Derivatives of piperazine, the method of production thereof and pharmaceutical composition

 

(57) Abstract:

The invention relates to piperazine derivatives of General formula I, in which R1denotes pyridyl or phenyl, unsubstituted or once substituted Ph or 2 - or 3-Tiepolo, R2indicates Ph1or Het. Connections are dopamine ligands with selective action against D4-receptor and can be used for treatment and prophylaxis of States of fear, depression, schizophrenia, obsessive ideas, Parkinson's disease, tardive dyskinesia, nausea and disorders of the gastrointestinal tract. Also described is a method of obtaining of piperazine derivatives and pharmaceutical composition thereof. 3 S. and 1 C.p. f-crystals, 1 PL.

The present invention relates to piperazine derivatives of the formula I

< / BR>
in which R1means once substituted Ph or 2 - or 3-tanila pyridyl or phenyl,

R2indicates Ph' or Het,

Ph and Ph' denote, respectively independently of one another phenyl, both of residue, respectively, can be unsubstituted or one-, two - or three-fold substituted by F, C1, Br, I, HE, OA, A, CF3, NO2CN, COA, CONH2, CONHA, CONA2or 2 - or 3-tanila,
2And or NO2and a denotes alkyl with 1-6 C-atoms,

and their physiologically acceptable salts.

The basis of the invention was based on the task of obtaining new compounds that could be used to manufacture medicines.

It was found that the compounds of formula I and their physiologically acceptable acid additive salts have valuable pharmacological properties. The compounds of formula I are dopamine ligands with selective action against D4-receptor compared with that with respect to D2 and D3 receptors (a method similar to that described in Creese and others in the European Journ. Pharmacol. 46, pages 377-381 (1977); using3N-spiroperidol as a ligand for dopamine receptors and cloned dopamine D4-, D3 - and D2-receptors of a person (source: Receptor Biology Inc., Baltimore MD 21227, USA)). Compounds according to the invention is suitable for treatment of diseases such as schizophrenia, cognitive impairment, fear, depression, nausea, late dyskinesia, disorders of the gastro-Ki is this additional impact as agonists 5-HT1Aand inhibiting re-uptake of 5-HT. These compounds exhibit further properties of agonists and antagonists of serotonin. They inhibit the binding of treated serotonin ligands with hippocampally receptors (see Cossery and other European Journ. Pharmacol. 140 (1987), pp. 143-155). In addition, when applying to observe changes in the accumulation of DOPA in the striatum and the accumulation of 5-NTR in N. Raphe (see Seyfried and others, European Journ. Pharmacol. 160 (1989), pp. 31-41). Further, they exhibit analgesic and hypotensive effect; thus, rats with the catheter in the waking state with spontaneous hypertension (SHR strain/Okamoto/NIH-MO-start-Kisslegg: the method according to Weeks and Jones, Proc. Soc. Exptl. Biol. Med. 103 (1960), pp. 646-648) pressure, which was measured directly after oral administration of compounds was markedly decreased. The proposed connection is also suitable for the prevention and treatment of the consequences of stroke (apoplexia cerebri), in particular stroke and cerebral ischemia.

With regard to the foregoing, the compounds of formula I and their physiologically acceptable acid salt additive can be used as pharmaceutical active substances for anxiolytics, antidepressants, antipsychotic products for other pharmaceutical active substances.

The object of the invention are derivatives of piperazine of the formula I and their physiologically acceptable acid additive salt.

Balance And represents alkyl with 1, 2, 3, 4, 5 or 6, especially 1 or 2 C-atoms, preferably methyl, but also ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl. OA represents preferably methoxy, and ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy. NHA is a preferred methylamino and ethylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino or tert-butylamino. NA2represents preferably dimethylamino, N-ethyl-N-methylamino, diethylamino, di-n-propylamino, diisopropylamino and di-n-butylamino. On this basis, NHA preferably denotes N-methylcarbamoyl and N-ethylcarbamate; CO-NA2means preferably N,N-dimethylcarbamoyl or N,N-diethylcarbamoyl.

The remainder R1means are preferably unsubstituted or once substituted 3-tanila phenyl, nezameshchenny or substituted once OA, CN, CF3, F, Br or C1-biphenyl or 2-, 3 - or 4-pyridyl, which is particularly preferably may be substituted 3-what about the preferred residue is 3-pyridyl.

The remainder R2means are preferably unsubstituted or one-, two-or three-fold substituted by F, C1, Br, HE, OA, A, CONH2, COA, CF3CN and/or NO2phenyl or correspondingly substituted Het, where Het preferably may represent a 1,4-benzodioxan, 2-, 3 - or 4-pyridyl, 2-, 4-, 5 - or 6-pyrimidinyl, 3 - or 4-pyridazinyl, 2 - or 3-pyrazinyl.

For the whole of the invention is generally true that all residues, such as Ph, which can repeatedly be present in the molecule may be identical or different values.

In accordance with this object of the invention are especially those compounds of the formula I, in which at least one of these residues has one of the abovementioned preferred meanings. Some preferred groups of compounds can be represented by the following formulas Ia-IC, which correspond to the formula I and in which not deciphered more residues are indicated in the formula I is, however,

in Ia R1represents in position 5 substituted 3-pyridyl;

in IB R2is a 2-pyrimidinyl;

in IB R1represents phenyl, and R2represents nezameshchenny the P> represents unsubstituted or one-, two - or three-fold substituted phenyl;

in Ia R1represents a biphenyl, and R2represents unsubstituted or once substituted 1,4-benzodioxane, benzofuranyl, pyridyl, pyrazinyl, pyridazinyl or pyrimidinyl;

in Ie R1has the meaning specified in Ia, a R2denotes one-, two - or three-fold substituted phenyl;

in If R1has the meaning specified in Ia, a R2means once substituted or unsubstituted pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl;

in Z R2is a 2-pyrimidinyl, and R1denotes a meta-substituted phenyl or position 5 is substituted by pyrid-3-yl;

in AI R2is a 2-pyrimidinyl, and R1denotes a substituted phenyl or substituted pyrid-3-yl, wherein the substituents are preferably co3F or 2 - or 3-thienyl;

in IK R1has the value specified in the Ia, and the Deputy is phenyl or o - or p-forfinal.

The object of the invention is further a method of obtaining derivatives of piperazine of the formula I and their salts, characterized in that the compound of formula II

< / BR>
in which R2have you specified predstavljaet a C1, VG, I, HE, O-CO, O-CO-Ph, O-SO2-Ar, where AG denotes phenyl or tolyl, and denotes alkyl or other reactionsare esterified HE or easily nucleophile substitutable leaving group, in which R1has the above significance, or that the compound of formula IV

H2N-R2IV

in which R2has the above meaning, is subjected to the interaction with the compound of the formula V

< / BR>
where X1and X2can have identical or different meanings or identify C1, Br, I, HE or reactive functionally modified IT-group, and R1has the above significance, or that the compound of formula VI

< / BR>
in which R2X1and X2have the above meanings, is subjected to the interaction with the compound of the formula VII

R1-CH2-NH2VII

in which R1has the above significance, or that any compound corresponding to the formula I, but instead of containing one or more hydrogen atoms of one or more recoverable groups and/or one or more additional C-C-bonds and/or C-N-bonds is treated with a reducing agent, or that any compound corresponding to the formula I, who see colonization and/or, if necessary, the remainder R1and/or R2turn in the remainder R1and/or R2due to the fact that, for example, OA-group split with the formation of Oh-groups and/or derivatizing CN-, COOH-, sooa-group and/or, for example, that alkylate primary or secondary N-atom and/or that the resulting base or acid of formula I by treatment with acid or base turn in one of their salts.

The reaction to obtain compounds of the formula I is carried out in the rest of the known methods, as described in the literature (for example, in a seminal publications such as Houben-Weyl, Methods der Organischen Chemie, ed. Georg Thieme Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc. New York; lined Germany application DE-OS 4101686), namely when the conditions are known and suitable for carrying out these reactions. You can also use well-known options that are not specified in this description in more detail.

Source materials for the proposed method when needed, you can also form in situ, not distinguishing them from the reaction mixture, and turn them directly into the compounds of formula I.

Compounds of formulas II and III in principle known; unknown these same compounds formula II is of formula II for the most part known and you can get them, for example, the interaction of bis(2-chloroethyl)amine or the corresponding ammonium chloride with aniline derivatives, aminonaphthalene or aminobiphenyl formula Ph'-NH2or aminosilane heterocyclic compounds of the formula Het-NH2.

Pyridine, benzyl compounds, derivatives of naphthalene or biphenyl of the formula III are generally known and most are commercially available products. Along with this, these compounds can be obtained electrophilic, and in certain cases also nucleophilic aromatic substitution of the known compounds. Above all, however, compounds of formula III can be obtained by introducing in the compounds of the formula R1-CH3for example , by radical substitution of residue L or from the conversion of the compound of formula III available balance L in the remainder of L. for example, you can atrificial IT-or to carry out nucleophilic substitution of the halogen.

The conversion of compounds of formulas II and III are carried out by methods known from the literature and used for the alkylation of amines. Component without the presence of solvent can be prepared in the melt, optionally in a closed tube or in autoclaves. As solvents can be used, for example, hydrocarbons, such as benzene, toluene, xylene; ketones, such as acetone, butanone; alcohols such as methanol, ethanol, isopropanol, N-butanol; ethers, such as tetrahydrofuran (THF) or dioxane; amides, such as dimethylformamide (DMF) or N-organic; NITRILES, such as acetonitrile, under certain conditions, also mixtures of these solvents with one another or mixtures with water. Adding acid binding means, such as a hydroxide, carbonate or bicarbonate of an alkaline or alkaline-earth metal or of another salt of a weak acid of the alkali or alkaline-earth metal, preferably potassium, sodium or calcium, or the addition of organic bases, such as triethylamine, dimethylaniline, pyridine or quinoline, or adding excess piperazine derivative of the formula II can have a positive effect. The reaction time depending on the applied conditions ranges from a few minutes up to 14 days, and the reaction temperature is in the range from 0 to 150, usually from 20 to 130oC.

The compounds of formula I can be obtained then by interaction of amines of the formula IV with compounds of the formula V. the Amines of formula IV, to whom dinani, and the nitro compounds can be obtained, as is well known, by nitriding aromatic hydrocarbon.

Obtaining compounds of formula V can be realized, for example, the restoration of the diesters of the formula alkyl-EA-CH2-N(CH2R1)-CH2-COO-alkyl to compounds of the formula HO-CH2-CH2-N(CH2R1)-CH2-CH2-OH and, if necessary, subsequent interaction with SOCl2accordingly with RVG3.

The compounds of formula V can be obtained also by the interaction of the secondary amines of the formula N(CH2-CH2X1)(CH2-CH2-X2) with halides of the formula R1-CH-Hal (Hal denotes C1, Br).

Next, to obtain the compounds of formula I are compounds of the formula VI is subjected to interaction with amines of the formula VII. The compounds of formula VI in its structure similar to the compounds of formula V can be obtained in a similar way. That is true for compounds of formula VII regarding amines of formula V. Amines of the formula VII, in addition, can also be obtained by known methods of synthesis of primary amines, such as, for example, the synthesis of Gabriel.

The interaction of compounds of formulas IV and V, respectively VI with compounds which ptx2">

There is further another possibility of obtaining compounds of the formula I, in which forproduct containing instead of the hydrogen atoms of one or more recoverable groups and/or one or more additional C-C-bonds and/or C-N-bonds is treated with a reducing agent, preferably at temperatures in the range from -80 to +250oWith and in the presence of at least one inert solvent.

Recoverable (replaced by hydrogen) groups are primarily oxygen in a carbonyl group, hydroxyl, arylsulfonate (for example, p-toluensulfonate), N-benzazolyl, N-benzyl or O-benzyl.

In principle it is possible compounds containing only one of the above groups, or compounds containing next to each other two or more such groups, respectively additional relationships, translate by recovery in the compound of formula I; at the same time you can restore the substituents in the group I contained in the initial connection. Preferably for this purpose use the evolving hydrogen or complex hydrides of metals; in addition, carry out the restoration of the wolf-Kishner and restore using gazoobraznymi hydrogen, the latter can be obtained, for example, processing of metals with weak acids or bases. Thus, in particular, it is possible to use a mixture of zinc and caustic liquor or a mixture of iron and acetic acid. Suitable for these purposes, the sodium or other alkali metal dissolved in an alcohol, such as ethanol, isopropanol, butanol, amyl or isoamyl alcohol or phenol. You can continue to use the alloy of aluminum and Nickel in aqueous-alcoholic solution, optionally with the addition of ethanol. For the formation of hydrogen is also suitable sodium amalgam or aluminum in aqueous-alcoholic or aqueous solution. The reaction can also be performed in a heterogeneous phase, and appropriate for this purpose, use water and benzene or toluene phase.

Particularly preferably used as the reducing agent complex metal hydrides, such as LiAlH4, NaBH4the hydride diisobutylaluminum or NaAl(OCH2CH2OCH3)2H2and DIBORANE, if necessary with the addition of catalysts such as BF3, AlCl3or LiBr. As solvents suitable for these purposes are primarily ethers, such as diethyl of epistemophilia using NaBH4as the solvent usable in the first place alcohols, such as methanol or ethanol, then water, and water spirits. The restoration of these methods preferably carried out at temperatures in the range from -80 to +150oWith, especially approximately from 0 to 100oC. Particularly preferably restore-CO-group in amido acid using LiAlH4in THF at temperatures in the range of from about 0 to 66oWith up to CH2groups.

Perhaps the next one or more carbonyl groups to restore according to the method of wolf-Kishner to CH2groups, for example, by treatment with anhydrous hydrazine in absolute ethanol under pressure and at temperatures in the range from 150 to 250oC. as the catalyst, it is preferable to use a sodium alcoholate. Technology recovery can be varied by using, in particular, the method of Huang-Minlon, consisting in the fact that the reaction is carried out using hydrazine hydrate in a high-boiling, mixed with water, a solvent such as diethylene glycol or triethylene glycol, in the presence of alkali, such as sodium hydroxide. The reaction mixture when it is boiled, usually for about 3-4 hours. Then the wolf-Kishner can also be performed at room temperature in dimethyl sulfoxide using a hydrazone.

Along with the above options, the recovery in some cases it is possible to carry out also using H2-gas in the presence of catalysts based on transition metals, such as Raney Nickel or palladium. This way you can, for example, Cl, Br, I, SH, and in certain cases, and Oh group replaced by hydrogen. Similarly, the nitro group by catalytic hydrogenation using Pd/H2methanol can be converted into NH2group.

Compounds corresponding to General formula I, but instead of containing one or more H atoms of one or more solvolysis groups may be subjected to solvolysis, especially hydrolysis, results in compounds of formula I. the starting materials for the solvolysis can be obtained, for example, by the reaction, in which the use of the compounds of formula II corresponding to the formula III, but instead of containing one or more H atoms of one or more solvolysis groups.

Then there is the possibility of the compound of formula I by known methods to turn into some other compound of formula I.

The compounds of formula I, where R1represents the balance, substituted CONH2, CONHA or CONA2can the CSO hydrolysis. Maybe next lanzamiento the compounds of formula I to first hydrolyze to the acid, and then these acids to lidirovat primary or secondary amines. It is preferable to expose the free carboxylic acid interaction with the amine under the conditions of peptide synthesis. This reaction is progressing preferably in the presence of means of dehydration, such as a carbodiimide, such as dicyclohexylcarbodiimide or N-(3-dimethylaminopropyl)-N-ethylcarbodiimide, anhydride papapostolou acid (compare Angew. Chem. 92, 129 (1980)), diphenylphosphinite or 2-ethoxy-N-etoxycarbonyl-1,2-dihydroquinoline, in an inert solvent, for example in a halogenated hydrocarbon, such as dichloromethane, in a simple ether, such as THF or dioxane, in amide, such as DMF or dimethylacetamide, a nitrile such as acetonitrile, at temperatures in the range of from about -10 to 40oC, preferably from 0 to 30oC.

However, it is particularly preferable to proceed in the reverse order, namely due to the removal of water from amides, for example, using trichloroacetamide/Et3N [see Synthesis (2), 184 (1985)] or POCl3[see Journ. Org. Chem. 26, 1003 (1961)], to obtain the NITRILES.

The obtained base of formula I can be perevedeny acid, which form physiologically acceptable salts. So, for these purposes can be used inorganic acids, for example sulfuric acid, halogen acids such as hydrochloric acid or Hydrobromic acid, phosphoric acids such as orthophosphoric acid, nitric acid, sulfamic acid, and also organic acids, in particular aliphatic, acyclic, analiticheskie, aromatic or heterocyclic one - or polybasic carboxylic, sulfonic or sulfuric acids, such as formic acid, acetic acid, propionic acid, pavlikova acid, diethyloxalate acid, malonic acid, succinic acid, Emelyanova acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, benzoic acid, salicylic acid, 2-phenylpropionate acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinamide acid, methane - or econsultation, ethicalfashion, 2-hydroxyethanesulfonic, benzosulfimide, p-toluensulfonate, naphthalenamine and naphthalenedisulfonate and louisanna acid.

Free base of formula I ID of sodium or potassium, sodium carbonate or potassium, provided that the molecule is not represented other azadnia group. In those cases where the compounds of formula I contain free acid groups, by treatment with bases can also provide education of salt. As grounds for these purposes, suitable hydroxides of alkali metals, hydroxides of alkaline-earth metals or organic bases as primary, secondary or tertiary amines.

The object of the invention is further the use of compounds of the formula I and their physiologically acceptable salts for the preparation of pharmaceutical compositions, especially for "non-chemical" technology. To this end one of them together with at least one carrier or auxiliary substance, and optionally in combination with one or more other active substances can be produced corresponding preparative forms.

The object of the invention is further funds, primarily pharmaceutical compositions containing at least one compound of the formula I and/or one of its physiological acceptable salts. These compositions can be used as drugs in medicine and veterinary medicine. In Kacie for enteral (for example, oral), parenteral or topical application and do not reacts with the new compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, vaseline. For enteral introduction of suitable especially tablets, coated tablets, capsules, syrups, tinctures, drops or suppositories, for parenteral solutions, preferably oily or aqueous solutions, and also suspensions, emulsions or implicate, for local application are ointments, creams or powders. New connections can be subjected to freeze-drying and the resulting lyophilizate can be used, for example, for the preparation of injection preparations. These compositions can be sterilized and/or enter into their composition excipients, such as antiadhesive, preservatives, stabilizers and/or wetting, emulsifying agents, salts for regulating the osmotic pressure, buffer substances, colorants, flavorings and/or flavorings. If necessary, they can also contain one or more other biologically active substances, for example one or more vitamins.

The compounds of formula I and their physiologically acceptable salts s for the treatment of diseases of the Central nervous system, such as state mental stress, depression, fear, schizophrenia, disorders of gastrointestinal tract, nausea, late dyskinesia, parkinsonism and/or psychosis, and side effects in the treatment of hypertension (for example, using a-methyldopa). In addition, the proposed connection can be used in endocrinology and gynaecology, for example for the treatment of acromegaly, hypogonadism, secondary amenorea, premenstrual syndrome, undesired puerperal (postpartum) lactation, then for prophylaxis and therapy of cerebral disorders (e.g. migraine), primarily in geriatrics, just as is the case with some of ergoalkaloidov and to struggle with the consequences of stroke (apoplexia cerebri), in particular stroke and cerebral ischemia. When this substance according to the invention, as a rule, appoint to receive the similarly famous, commercially available drugs, such as parlodel, dihydroergocornine and others), preferably in dosages of 0.2 to 500 mg, especially from 0.2 to 50 mg one single dose. The daily dose is preferably from about 0.001 to 10 mg/kg of body weight. Low dosage form is sustained fashion from about 0.001 to 10 mg/kg of body weight. Low dosage (about 0.2-1 mg one single dose; approximately 0.001 to 0.005 mg/kg body weight) is recommended for this primarily as anti-migraine; for all other indications, it is preferable to prescribe the dosage from 10 to 50 mg per intake. However, assigned to a particular patient the appropriate dose depends on various factors, such as the effectiveness of the compound, the age, body weight, General health, sex, characteristics of food, time and specific destination, speed selection, combination of drugs and the severity of the corresponding disease, require this therapy. Preferred oral administration.

In the following examples, the term "normal processing" means that, if necessary, water is added, extracted with dichloromethane, the phases are separated, the organic phase is dried over sodium sulfate, filtered, evaporated and purified by chromatography on silica gel and/or by crystallization. All temperatures are listed inoC. Rfthe figures were obtained using thin-layer chromatography on silica gel. M++1-characteristics was determined by the method MS (FAB) [mass spectroscopy with bombs is, for example, radical chlorination of 3-methyl-5-phenylpyridine] and of 1.62 g of 1-phenylpiperazine dissolved in 200 ml of acetonitrile and stirred for six hours at room temperature. After the usual processing gain 1-phenyl-4- [(5-phenyl-3-pyridyl)methyl]piperazine with tPL83-85oC.

In a similar way interaction connection "AND"

with 1-(2-forfinal)piperazine get 1-(2-forfinal)-4-[(5-phenyl-3-pyridyl) methyl] piperazine, trihydrochloride, tPL217-219oC;

with 1-(2-methoxyphenyl)piperazine get 1-(2-methoxyphenyl)-4-[(5-phenyl-3-pyridyl) methyl] piperazine, the dihydrate of trihydrochloride, tPL235-236oC;

with 1-(2-pyridyl)piperazine get 1-(2-pyridyl)-4-[(5-phenyl-3-pyridyl) methyl] piperazine, tPL103-105oC;

with 1-(3-triptoreline)piperazine get 1-(3-triptoreline)-4-[ (5-phenyl-3-pyridyl) methyl] piperazine, trihydrochloride, tPL216-219oC.

In a similar way by the interaction of 2-chloromethyl-4-phenylpyridine

1-phenylpiperazine get 1-phenyl-4-[(4-phenyl-2 - pyridyl) methyl] piperazine;

with 1-(2-forfinal)piperazine get 1-(2-forfinal)-4-[(4-phenyl-2-pyridyl) methyl] piperazine;

with 1-(2-methoxyphenyl)piperazine get 1-(2-methoxyphenyl)-4- [(4-fanperson;

with 1-(3-triptoreline)piperazine get 1(3-triptoreline)-4- [(4-phenyl-2-pyridyl) methyl] piperazine;

with 1-(2-pyrimidinyl)piperazine get 1-(2-pyrimidinyl)-4-[(4-phenyl-2-pyridyl) methyl] piperazine.

In a similar way by the interaction of 2-chloromethyl-4- (4-forfinal)pyridine

1-phenylpiperazine get 1-phenyl-4-[(4-(4-forfinal)-2-pyridyl) methyl] piperazine;

with 1-(2-forfinal)piperazine get 1-(2-forfinal)-4- [(4-(4-forfinal) -2-pyridyl)methyl] piperazine;

with 1-(2-methoxyphenyl)piperazine get 1-(2-methoxyphenyl)-4-[(4-(4-forfinal) -2-pyridyl)methyl] piperazine;

with 1-(2-pyridyl)piperazine get 1-(2-pyridyl)-4-[4-(4- forfinal) -2-pyridyl)methyl] piperazine;

with 1-(3-triptoreline)piperazine get 1-(3-triptoreline) -4- [(4- (4-forfinal) -2-pyridyl)methyl] piperazine;

with 1-(2-pyrimidinyl)piperazine get 1-(2-pyrimidinyl)-4-[(4-(4-forfinal)-2-pyridyl)methyl] piperazine, the dihydrate of trihydrochloride, tPL193-195oC;

1-(5-ftorpirimidinu-2-yl)piperazine get 1-(5-ftorpirimidinu-2-yl)-4-[(4-(4-forfinal)-2-pyridyl)methyl] piperazine.

Example 2

Analogously to example 1, on the basis of 1.10 g of 3-chloromethyl-5-(4-forfinal) pyridine ("B") [get, for example, radical hlola at room temperature after the usual processing gain 1-(2-pyrimidinyl)-4-[(5-(4-forfinal)-3-pyridyl) methyl] piperazine, tPL97-98oC.

In a similar way interaction connection "B"

1-(1,4-benzodioxan-6-yl)piperazine get 1-(1,4-benzodioxan-6-yl)-4-[(5-(4-forfinal)-3-pyridyl)methyl] piperazine, trihydrochloride, tPL256-259oC;

1-(4-nitrophenyl)piperazine get 1-(4-nitrophenyl-4-[(5-(4- forfinal)-3-pyridyl) methyl] piperazine, dihydrochloride, tPL264oC;

1-(3,5-dichloro-4-methoxyphenyl)piperazine get 1-(3,5-dichloro-4-methoxyphenyl) -4-[(5-(4-forfinal)-3-pyridyl) methyl] piperazine, dihydrochloride, tPL163oC;

1-(4-methoxyphenyl)piperazine get 1-(4-methoxyphenyl)-4-[(5- (4-forfinal) -3-pyridyl) methyl] piperazine, trihydrochloride, tPL211oC;

1-(3,4-acid)piperazine get 1-(3,4-acid)-4-[(5- (4-forfinal) -3-pyridyl) methyl] piperazine, trihydrochloride, tPL244oC;

with 1-(2-forfinal)piperazine get 1-(2-forfinal)-4-[(5-(4- forfinal)-3-pyridyl) methyl] piperazine, dihydrochloride, tPL210oC;

1-(3,5-dimethyl-4-methoxyphenyl)piperazine get 1-(3,5-dimethyl-4-methoxyphenyl) -4- [(5- (4-forfinal) -3-pyridyl) methyl] piperazine, trihydrochloride, tPL251oC;

with 1-(2-nitrophenyl)piperazine get 1-(2-nitrophenyl)-4-pyrid-2-yl)piperazine get 1-(3-chloro-5-triptoreline-2-yl) -4-[(5-(4-forfinal)-3-pyridyl) methyl] piperazine, the dihydrochloride, tPL153oC;

with 1-(3-methoxyphenyl)piperazine get 1-(3-methoxyphenyl)-4-[(5- (4-forfinal) -3-pyridyl) methyl] piperazine, trihydrochloride, tPL232oC;

with 1-(2-hydroxyphenyl)piperazine get 1-(2-hydroxyphenyl)-4-[(5- (4-forfinal) -3-pyridyl) methyl] piperazine, dihydrochloride, tPL239oC;

with 1-(2-pyrazinyl)piperazine get 1-(2-pyrazinyl)-4-[(5-(4-forfinal)-3-pyridyl) methyl] piperazine, dihydrochloride hydrate, tPL140oC;

1-(4-forfinal) piperazine get 1-(4-forfinal)-4- [(5-(4-forfinal)-3-pyridyl) methyl] piperazine, dihydrochloride, tPL181oC;

with 1-(3-trifluoromethyl-4-chlorophenyl)piperazine get 1-(3-trifluoromethyl-4-chlorophenyl) -4-[(5-(4-forfinal)-3-pyridyl) methyl] piperazine, sesquihydrate, tPL230oC;

with 1-(2-were) piperazine get 1-(2-were)-4-[(5-(4-forfinal)-3-pyridyl) methyl] piperazine, dihydrochloride, tPL258oC;

1-(4-chlorophenyl)piperazine get 1-(4-chlorophenyl)-4-[(5-(4-forfinal)-3-pyridyl)methyl]piperazine, dihydrochloride hydrate, tPL135oC;

with 1-(2-pyridyl)piperazine get 1-(2-pyridyl)-4-[(5-(4-forfinal)-3-pyridyl)methyl]piperazine, the dihydrate of trihydrochloride, tPL203oPL172oC;

with 1-(3-triptoreline)piperazine get 1-(3-triptoreline) -4-[(5-(4-forfinal)-3-pyridyl) methyl] piperazine, sesquihydrate, tPL237oC;

1-(4-methylcarbonate)piperazine get 1-(4-methylcarbonate) -4-[(5-(4-forfinal)-3-pyridyl) methyl] piperazine, sesquihydrate, tPL211oC;

1-phenylpiperazine get 1-phenyl-4-[(5-(4-forfinal)-3-pyridyl) methyl] piperazine, dihydrochloride hydrate, tPL207oC.

Example 3

Analogously to example 1, from 3-biphenylmethanol ("In") [get, for example, radical substitution of 3-methylbiphenyl], interaction with 1-(2-methoxyphenyl)piperazine get 1-(2-methoxyphenyl)-4-(3-biphenylyl)piperazine, maleate, tPL158-160oC. in a Similar way interaction connections "IN"

1-phenylpiperazine get 1-phenyl-4- (3-biphenylyl) piperazine, maleate, tPL181-183oC;

1-(4-tianfeng)piperazine get 1-(4-tianfeng)-4-(3-biphenylyl) piperazine, tPL139oC;

with 1-(2-methoxy-5-aminocarbonylmethyl)piperazine get 1-(2-methoxy-5-aminocarbonylmethyl) -4-(3-biphenylyl) piperazine, dihydrochloride, tPL193-196oC;

with 1-(2-methods/SUB>227-229oC.

Example 4

To a suspension of 200 mg of NaOH (solid) in 22 ml of dimethyl ether of diethylene glycol at a temperature of 100oWith added with stirring 1.0 g of 2-[4-(3-bromobenzyl)piperazine derivatives] pyrimidine, to 0.72 g of 4-triftormetilfullerenov acid, 56 mg tetranitroaniline, suspended in 10 ml of dimethyl ether of diethylene glycol. Then heated to 150oWith and continue stirring for 1.5 hours. After cooling, the reaction mixture is mixed with 50 ml policecontributing model HC1 aqueous solution and extracted twice with 10 ml dichloromethane, respectively, dried over Na2SO4and remove the solvent. The residue is dissolved using a small number of simple ether and chromatographic on the simple silica gel with ether/petroleum ether in the ratio 3:2. The result is 1-(2-pyrimidinyl)-4-(4'-trifluoromethyl-3-biphenylyl)piperazine in the form of oil, Rf= 0,44 (simple ether/petroleum ether 3:2). After treatment of the ether solution model HC1 receive hydrochloride 1-(2-pyrimidinyl) -4-(4'-trifluoromethyl-3-biphenylyl)piperazine.

Example 5

To a solution of 0.75 ml 3-bromothiophene in 1 ml of simple ether at a temperature of -78oWith added dropwise 5,2 suspended in 3 ml of THF/simple ether (1:1 ratio), and allowed to warm to room temperature. Further stirred for 30 minutes to form two phases, re-cool and add to 11.2 mg PdCl2(dppf). Stirring is continued for about 12 hours, allowing the temperature to rise to room temperature. For further processing acidified with 1-molar solution model HC1, extracted twice respectively with 30 ml ethyl ester acetic acid, dried over Na2SO4and remove the solvent. The residue is dissolved using a small number of simple ether and chromatographic on the simple silica gel with ether/petroleum ether in the ratio 1:1. The result is 1-(2-pyrimidinyl)-4-(3-(3-thienyl)benzyl)piperazine in the form of an oily residue. After treatment of the ether solution of maleic acid get maleate 1-(2-pyrimidinyl)-4-(3-(3-thienyl)benzyl)piperazine, tPL208oC.

Example 6

Analogously to example 3, from 4'-trifluoromethyl-3-biphenylmethanol ("G") [get, for example, radical substitution of the 4'-trifluoromethyl-4-methylbiphenyl] , interaction with 1-(2-methoxide - nil)piperazine get 1-(2-methoxyphenyl)-4-(4'-trifluoromethyl-3-biphenylyl) piperazine.

In a similar way operatin;

with 1-(2-aminocarbonylmethyl-5-yl)piperazine get 1-(2-aminocarbonylmethyl-5 - yl)-4-(4'-vermeil-3-biphenylyl-Tyl)piperazine;

1-(4-triptoreline)piperazine get 1-(4-triptoreline) -4-(4'-vermeil-3-biphenylyl) piperazine;

with 1-(2-methoxy-5-aminocarbonylmethyl)piperazine get 1-(2-methoxy-5-aminocarbonylmethyl) -4-(4'-vermeil-3-biphenylyl)piperazine;

with 1-(2-methoxy-5-triptoreline)piperazine get 1-(2-methoxy-5-triptoreline) -4-(4'-vermeil-3 - biphenylyl) piperazine.

Example 7

A solution of 1.6 g of 1-pyrimidine-2-reperusing in 200 ml of THF is mixed with a 2.75 g of 3-chloromethyl-4'-triptoreline ("D") [get, for example, radical chlorination of 3-methyl-4'-triptoreline], dissolved in 30 ml of THF, and stirred for four hours at room temperature. After the usual processing gain 1-pyrimidine-2-yl-4-[(4'-trifluoromethyl-3-biphenylyl)methyl] piperazine.

In a similar way interaction connection "D"

with 3-chloromethyl-4'-methoxybiphenyl get 1-pyrimidine-2-yl-4-[(4'-methoxy-3-biphenylyl)methyl] piperazine, dihydrochloride, tPL227oC;

with 3-chloromethyl-2'-forutenom get 1-pyrimidine-2-yl-4-[(2'-fluoro-3-rimidine-2-yl-4-[(3'-methoxy-3-biphenylyl)methyl]piperazine, maleate, tPL170oC;

with 3-chloromethyl-2'-methoxybiphenyl get 1-pyrimidine-2-yl-4-[(2'-methoxy-3-biphenylyl)methyl]piperazine, maleate, tPL145oC;

with 3-chloromethyl-3'-forutenom get 1-pyrimidine-2-yl-4-[(3'-fluoro-3-biphenylyl) methyl] piperazine, maleate, tPL183oC;

with 3-chloromethyl-4'-forutenom get 1-pyrimidine-2-yl-4-[(4'-fluoro-3-biphenylyl) methyl] piperazine, maleate, tPL198oC;

with 3-(2-thienyl)benzylchloride get 1-pyrimidine-2-yl-4-[3-(2-thienyl)benzyl] piperazine, maleate,PL181oC;

3-(3-thienyl)benzylchloride get 1-pyrimidine-2-yl-4-[3-(3-thienyl)benzyl] piperazine, maleate,PL208oC;

4-(2-thienyl)benzylchloride get 1-pyrimidine-2-yl-4-[4-(2-thienyl)benzyl] piperazine;

4-(3-thienyl)benzylchloride get 1-pyrimidine-2-yl-4-[4-(3-thienyl)benzyl]piperazine;

2-(2-thienyl)benzylchloride get 1-pyrimidine-2-yl-4-[2-(2-thienyl)benzyl]piperazine;

2-(3-thienyl)benzylchloride get 1-pyrimidine-2-yl-4-[2-(3-thienyl) benzyl] piperazine;

with 3-(2-thienyl)-5-chloromethylpyridine get 1-pyrimidine-2-yl-4-[3-(2-thienyl)pyrid-5-ylmethyl] piperazine;

3-(3-thienyl)-5-chloromethylpyridine get 1-pyrimidine-2-yl-4-[3-(3-thienyl)pyrid-5-ylmethyl] piperylene example 1], 1.8 g of the hydrochloride of pyridine and 50 ml of pyridine is boiled for 3 hours. Then cooled, evaporated, conduct normal processing and is obtained 1-(2-hydroxyphenyl)-4-[(5-phenyl-3-pyridyl) methyl] piperazine.

Similar by ether cleavage

from 1-(2-methoxyphenyl)-4-[(4-phenyl-2-pyridyl)methyl] piperazine get 1-(2-hydroxyphenyl)-4-1(4-phenyl-2-pyridyl)methyl] piperazine;

from 1-(2-methoxyphenyl)-4-[(4-(4-forfinal)-2-pyridyl)methyl] piperazine get 1-(2-hydroxyphenyl)-4-[(4-(4-forfinal)-2-pyridyl) methyl] piperazine;

from 1-(3,5-dichloro-4-methoxyphenyl)-4-[(5-(4-forfinal)-3 - pyridyl) methyl] piperazine get 1-(3,5-dichloro-4-hydroxyphenyl)-4- [(5-(4-forfinal) -3-pyridyl) methyl] piperazine;

from 1-(4-methoxyphenyl)-4-[(5-(4-forfinal)-3-pyridyl) methyl] piperazine get 1-(4-hydroxyphenyl)-4-[(5-(4-forfinal)-3-pyridyl) methyl] piperazine;

from 1-(3,4-acid)-4-[(5-(4-forfinal)-3-pyridyl) methyl] piperazine get 1-(3,4-dihydroxyphenyl)-4-[(5-(4-forfinal)-3-pyridyl) methyl] piperazine;

from 1-(3,5-dimethyl-4-methoxyphenyl)-4-[(5-(4-forfinal)-3-pyridyl) methyl] piperazine get 1-(3,5-dimethyl-4-hydroxyphenyl)-4-[(5-(4-forfinal) -3-pyridyl) methyl] piperazine;

from 1-(3-methoxyphenyl)-4-[(5-(4-forfinal)-3-pyridyl) methyl] piperazine receive piperazine get 1-(2-hydroxyphenyl) -4- (3-biphenylyl) piperazine;

from 1-(2-methoxy-5-aminocarbonylmethyl)-4-(3-biphenylyl) piperazine get 1-(2-hydroxy-5-aminocarbonylmethyl)-4-(3 - biphenylyl) piperazine;

from 1-(2-methoxy-5-tianfeng)-4-(3-biphenylyl) piperazine get 1-(2-hydroxy-5-tianfeng)-4-(3-biphenylyl) piperazine;

from 1-(2-methoxy-5-aminocarbonylmethyl)-4-(2'-cyan-4-biphenylyl) piperazine get 1-(2-hydroxy-5-aminocarbonylmethyl) -4- (2' -cyan - 4-biphenylyl) piperazine;

from 1-(2-methoxy-5-tianfeng)-4-(2'-cyan-4-biphenylyl)piperazine get 1-(2-hydroxy-5-tianfeng)-4-(2'-cyan-4-biphenylyl)piperazine.

Example 9

A mixture of 130 mg of 1-(3-biphenylyl)piperazine, 53 mg of 3-bromoanisole, 57 mg of tert-butylalcohol sodium and 8 mg [PdCl2{P(o-tolyl)3}2] in 10 ml of toluene is heated for 3 hours to 100oC. After cooling to room temperature the reaction mixture is diluted with 40 ml of simple ether and washed with saturated solution of NaCl. The organic phase is separated, dried over PA2SO4and remove the solvent. The residue is dissolved using a small number of simple ether and chromatographic on silica gel. The result is 1-(3-methoxyphenyl)-4-(3-biphenylyl) piperazine in the form of an oily residue, MS (FA dosage forms.

Example: Vials for injection solutions

A solution of 100 g of the active substance of the formula I and 5 g of disodium hydrogen phosphate in 3 l of double-distilled water was adjusted to 2n. hydrochloric acid to pH 6.5, sterile filtered, filled flask, lyophilized sealed and sterile. Each vial contains 5 mg of active substance.

Example B: Suppositories

A mixture of 20 mg of the active substance of the formula I, and 100 g of soya lecithin and 1400 g of cocoa butter is melted, poured into molds and allowed to harden. Each suppository contains 20 mg of active substance.

Example: Solution

Prepare a solution of 1 g of the active substance of the formula I, 938 g NaH2RHO42H2Oh, 28,48 g Na2HPO412H2O and 0.1 g of benzalkonium chloride in 940 ml of double-distilled water. Then set to pH 6.8, made up to a volume of 1 l and sterilized by irradiation. This solution can be applied in the form of eye drops.

Example D: Ointment

When observing aseptic conditions prepare a mixture of 500 mg of the active substance of the formula I with 99.5 g of petroleum jelly.

Example D: Tablets

Prepare a mixture of 1 kg of active substance of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg t the TKA contains 10 mg of active substance.

Example E: Bean

Analogously to example D is pressed tablets, which then conventional technology is applied a coating of sucrose, potato starch, talc, tragant and dye.

Example G: Capsules

2 kg of active substance of the formula I fill in the conventional technology tverdoplamennoe capsules so that each capsule contains 20 mg of active substance.

Example 3: Ampoules

A solution of 1 kg of active substance of the formula I in 60 l of double-distilled water is poured into ampoules subject aseptic conditions, lyophilized sealed and sterile. Each ampoule contains 10 mg of active substance.

REPORT ON PHARMACOLOGICAL TRIALS

Table 1 presents the values of the constants(IC50) inhibition of binding titiraupenga of spiperone with D2-, D3 -, and D4-receptors in the striatum (the striatum) rats for a number of compounds of General formula I. the Tests were conducted in accordance with the methodology described Schwarcz, etc., J. Neuro-Chemistry, 34, 772-778 (1980), and Creese and others, European J. Pharmacol, 46, 377-381 (1977).

The values of the IC50are given in nm x liter-1the melting point is in theoC.

Presented in table 1 the results of the tests convincingly demon what his concerns with D4-receptors in the striatum (the striatum).

Thus, the claimed compounds can be used as active substances for neuroleptic funds, anxiolytics, depressants and/or for drugs intended for the treatment of Parkinson's disease.

1. Derivatives of piperazine of the formula I

< / BR>
in which R1denotes pyridyl or phenyl, unsubstituted or once substituted Ph or 2 - or 3-tanila;

R2indicates Ph' or Het;

Ph denotes phenyl, unsubstituted or once substituted by F, CF3, OA or A;

Ph' denotes a phenyl which may be unsubstituted or one-, two - or three-fold substituted by F, Cl, HE, OA, AS, CF3, NO2CN, COA, CONH2, CONHA, CONA2;

Het represents an unsaturated cyclic heterocyclic residue with 6 atoms of the cycle containing 1 or 2 nitrogen atom, or benzodioxolyl, heterocyclic residue may be substituted once by fluorine;

And denotes alkyl with 1-6 carbon atoms,

and their physiologically acceptable salts.

2. Connection on p. 1, selected from the group including

(a) 1-(2-pyrimidinyl)-4-(3-(3-cyaniventer)piperazine,

(b) 1-[5-(4-forfinal)pyrid-3-ylmethyl] -4-(2-pyrimidyl)piperazine,

() 4-[4-(3-
(d) 1-(3'-fluoro-3-biphenylyl)-4-(2-pyrimidinyl)piperazine,

and also their salts.

3. The method of obtaining of piperazine derivatives of the formula I on p. 1 and their salts, which consists in the fact that the compound of formula II

< / BR>
in which R2has the specified value,

subjected to interaction with the compound of the formula III

R1-CH2-L III

in which L represents CL, Br, I, HE, O-CO -,-CO-Ph, O-SO2-Ar, where AG denotes phenyl or tolyl, and denotes alkyl, or another reactionsare esterified HE group, or easily nucleophile substitutable leaving group;

R1has a specified value, and/or, if necessary, the remainder R1and/or R2turn in the remainder R1and/or R2in particular, OA-group split with the formation of the Oh-group,

and/or received by a base or acid of formula I by treatment with acid or base turn in one of their salts.

4. Pharmaceutical composition having a selective effect against D4-receptor, characterized in that it contains at least one compound of General formula I and/or one of its physiologically acceptable salts.

 

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< / BR>
where R1benzyl, thienyl, chloranil, tetramethylene pentamethylbenzyl, phenyl, unsubstituted or monosubstituted by a halogen atom, a nitro-group, stands, metaxylem or trifluoromethyl, phenyl, disubstituted by chlorine atoms or methoxypropane,

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R6hydroxyl, methoxyl,

A group of the formula

< / BR>
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X N-methyl-aminogroup or sulfur atom, and the group-CHR7associated with the group-NR2-,

B a carbon-carbon bond or unbranched Allenova group with 2-4 carbon atoms,

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< / BR>
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