, acetic, oxalic, tartaric, toluene sulphonic acid and the like, addition salts which are stable in ' water, in which form the products can likewise by used.

The 6-basic substituted morphanthridines and their acid 1 addition salts described above are new compounds which are used as active substances in medicines or as intermediates for the manufacture of such substances. In particular the products are useful as neuroplegics, neuroleptics and analgesics. This utility is manifested pharmacologically by considerable depression of motility in mice, which can be shown by measuring the locomotor activit in accordance with the method of Caviezel and Baillod [Pharm. Acta Helv. 33, 469 (1958)]. For instance, 6-(4-methyl- l-piperazinyl)-8-methyl-morphanthridine administered to mice in an amount of 0.062 mg/kg p.o. depresses the locomotor activity of the test animals to 50$ of the controls (ED 50), the compound having a toxicity (LD 50) of 30 mg/kg p.o. (in mice). parations may be, for example, In the form of tablets, dragees, or solutions for injection, one dosage unit containing from 1 to 50 mg of active substance, depending on its nature, on the route of administration and on the physician's prescription, the effective daily dose amounting to from 10 to 500 mg of active substance.

Example 1 A mixture of 8.0 gm of , 6-dihydro-6-oxo-8-methyl-morphanthridine, 2.5 ml of Ν,Ν-dimethylaniline and 80 ml of phosphoroxychloride is heated during 4 hours under reflux. The excess of phosphoroxychloride is then completely removed by di-stillation in vacuo, and the residue is dissolved in 150 ml of xylene. The solution is poured on ice-water. The organic phase is separated, washed with diluted hydrochloric acid, soda solution and water, and dried with sodium sulphate. To the xylene solution containing the imidechloride, 15 ml of N-methylpiperazine are added, and the mixture is heated for 5 hours under reflux. Upon cooling to room temperature, the reaction mixture is exhaustively extracted with diluted hydrochloric acid. The acid extracts are alkalized by addition of soda lye, and the base is extracted by shaking with ether. The ethereal extracts are washed with water and dried over sodium sulphate. The residue is crystallized from ether/petroleum ether, yielding 7.6 gm of 6-(4-methyl-l-piperazin-yl)-8-methyl-morphanthridine in the form of prisms of melting point 113-115°C.

Example 2 mixture of 10 gm of 2-[(4-methyl-l-piperazinyl)carbox-amido]- ' -methyl-diphenylmethane and 100 ml of phosphorous oxy- mixture is evaporated to dryness in_ a2u2' ^ne resi^ue is treated with ice-water and rendered alkaline by addition of concentrated soda lye. The extract obtained by extraction of the alkaline solution with ether is washed with water and then in turn exhaustively extracted by shaking with diluted aqueous hydrochloric acid. The aqueous acidic phase is rendered alkaline by addition of concentrated soda lye. The separated basic material is extracted by shaking with ether. The ethereal phase is washed with water, dried with sodium sulphate, and concentrated to dry- ness. The residue yields from ether/petroleum ether 6.3 gm of 6-(4-methyl-l-piperazinyl)-8-methyl-morphanthridine in the form of prismatic crystals of metling point 113-115°C. This product can be shown to be identical with the product obtained according to Example 1.

Example 3 A solution of 1.42 gm of methyl iodide in 30 ml of benzene is added drop by drop into a solution of 5.82 gm of 6-(l-piperazin-yl)-8-methyl-morphanthridine in 50 ml of benzene heated to 60°C. The mixture is heated under reflux during 30 minutes. After cool-ing, the hydroiodide of the starting material is filtered off by suction and the filtrate is evaporated to dryness in vacuo. The residue is recrystallized from ether/petroleum ether, yielding 2.5 gm of 6-( -methyl-l-piperazinyl)-8-methyl-morphanthridine in the form of prismatic crystals of melting point 113-H5°C. The product is identical with the product obtained according to Example 1.

In a like manner as in the Examples previously mentioned there are obtained from the corresponding starting materials, for instance, 6-(l-piperazinyl)-8-raethyl-morphanthridine of 6- ( 4-hydroxyethyl-l-piperazinyl ) -8-raethyl-morphanthridine , the maleate of which having a melting point of 157-l6l°G (from acetone/ether) .

Production of tablets For the manufacture of tablets, the products of this invention can be mixed with lactose and granulated with water, 0.5 % sodium alginate or 1 gelatine solution. The dried granul-ate is compressed into tablets in the presence of about 5 ° of talcum, 5 of corn starch and 0.1 of magnesium stearate. In this way, there are obtained, e.g. tablets of the following com-position: 6-(4-Methyl-l-piperazinyl)-8-methyl- morphanthridine 10 rag Lactose 80 rag Corn starch 5 mg Talcum 5 mg Magnesium stearate 0.1 mg These 100 mg tablets possess psycholeptic action. They are administered orally in a dosage of 3 to 6 tablets per day in the treatment of patients suffering from psychotic excite-merit. 28036/2

Claims (1)

CLAIMS morphanthridines of the general formulas wherein R is is lower or lower having not more than carbon and is lower and physiologically acceptable acid addition salts A process for the preparation of morphanthridines of the formula I in
1. Claim 1 and of cally acceptable acid addition salts said which prises either treating a reaction mixture containing nitrilium or of the wherein is lower with a piperazine of the formula 12 H has the same meaning as in Claim or subjecting a urea derivative of the general formula wherein and have the same meaning as in Claim to or an acid amide or thioaiaide of the general formulas wherein and have the same meaning as in Claim and Y is a sulphur or an oxygen to intramolecular condensation o reacting an amine of the general 13 wherein is lower with a reactive ester of an alcohol of the general wherei R and have the same meaning as in Claim the reaction product being isolated in the form of the free base or in the form of an acid addition H insufficientOCRQuality