CS264264B2 - As-triazine condensed derivatives,preparation method therefor - Google Patents

Description

Process for the preparation of condensed as-triazine derivatives

The present invention relates to a new, more preferred process for the preparation of partially novel fused as-triazine derivatives of the formula I into a (C 1 -C 4) alkyl and / or (C 1 -C 4) alkoxy group. Z is buta-1,3-dienyl or of formula (a) an alkyl group having from 1 to 10 and CS 264 264 B2 and isomers thereof wherein

R 1 is carbon or phenyl or naphthyl, the latter two being optionally substituted by one or more substituents which are halogen, nitroamino, hydroxy, C 1 -C 4 alkyl and / or C 1 -C 4 alkoxy,

R 2 is hydrogen, halogen, C 1 -C 14 alkyl or phenyl or naphthyl, the latter two being optionally substituted by one or more substituents which are halogen, nitro, amino, hydroxy

and

A ^- represents an anion of a physiologically acceptable organic or inorganic acid, preferably a halide, perchlorate or sulfonate anion.

The term "alkyl" as used herein refers to a straight or branched chain alkyl group (for example, methyl, ethyl, η-propyl, isopropyl, tert-butyl, etc.). These alkyl radicals preferably have 1 to 6 carbon atoms, and preferably 1 to 4 carbon atoms. The term "alkoxy" is used to denote a straight or branched-chain alkoxy group (such as methoxy, ethoxy, isopropoxy, etc.). The term "halogen" includes fluorine, chlorine, bromine and iodine atoms.

A ^{- is} preferably, for example, a chloride, bromide or iodide anion or perchlorate, methanesulfonate, ethanesulfonate or p-toluenesulfonate anion.

Compounds of formula I wherein R 2 is halogen and other symbols are as defined above are novel. Other compounds of this general formula are known (DOS No. 3,218,386).

Known compounds of formula I, i.e. compounds in which R 2 has the meaning other than halogen and R, Z and A ^- are as defined above, were prepared to the, still time-consuming multistep synthesis described in DE-OS no. 3128386, the resulting the products were obtained in a relatively low yield.

These disadvantages are overcome by the process according to the invention, characterized in that a compound of the zwitterion type II

where

R1, R2 and Z are as defined above, and -R3 is hydrogen or alkyl of up to 4 carbon atoms, reacted with an acid of formula III

H + A (III) wherein A ^- has the previously listed DEIN -the meaning, and the obtained -compound of formula I are optionally separated into its isomers and / or, if desired, the anion A ^- is exchanged for another -anion

AND.

According to a preferred embodiment of the process according to the invention, compounds of formula I are prepared in which Z represents a group of formula b). According to a further preferred embodiment of the process according to the invention, compounds of the formula I are prepared in which R 1 is phenyl optionally substituted by halogen in the 4-position, preferably 4-chlorophenyl. According to yet another preferred embodiment of the process according to the invention, the compounds of the general formula I are prepared in which:

R 2 is hydrogen, halogen, methyl or phenyl.

According to a particularly preferred embodiment of the process according to the invention, 1- (4-chlorophenyl) -α-as-triazino [6,1-a] isoquinolinium bromide is prepared.

The novel compounds of the formula I as defined above have useful pharmacological properties and in particular have an effect as antidepressants. Particularly useful pharmacological activity are those compounds of formula I wherein R 2 is chlorine.

In the process according to the invention, a compound of the type "Zwitterion" of the formula II is reacted with an acid of the formula III. The reaction is carried out in an anhydrous medium. As reaction medium, it is preferable to use solvents in which the anion-containing acid A 'is soluble.

As anhydrous inert organic solvents, for example:

halogenated hydrocarbons (such as chloroform, carbon tetrachloride or chlorobenzene), aromatic hydrocarbons (such as xylene, toluene or benzene), dialkyl amides (such as dimethylformamide), dialkyl sulfoxides (such as dimethyl sulfoxide), cyclic ethers (such as tetrahydrofuran or dioxane), for example aliphatic diethyl ether), other hydrocarbons (e.g. n-hexane or petrol) or acetonitrile or mixtures thereof.

A particularly preferred solvent is acetonitrile. The reaction may be carried out at a temperature in the range of from 0 to 150 ° C, preferably at a temperature of from 15 to 35 ° C.

The starting compounds of formula (II) are novel compounds and their conversion into compounds of formula (I) is a novel type reaction.

The reaction mixture can be worked up by methods known per se.

If desired, the compound of the formula I can be separated into its isomers by methods known per se.

In the compound of formula (I), the anion can optionally be exchanged for another anion by methods known per se. Thus, for example, a compound of formula I containing an anion A ^- chloride anionine can be converted to the corresponding compound of formula I

I containing as perchlorate anion by reaction with perchloric acid. Compounds of formula I containing a bromide anion as A may be prepared from compounds of formula I containing another anion, for example perchlorate anion, by reaction with tetrabutylammonium bromide.

The starting materials of the formula I are new compounds whose production process is protected in the Czech Republic. No. 264,262.

An advantage of the process according to the invention is that the compounds of the formula I can be prepared in one step in excellent yield.

The novel compounds of formula (I), like the known compounds of formula (I), can be formulated into pharmaceutical compositions containing as active ingredient at least one compound of formula (I) wherein R; represents halogen and R 3, A ^- and Z are as defined above, in association with suitable inert pharmaceutical carriers and / or excipients.

These pharmaceutical compositions can be prepared by methods known in the pharmaceutical industry.

The compositions may be solid (e.g. tablets, capsules, coated pills, dragees), semi-solid (i.e. ointments) or liquid (e.g. solutions, suspensions, emulsions) and may be finalized to a form suitable for oral or parenteral administration.

The pharmaceutical compositions may contain carriers. These carriers can be solid carriers, fillers, sterile aqueous solutions or non-toxic organic solvents. Tablets suitable for oral administration may contain sweetening and / or other excipients (e.g. starch, preferably potato starch), binders (e.g. polyvinylpyrrolidone, gelatin), lubricants (e.g. magnesium stearate, sodium lauryl sulfate or talc) or other additives (e.g. sodium citrate, carbonate) The aqueous suspensions and elixirs suitable for oral administration may further contain flavors, colorants, emulsifiers, diluents (e.g. water, ethanol, propylene glycol or glycerol, etc.).

Parenteral compositions may contain pharmaceutically acceptable solvents (for example, sesame oil, peanut oil, aqueous propylene glycol, dimethylformamide, etc.) or water when water-soluble active ingredients are used. The aqueous solutions may be buffered with a suitable buffer solution or may be isotonized with a suitable buffer. Aqueous solutions are particularly suitable for intravenous, intramuscular or intraperitoneal administration, and sterile aqueous solutions are prepared by known methods.

The daily dose of the active ingredient of the formula I can vary within wide limits and depends on several factors, in particular the effectiveness of the active ingredient used, the mode of administration and the condition of the patient.

Further details relating to the invention are given in the following examples. The examples are illustrative only and do not limit the scope of the invention in any way.

Example 1

Preparation of 4-phenyl-as-triazino [1,6-aquinolinium perchlorate

2.58 g (0.01 mol) of 4-phenyl-4-hydroxy-as-triazino [1,6-a] quinolin-11-ium-3 (4H) -Idu was treated with 1 ml of 70% perchloric acid in 8 ml of acetonitrile. After dissolution of the product, ether was added. 3.1 g of the desired compound are obtained in the form of needle crystals. Yield 90%, mp 3210-321 ° C.

Example 2

Preparation of 4- (4-chlorophenyl) -as-triazino [1,6-a] quinolinium perchlorate

2.58 g (0.01 mol) of 4- (4-chlorophenyl) -4-hydroxy-as-triazolo [1,6a] quinolin-11-ium-3- (4H) -ide were treated with 1 ml 70% perchloric acid in 8 ml acetonitrile. After the starting material is dissolved, ether is added. 3.0 g of the desired compound are obtained in the form of needle crystals. Yield 85%, mp 293 ^C C.

Example 3

Preparation of 4- (4-fluorophenyl) -as-triazino [1,6-a] quinolinium perchlorate

4- (4-Fluorophenyl) -4-hydroxy-3,4-dihydro-as-triazino [1,6-ajinoimide chloride] was reacted with 70% perchloric acid in acetonitrile to give the title compound in a yield of 89%, m.p. 282 °

Example 1 and 4

Preparation of 1,3-diphenylpyrido (2,1-f) -as-triazinium bromide

The procedure described in Example 1 was followed except that 1,3-diphenyl-1-hydroxypyrldof 2,14: -as-triazinium-2- (1H) -ide was used as the starting material. The obtained 1,3-diphenylpyrido (2,1-1H-as-triazinium perchlorate) was treated with tetrabutylammonium bromide to give the title compound in a yield of 93%, mp 279-280 ° C.

Example 5

Preparation of 1-phenyl-3-methylipyrido (2,1-f) -as-triazinium perchlorate

The procedure described in Example 3 was followed except that 1-phenyl-1-hydroxy-3-methyl-1,2-dihydropyrido [2,1-f] -as-triazinium chloride was used as starting material. The title compound is obtained in 96% yield. Melting point 271 ° C. Example 6

3.91 g (0.01 mole) of 1- (4-chlorophenyl) -as-triaziino [6,1-a] isoquinolinium perchlorate are treated with 3.12 g of tetrabutylammonium bromide in 8 ml of acetonitrile. The desired compound is precipitated by addition of ether. 3.26 g of the desired compound are obtained, yield 90%, mp 264-265 ° C.

Preparation of 1- (4-chlorophenyl) -as-triazino [6,1-a] isoquinolinium bromide

Claims (2)

OF THE INVENTION A process for the preparation of fused as-triazine derivatives of the general formula I or bj (I) and their isomers, wherein (b) and A is an anion of a physiologically acceptable organic or inorganic acid, preferably a halide, perchlorate or sulphonate anion, characterized in that the compound of the formula II is of the zwitterion type R 1 is C 1 -C 10 alkyl or phenyl or naphthyl, the latter two being optionally substituted by one or more substituents halogen, nitro, amino, hydroxy, C 1 -C 4 alkyl and / or (C 1 -C 4) alkoxy group, R 2 is hydrogen, halogen, C 1 -C 14 alkyl, or phenyl or naphthyl, the latter two being optionally substituted by one or more substituents halogen, nitro, amino, hydroxy, C 1 -C 4 alkyl and / or (C 1 -C 4) alkoxy, Z is buta-l, 3-dienylskupinu or a group of formula and (a.) A R ₃ Θ ' N ® T (h where R 1, R 2 and Z are as defined above and R 3 is hydrogen or C 1 -C 4 alkyl, reacted with an acid of formula III H + A- (III) wherein A ^- is as defined above, and the compound of formula I obtained is optionally resolved into its isomers and / or optionally anion A ^{- is} exchanged for another anion A. 2. A method according to claim 1, characterized in that: starting from compounds of the above formulas to give a compound of formula (I) wherein A ^- is a halide or perchlorate ion and the other symbols are as defined above. Severography, N. Plant 7, Moat Price 2,40 Kčs