Pyridyl - or pyrimidinediamine derivative of piperazine or 1,4-disallocation or their pharmacologically active acid additive salts with psychotropic action


(57) Abstract:

Usage: for the treatment of mental disorders. Products: pyridyl - and pyrimidinediamine derivative of piperazine or 1,4-disallocation General formula 1 , where R1is hydrogen or fluorine; X is oxygen, sulfur or methylene; n = 2 or 3; And - 2-Peregrina group C5H2NR2R3or 2-piramidalnaya group C4H3N2moreover, when a represents 2-pyramidalnou group, X is oxygen or methylene, and n = 2, R2is hydrogen or chlorine; R3is hydrogen, lower alkyl, chlorine, hydroxy, lower alkoxy, nitro, trifluoromethyl, carbarnoyl, N - methylcarbamoyl, morpholinosydnonimine or piperidinecarboxylate group or their pharmacologically active acid additive salt. Reagent 1: compound of General formula in which R1, X and n have the specified values, Reagent 2: 2X-C5H2NR2R3or 2-Z-C4H3N2where R2and R3have the specified values, Z is halogen. Conditions: the heating in the presence of a base. table 1.

The invention relates to new biologically active pyridyl - or pyrimidinediamine derivative of piperazine or 1,4-disallocation or pharmacologist of mental disorders there is an urgent need for effective drugs, which are more effective and which are less side effects than the drugs that are in clinical use at present. Antiserotonin drugs currently used, give the number of painful extrapyramidal movement disorders (such as acute dystonic reactions, and late dykinesia) and are unsatisfactory in respect of the improvement of negative symptoms (for example, limited or blunted emotional arousal) of schizophrenia. The main problem with antidepressants is that they do not soften the depression 30-40% of patients. Tranquilizers or anxiolytics are usually associated with properties of drug addiction or alcoholism.

In the technique known derivatives of pyridyl - and pyrimidinylpiperazine pharmacologically active in the Central nervous system (1-2). Can be referred to some characteristic examples of their representatives. Azaperone neuroleptic medication butyrophenone series, is a sedative drug for pigs. The anxiolytic drug is buspirone. It is considered that the anxiolytic effect is intermediate or manifested through the impact on NT receptors.

According to the invention offers novel compounds having the General formula I

FXCH2CH2CH2N II III where R2is hydrogen or chlorine; R3is hydrogen, lower alkyl, chlorine, hydroxy, lower alkoxy, nitro, trifluoromethyl, carbarnoyl, N-methylcarbamoyl, morpholinosydnonimine or piperidinecarboxylate group. Moreover, when a is pyramidalnou group, X is oxygen or methylene, and n = 2.

The compounds of formula I have basic properties and, consequently, they can transform into their therapeutically active acid additive salts by treatment with inorganic acid, or organic acids such as acetic, propanoic, glycolic, lactic, malic, oxalic, succinic, fumaric, tartaric, citric and AMOVA acid.

Salt form, in contrast, can become a form of free base by treatment with alkali.

The compounds of formula 1 and their pharmaceutically acceptable salts have valuable pharmacological properties, making them useful you can also continue to treat stress and anxiety in animals. Compounds according to the invention exhibit psychotropic properties. For example, they discover an affinity to 5-HT2and D2binding sites in the brain. In tests on the behavior of the models, these compounds exhibit konechnostey profile actions, i.e., they find a strong effect in trials on research or explorative behavior, for example, to test the phenomenon of the stairs.

Connection with combined 5-HT2/D2means, for example, clozapine, have an antipsychotic effect with a low degree of extrapyramidal side effects; in Addition, it was found that compounds with a mean of 5-HT2binding site affect depressive illness and in a state of anxiety.

For therapeutic purposes effective amount of any of the described, the pharmacologically active compounds of the formula l can be assigned to receive according to conventional methods purpose and in the usual forms, such as oral methods of assignment in the form of solutions, emulsions, suspensions, pills, tablets and capsules, in pharmaceutically acceptable media, and parenteral, in the form of sterile solutions. For parenteral assignment method actd, or parenteral acceptable oil, for example, the arachnid oil.

Although effective, are very small amounts of active materials of the invention, when it comes to minor or minor treatment or in cases assigned to regions with relatively low body weight, dosage units are usually between 2 mg and above, and preferably 10.25 or 50 mg or even higher, depending on the condition being treated, the age and weight of patients, as well as from the response to the medication.

The standard dose may be about 0.1-100 mg, preferably 10-50 mg Daily or daily pre-dose ranges from 10 to 200 mg. Exact individual dosages as well as daily doses, of course, are determined according to standard medical principles under the direction of a physician or veterinarian.

The compounds of formula I can be obtained using conventional methods.

Method 1.


The compound of formula II in which R1and X have the meanings given above, is a suitable removable group, such as halogen and alkyl - or arylsulfonate undergoes interaction with compounds which are eating the standard techniques of N-alkylation.

Method 2.


The compound of formula IV in which R1, X and n have the meanings previously defined, is subjected to the interaction with the compound of the formula V or VI, where R2and R3have the meanings defined above, and Z represents a removable group, for example halogen.

The invention is illustrated by the following examples in which the compounds indicated code numbers, a : b, where a is the number of the example that describes how to get the connection in question, and b refers to the ordinal number of the connection in question, obtained according to this example. Thus, compound 1:2 means the second compound obtained according to example 1.

Structures of the compounds are confirmed by analysis of the NMR, mass spectra and elemental analysis. When given the melting point, they are unadjusted.

P R I m e R 1. 4[4-(p-Forfinal)butyl]-1-(2-pyridyl)piperazin-fumarate.

6.0 g (0,0323 mole) of 4-(p-forfinal)of butyl chloride, 5.3g (0,0323 mole) paradiseparadise, and 5.2 g of sodium carbonate and 0.1 g of iodine are heated with 25 ml of xylene at 150aboutC (oil bath temperature) for 20 h

After ohlord billaut 25 ml simple ether. The organic solution is washed three times with 25 ml of water and finally once with 25-ml-mi saturated solution of sodium chloride.

Evaporation of the solvent gives the crude base, which is crystallized using cyclohexane. The melting point of the obtained free base is 57-58aboutC.

The free base is then dissolved in a mixture of ethanol/simple ether, and using an excess of fumaric acid in ethanol was deposited fumarate.

Recrystallization from ethanol gave 4.8 g of target compound (1:1) so pl. 160-161aboutC.

P R I m m e R 2. Dichlorhydrate 4-[4-(p-forfinal)butyl]-1-[2-(3-carbamoylmethyl)]PI - perazine.

5.9 g (0,025 mol) of 1-[4-(p-forfinal)butyl]piperazine, 3,9 g (0,025 mol) amide 2-chloronicotinic acid and 3.1 g of sodium carbonate are heated under reflux with 20 ml of toluene for 20 hours

After cooling, get a solid mixture, which was dissolved in ethyl acetate and water. Toluene/an ethyl acetate phase is separated, and then washed with water and sodium chloride solution and then dried with sodium sulfate.

Evaporation of the solvent gives the crude free base which is recrystallized from toluene. Patanol, and an excess of hydrochloric acid in ethanol precipitated dichlorhydrate. Recrystallization gives 3.0 g of target compound (2:1), so pl. 210-213aboutC.

Using basically the same procedure get the following compounds (isolated and purified using instant chromatography in pure form or in the form of corresponding salts) from the appropriate starting materials.

2:2 4[3-(p-Pertenece)propyl]-1-[6-chloro-2-pyridyl]piperazine-

hydrochloride, T. pl. 185-186aboutWITH

2:3 Hemihydrate hydrochloride of 4-[3-(p-pertenece)propyl]-

1- [2-pyrimidyl]piperazine, so pl. 208-210aboutWITH

2:4 Dichlorhydrate 4-[3-(p-pertenece)propyl]-1-[2-Piri-

DIL] piperazine, so pl. 233-235aboutC.

2:5 Dichlorhydrate 4-[3-(p-pertenece)propyl]-1-[3-carbarnoyl-

2-pyridyl]piperazine, so pl. 240-242aboutC.

2:6 Hydrochloride 4-[4-(p-forfinal)butyl]-1-[2-pyrimidyl] PI

perazine, so dps, 197-198aboutC.

2:7 Fumarate 4-[4-(p-forfinal)butyl-1-[2-pyridyl] Pipera-

Zina, so pl. 160-161aboutC.

2:8 Hydrochloride 4-[3-(p-pertenece)propyl]-1-[3-nitro-2-

pyridyl]-piperazine, so pl. 182-183aboutC.

2:9 Hydrochloride 4-[4-(p-forfinal)butyl]-1-[6-chloro-2-Piri-

DIL] piperazine, so pl. 150-151about


2:11 the Oxalate of 4-[3-(p-pertenece)propyl]-1-[3-carbamyl-2 - Piri-

DIL]-[1,4-disallocation], so pl. 148-150aboutWith /Foundation,

so PL, 140-141aboutWITH

2:12 Polyisopropene-hemihydrate of dichlorhydrate 4-[4-(p-fluoro-

phenyl)-butyl]-1-[3-ethoxy-2-pyridyl]piperazine, so pl. 168-169aboutWITH

2:13 Fumarate 4-[4-(p-forfinal)butyl]-1-[6-methyl-2-Piri-

DIL]piperazine, so pl. 172-173aboutWITH

2:14 Dichlorhydrate 4-[3-(3,4-divergence)propyl]-1- [6-methyl-

2-pyridyl]piperazine, decomp. 230aboutWITH

2:15 1,5 hydrochloride 4-[3-(3,4-divergence)propyl]-1- [3-(N-me-

etilcarbitol)-2-pyridyl]piperazine, so pl. 211-213aboutWITH

2:16 Dichlorhydrate 4-[3-(p-pertenece)propyl]-1-[3-hydroxy-

2-pyridyl]piperazine, so pl. 240about(Base so pl. 105aboutC).

2:17 of the Hydrochloride of 4-[3-(p-pertenece)propyl]-1-[3-trifluoromethyl-

6-chlor-pyridyl]piperazine, so pl. 190aboutC.

2:18 Dichlorhydrate 4-[3-(p-pertenece)propyl]-1-[3-carbarnoyl-2-

pyridyl]piperazine, so pl. 205aboutWITH

2:19 Dichlorhydrate 4-[3-(p-fortifies)propyl]-1-[2-Piri-

DIL] piperazine, so pl. 150aboutWITH

2:20 4-[3-(p-Pertenece)propyl]-1-[5-morpholinomethyl-2 - Piri-


2:21 4-[4-(p-forfinal)butyl]-1-[3-piperidinylcarbonyl - 2-Piri-
Westside mainly as described by the authors Leysen et al (Mot Parmacol 21, 301-14, 1982) using 3N-ketanserina as a ligand.

The results are given in the table.

The connection is similar in structure formula

F-X-(CH2)3NN-Y where X SNON, Y = F has no significant affinity for receptor 5 HT2.

As the experience of long-term work of inventors with compounds of similar structure, they have no reason to assume the occurrence of any serious problems associated with toxicology and tested doses, is effective in pharmacological terms, connection not found any signs of toxicity.

P o m e R 4. The following preparative forms are typical representatives for all pharmacologically active compounds of the present invention. An example of a suitable capsule formulation:

The capsule mg

The active ingredient in the form of salts 10 Lactose 250 Starch 120 magnesium Stearate 5 Total 385

In the case of a higher number of active ingredients amounts of lactose may be reduced.

An example of a suitable formulation in tablet form

The capsule mg

The active ingredient in the form of salts 10 Potatoes Solutions for parenteral application by injection can be prepared in aqueous solution of water-soluble pharmaceutically acceptable salt of the active substance preferably in a concentration of from about 0.5% to 5% by weight. These solutions may also contain stabilizing agents and/or buferiruemoi agents and can conveniently be provided in various dosage vials.

Pyridyl - or pyrimidinediamine derivative of piperazine or 1,4-disallocation General formula


where R2is hydrogen or chlorine;

R3is hydrogen, lower alkyl, chlorine, hydroxy, lower alkoxy, nitro, trifluoromethyl, carbarnoyl, N-methylcarbamoyl, morpholinosydnonimine or piperidinecarboxylate group, and when A - piramidalnaya group, X is oxygen or methylene, and n = 2,

or their pharmacologically active acid additive salts with psychotropic action.


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