Derivatives of n-(aryloxyalkyl)-heteroarylboronic and heteroarylboronic and pharmaceutical composition based on them

 

(57) Abstract:

Derivatives of N-(aryloxyalkyl)-heteroarylboronic and heteroarylboronic formula 1, where X Is-O-, -S-, -NH - or-N(R2)-; p = 1; Y is H, Cl, Br, F; R2- benzoyl; Z is-CH - or-N-; n = 2, 3, 4, 5; R is H, alkyl, alkoxyl, hydroxyl, bromine, alkylamino, alkylthio, TRIFLUOROACETYL, aminocarbonyl, -CO-alkyl, -COO-alkyl, -CO-Ph, -CH(OR3); R3- H, lower alkyl, m = 1, 2, 3, or their pharmaceutically acceptable salts possess antipsychotic and/or analgesic activity. 2 C. and 58 C.p. f-crystals, 3 PL.

The invention relates to substituted N-(aryloxyalkyl)-heteroarylboronic and-heteroarylboronic having antipsychotic activity, and their use as antipsychotic drugs.

Widespread therapeutic treatment of patients with schizophrenia introduction of neuroleptic drugs such as chlorpromazine, haloperidol, sulpiride and chemically closely related compounds. If the management of the symptoms of schizophrenia are successful, the treatment with these drugs does not lead to recovery psychotic patient who almost certainly recurs, if you stop the medication. Constantly things is, some known antipsychotics cause unwanted side effects. For example, the side effects of many antipsychotic drugs include extrapyramidal symptoms, such as rigidity and tremor, continuous excited walking, facial grimasnichane and involuntary facial movements and podderzhivanie limbs. Normal is hypotension. Thus, there is also a need in the field of antipsychotic drugs that cause less severe manifestations of these common side effects.

In addition, there is a need for drugs that can cause other biological actions. For example, removing the pain of aspiration in the elderly, which led to the discovery of natural and synthetic analgesics. Nevertheless, the need for reliable and effective analgesics and at the present time.

The present invention aims to fill these needs in this area offer the compounds of formula

< / BR>
in which X represents-O-, -S-,

< / BR>
p = 1 or 2;

Y is hydrogen, alkyl with 1-6 carbon atoms, -OH, a chlorine atom, a bromine atom, a fluorine atom, the atom yo and atoms, if p=2 and X is-O-;

R2selected from the group comprising lower alkyl, aryl lower alkyl, aryl, cycloalkyl, aroyl, alkanoyl and phenylsulfonyl;

Z represents-OH or-N-;

n = 2-5;

R is hydrogen, alkyl, alkoxy with 1-6 carbon atoms, hydroxyl, carboxyl, chlorine atom, fluorine atom, bromine atom, iodine atom, amino, mono or dialkylamino with 1-6 carbon atoms, -NO2, lower alkylthio, -OCF3, cyano, acylamino, -CF3, TRIFLUOROACETYL, aminocarbonyl,

< / BR>
where alkyl is lower alkyl, aryl is phenyl or

< / BR>
R1is hydrogen, lower alkyl, alkoxy with 1-6 carbon atoms, hydroxy, chlorine atom, fluorine atom, bromine atom, iodine atom, C1-C6-alkylamino, -NO2, -CN, -CF3, -OCF3; heteroaryl is

< / BR>
Q represents-O-, -S-, -NH, -CH=N;

R3is hydrogen, lower alkyl or acyl and

m=1-3,

or its pharmaceutically acceptable acid additive salt.

This invention also provides a pharmaceutical composition that includes a compound according to the invention and pharmaceutically acceptable carrier. In one implementation of the invention the pharmaceutical composition is an antipsychotic comp is goticheskoe action.

Compounds according to the invention are useful as antipsychotic drugs and as an analgesic means. Compounds according to the invention can contain a variety of different substituents and chemical groups. Used in the description, the term "lower" referred to in connection with the description of a specific group means that this group contains from 1 to 6 carbon atoms.

The term "alkyl" used in the description refers to a hydrocarbon group with a straight or branched chain, containing no unsaturated bonds, such as methyl, ethyl, isopropyl, 2-butyl, neopentyl or n-hexyl.

The term "alkoxy" used in the description refers to a monovalent substituent containing an alkyl group linked through an ether oxygen having its free valence bond from the ether oxygen, i.e., methoxy, ethoxy, propoxy, butoxy or intoxi.

The term "alkylene" used in the description, refers to bivalent radical of the lower branched or unbranched alkyl group having valence bonds on two of its terminal carbon atoms, for example ethylene (-CH2CH2-), propylene (-CH2CH2CH2- or isopropylaniline ring, containing from 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclodecyl and the like.

The term "alkanoyl" used in the description applies alkylcarboxylic part of the molecule containing from 2 to 11 carbon atoms, i.e.

< / BR>
and so on.

The term "albanova acid" refers to compounds formed by the combination of a carboxyl group with a hydrogen atom or alkyl group. Examples alkanovykh acids are formic acid, acetic acid, propanoic acid, 2,2-dimethyloxetane acid, hexanoic acid, octanoic acid, cekanova acid and the like.

The term "alkanoyl" refers to a radical formed by removal of the hydroxyl functions of alanovoy acid. Examples alkanoyl groups are formyl, acetyl, propionyl, 2,2-dimethylethyl, hexanoyl, octanoyl, decanoyl and the like.

The term "aryl-lower alkyl" refers to compounds in which "aryl" and "lower" alkyl" is defined above.

The term "lower alkylthio" refers to a monovalent substituent having the formula lower alkyl-S-.

The term "phenylsulfonyl" refers to a monovalent substituent, BR>
< / BR>
Unless otherwise indicated, the term "halogen" used in the description, belongs to the family of Halogens selected from the group comprising fluorine, chlorine, bromine and iodine.

Throughout the description and in the accompanying claims given chemical formula or name will include all geometric and stereoisomers of the compounds, if any.

A. Compounds according to the invention.

Compounds according to the invention can be represented by the following formula:

< / BR>
Deputy X in formula 1 is selected from the group consisting of-O-, -S-, -NH - or If the Deputy X is-O-, the compounds according to the invention contain a 1,2-benzisoxazole cycles, and if X is-S-, the compounds according to the invention contain a 1,2-benzisothiazole cycles. If X is-NH - or the compounds according to the invention contain indazol cycles.

If p=1 in the formula 1, then Deputy Y is selected from the group comprising hydrogen, lower alkyl, hydroxyl, halogen, lower alkoxy, -CF3, -NO2and-NH2. Deputy Y is preferably a 5 - or 6-position of the ring. In addition, in the preferred implementation of the invention Deputy Y is hydrogen, chlorine and-position of the ring.

If p= 2 in formula 1 and X is-O-, each Y-Deputy may be independently from each other selected from among lower alkoxygroup and preferably of methoxypropyl.

In formula 1, n may be 2, 3, 4 or 5, and preferably 2, 3 or 4. In a particularly preferred compounds according to the invention n = 3.

When X in the compounds according to the invention represents the substituent R2selected from the group consisting of lower alkyl, aryl-lower alkyl, aryl, cycloalkyl, aroyl, alkanoyl and phenylsulfonyl.

Deputy Z in the formula 1 may be , and in this case, the compounds according to the invention are derived heteroarylboronic, or , in this case, the connections are derived heteroarylboronic. Preferred compounds according to the invention are heteroarylboronic.

Compounds according to the invention may contain one, two or three R-substituent. The substituent R can be hydrogen, alkyl, alkoxy with 1-6 carbon atoms, hydroxyl, carbonyl, chlorine atom, fluorine atom, bromine atom, iodine atom, amino, C1-C6-mono - or dialkylamino, -NO2, lower alkylthio, -OCF3, cyano, acylamino, -CF3, TRIFLUOROACETYL am/SUB> is hydrogen, lower alkyl, alkoxy with 1-6 carbon atoms, actigraphy, chlorine atom, fluorine, bromine, iodine, C1-C6-alkylamino, -NO2, -CN, -CF3, -OCF3;

heteroaryl is a

Q is-O-, -S-, -CH=N;

R3is hydrogen, lower alkyl or allyl;

m=1, 2, or 3.

If the compounds according to the invention contain two or three R-substituent, each substituent R can be chosen independently from each other among the above substituents. Preferably each R is Deputy selected from the group comprising hydrogen, alkyl with 1-3 carbon atoms, alkoxy with 1-3 carbon atoms, hydroxy, acyl, alkanoyl, chlorine atom, bromine atom, fluorine atom, iodine atom, C1-C3-alkylamino, nitro, trifluoromethyl, -OCF3,

Compounds according to the present invention was prepared as follows. The substituents R, R1, R2, R3X, Y and Z and the integers m, n and p have the above values, unless otherwise indicated.

C. Obtaining the compounds according to the invention.

Compounds according to the invention can be obtained by the interaction of the piperidine or piperazine of the formula

< / BR>
at alkylating conditions with a compound of formu what I piperidino, the piperazines and alkylating agents of the above formula, will be described below in detail.

1. Obtaining 3-(1-unsubstituted-4-piperazinil)-1H-indazols.

Compounds of the formula

< / BR>
for use in the synthesis indazolinone of piperazines according to the invention can be obtained as follows.

Chose substituted arrowy ester of formula 7

< / BR>
in which R5represents lower alkyl and Hal is selected from the group of Halogens, including chlorine atom, bromine and iodine. An ester of formula 7 was subjected to interaction with a hydrazine of the formula H2NNH2in standard conditions of formation of hydrazine. Typically the reaction is carried out in directionspanel solvent, i.e., in ethanol, methanol or toluene at temperatures from room temperature up to temperatures of formation of phlegmy solvent for 4 to 16 h with the formation of the hydrazide of formula 8

< / BR>
The hydrazide of formula 8 was subjected to reaction with halide phenylsulfonyl formula

< / BR>
in which Hal is a halogen selected from the group including a chlorine atom and bromine, with the formation of the compounds of formula

< / BR>
The compound of formula 11 interacts with the compound of the formula 12

< / BR>
in which Rthe e, such as tetrahydrofuran, toluene or diethyl ether, at 5 - 50oC for 1 to 16 h with the formation of the compounds of formula

< / BR>
The compound of formula 13 is then subjected to interaction with a condensing agent such as copper, copper alloy and bronze or copper oxide, in a solvent such as dimethylformamide, dimethylacetamide or tetramethylrhodamine, in the range of 120 to 177oC for 1 to 16 h with the formation of piperazinediones of phenylsulfonylacetate formula

< / BR>
Tiananamen piperazineethanesulfonic then formed in the interaction of the compounds of formula 14 with a traditional source of cyanide, such as halide, cyanide, i.e., Enrichment or ClCN, under normal conditions of cyanidation, typically in an inert solvent, such as dimethylsulfoxide or chloroform at ambient temperature for 2 to 16 h with the formation of compounds of formula 15

< / BR>
The compound of formula 15 is then subjected to repair using a metal hydride, e.g. lithium aluminum hydride (LiAlH4). Usually the recovery is carried out in the standard reduction conditions in a solvent such as tetrahydrofuran or diethyl ether in the range of 35 - 67oC for 6 to 16 h with the formation of compounds of povedeniya formula 14 with a strong base, such as an alcoholate of a metal, i.e. sodium methylate, sodium ethylate or butyl sodium, or potassium hydroxide in tetrahydrofuran to form compounds of formula 17

< / BR>
This reaction is typically conducted in a polar solvent such as, for example, methanol or ethanol in the temperature range from room temperature up to 50oC for 1 to 16 hours

The alternate connection of the formula 17 can be obtained by reduction of compounds of formula 14 with lithium aluminum hydride (LiAlH4in the previously described conditions.

The compound of formula 17 in turn can be subjected to interaction with a cyanation reagent, as described above, with the formation of canasatego of piperazineethanol formula

< / BR>
which in turn can be restored by a metal hydride, as described previously, with the formation of compounds of formula 16.

In an alternative implementation, the compound of formula 18 can be subjected to contact with an aqueous mineral acid, for example sulfuric or chloride-hydrogen acid, in the range of 50 - 120oC for 2-16 h with the formation of compounds of formula 16.

2. Obtaining 3-(1-unsubstituted-4-piperazinil)-1,2-benzisoxazole.

The compound of formula 19

The
mules 19 useful for the synthesis of benzisoxazoles of piperazines according to the invention.

3. Obtaining 3-(1-unsubstituted-4-piperazinil)-1,2-benzisothiazole.

The connection formulas

< / BR>
for use in the synthesis benzisothiazolinone of piperazines according to the invention can be obtained by the method described in J. Med. Chem. 1986, 29: 359 and in the United Kingdom patent N 2163432 A.

4. Obtaining 3-(1-unsubstituted 4-piperidinyl)-1H-indazols.

The compound of formula 21 or 22

< / BR>
for use in the synthesis indazolinone of piperidine according to the invention can be obtained using known methods. For example, suitable methods are described in substantial detail in U.S. patent N 4710573.

5. Obtaining 3-(1-unsubstituted 4-piperidinyl)-1,2-benzisoxazole.

The connection formulas

< / BR>
can be obtained is known from several sources methods. For example, U.S. patent N 4355037 contains a detailed description of the compounds of formula 23 and methods of producing compounds. Additional disclosures about the methods of preparing compounds of formula 23 can be found in U.S. patent N 4327103 and Strupczewski et al., J. Med. Chem., 28: 761-769 (1985). The compounds of formula 23 can be used in the synthesis benzisoxazoles of piperidine according to the invention.

6. Obtaining 3-(1-Nezami is with in the synthesis of N-(aryloxyalkyl) -heteroarylboronic according to the invention. Specific benzisothiazol formula

< / BR>
can interact with an alkylating agent, described earlier, with the formation of N-(aryloxyalkyl)-heteroarylboronic according to the invention. The compounds of formula 24 and the methods for their preparation are described in detail in U.S. patent N 4458076.

7. Receiving alkylating funds.

The compounds described in sections 1-6 above, can interact with alkylating means of the formula

< / BR>
with the formation of N-(aryloxyalkyl) -heteroarylboronic and piperazines according to the invention. Alkylating means and methods for their preparation are described in U.S. patent N 4366162. Additional information can be found in the publication of South Africa ZA 8614522.

8. Alkylation of heteroarylboronic and-piperazines for producing compounds according to the invention.

Heteroarylboronic and-piperazines, described in sections 1-6, can interact at alkylating conditions with alkylating agents, described in section 7, with the formation of compounds according to the invention. The reaction can be conducted by dissolving the reagents in an inert solvent, such as dimethylformamide, acetonitrile or butanol, and the interaction of the reagents in the interval temperaturerange. Examples of suitable bases are carbonates of alkali metals such as potassium carbonate, sodium carbonate or sodium bicarbonate. The reaction can be carried out with catalytic amounts of alkaline iodide or without it, such as potassium iodide or sodium iodide, in a period of time sufficient for the formation of compounds of formula 1 according to the invention. In General, the alkylation reaction is conducted within 4-16 hours depending on the reactivity of the reagents. The reaction temperature may vary from 50 to 120oC. the reaction Product can be isolated by treatment with water, extracting the product into an organic solvent not miscible with water, washing, drying and concentrating the organic solvent to obtain the free base and then, if indicated, treatment of the obtained compound in an acid additive salt in the traditional way.

The following examples are typical of the compounds according to the invention, which can be obtained by the method described above:

1-/4-/3-/4-(1H-indazol-3-yl)-1-piperazinil/ -propoxy/-3 - methoxyphenyl/-Etalon;

1-/4-/3-/4-(1,2 -benzisoxazol-3-yl)-1-piperidinyl/ -propoxy/-3 - methoxyphenyl/-Etalon;

1-/4-/3-/4-(6- fluoro-1,2-benny/-butoxy/-3 - methoxyphenyl/-Etalon;

1-/4-/4-/4-(6- fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl/- butoxy/-3 - methoxyphenyl/-Etalon;

fumarate 1-/4-/2-/4-(1,2 -benzisoxazol-3-yl)-1-piperidinyl/- etoxy/-3 - methoxyphenyl/-ethanone;

fumarate 1-/4-/4-/4-(1H-indazol-3-yl) -1-piperazinil/-butoxy/-3 - methoxyphenyl/-ethanone;

1-/4-/2-/4-(6- fluoro-1,2-benzisoxazol-3-yl)-1-piperidyl/- etoxy/-3-methoxyphenyl/-Etalon;

4-/3-/4-(6- fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl/- propoxy/-3-methoxy-methylbenzylamino;

1-/4-/3-/4-(1,2- benzisoxazol-3-yl) -1-piperidinyl/-propoxy/-3 - methoxyphenyl/-Etalon;

1-/4-/3-/4-(6- fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl/- propoxy/-3 oksifenil/-Etalon;

1-/4-/3-/4-(6- fluoro-1H-indazol-3-yl)-1-piperazinil/- propoxy/-3 - methoxyphenyl/-Etalon;

1-/4-/4-/4-(6-fluoro-1H-indazol-3-yl)-1-piperazinil/-butoxy/-3 - methoxyphenyl/-Etalon;

1-/4-/3-/4-(1H - indazol-3-yl) -1-piperidinyl/ -propoxy/-3 - methoxyphenyl/-Etalon;

1-/4-/3-/4-(6-chloro-1,2-benzisoxazol-3-yl)-1-piperidinyl/- propoxy/-3 - methoxyphenyl/-Etalon;

fumarate 1-/4-/4-/4-(6-chloro-1,2-benzisoxazol-3-yl)-1-piperidinyl/- butoxy/-3-methoxyphenyl/ -ethanone;

1-/4-/3-/4-(5-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl/- propoxy/-3 - methoxyphenyl/-Etalon;

fumarate 6-fluoro-3-/1-/3-(2- methoxyphenoxy)-propyl/ -4-piperidinyl/- 1.2 benzisoxazol is(1H - indazol-3-yl) -1-piperidinyl/-butoxy/-3 - methoxyphenyl/-Etalon;

1-/4-/2-/4-(6-chloro-1,2-benzisoxazol-3-yl)-1-piperidinyl/- etoxy/-3-methoxyphenyl/-Etalon;

fumarate 1-/3-/3-/4-(6-fluoro-1,2-benzisoxazol-3-yl)-1 - piperidinyl/-propoxy-phenyl/-ethanone;

1-/4-/3-/4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl/- propoxy/-2 - were/-Etalon;

1-/2-/3-/4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl/- propoxy/-5-were/ -Etalon;

profumata-/4-/3-/4-(6-fluoro-1,2-benzisoxazol-3-yl)-1 - piperidinyl/-propoxy/ -3-methoxyphenyl)-ndimethylacetamide

6-chloro-3- (1-piperazinil)-1H-indazol;

1-/4-/3-/4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl/ -propoxy/-3 - methoxyphenyl/-Etalon;

profumata 1-/4-/3-/4-(6-fluoro-1,2-benzisoxazol-3-yl)-1 - piperidinyl/-propoxy/ -3-methoxyphenyl/-ethanone;

1-/4-/3-/4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl/- propoxy-phenyl/ -Etalon;

1-/4-/3-/4-(6-chloro-1H-indazol-3-yl)-1-piperazinil/-propoxy/-3 - methoxyphenyl/-Etalon;

1-/4-/4-/4-(1,2- benzisothiazol-3-yl) -1-piperazinil/-butoxy/-3 - methoxyphenyl/-Etalon;

4-/3-/4-(6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl/- propoxy/-3-methoxybenzonitrile;

1-/4-/4-/4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl/ -butoxy/-3 - methoxyphenyl/-Etalon;

sesquifumarate 1-/4-/3-/4-(1- benzoyl-6-fluoro - 1H-indazol-3-yl)-1 - piperazinil/-propoxy/-3 - methoxyphenyl/-ethanone;

1-/4-/4-/a-3-yl) -1 - piperazinil/-propoxy/ -3-methoxyphenyl/-ethanone;

1-/3-/5-dibromo-4-/3-/4- (6-fluoro - 1,2-benzisoxazol-3-yl)-1 - piperidinyl/-propoxy-phenyl/-Etalon;

1-/4-/2-/4-(1,2 -benzisothiazol-3-yl) -1-piperazinil/ -etoxy/-3 - methoxyphenyl/-Etalon;

6-fluoro-3-/1- (3-phenoxypropan)-4-piperidinyl/- 1,2-benzisoxazol;

1-/4-/2-/4-(6-chloro-1H-indazol-3-yl) -1-piperazinil/-etoxy/-3 - methoxyphenyl/-Etalon;

1-/4-/3-/4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl/- propoxy/-3-methylmercaptopurine/ -Etalon;

1-/4-/4-/4-(1,2 -benzisothiazol-3-yl) -1-piperidinyl/-butoxy/-3 - methoxyphenyl/-Etalon;

1-/4-/3-/4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl/- propoxy/-3 - methoxyphenyl/-phenylmethane;

1-/3-bromo-4-/3-/4-(6- fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl/- propoxy-phenyl/ -Etalon;

hydrochloride 3-/1-/3-/4- (1-ethoxyethyl)-2 - methoxyphenoxy/propyl/-4 - piperidinyl/-6 - fluoro-1,2-benzisoxazole;

fumarate 3-/1-/3-/4-(1- acetoxyethyl)-2 - methoxyphenoxy/-propyl/-4 - piperidinyl/-6 - fluoro-1,2-benzisoxazole;

1-/4-/3-/4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl/- propoxy/-methoxyphenyl/ -pentanone;

profumata 2-/3-/4-(6-fluoro-1,2-benzisoxazol-3-yl)-1 - piperidinyl/-propoxy/ -N methylbenzenamine;

3-(1-/3-(4-bromo-2-methoxyphenoxy) -propyl/-4-piperidinyl)-6 - fluoro-1,2-benzisoxazol;

1-/4-/3-/4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl/benzamide;

1-/4-/3-/4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl/- propoxy/-3-(methylamino) -phenyl/-alanon and

1-/4-/3-/4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl/- propoxy/-3-ethoxyphenyl/ -Etalon.

Compounds according to the present invention are useful for the treatment of psychosis due to their ability to cause antipsychotic response in mammals. Antipsychotic activity was determined by the test of climbing mice on the walls of the cells according to the method similar to that described P. Protais et al. Psychopharmacol. 50:1 (1976) and B. Costall. Eur. J. Pharmacol., 50:39, (1978).

Experimental animals were the males of mice SC-1 weighing 23-27 g, which contained groups in standard laboratory conditions. Mice were placed individually in wire cages (10 x 25 cm) and left for one hour to adapt and explore a new environment. Then subcutaneously were injected with 1.5 mg/kg of apomorphine, the dose which causes a climbing wall in all experimental animals within 30 minutes. Compounds to be tested for antipsychotic activity, were intraperitoneally injected with, or introduced oral dose with different time intervals, i.e. 30 minutes, 60 minutes and so on, until the introduction of apomorphine in provoking dose of 10-60 mg/kg

For Orangerie mouse (rearing) - Points

4 paws on the floor (rearing was not observed) - 0

Two paws on the wall (standing on hind legs) - 1

Four paws on the wall (full scale) - 2

Mouse, consistently climbing wall to the injection of apomorphine, were not taken into account.

When fully developed, caused by apomorphine lifting up the animals hung on the walls of the cells, often without movement for a long period of time. In contrast, rearing due to locomotor stimulation usually lasts only a few seconds.

Indicators of climbing to the height were summed individually (the maximum score of 6 from three indications for mouse), and total score of the control group (receiving media intraperitoneally and apomorphine subcutaneously) was taken as 100%. The values of effective dose (ED50) with 95% limit of confidence calculated by the method of linear regression for some compounds according to the present invention, as well as to standard antipsychotics, are presented in table 1.

Antipsychotic response is achieved if the compounds according to the present invention are introduced to a subject requiring such treatment as an effective oral the of each particular patient should be installed specific dose regimes, consistent with individual need and the professional training of persons, misleading or controlling the introduction of the mentioned compounds. You should also understand that some here doses are only approximate and should not in any way limit the scope or practice of this invention.

Some compounds according to the present invention are also useful as analgesic agents as to their ability to alleviate pain in mammals. Analgesic usefulness has been demonstrated in the test letters (scratch pads) in mice caused by the introduction of fenilalanina, a standard test for analgesia, described in Proc. Soc. Exptl. Biol. Med. 95: 729 (1957). So, for example, subcutaneous dose that causes approximately 50% inhibition of symptom letters in mice (ED50) obtained in this experiment are shown in table 2.

Analgesia is achieved, if the patient in need of such treatment is administered an effective oral, parenteral or intravenous dose of from 0.01 to 100 mg/kg of body weight per day. It should be understood, however, that the scheme of a medicament is provided in accordance with the personal needs of the patient and professional the AMB, that the foregoing doses are only approximate, and they in no way limit the scope or implementation of the present invention.

Was also performed the following experiments to determine the antipsychotic activity (MCA), analgesic activity (PQW) and toxicity (ALD50some compounds of the invention.

Antipsychotica activity was determined by inhibition of apomorphine-induced climbing up (climbing) mice at 20 mg/kg, intraperitoneally 30 minutes. Analgesic activity was determined in mice by inhibition of familienaam caused by painful cramps mice at 20 mg/kg, subcutaneously 30 minutes. Toxicity was measured in acute lethal dose (ALD50mg/kg, intraperitoneally). The results are presented in table 3.

To confirm the advantages of the invention associated with less toxicity, the results of the testing of representative compounds of the invention 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl] - propoxy]-3-methoxyphenyl] -ethanone (hereinafter referred to for brevity, "connection") in comparison with chlorpromazine. Held: trial (a) on the stereotype in rats caused apomorfina which was conducted with the connection and chlorpromazine compounds that prevent antagonism APO-'s dopamine receptors in nigrostriatal system of the brain, and the antagonism of this behavior is a predictor of the propensity to develop extrapyramidal side effects (EPS) and late (late) dyskinesias (disorders of voluntary movements) ("TO"); the results obtained in this standard test on animals, the following:

chlorpromazine: ED50= 5,75 mg/kg, i.p.,

connection: U50= 34.8 mg/kg, i.p.,

therefore, the connection is less likely (at a ratio of 1/6) compared with chlorpromazine may also be side effects of EPS and TO (i.e., toxicity).

From table 1, given in the application, it is clear that "connection" is 13.6 times more potent than chlorpromazine in test rearing mice ("CMA"), which is an indicator of antipsychotic effectiveness; the results of the MCA and the results of the APO-S, above, was calculated therapeutic index as follows:

therapeutic index ("TR") = ED50(MCA)/U50(APO-S),

chlorpromazine: TR = 5,75,

"connection": TR = 366,

and accordingly "connection" significantly superior to chlorpromazine.

Test the total effect on nigrostriatal dopamine system, inducing catalepsy) cataleptic symptoms in rodents compared with parkinsonopodobnyj extrapyramidal side effects observed clinically when prescribing antipsychotic funds; the results obtained in this standard test on animals, the following:

chlorpromazine: 83% inducing catalepsy 1.00 mg/kg, i.p.,

"connection": 10% inducing catalepsy 10,00 mg/kg, i.p.,

consequently, the "connection" is superior to chlorpromazine from the point of view of the lesser side effects (toxicity).

1. Inhibition apomorfina stereotypie in rats.

Purpose.

The selection of neuroleptic compounds that act directly on the dopaminergic system by blocking the action of apomorphine on postsynaptic dopamine receptors (Andenetal, 1967; Ernst., 1967).

Method.

Used groups of male Wistar rats (125-200 g), and food and water were available without restrictions (fill). Drugs were prepared using distilled water and, if they were insoluble, adding a suitable surfactant. The mode of appointment could vary, and the amount of dose is 10 ml/kg

For the primary IC is promised in individual clear plastic cages (24 x 14 x 13 cm). The control group received the filler. Apomorphine HCl (Merck and Co.) were prepared at a concentration of 15 mg/10 ml in 0.03% of the original ascorbic acid solution prepared using 30 mg of ascorbic acid in 100 ml of 1 salt solution to increase the stability of apomorphine HCl in solution. Apomorphine HCl was administered in the dose of 1.5 mg/kg s.c. (subcutaneously) with the dose volume of 1 ml/kg, 50 minutes after a dose of means observed stereotypical behavior. Stereotypically activity is defined as prinucovania, licking or chewing behavior, which is subdivided as follows: constant prinucovania, licking or chewing without interruption; the animal is considered to be protected if this behavior stops.

The percentage efficiency of the tool is determined by the number of protected animals in each group.

Definition of response to dose is carried out in the same manner as the primary screening except that used a group of 10 and the animals were given a dose of the drug at random. One group received the filler. The index ED50for stereotypie were calculated with probit analysis.

Links.

Anden, N. E., Rubenson, A., Fuxe, K. ne on gnaning compulsion in rats.

Psychopharmacological (Berl.) 10: 316-323, 1967.

2. Catalepsy.

Method.

Used groups of male Wistar rats (150 - 300g). The animals were kept in colony with controlled climatic conditions. Food and water were available without restrictions. On the day of testing, animals were brought to the laboratory and divided into groups of six.

Drugs were prepared in distilled water and was administered i.p. (intraperitoneally) in the dose volume 10 ml/kg

The test was carried out after 1, 2, 3, 4, 5 and 6 h after injection of the dose and was carried out in the presence of "white noise". Test for catalepsy is to place an individual animal in a white, translucent plastic box (26 x 20 x 15 cm) with wooden pins mounted horizontally at 10 cm from the floor and 4 cm from one end of the box. The floor was covered with approximately 2 cm of the layered material. Animals were allowed to adapt to the box for two minutes. At the end of two minutes, each animal was gently covered around the shoulders and front legs and gently placed on the lintel (the barrier). We determined the amount of time that an animal spends at least one front paw on the bar. When the animal took away his legs, REGISTRADA time trials and time spent on the bar, were recorded for each experiment at each time of testing during the time period, if the animal remains on the bar within 60 C.

An animal was considered catalepticos, if it remained on the bar within 60 C.

The percentage of catalepsy is calculated as follows:

< / BR>
Compounds according to the invention, being effective themselves, may be prepared as drugs and introduced in the form of their pharmaceutically acceptable additive salts because of their stability, convenience of crystallization, increased solubility and the like. Preferred pharmaceutically acceptable additive salts include salts of mineral acids, such as chloride-hydrogen acid, sulfuric acid, nitric acid and the like; salts of monobasic carboxylic acids, for example acetic acid, propionic acid and the like; salts of dibasic carboxylic acids, for example maleic acid, fumaric acid and the like and salts trekhosnovnykh carboxylic acids, such as carboxyesterase acid, citric acid, and the like.

Effective amounts of compounds according from the ut to be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic injection of the compounds according to the invention can be embedded in the media and used in the form of tablets, granules, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like. These preparations may contain at least 0.5% of active compound according to the invention, but this number can vary depending on the particular form and may typically be 4 to 70% by weight of the dosage form. The number of active compound in such compositions is such that it achieves an appropriate dose. Preferred compositions and preparations according to the present invention are prepared so that the form of dosage units for oral administration contain 1 to 300 mg of active compounds according to the invention.

Tablets, pills, capsules, wafers, and the like may also contain the following ingredients: a binder such as microcrystalline cellulose, tragakant or gelatin; an excipient such as starch or lactose; a dispersing agent, such as alginic acid, primogel, corn starch and the like; a lubricant such as magnesium stearate or sterates, a moving vehicle, such as colloidalsilver or orange flavor. If the dosage unit form is a capsule, it may contain in addition to materials of the above type, a liquid carrier such as fatty oil. Other forms of dosage units may contain different materials that modify the physical form of the dosage unit, for example coating. So, for example, tablets or pills may be coated with sugar, shellac or other dissolving in intestinal epithelial means. A syrup may contain, in addition to the active compounds, sucrose as sweets and certain preservatives, dyes and aromatic agents. The materials used for preparing these various compositions should be pharmaceutically pure and non-toxic in the quantities used.

For the purpose of parenteral therapeutic introduction of the active compounds according to the invention can be put into solution or suspension.

These preparations should contain at least 0.1% of active compound, but this number can vary from 0.5 to 50.0% by weight of the preparation. The number of active compound in such compositions is such that it provides the desired dose. Preferred compositions and preparations of the LMS 100 mg of active compound.

The solutions or suspensions may also include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; hepatoblastoma tools such as ethylenediaminetetraacetic acid; buffers such as acetate, citrate or phosphate buffers, and means for maintaining the tonicity such as sodium chloride or dextrose. Preparations for parenteral administration can be enclosed in ampoules, free syringes or containers for multiple doses, made of glass or plastic.

The following examples are only illustrative and may not be considered as limiting the scope of the invention. All temperatures are given in degrees Celsius (oC) if not specified.

Example 1.

Getting 1-/4-/3-/4-(1H - indazol-3-yl)-1 - piperazinil/-propoxy/ -3-methoxyphenyl/ ethanone.

(A) Synthesis of 2-vinylsulfonylacetamido-2-bromobenzoyl acid.

To a solution of hydrazide 2-bromobenzonitrile (78,3 ml). After the end of the additives, the reaction mixture was stirred at room temperature for 4 h, then was poured into a mixture of ice and chloride-hydrogen acid to precipitate a yellow solid, 135, the Product was recrystallized from isopropanol and received 125 g 2-vinylsulfonylacetamido 2 bramantino acid, melting point 154 - 156oC.

(B) Synthesis -chloro-2-bromobenzaldehyde of phenylsulfonylacetate.

The mixture phenylsulfonylacetate 2 bramantino acid (125 g, 0.35 mol) and chloride taanila (265 ml) was stirred and heated under reflux for 2 hours After 15 minutes of boiling under reflux, the solid is passed into the solution. The reaction mixture was cooled and then poured into hexane. The obtained white solid was collected and received 124 g-chloro-2-bromobenzaldehyde of phenylsulfonylacetate, melting point 120 - 122oC.

(C) Synthesis of 1-//(phenylsulfonyl) -hydrazono/-(2-bromophenyl) methyl/-4-methylpiperazine.

To mix the solution-chloro-2 - bromobenzaldehyde of phenylsulfonylacetate (271,1 g to 0.72 mol) in tetrahydrofuran (tetrahydrofuran two liters) under nitrogen atmosphere was added dropwise N-methylpiperazine (159 g, 1.6 mol). The reaction mixture p is nnow the mixture was cooled in an ice bath and then filtered to remove the formed hydrochloride and piperazine. The filtrate was concentrated to obtain a brown resin. The resin was washed with hot acetonitrile, the mixture was cooled in an ice bath and chilled filtered to remove unwanted by-product. Then the filtrate was concentrated to obtain 392,9 g brown resin crude 1-//(phenylsulfonyl) -hydrazono/- (2-bromophenyl)-methyl/ -4-methylpiperazine.

(D) Synthesis of 3-(4-methyl-1-piperazinil)-1-phenylsulfonyl-1H - indazole.

A mixture of 1-//(phenylsulfonyl) -hydrazono/-(2 - bromophenyl)methyl-4 - methylpiperazine (31.0 g, 0.08 mol) bronze copper (3.1 g), potassium carbonate (11.5 g) and dimethylformamide (500 ml) was stirred and heated under reflux for 1.5 hours, the Reaction mixture was poured into water and the aqueous suspension was vigorously stirred with ethyl acetate. Containing two phase mixture was filtered through celite and consistently divided layers. The aqueous portion was extracted with another portion of ethyl acetate and the combined extracts were washed with water and dried (magnesium sulfate). Concentration of the extract obtained solid substance, which when crushed with simple ether gave 19.7 g of a solid substance. The solid is recrystallized from isopropanol and got to 17.7 g (60%) of product, melting point 158 - 161oC. H is in the form of colourless crystals indazole, 3-(4-methyl-1-piperazinil) -1-phenylsulfonyl-1H-indazole, melting point 160 - 161oC.

Elemental analysis for C18H20N4O2S:

calculated (%): C 60,66; H 5,66; N 15,72;

found (%): C 60,45; H 5,62; N 15,61.

(E) Synthesis of 4-/1-(phenylsulfonyl) -1H-indazol-3-yl/-1 - piperidinecarbonitrile.

To a stirred mixture of 3-(4-methyl-1-piperazinil)-1-phenylsulfonyl-1H-indazole (237 g, 0.67 mol), potassium carbonate (102 g of 0.74 mol) and dimethyl sulfoxide (2000 ml) under nitrogen atmosphere was added CYANOGEN bromide (72 g of 0.68 mol), dissolved in dimethyl sulfoxide (525 ml). The reaction mixture was stirred at ambient temperature for 5.5 h and then poured into water (7.0 l). Solid, precipitated precipitated from solution, was collected by filtration, well washed with water and got 168 g (68%) of product. The sample weight is 5.2 grams twice recrystallized from a mixture of ethanol - water and obtained 4.0 g 4-/1-(phenylsulfonyl) -1H-indazol-3-yl/ -1-piperidinecarbonitrile, melting point 178-180oC.

Elemental analysis for C18H17N5O2S:

calculated (%): C 59,01; H 4,63; N 19,06;

found (%): C 59,01; H 4,63; N KZT 19.09.

(F) Synthesis of 3-(1-piperazinil)-1H-indazole.

To a stirred mixture of 4-/1-(phenylsulfonyl) -1H-Inda (880 ml, 0.88 mol) of 1 M solution of lithium aluminum hydride in tetrahydrofuran. After the end of the additives, the reaction mixture was heated under reflux and stirred for 6 h, was stirred at room temperature for 1 h and left overnight at room temperature. The reaction was suppressed by careful addition of water dropwise. After the conversion of the hydrogen evolution reaction mixture was filtered and the filter cake lithium salts were thoroughly washed with tetrahydrofuran, the filtrate was combined with the filtrate of the second series (original material from two processes together was 300 g, i.e., 0.82 mol) and the combined extracts were concentrated to obtain 372 g of yellow solid, suspended in water. An attempt was made to distribute the product in water and dichloromethane, but the product was only slightly soluble in dichloromethane. Therefore, two-phase slurry product was filtered through a funnel with horizontal layers and assembled the white product was dried and received 121, Two phases of the filtrate were separated and the aqueous phase was again extracted with dichloromethane. All of the dichloromethane phase was combined, twice washed with water, dried with magnesium sulfate and concentrated to obtain 41 g of brown residue. The remainder roC. an NMR Spectrum and mass spectrum were in agreement with the structure. The recrystallization of 10 g of the product from toluene was obtained 7.5 g of 3-(1-piperazinil)-1H-indazole, melting point 153 to 155oC.

(G) 3-(4-Methyl-1-piperazinil) -1H-indazol.

Stir a mixture of 3-(4-methyl-1-piperazinil) -1-phenylsulfonyl - 1H-indazole (13.5 g, of 0.038 mol), methanol (150 ml) and 25% sodium methylate in methanol (15.3 ml) was heated under reflux for 2.5 hours, the Reaction mixture was concentrated to approximately one-tenth of the volume and to the mixture was added water, received a red solution. The solution was extracted with dichloromethane, the extract was washed with water, dried with magnesium sulfate, the solvent was concentrated and obtained 6.6 g are colored pink solid. By recrystallization from a mixture of toluene - hexane were obtained 4.3 g (52%) of 3-(4-methyl-1-piperazinil) -1H-indazole in the form of solid substances not quite white, melting point 111-113oC.

Elemental analysis for C12H16N4:

calculated (%): C 66,64; H 7,46; N 25,91;

found (%): C 66,83; H 7,42; N 25,69.

(H) 4-(1H - Indazol-3-yl) -1-piperidinecarbonitrile.

To a stirred mixture of CYANOGEN bromide (5.3 g, 0.05 mol), potassium carbonate (K2CO3and 7.1 g) and dimethyl sulfoxide (60 ml). The reaction mixture was stirred at ambient temperature for one hour and then poured into water. The aqueous suspension was extracted with ethyl acetate, the ethyl acetate washed with water, dried with magnesium sulfate, concentrated and received 7,8 g (67%) solids, painted in yellow color. This sample was combined with another and twice recrystallized from toluene, had been pure for analysis of 4-(1H-indazol-3-yl) -1-piperidinecarbonitrile in the form of a white solid, melting point 120-122oC.

Elemental analysis for C12H13N5:

calculated (%): C 63,42; H 5,75;

found (%): C 63,04; H of 5.84.

(I) Synthesis of 3-(1-piperazinil)-1H-indazole.

A mixture of 4-(1H-indazol-3-yl) -1-piperidinecarbonitrile (8.0 g 0.04 mol) and 25% sulfuric acid (100 ml) was stirred at reflux for 4.5 hours, the Reaction mixture was cooled in an ice bath and was podslushivaet added dropwise a 50% sodium hydroxide. The basic solution was extracted with ethyl acetate. The ethyl acetate was washed with water, dried with magnesium sulfate and was received with 5.2 g (73%) of the desired compound in the form of a solid substance. The solid is twice was led from toluene and received 3.0 g of 3-(1-piperazinil) -1H-indazole, the point has been melted down the

found (%): C 65,21; H 6,99; N 27,80.

(K) the Synthesis 1-/4-/3-/4-(1H - indazol-3-yl) -1-piperazinil/- propoxy/-3-methoxyphenyl/ -ethanone.

A mixture of 3-(1-piperazinil) -1H-indazole (4.0 g, 0.02 mol), potassium carbonate (K2CO3, 3.0 g, 0,022 mol), 1-/4-(3-chloropropoxy)-3-methoxyphenyl)-ethanol (5.3 g, 0.02 mol), a few crystals of potassium iodide and dimethylformamide (60 ml) was stirred at 90oC 5 h the Reaction mixture was poured into water and the aqueous mixture was extracted with ethyl acetate. The extract was washed with brine, dried with magnesium sulfate, the solvent was concentrated and received a white solid, which was triturated with diethyl ether, collected and received 7.0 g of product. After two precrystallization of absolute ethyl alcohol was obtained with 5.3 g (64%) of pure for analysis 1-/3-/4-(1H-indazol-3-yl)-1-piperazinil/ -propoxy/-3-methoxyphenyl/- ethanone, melting point 155-157oC.

Elemental analysis for C23H28N4O3:

calculated (%): C 67,62; H 6,91; N 13,72;

found (%): C 67,45; H 6,74; N 13.56MHz.

Example 2.

1-/4-/3-/4- (1,2-Benzisoxazol-3-yl)-1-piperidinyl/ -propoxy/- 3-methoxyphenyl/-Etalon.

A mixture of the hydrochloride of 3-(4-piperidinyl) -1,2-benzisoxazole (4.8 g, 0.02 mol), potassium carbonate (5.2 g, 0.04 mol of the amide (60 ml) was stirred at 90oC for 16 h, the Reaction mixture was poured into water and the aqueous mixture was extracted with ethyl acetate. The extract was washed with water, dried with magnesium sulfate, concentrated and received a brown oil. The oil was chromatographically on a Waters Prep 500 using a column of silica gel and a mixture of ethyl acetate - diethylamine (2%) as eluent. Concentration of the appropriate fractions were received of 3.9 g of the product in the form of solid substances not quite white. By recrystallization from absolute ethyl alcohol was obtained 2.6 g(33%) 1-/4-/3-/4- (1,2-benzisoxazol-3-yl)-1-piperidinyl/ -propoxy/-3 - methoxyphenyl/-ethanone, the melting point of 102-104oC, in the form of colorless needles.

Elemental analysis for C24H28N2O4:

calculated (%): C 70,56; H 6,91; N 6,66;

found (%): C 70,73; H 6,93; N 6,85.

Example 3.

1-/4-/3-/4- (6-Fluoro-1,2 - benzisoxazol-3-yl) -1-piperidinyl/- propoxy/-3-methoxyphenyl/ -Etalon.

Stir a mixture of 6-fluoro-3- (4-piperidinyl)-1,2-benzisoxazole hydrochloride (5.1 g, 0.02 mol), potassium carbonate (5.2 g, 0.04 mol), 1-/4-(3-chloropropoxy) -3-methoxyphenyl/-ethanone (5.3g, of 0.022 mol) and dimethylformamide (60 ml) was heated at 90oC for 16 h, the Reaction mixture was poured into water and the aqueous mixture was extracted with what Agogo substances. By recrystallization (twice) from ethyl alcohol was obtained 5.0 g(58%) 1-/4-/3-/4-(6 -fluoro-1,2 - benzisoxazol-3-yl) -1-piperidinyl/- propoxy/-3-methoxyphenyl/ -ethanone in a solid beige color, melting point 118-120oC.

Elemental analysis for C24H27FN2O4:

calculated (%): C 67,60; H 6,38; N 6,57;

found (%): C 67,47; H 6,40; N 6,53.

Example 4.

1-/4-/4-/4-(1,2- Benzisoxazol-3-yl) -1-piperidinyl/-butoxy/- 3-methoxyphenyl/-Etalon.

A mixture of the hydrochloride of 3-(4-piperidinyl) -1,2-benzisoxazole (4.3 g, 0.018 mol), potassium carbonate (5.5 g, 0.04 mol) and 1-/4-(4-bromobutoxy)-3-methoxyphenyl)-ethanone (5.5 g, 0.018 mol) in dimethylformamide (60 ml) was stirred and heated at 75oC for 16 h, the Reaction mixture was poured into water and was extracted with ethyl acetate. The ethyl acetate was washed with water, dried with magnesium sulfate, the solvent was concentrated and obtained 7.2 g solid beige color. By recrystallization (twice) from ethyl alcohol was obtained 3.3 grams(43%) 1-/4-/4-/4- (1,2-benzisoxazol-3-yl)-1-piperidinyl/ -butoxy/- 3-methoxyphenyl/-ethanone, melting point 99-101oC.

Elemental analysis for C25H30N2O4:

calculated (%): C 71,11; H 7,16; N 6,63;

found (%): C 70,76; H 7,24; N 6,58.the Thanon beach.

Stir a mixture of the hydrochloride of 6-fluoro-3- (4-piperidinyl)-1,2-benzisoxazole (of 5.1 g, 0.02 mol), potassium carbonate (5.2 g, 0.04 mol), 1-/4-(4-bromobutoxy) -3-methoxyphenyl)-ethanone (6.6 g, of 0.022 mol) and dimethylformamide (60 ml) was heated at 75oC 5 h the Reaction mixture was poured into water and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate was washed with water, dried with magnesium sulfate and the solvent was concentrated initially to obtain the oil, which was aterials during curing. The solid is triturated with hexane, collected and received and 7.7 g of the product as a waxy solid. The connection chromatographically on a Waters Prep 500 using a column of silica gel and elwira a mixture of dichloromethane - methanol (5%). Concentration of the appropriate fractions were obtained 5,1 g not quite white solids- 1-/4-/4-/4-(6- fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl/ -butoxy/- 3-methoxyphenyl/-ethanone, which was recrystallized from ethanol to yield 3.2 g (36%) as fluffy white needles, melting point 88-90oC.

Elemental analysis for C25H29FN2O4:

calculated (%): C 68,16; H 6,94; N 6,36;

found (%): C 67,96; H of 6.49; N 6,29.

Example 6.

1-/4-/2-/4- (1,2-Benzisoxazol-3-yl)-1-piperidine (4.8 g, 0.02 mol), potassium carbonate (5.2 g, 0.04 mol), 1-/4-(2-chloroethoxy) -3-methoxyphenyl/-ethanone (5.0 g, of 0.022 mol) and dimethylformamide (90 ml) was heated at 90oC for 16 h, the Reaction mixture was poured into water and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate was washed with water, dried with magnesium sulfate and the solvent was concentrated to obtain oil. When keeping the oil was aterials to substance beige color. The crude solid is recrystallized twice from ethanol and obtained 5.9 g not quite white solid. The solid was dissolved in ethyl acetate and was added fumaric acid (1.2 g, 1.1 equivalent). The mixture was heated briefly on the steam bath and then was stirred at ambient temperature for two hours. Original green oil precipitated and the supernatant layer was decanted. Added ether to the supernatant layer dekotirovaniem and gathered 4.0 g of white fumaric salt. Salt twice recrystallized from a mixture of ethanol - ether and was obtained 1.7 g (17%) fumarata 1-/4-/2-/4-(1,2- benzisoxazol-3-yl) -1-piperidinyl/-etoxy/- 3-methoxyphenyl/-ethanone, melting point 127-129oC.

Elemental analysis for C23H26N2O4:

calculated (%): C 63,52; H of 5.92; N 5,49;

Stir a mixture of 3-(1-piperazinil) -1H-indazole (4.0 g, 0.02 mol), potassium carbonate (3.0 g, is 0.023 mol), 1-/4-(4-bromobutoxy) -3-methoxyphenyl/-ethanone (5.3g) and dimethylformamide (60 ml) was heated at 75oC 6 h

The reaction mixture was poured into water and the white solid precipitated from solution. The solid is collected, dried and obtained 7.2 g of the crude product. The crude solid is recrystallized twice from ethanol and obtained 4.1 g of free base which was converted to its fumaric salt by adding fumaric acid (1.1 g) to the compound dissolved in heated under reflux acetone. Received fumaric salt was recrystallized from ethanol and obtained 3.8 g (35%) fumarata 1-/4-/4-/4- (1H-indazol-3-yl) -1-piperazinil/-butoxy/- 3-methoxyphenyl/-ethanone in the form of a white solid, melting point 163-165oC.

Elemental analysis for C24H30N4O3C4H4O4:

calculated (%): C 62,44; H 6,36; N THE 10.40;

found (%): C 62,28; H 6,62; N 10,34.

Example 8.

1-/4-/2-/4-(6 -Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl/- etoxy/-3-methoxyphenyl/ -Etalon.

Stir a mixture of the hydrochloride of 6-fluoro-3- (4-Piperi) and dimethylformamide (90 ml) was heated at 90oC 16 hours. The reaction mixture was poured into water and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate was washed with water, dried with magnesium sulfate and concentrated to obtain 7.4 g of the solid yellow color. The solid is recrystallized from ethanol and obtained 3.1 g(38%) 1-/4-/2-/4- (6-fluoro-1,2 - benzisoxazol-3-yl) -1-piperidinyl/-etoxy/- 3-methoxyphenyl/-ethanone in the form of a slightly yellow flakes, melting point 132-134oC.

Elemental analysis for C23H25FN2O4:

calculated (%): C 66,98; H 6,11; N 6,79;

found (%): C 66,90; H 6,20: N 6,74.

Example 9.

4-/3-/4-(6-Fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl/- propoxy/-3-methoxy-methylbenzylamino.

To the mixture 1-/4-/3-/4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl/- propoxy/-3-methoxyphenyl/ -ethanone (4.0 g, 0,009 mol) in methanol - tetrahydrofuran (60 ml) in the ratio 1:1) under stirring was added sodium borohydride (0.4 g, 0.01 mol). After the initial allocation of gas all undissolved substances were passed into the solution. The reaction mixture was stirred at ambient temperature for three hours, and thin-layer chromatography at this time showed the presence of very small amount of starting ketone. Therefore, to relax ografia showed complete disappearance of starting material. The reaction mixture was concentrated to obtain not quite white residue, which was diluted with water, collected and obtained 3.4 g of alcohol. It was recrystallized from toluene (twice, with the processing of charcoal) and received 2.7 g(67%) 4-/3-/4-(6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl/- 3-methoxy-- methylbenzimidazole in the form of a white solid, the melting point of 136-138oC.

Elemental analysis for C24H29FN2O4:

calculated (%): C 67,27; H 6,82; N 6,54;

found (%): C 67,59; H 6,89; N 6,47.

Example 10.

1-/4-/3-/4-(1,2 -Benzisoxazol-3-yl) -1-piperidinyl/- propoxy/-3-methoxyphenyl/ -Etalon.

A mixture of 3-(4-piperidinyl) -1,2-benzisothiazole (3.0 g, 0,0137 mol), potassium carbonate (2.3 g, mol 0,0155), 1-/4-(3-chloropropoxy)-3-methoxyphenyl/-ethanone (4.0 g, 0,0165 mol), potassium iodide (200 mg) and acetonitrile (100 ml) was stirred at reflux under nitrogen atmosphere for 24 hours the Cooled reaction mixture was filtered and the filter residue was washed well with acetonitrile. The filtrate was concentrated to an oily residue, which was distributed between water and ethyl acetate. The ethyl acetate extract was well washed with water, dried with magnesium sulfate, concentrated to provale and received 4,2 g solid beige color. The compound was recrystallized from ethanol and obtained 3.5 g, and the second recrystallization from ethanol (using decolorizing charcoal) gave 2.4 g(41%) 1-/4-/3-/4-(1,2- benzisothiazol-3-yl) -1-piperidinyl/- propoxy/-3-methoxyphenyl/-ethanone, the melting point of 93-95oC.

Elemental analysis for C24H28N2O3S:

calculated (%): C 67,90; H of 6.65; N 6,60;

found (%): C 67,89; H is 6.61; N 6,59.

Example 11.

1-/4-/3-/4-(6- Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl/- propoxy/-3 oksifenil/ -Etalon.

(A) Synthesis of 1/-4-(3-chloropropoxy) -3 oksifenil/-ethanone.

To a stirred solution of 1-/4-(3-chloropropoxy) -3-methoxyphenyl/-ethanone (10.0 g, 0,041 mol) in methylene chloride (120 ml), cooled to -50oC (a mixture of dry ice - methanol) was added dropwise 1 M tribromide boron in methylene chloride (123 g, 0.12 mol). The temperature was maintained between -40 and -50oC. After completion of the additive reaction mixture was allowed to raise the temperature to -30oC and was controlled by thin-layer chromatography (approximately 15 min after the end of the additives of boron TRIFLUORIDE). Was added dropwise saturated acidic sodium carbonate, not allowing the temperature to rise to 0oC for the most part the project solution, the organic layer was collected. Layer was washed with brine, dried with magnesium sulfate, concentrated to obtain 8.1 g of dark brown oil, which was aterials during curing. The product was chromatographically on the chromatograph Waters Prep 500 (two columns of silica gel, a mixture of 2% methanol and methylene chloride as eluent). After concentration of appropriate fractions were obtained 5.8 g of sticky brown solid. It was recrystallized from isopropyl ether (with flashing yellow supernatant layer of isopropyl ether with a dark brown oil residue) and was originally received 2.5 g of yellow solid. By concentrating the mother liquor was received additional 0.5 g of product, melting point 110-113oC.

(B) Synthesis 1-(4-/3-/4-(6- fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl/ -propoxy/-3 oksifenil/ -ethanone.

Stir a mixture of 6-fluoro-(4-piperidinyl) -1,2-benzisoxazole (2.8 g, of 0.013 mol), sodium bicarbonate (1.1 g), several crystals of potassium iodide, 1-/4-(3-chloropropoxy) -3 oksifenil/-ethanone and acetonitrile (100 ml) was heated under reflux for 16 hours, the Reaction mixture was poured into water and the aqueous mixture was extracted with ethyl acetate. The organic extract was washed what was maturational liquid chromatograph Waters Prep 500 silica gel, elwira a mixture of 7% methanol - methylene chloride. Concentration of the appropriate fractions were obtained yellow oil, which after conditioning gave 3.5 g of the compound as pale yellow solid. The solid is recrystallized from ethanol and obtained 2.7 g(50%) 1-/4-/3-/4- (6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl/- propoxy/-3 oksifenil/ -ethanone in the form of a pale yellow solid, melting point 122-124oC.

Elemental analysis for C23H25FN2O4:

calculated (%): C 66,98; H 6,11; N 6,79;

found (%): C 66,97; H 6,20; N 6,69.

Example 12.

Stir a mixture of 6-fluoro-3- (1-piperazinil)-1H-indazole (2.3 g, 0.01 mol), potassium carbonate (1.5 g), 1-/4-(3-chloropropoxy) -3-methoxyphenyl/-ethanone (2.8 g, to 0.011 mol), a few crystals of potassium iodide and dimethylformamide (60 ml) was heated at 90oC for 16 h, the Reaction mixture was poured into water and the aqueous suspension was extracted with ethyl acetate. The ethyl acetate was washed with water, dried with magnesium sulfate, concentrated and received 5.0 g of a yellow oil. The oil was chromatographically on a Waters Prep 500 using a column of silica gel and elwira a mixture of methylene chloride - methanol (7%). The concentration of the desired fractions was not received from the Lee of toluene. Received 2.6 g 1-/4-/3-/4- (6-fluoro-1H-indazol-3-yl)-1-piperazinil/- propoxy/-3-methoxyphenyl/ -ethanone in the form of a white solid, the melting point of 135-137oC.

Elemental analysis for C23H27FN4O3:

calculated (%): C 64,77; H 6,38; N 13,14;

found (%): C 64,66; H 6,21; N 13,02.

Example 13

1-/4-/4-/4-(6-Fluoro-1-1H-indazol-3-yl)-1-piperazinil/- butoxy/-3-methoxyphenyl/-Etalon.

Stir a mixture of the hydrochloride of 6-fluoro-3- (1-piperazinil)-1H-indazole (5 g, 0.019 mol), potassium carbonate (5.8 g), 1-/4-(4-bromobutoxy) -3-methoxyphenyl/ethanone (6.3 g, 0,021 mol) and dimethylformamide (80 ml) was heated at 75oC 6 h the Reaction mixture was poured into water, and the solution was dropped not very white solid. The solid is collected, dried and received 4.5 g of the crude product. The compound was recrystallized three times from ethanol and obtained 3.0 g not quite white solid. The solid was chromatographically on a Waters Prep 500 using a column of silica gel and elwira a mixture of methylene chloride - methanol (7%). Concentration of the appropriate fractions were obtained 2.3 g not quite white solid, which was then recrystallized from ethanol and obtained 1.9 g (26%) of pure for analysis 1-/4-/4-/4- (6-Itementry analysis for C24H29FN4O3:

calculated (%): C 65,44; H is 6.54; N 12,72;

found (percent): C, compared with 65.38; H of 6.49; N 12,60.

Example 14.

1-/4-/3-/4-(1H - Indazol-3-yl) -1-piperidinyl/propoxy/-3 - methoxyphenyl/alanon.

A mixture of 3-(4-piperidinyl) -1H-indazole (3.0 g, 0.015 mol), potassium carbonate (1.6 g), 1-/4-(3-chloropropoxy)-3-methoxyphenyl/ethanone (5.3g, of 0.022 mol), a few crystals of potassium iodide and acetonitrile (100 ml) was stirred and heated under reflux for 16 hours, the Reaction mixture was poured into water and the solution was separated precipitate white solids. The solid is collected, dried and got a 5.1 g of the product. By recrystallization from ethanol was obtained 3.6 g of the compound which was subjected to preparative high-performance liquid chromatography on silica gel, elwira a mixture of methylene chloride - methanol in the ratio 9:1 and was obtained 3.0 g (49%) not quite white solid. By recrystallization from ethanol was obtained pure for analysis 1-/4-/3-/4- (1H-indazol-3-yl) -1-piperidinyl/-propoxy) -3 - methoxyphenyl/Etalon in the form of a white solid, melting point 171-173oC.

Elemental analysis for C24H29N3O3:

calculated (%): C 70,74; H 7,17; N 10,31;

found (%): C 70,52; H 7,27; N 10 the/ -Etalon.

Stir a mixture of 6-chloro-3- (4-piperidinyl) -1,2-benzoxazole (4.7 g, 0.02 mol), 1-/4-(3-chloropropoxy) -3-methoxyphenyl/-ethanone (4.8 g, 0.02 mol), potassium carbonate (2.8 g), several crystals of potassium iodide and acetonitrile (120 ml) was heated under reflux for 16 hours, the Reaction mixture was filtered, the filtrate was concentrated and received a yellow mixture of solids with oil. The residue was chromatographically on a Waters Prep 500 using a column of silica gel and elwira a mixture of methylene chloride - methanol (5%). The concentration of the desired fractions were obtained 3.2 g of a solid substance beige color, which after recrystallization from ethanol gave 2.7 g(31%) 1-/4-/3-/4- (6-chloro-1,2 - benzisoxazol-3-yl) -1-piperidinyl/-propoxy)- 3-methoxyphenyl/ethanone in a solid beige color, melting point 116-118oC.

Elemental analysis for C24H27ClN2O4:

calculated (%): C 65,08; H 6,14; N 6,32;

found (%): C 65,35; H 6,22; N 6,28.

Example 16.

Fumarate 1-/4-/4-/4- (6-chloro-1,2-benzisoxazol-3-yl)-piperidinyl/ butoxy/-3 - methoxyphenyl/ethanone.

Stir a mixture of 6-chloro-3-(4-piperidinyl) -1,2-benzisoxazole (4.7 g, 0.02 mol), 1-/4-(4-bromobutoxy) -3-methoxyphenyl/-ethanone (6.0 g, 0.02 mol), potassium carbonate (2.8 g) and oceancatalogue to 9.9 g of brown oil. The oil was chromatographically on a Waters Prep 500 using a column of silica gel and elwira a mixture of methylene chloride - methanol (5%). Concentration of the appropriate fractions gave 2.3 g not quite white solid. The solid was dissolved in ethanol, the ethanol was evaporated and the resulting brown solid was dissolved in heated under reflux acetone. After cooling, the white solid was crystallized from a calculation with the release of 2.2 g (19%) fumarata 1-/4-/4-/4- (6-chloro-1,2-benzisoxazol-3-yl)-1-piperidinyl/ -butoxy)- 3-methoxyphenyl/ethanone in the form of a white solid, melting point 139-141oC.

Elemental analysis for C25H29ClN2O4C4H4O4:

calculated (%): C 60,78; H 5,80; N 4,89;

found (%): C 60,69; H 5,74; N 4,85.

Example 17.

1-/4-/3-/4-(5- Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl/- propoxy/-3-methoxyphenyl/ -Etalon.

A mixture of 5-fluoro-3- (4-piperidinyl) -1,2-benzisoxazole (2.2 g, 0.01 mol), 1-/4-(3-chlorophenoxy) -3-methoxyphenyl/-ethanone (2.4 g, 0.01 mol), potassium carbonate (1.4 g), several crystals of potassium iodide and acetonitrile (100 ml) was stirred and heated under reflux for 8 hours, the Reaction mixture was poured into water and the aqueous mixture is extra and got a 4.0 g of a white solid. The solid was chromatographically on high performance liquid chromatograph Waters Prep column using silica gel and elwira a mixture of methylene chloride - methanol (5%). Concentration of the appropriate fractions were obtained 2.0 g(47%) 1-/4-/3-/4-(6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl/- propoxy/-3-methoxyphenyl/ -ethanone as a crystalline solid, melting point 103-105oC.

Elemental analysis for C24H27FN2O4:

calculated (%): C 67,59; H 6,38; N 6,57;

found (%): C 67,50; H 6,74; N 6,53.

Example 18.

Fumarate 6-fluoro-3-/1-/3- (2-methoxyphenoxy) -propyl/-4 - piperidinyl/ -1,2-benzisoxazole.

Stir a mixture of 6-fluoro-3- (4-piperidinyl)-1,2-benzisoxazole (2,45 g, 11.1 mmol), potassium carbonate (2.0 g) and 3-(2-methoxyphenoxy) -propylchloride (3.5 g, to 17.4 mmol) in acetonitrile (40 ml) was heated at 90oC 4 h after the reaction the solvent was removed and the solids were dissolved in dichloromethane (100 ml). The solution was washed with water and brine, then dried over magnesium sulfate. The crude material was combined with 1.2 g of the crude material obtained in the same way (using 0.5 g of starting material). The combined material was purified by rapid chromatography is. is racchi containing pure product were collected and concentrated to a light oil (3,68 g). This oil was treated with fumaric acid (1,14 g, 9.8 mmol) in ethanol (13 ml). The obtained crystals fumarata 6-fluoro-3- /1-/3-(2-methoxyphenoxy) -propyl/-4-piperidinyl/-1,2 - benzisoxazole weighing 4,01 g (60%), melting point 169-170oC.

Elemental analysis for C22H25FN2O3C4H4O4:

calculated (%): C 62,39; H of 5.84; N the ceiling of 5.60;

found (%): C 62,37; H 5,88; N the ceiling of 5.60.

Example 19.

1-/3-/4-/6-Fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl/- propoxy/-4-methoxyphenyl/ -phenylmethane.

Stir a mixture of 6-fluoro-3- (4-piperidinyl)-1,2-benzisoxazole (2,01 g, 9,13 mmol), potassium carbonate (2.0 g), 1-/3-(3-chloropropoxy) -4-methoxyphenyl/-phenylmethanone (3,93 g, 11.3 mmol) and acetonitrile (50 ml) was heated under reflux 4 h In the end of the reaction the solvent is evaporated and the residue was distributed between water (150 ml) and dichloromethane (400 ml). The dichloromethane solution was washed with water and brine (100 ml), dried over magnesium sulfate, and then concentrated to oil. Purification was performed by rapid chromatography on a column of silica gel (silica 40 g, allerona dichloromethane, 300 ml, a mixture of 1% methanol - dichloromethane, Ala from ethanol (150 ml) was received 1-/3-/4- (6-fluoro-1,2 - benzisoxazol-3-yl) -1-piperidinyl/- propoxy/-4-methoxyphenyl/-phenylmethanone in the form of white crystals, 0.07 g (63%), melting point 140-141oC.

Elemental analysis for C29H29FN2O4:

calculated (%): C 71,30; H 5,98; N 5,73;

found (%): C 71,09; H 5,98; N 5,73.

Example 20.

1-/4-/4-/4- (1H-Indazol-3-yl) -1-piperidinyl/-butoxy/ -3-methoxyphenyl/-Etalon.

A mixture of 3-(4-piperidinyl) -1H-indazole (3.4 g, to 0.016 mol), 1-/4-/4-bromobutoxy) -3-methoxyphenyl/-ethanone (5.0 g, to 0.016 mol), potassium carbonate (2.2 g), and acetonitrile (100 ml) was stirred and heated under reflux for 6 hours, the Reaction mixture was poured into water and the resulting yellow solid is collected and received with 5.3 g of the product. The compound was recrystallized from acetonitrile and then from ethyl acetate and obtained 3.0 g (45%) of a slightly yellow solid 1-/4-/4-/4- (1H-indazol-3-yl) -1-piperidinyl/-butoxy/-3 - methoxyphenyl/-ethanone, the melting point of 133-135oC.

Elemental analysis for C25H31N3O3:

calculated (%): C 71,23; H 7,41; N BECOMES 9.97;

found (%): C 70,85; H to 7.61; N 9,81.

Example 21.

1-/4-/2-/4-(6-Chloro - 1,2-benzisoxazol-3-yl) -1-piperidinyl/- etoxy/-3-methoxyphenyl/-Etalon.

Stir a mixture of 6-fluoro-3-(4-piperidinyl) -1,2-benzisoxazole (4.6 g, 0.019 mol), 1-/4-(2-chloroethoxy)-3-methoxyphenyl)-ethanone (4.3 g, 0,nd a refrigerator for 16 hours The reaction mixture was filtered, the filtrate was concentrated to obtain 8.0 g of a yellow solid. The solid was chromatographically on a liquid chromatograph Waters Prep 500 (a column of silica, eluent of a mixture of methylene chloride - methanol, 5%). Concentration of the appropriate fractions were obtained 3.2 g of light yellow solid, which after recrystallization from acetic acid ethyl ester was obtained 2.3 g(28%) 1-/4-/2-/4- (6-chloro-1,2-benzisoxazol-3-yl)-1-piperidinyl/- etoxy/-3-methoxyphenyl/-ethanone (28% yield) as a pale yellow solid, the melting point of 133-135oC.

Elemental analysis for C23H25ClN2O4:

calculated (%): C 64,41; H 5,88; N 6,53;

found (%): C 64,35; H by 5.87; N 6,41.

Example 22.

3-(3-Bromopropane-4-methoxyphenyl) -phenylmethanone.

A solution of 3-hydroxy-4-methoxybenzophenone (4.6 g, 20 mmol) in dimethylformamide (35 ml) was treated with sodium hydride (600 mg, 25 mmol) at 0oC for 20 min, then one portion was added 1,3-dibromopropane (5 g, of 24.7 mmol). The mixture was heated at 90oC 1 h and then stirred at room temperature for 2 hours In the end of the reaction the mixture was poured into water (500 ml) and was extracted with ethyl acetate (400 ml). An ethyl acetate solution is washed is quickly chromatography on a column of silica gel (silica, 85 g, eluent a mixture of hexane - dichloromethane in the ratio of 3:1, 1.6 l, hexane - dichloromethane in the ratio of 3:7, 1.4 l). Thus obtained pure product in the form of oil weighed of 4.67 g (66%). Recrystallization twice from isopropyl ether (500 ml) gave 2,42 g pure for analysis of 5-(3-bromopropane-4-methoxyphenyl)-phenylmethanone, the melting point of 81-83oC.

Elemental analysis for C17H17BrO3:

calculated (%): C 58,47; H 4,91;

found (%): C 58,63; H 4,82.

Example 23.

Fumarate 1-/3-/3-/4- (6-fluoro-1,2 - benzisoxazol-3-yl) -1 - piperidinyl/-propoxy-phenyl/-ethanone.

A mixture of the hydrochloride of 6-fluoro- (4-piperidinyl) -1,2-benzisoxazole (4,53 g of 20.5 mmol), potassium carbonate (4.5 g), 1-/3-(3-chloropropoxy) -phenyl/-ethanone (6.4 g, 29 mmol) in acetonitrile (60 ml) was heated under reflux 5 hours Upon completion of the reaction the solvent was removed and the residue was extracted into dichloromethane (300 ml). Inorganic insoluble substances were filtered off. The dichloromethane solution was concentrated to small volume (10 ml) and was purified by chromatography on a column (silica, 75 g, eluent served as dichloromethane, 900 ml and a mixture of 2% methanol - dichloromethane, 800 ml). The fractions containing pure product were combined and concentrated the crystallization from ethanol received 2,53 g fumarata 1-/3-/3-/4-(6-fluoro-1,2-benzisoxazol-3-yl)-1 - piperidinyl/-propoxy-phenyl/-ethanone in the form of white crystals, so pl. 172-174oC.

Elemental analysis for C22H25FN2O3C4H4O4:

calculated (%): C 63,27; H 5,70; N 5,47;

found (%): C 63,04; H 5,63; N 5,43.

Example 24.

1-/4-/3-/4- (6-Fluoro-1,2 - benzisoxazol-3-yl) -1 - piperidinyl/-propoxy/ -2-were/-Etalon.

Stir a mixture of the hydrochloride of 6-fluoro-(4-piperidinyl) -1,2-benzisoxazole (5.5 g, 21.6 mmol), potassium carbonate (3.5 g), 1-/4-(3-bromopropane)-2-were/-ethanone (4.83 g, 17.8 mmol) in dimethylformamide (25 ml) was heated at 120oC 5 o'clock At the end of the reaction the solvent was removed, the residue was extracted into dichloromethane (300 ml) and the solution was washed with water and brine. The organic solution was dried and evaporated to a crude oil. Purification was performed column chromatography on silica gel (80 g, was suirable dichloromethane, 1.0 liter of a mixture of 1% methanol - dichloromethane, 1.2 l, with a mixture of 2% ethanol - dichloromethane, 1.2 l). The most pure fractions were combined and received only 2.91 g of solid substance. By recrystallization from dichloromethane and ethanol were obtained 1-/4-/3-/4-(6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl/-propoxy/- 2-were/-Etalon as off-white crystals, melting point 113-114oC.

Elemental analysis for C24H27FN 1-/3-/3-/4- (6-Fluoro-1,2-benzisoxazol-3-yl)-1 - piperidinyl/ -propoxy/-5-were/ -Etalon.

A mixture of the hydrochloride of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2,87 g, 11,23 mmol), potassium carbonate (2.50 g), 1-/2-(3-bromopropane)-5-were/-ethanone (3,74 g of 13.8 mmol) in dimethylformamide (10 ml) and acetonitrile (50 ml) was heated at 95oC 6 h after the reaction, the solvent was concentrated and the mixture was extracted into dichloromethane (300 ml). The organic solution was washed with water and brine, dried over magnesium sulfate, then concentrated to a crude oil. Purification was performed by rapid chromatography on a column of silica gel (silica, 60 g, was suirable mixtures of 1% methanol - dichloromethane, 1.2 l, and 3% methanol - dichloromethane, 600 ml). Thus obtained material was led from a small volume of ether and hexane and received 2,13 g (46%) not quite white 1-/3-/3-/4- (6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl/ -propoxy/- 5-were/-ethanone, melting point 92-93oC.

Elemental analysis for C24H27FN2O3:

calculated (%): C 70,22; H 6,63; N 6,82;

found (%): C 70,21; H of 6.96; N for 6.81.

Example 26.

Profumata N-/3-/3-/4-(6-fluoro-1,2-benzisoxazol-3-yl)-1 - piperidinyl/ -propoxy/-4-methoxyphenyl/ -ACET the (3,67 g, to 26.6 mmol), N-/3-(3-bromopropane) -4-methoxyphenyl)-ndimethylacetamide (5,56 g of 18.6 mmol) in dimethylformamide (75 ml) and acetonitrile (100 ml) was heated at 100oC 3 hours At the end of the reaction the solvent was concentrated and the mixture was extracted into dichloromethane (500 ml). The organic solution was washed with water (500 ml) and brine (400 ml), dried, then concentrated to a crude oil. Purification was carried out by rapid chromatography on a column of silica gel (silica, 65 g, suirable a mixture of 1% methanol - dichloromethane, 1.2 l and a mixture of 3% methanol - dichloromethane, 500 ml). Thus obtained material in the form of oil weighed 2,33 g (34.3 per cent). The material was dissolved in ethanol and treated with a solution of fumaric acid (661 mg) in ethanol. Received N-/3-/3-/4- (6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl/ -propoxy/-4 - methoxyphenyl/-ndimethylacetamide, profumata, in the form of off-white crystals weighing 2.17 g, a melting point of 205-206oC.

Elemental analysis for C24H28FN3O40.5 C4H4O4:

calculated (%): C 62,50; H equal to 6.05; N TO 8.41;

found (%): C 62,30; H equal to 6.05; N 8,32.

Example 27.

To a stirred suspension of 4-(6-chloro-1-phenylsulfonyl-1H-indazol-3-yl) -1-piperidinecarbonitrile (192.5 kg g 0,479 mol) in dry tetrahydrofuran (3.5 l is uranium, 0,958 mol). After completion of the additive, the reaction mixture was heated under reflux and stirred under nitrogen for 4 h, the Reaction mixture was cooled to 4oC in an ice bath with salt and excess lithium aluminum hydride was decomposed careful, dropwise addition of water. The mixture is vigorously stirred an additional 30 min and then filtered through a glass funnel with horizontal layers. The filter residue is well washed with tetrahydrofuran (three times 500 ml) and then with methanol (two times 600 ml), the filtrate was concentrated to obtain 151,0 g beige resin. Rubbing with diethyl ether there was obtained a solid which was collected, dried and received 75,0 g (66%) of the desired indazole. The sample weight of 4.0 g was recrystallized from toluene and obtained 3.2 g, from which after a second recrystallization from toluene (using decolorizing charcoal) was obtained 2.1 g (35%) solid beige color 6-chloro-3- (1-piperazinil) -1H-indazole, the melting point of 135-137oC.

Elemental analysis for C11H13ClN4:

calculated (%): C 55,82; H 5,54; N 23,67;

found (%): C 55,91: H 5,54; N 23,41.

Example 28.

1-/4-/3-/4- (6-Fluoro-1H-indazol-3-yl)-1-piperidinyl/ -propoxy/- 3-methoxyphenyl/-Etalon.

Elemental analysis for C24H28FN3O3:

calculated (%): C 67,57; H 6,63; N 9,88;

found (%): C 67,59; H is 6.61; N 9,96.

Example 29.

Profumata 1-/4-/3-/4-(6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl/-propoxy/- 3-were/-ethanone.

Stir a mixture of the hydrochloride of 6-fluoro-3- (4-piperidinyl)1,2-benzisoxazole (3.0 g, 11.7 mmol), potassium carbonate (3.0 g) and 1-/4-(3-bromopropane) -3-were/-ethanone (3,19 g) in dimethylformamide (20 ml) and acetonitrile (50 ml) was heated at 95oC 4 h after the reaction, the solvent was concentrated to 30 ml, and then distributed between water (200 ml) and dichloromethane (300 ml). The dichloromethane solution was separated, washed with water and brine, then dried over magnesium sulfate. The crude product after evaporation of the races is armetale, 600 ml, 2% methanol in dichloromethane, 600 ml). Thus obtained material was a light yellow oil, weight 2,07 g (43%). This oil was dissolved in ethanol and treated with a solution of fumaric acid (585 mg) in methanol. After cooling to 0oC formed crystals of profumata 1-/4-/3-/4- (6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl/- propoxy/-3-were/ -ethanone. It was collected and received 1.5 g, melting point 185-187oC.

Elemental analysis for C24H27FN2O30.5 C4H4O4:

calculated (%): C 66,65; H 6,24; N 5,98;

found (%): C 66,69; H 6,23; N 5,95.

Example 30.

1-/4-/3-/4- (6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl) -propoxy - phenyl/-Etalon.

A mixture of 6-fluoro-3-(4-piperidinyl) -1,2-benzisoxazole (3,27 g of 14.8 mmol), potassium carbonate (3.0 g), 1-/4-(3-bromopropane)-phenyl/-ethanone (4.5 g, 17.5 mmol) in acetonitrile (60 ml) was heated under reflux 4 h the Solvent was removed. The residue was dissolved in dichloromethane (300 ml) and washed with water and brine, then dried over magnesium sulfate. The crude product after evaporation of the solution was purified by rapid chromatography (silica, 60 g, was suirable 1% methanol in dichloromethane, 1 l). The most pure fractions were combined the 11-112oC.

Elemental analysis for C23H25FN2O3:

calculated (%): C 69,69; H 6,36; N 7,07;

found (%): C 69,60; H 6,38; N 7,07.

Example 31.

1-/4-/3-/4- (6-Chloro-1H-indazol-3-yl)-1-piperazinil/ -propoxy/- 3-methoxyphenyl/-Etalon.

A mixture of 6-chloro-/3- (1-piperazinil)/-1H-indazole (3.4 g, to 0.016 mol), potassium carbonate (2.5 g, 0.018 mol), 1-/4-(3-chloropropoxy) -3-methoxyphenyl/-ethanone (3.8 g, to 0.016 mol), potassium iodide (200 mg) and acetonitrile (125 ml) was stirred in nitrogen atmosphere at reflux for 30 h After keeping at room temperature for 40 h, the reaction mixture was filtered and the filter residue is well washed with acetonitrile. The filtrate was concentrated to an oily solid, which was distributed between water and ethyl acetate. An ethyl acetate extract was washed with water, dried over magnesium sulfate and concentrated to obtain 6.9 g of a dark oil, which was aterials after two days of curing in a vacuum. The product was purified preparative high performance liquid chromatography (Waters Associates Prep LC/System 500, using two columns of silica gel and a mixture of 6% of methanol in methylene chloride as eluent) and got to 4.2 g of the product. Material p is azinil/-propoxy/- 3-methoxyphenyl/-ethanone in the form of crystals, the melting point 132-134oC.

Elemental analysis for C23H27ClN4O3S:

calculated (%): C 62,37; H 6,14; N 12,65;

found (%): C 62,49; H 6,16; N 12,60.

Example 32.

1-/4-/4-/4- (1,2-Benzisothiazol-3-yl)-1-piperazinil/ -butoxy/- 3-methoxyphenyl/-Etalon.

A mixture of 3-(1-piperazinil) -1,2-benzisothiazole (4.0 g, mol 0,0182), 1-/4-(4-bromobutoxy) -3-methoxyphenyl/-ethanone (6.0 g, 0,0200 mol), potassium carbonate (3.0 g, 0,0218 mol), potassium iodide (200 mg) and acetonitrile (125 ml) was stirred while heating under reflux in an atmosphere of nitrogen for 5 hours the Greater part of the solvent was removed in vacuo and the resulting gummy residue was distributed between ethyl acetate and water. The organic extract was washed with water, dried with magnesium sulfate, concentrated and received 7,8, Purification preparative high performance liquid chromatography (Waters Associates Prep LC/System 500, using two columns of silica gel and a mixture of 4% methanol and methylene chloride as eluent) was obtained 6.5 g wet, not quite white solid product. The product is twice recrystallized from toluene and obtained 3.1 g(39%) 1-/4-/4-(1,2- benzisothiazol-3-yl)-1-piperazinil/-butoxy/ - 3-methoxyphenyl/-ethanone in the form of a solid white t is calculated (%): C 65,58; H OF 6.65; N 9,56;

found (%): C 65,74; H 6,66; N 9,54.

Example 33.

4-/3-/4-(6-Fluoro-1,2-benzisothiazol-3-yl) -1-piperazinil/- propoxy/-3-methoxybenzonitrile.

A mixture of 6-fluoro-3-(4-piperidinyl) -1,2-benzisothiazole (3.0 g, to 13.6 mmol), potassium carbonate (2.8 g), 4-(3-bromopropane) -3-methoxybenzonitrile (4.0 g, of 14.8 mmol) in acetonitrile (70 ml) was heated under reflux for 3 hours To the end of the reaction the solvent was removed on a rotary evaporator. The organic material was extracted into dichloromethane (250 ml), and inorganic substances were filtered off. The dichloromethane solution was concentrated to a crude oil. Purification was performed by chromatography on a column of silica gel (silicon dioxide, 55 g, suirable dichloromethane, 600 ml). Thus obtained material was led from a small amount of dichloromethane. By recrystallization from ethanol (25 ml) was obtained 3.8 g(68%) 4-/3-/4-(6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl/- propoxy/-3-methoxybenzonitrile in the form of white crystals, melting point 107-108oC.

Elemental analysis for C23H24FN3O3:

calculated (%): C 67,47; H 5,91; N 10,26;

found (%): C 67,32; H 5,90; N 10,24.

Example 34.

1-/4-/4-/4-(6-Fluoro-1H-indazol-3-yl) -1-piperidinyl/- butox is bromobutoxy) -3-methoxyphenyl/-ethanone (2.6 g, 0,0086 mol), potassium carbonate (1.2 g) and acetonitrile (75 ml) was heated under reflux for 6 hours, the Reaction mixture was poured into water and the white solid was precipitated from solution. It was collected, dried and obtained 3.2 g of product. The product was recrystallized from ethanol and obtained 2.7 g(71%) 1-/4-/4-/4- (6-fluoro-1H-indazol-3-yl)-1-piperidinyl/ -butoxy-3 - methoxyphenyl/ -ethanone in the form of a brilliant white flakes, melting point 158-160oC.

Elemental analysis for C25H30FN3O3:

calculated (%): C 68,32; H 6,88; N 9,56;

found (%): C 68,00; H 6,93; N 9,51.

Example 35.

Sesquifumarate 1-/4-/3-/4-(1 -benzoyl-6-fluoro-1H-indazol-3-yl) -1-piperazinil/- propoxy/-3-methoxyphenyl/ -ethanone.

The mixture 1-/4-/3-/4-(6-fluoro-1H-indazol-3-yl)-1-piperazinil/- propoxy/-3-methoxyphenyl/ -ethanone (3.2 g, 0,0075 mol) and benzoyl chloride (15 ml) was heated on the steam bath for 15 minutes the Reaction mixture was cooled and was added ether. Insoluble no white substance was collected and obtained 4.4 g of product in the form of chloride-hydrogen salt. Salt was converted to free base in water with ammonium hydroxide and after ekstrativnyh processing methylene chloride was isolated 3.0 g of the free base in the form of a white solid. Free arawai bath for 15 minutes. After incubation at ambient temperature for 4 days to gather 2.0 g not quite white fumaric salt, while the concentration of the filtrate gave additional 1.0 g of salt. By recrystallization, first from ethyl acetate and then from ethanol was obtained 1.4 g (26%) of sesquifumarate 1-/4-/3-/4- (1-benzoyl-6-fluoro-1H-indazol-3-yl) -1-piperazinil/- propoxy/-3-methoxyphenyl/-ethanone, melting point 138-140oC.

Elemental analysis for C30H31FN4O41,5 C4H4O4:

calculated (%): C 61,35; H of 5.29; N 7,95;

found (%): C 61,68; H 5,31; N 8,25.

Example 36.

1-/4-/4-/4-(6-Chloro-1H-indazol-3-yl) -1-piperazinil/- butoxy/-3-methoxyphenyl/ -Etalon.

A mixture of 6-chloro-/3- (1-piperazinil)/-1H-indazole (4.0 g, is 0.017 mol), potassium carbonate (2.8 g, at 0.020 mol), 1-/4-(4-bromobutoxy) -3-methoxyphenyl/-ethanone (5.7 g, 0.019 mol), potassium iodide (100 mg) and acetonitrile (125 ml) was stirred at reflux under nitrogen atmosphere for 18 h the Cooled reaction mixture was poured into water, formed not quite white solid was collected by filtration, was dried and obtained 7.0 g of product. The connection twice recrystallized from toluene and received 6,2, Further purification was performed Vysokoe the e eluent and two columns of silica gel) and received 5.3g brilliant crystals color beige, which was recrystallized four times from toluene and obtained 3.1 g of white solid. Pure for analysis of the material received, followed by recrystallization from dimethylformamide and received 2.5 g(32%) 1-/4-/4-/4- (6-chloro-1H-indazol-3-yl)-1-piperazinil/- butoxy/-3-methoxyphenyl/ -ethanone in the form of not-quite-white powder, melting point 189-191oC.

Elemental analysis for C24H29ClN4O3:

calculated (%): C 63,08; H 6,40; N OF 12.26;

found (%): C 62,86; H to 6.57; N 12,49.

Example 37.

1-/4-/3-/4-(1,2 -Benzisothiazol-3-yl) -1-piperazinil/- propoxy/-3-methoxyphenyl/ -ethanone profumata.

A mixture of 3-(1-piperazinil) -1,2-benzisothiazole (4.0 g, 0,0182 mol), potassium carbonate (3.0 g, 0,0218 mol), potassium iodide (200 mg), 1-/4-(3-chloropropoxy) -3-methoxyphenyl/-ethanone (5.3g, 0,0200 mol) and acetonitrile (125 ml) was heated under reflux with stirring in a nitrogen atmosphere for 36 h the Cooled reaction mixture was filtered and the filter residue is well washed with acetonitrile. The filtrate was concentrated to obtain 10.7 g of oily residue, which was extracted with ethyl acetate. An ethyl acetate extract was washed with water, dried with magnesium sulfate and concentrated to obtain 8.0 g of dark mA the I two columns of silica gel and a mixture of 3% methanol in methylene chloride as eluent). Concentration of the appropriate fractions were obtained 4.6 g of a red oil, which was aterials during curing. Sample 3.4 g was dissolved in ethyl acetate (100 ml) was added fumaric acid (0.95 g). The mixture was stirred under heating at moderate temperatures back of the refrigerator 1 h and then at ambient temperature for 1.5 hours Received a beige solid was collected by filtration, dried and obtained 4.0 g of product. Product two times was led from ethanol and obtained 2.7 g (27%) of profumata 1-/4-/3-/4- (1,2-benzisothiazol-3-yl)-1-piperazinil/- propoxy/-3-methoxyphenyl/ -ethanone in the form powder colour beige, the melting point of 186-188oC.

Elemental analysis for C23H27N3O3S 0.5 C4H4O4:

calculated (%): C 62,09; H the 6.06; N 8,69;

found (%): C 62,01; H the 6.06; N 8,68.

Example 38.

Stir a mixture of 6-fluoro-3-(4-piperidyl) -1,2-benzisoxazole (2.0 g, 9.0 mmol), potassium carbonate (1.3 g), 1-/4-(3-bromopropane) -3,5-dibromophenyl/-ethanone (2.65 g, 9.0 mmol) and acetonitrile (50 ml) was heated under reflux for three hours. At the end of the reaction the solvent is evaporated and the residue was extracted into dichloromethane (150 ml). Insoluble substances were filtered off. Dichloromethane solution of concentration is the quality of eluent served as dichloromethane, 300 ml, and 1% methanol in dichloromethane, 600 ml). Thus purified product to the colorless oil was utverjdala during curing. By recrystallization from ethanol was obtained 1-/3,5-dibromo-4-/4-(6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidyl/- propoxy-phenyl/-Etalon in the form of white crystals (with 2.93 g, 57%), melting point 102-103oC.

Elemental analysis for C23H23Br2FN2O3:

calculated (%): C 49,84; H 4,18; N OF 5.05;

found (%): C 49,91; H 4,11; N 4,98.

Example 39.

1-/4-/2-/4-(1,2 -Benzisothiazol-3-yl) -1-piperazinil/- etoxy/ -3-methoxyphenyl/-Etalon.

A mixture of 3-(1-piperazinil)-1,2-benzisothiazole (4.0 g, mol 0,0182), 1-/4-(2-chloroethoxy) -3-methoxyphenyl/-ethanone (4.3 g, 0,0200 mol), potassium carbonate (3.0 g, 0,0218 mol), acetonitrile (125 ml) and catalytic amounts of potassium iodide were heated under reflux and stirred under nitrogen atmosphere for 24 hours At this point in the reaction mixture was added an additional amount of potassium carbonate (1.0 g, 0,0072 mol) and an alkylating agent (0.4 g, 0,0017 mol) and heated under reflux was resumed for 24 hours the Reaction mixture was cooled to room temperature and filtered. The filter cake was rinsed with acetonitrile and the filtrate was concentrated to obtain the magnesium sulfate, concentrated and received 9.2 grams of oil. Purification preparative high performance liquid chromatography (Water Associates Prep LC/System 500, using two columns of silica gel and a mixture of 3% methanol - methylene chloride as eluent) gave 3.8 g juicy, beige resin, which was quickly aterials. The connection twice recrystallized from ethanol and obtained 2.1 g(28%) 1-/4-/2-/4-(1,2 -benzisothiazol-3-yl) -1-piperazinil/- etoxy/-3-methoxyphenyl/-ethanone in a solid beige color, melting point 98-100oC.

Elemental analysis for C22H25N3O3:

calculated (%): C 64,21; H 6,12; N OF 10.21;

found (%): C 64,05; H 6,09; N 10,12.

Example 40.

6-Fluoro-3-/1- (3-phenoxypropan) -4-piperidinyl/-1,2 - benzisoxazol.

A mixture of 6-fluoro-3-(4-piperidinyl) -1,2-benzisoxazole (4.0 g, 0,0182 mol), potassium carbonate (3.0 g, 0,0218 mol), potassium iodide (100 mg), 3-chlorpromazine (3.4 g, 0,0200 mol) and acetonitrile was stirred at reflux under nitrogen atmosphere for 30 hours, the Reaction mixture was poured into water and the aqueous mixture was extracted with ethyl acetate. An ethyl acetate extract was washed with brine, dried with magnesium sulfate, concentrated and obtained 6.2 g of a viscous solid beige is inil/ -1,2-benzisoxazol in the form of a solid light beige color with a yield of 47%, the melting point of 78-80oC.

Elemental analysis for C21H23FN2O2:

calculated (%): C 71,17; H is 6.54; N OF 7.90;

found (%): C 71,00; H of 6.52; N 7,81.

Example 41.

1-/4-/2-/4-(6-Chloro-1H-indazol-3-yl) -piperazinil/-etoxy/- 3-methoxyphenyl/-Etalon.

A mixture of 6-chloro-/3-(1-piperazinil) -1H-indazole (2.1 g, 0,0089 mol), potassium carbonate (1.5 g, 0,0107 mol), potassium iodide (100 mg), 1-/4-(2-chloroethoxy)-3-methoxyphenyl/-ethanone (2.2 g, 0,0098 mol) and acetonitrile (70 ml) was stirred at reflux for 48 h under nitrogen atmosphere. The cooled reaction mixture was poured into water and the aqueous mixture was extracted with ethyl acetate. The organic extract was washed with water, dried with magnesium sulfate, concentrated and obtained 6.0 g of a light yellow oil. The oil was purified preparative high performance liquid chromatography (Water Associates Prep LC/System 500, using two columns of silica gel and a mixture of 5.5% of methanol and methylene chloride as eluent). The concentration of the latter fractions were obtained 1.6 g not quite white solid. It was combined with an additional sample (only 3.4 g) and after two precrystallization from ethanol was obtained 2.1 g(23%) 1-/4-/2-/4-(6-chloro-1H-indazol-3-yl) -piperazinil/-etoxy/- 3-methods the analyses for C22H25ClN4O3:

calculated (%): C 61,61; H 5,88; N 13,06;

found (%): C 61,66; H by 5.87; N 13,06.

Example 42.

1-/4-/3-/4-(6-Fluoro-1,2-benzisoxazol-3-yl) -piperidinyl/- propoxy/-3-methoxyphenyl/ -2,2,2-triptoreline.

A mixture of 6-fluoro-3-(4-piperidinyl) -1,2-benzisoxazole (1.5 g, 0,0067 mol), potassium carbonate (0.88 g), potassium iodide (0.1 g) and acetonitrile (50 ml) was stirred and heated under reflux for 16 hours After cooling, the reaction mixture was poured into water and the aqueous mixture was extracted with ethyl acetate. The extract was washed with water, dried with magnesium sulfate and the solvent was concentrated to an oil, which when pumping at high vacuum gave 3.2 g of waxy solid. The solid was chromatographically on preparative liquid chromatograph Waters (a column of silica, eluruume a mixture of 3% methanol - dichloromethane). Concentration of the appropriate fractions gave 1.8 g(56%) 1-/4-/3-/4-(6-fluoro-1,2-benzisoxazol-3-yl) -piperidinyl/-propoxy/- 3-methoxyphenyl/ -2,2,2-triftoratsetofenona in the form of a solid substance with a melting point of 94-96oC.

Elemental analysis for C24H24F4N2O4:

calculated (%): C 60,00; H to 5.03; N OF 5.83;

found (%): C 60,01; H is 5.06; N 5,68.

.

Stir a mixture of 6-fluoro-3-(4-piperidinyl) -1,2-benzisoxazole (1.88 g, 8.5 mmol), potassium carbonate (1.8 g) and 1-/4-(3-bromopropane)-3-methylmercapto)-ethanone (2.3 g, 7.6 mmol) in acetonitrile (100 ml) was heated under reflux 4 hours To the end of the reaction the solvent was concentrated, then diluted with dichloromethane (250 ml). Insoluble substances were filtered off. The dichloromethane solution was concentrated to dryness and got the oil. The oil was purified by rapid chromatography on a column of silica gel (silicon dioxide, 54 g, elwira dichloromethane, 500 ml, a mixture of 1% methanol - dichloromethane, 1.1 l). The most pure fractions were combined and received a colorless oil, which was aterials to not quite white solid (2.4 g). By recrystallization from ethanol (100 ml) was received 2.15 g 1-/4-/3-/4-(6-fluoro-1,2-benzisoxazol-3-yl) -piperidinyl/- propoxy/- 3-methylmercaptopurine/-ethanone in the form of needle-like crystals, melting point 150-152oC.

Elemental analysis for C24H27FN2O3S:

calculated (%): C 65,14; H x 6.15; N 6,33;

found (%): C 65,09; H 6,10; N 6,25.

Example 44.

1-/4-(3-Bromopropane) -3-bromophenyl/-Etalon.

Stir a mixture of 3-bromo-4-oxazolidinone (4.5 g, of 21.2 mmol), carbonate Kali is the solvent was removed and the residue was dissolved in dichloromethane (400 ml) and filtered. The dichloromethane solution was concentrated to oil. Oil was added to isopropyl ether and stirred to cause crystallization of (4.1 g, 58%). The solid is recrystallized from isopropyl ether and was obtained 3.5 g of 1-/4-(3-bromopropane) -3-bromophenyl/-ethanone in the form of brilliant crystals, melting point 83-84oC.

Elemental analysis for C11H12Br2O2:

calculated (%): C 39,31; H 3,60;

found (%): C 39,80; H 3,55.

Example 45.

1-/4-(3-Bromopropane) -3,5-dibromophenyl/-Etalon.

Stir a mixture of 3,5-dibromo-4-oxazolidinone (3.0 g, 10.1 mmol), potassium carbonate (2.6 g, 20.3 mmol), 1,3-dibromopropane (4.0 g, to 19.8 mmol) in acetonitrile (100 ml) was heated under reflux 5 hours the Solvent was removed. The crude product was extracted in dichloromethane (150 ml) and the insoluble inorganic substance was filtered. The solution was again concentrated to dryness. Purification was performed by rapid chromatography on silica gel (45 g, silicon dioxide, suirable a mixture of hexane - dichloromethane 1:1). The thus obtained material (2.8 g) is recrystallized twice from isopropyl ether and was obtained pure for analysis of 1-/4-(3-bromopropane) -3,5-dibromophenyl/-Etalon, t is prohibited (%): C 31,84; H 2,67;

found (%): C 31,97; H 2,63.

Example 46.

1-/4-/4-/4-(1,2 -Benzisothiazol-3-yl) -1-piperidinyl/-butoxy/- 3-methoxyphenyl/-Etalon.

Stir a mixture of 3-(4-piperidinyl) -1,2-benzisothiazole (2.6 g, mol 0,0119), 1-/4-(4-bromobutoxy)-3-methoxyphenyl/-ethanone (3,9 g, 0,0131 mol), potassium carbonate (2.0 g, 0,0143 mol), potassium iodide (200 mg) and acetonitrile (125 ml) was heated under reflux in nitrogen atmosphere for 18 hours, the Reaction mixture was cooled to ambient temperature and filtered. The filter residue is well washed with fresh acetonitrile and the filtrate was concentrated to obtain wet brown solid. The residue was diluted with water and the aqueous suspension was extracted with methylene chloride. The organic extract was washed with water, dried with magnesium sulfate and concentrated to obtain 6.5 g of a dark oil. The oil was purified preparative high performance liquid chromatography (Waters Associates Prep LC/System 500, using 2 columns of silica gel and a mixture of 5% methanol - methylene chloride) and received 4.5 g solid beige color. Sample 3.1 g (0,0071 mol) was dissolved in absolute ethanol (80 ml) was added oxalic acid (0,067 g, 0,0074 mol). The solution was heated with neck refrigerator at the resulting suspension was diluted with anhydrous ether (150 ml) and stirred for five minutes. The solid is collected, dried and obtained 3.1 g of a solid substance in a light beige color. Salt perekristalizovanny from ethanol and obtained 2.8 g of product. This connection was again converted to the free base 50% sodium hydroxide and received 2.4 g, which immediately crystallized from ethanol gave 1.5 g(28%) 1-/4-/4-/4-(1,2 -benzisothiazol-3-yl) -1-piperidinyl/-butoxy/- 3-methoxyphenyl/-ethanone in the form of a beige color powder, melting point 78-80oC.

Elemental analysis for C25H30N2O3S:

calculated (%): C 68,46; H 6,91; N 6,39;

found (%): C 68,34; H 6,85; N 6,33.

Example 47.

1-/4-/3-/4-(6-Fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl/- propoxy/-3-methoxyphenyl/ -phenylmethane.

A mixture of 6-fluoro-3-(4-piperidinyl) -1,2-benzisoxazole (2.2 g, 10 mmol), potassium carbonate (2.3 g), 1-/4-(3-bromopropane)-3-methoxyphenyl/-phenylmethanone (3,47 g, 10 mmol) in acetonitrile (100 ml) was heated under reflux for 3 hours At the end of the reaction, the acetonitrile was concentrated and the mixture was extracted into dichloromethane (200 ml). Insoluble substances were filtered off and the solvent evaporated to an oil. Purification was performed by rapid chromatography on a column of silica gel (silica, 50 g, was suirable dichloromethane, 600 ml, scale 4,24 g (87%) not quite white solid. Recrystallization from ethanol (75 ml) gave 3.9 g 1-/4-/3-/4-(6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl/- propoxy/-3-methoxyphenyl/ -phenylmethanone in the form of off-white crystals, melting point 128-130oC.

Elemental analysis for C29H29FN2O4:

calculated (%): C 71,30; H 5,98; N 5,73;

found (%): C 71,31; H of 5.99; N 5,75.

Example 48.

1-/3-Bromo-4-/3-/4- (6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl/- propoxy-phenyl/ -Etalon.

A mixture of 6-fluoro-3-(4-piperidinyl) -1,2-benzisoxazole (2.1 g, 9.5 mmol), potassium carbonate (2.0 g), 1-/3-bromo-4- (3-bromopropane)-phenyl/ -ethanone (3.1 g, 9.2 mmol) in acetonitrile (100 ml) was heated under reflux for 3 hours At the end of the reaction the solvent was evaporated and the mixture was extracted into dichloromethane (200 ml). The insoluble fraction was filtered. Dichloromethane was again concentrated. The crude residue was purified by chromatography on silica gel (one column of silicon dioxide, 49 g, eluent served as dichloromethane, 500 ml, a mixture of 3% methanol - 97% dichloromethane, 600 ml). Thus obtained product (3,26 g, 72%) was recrystallized from ethanol (40 ml) and was obtained 3.0 g of 1-/3-bromo-4-/3-/4- (6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl/- propoxy-phenyl/-ethanone in the form of light yellow crystals, that is Leno (%): C 58,12; H 5,09; N OF 5.89;

found (%): C 57,64; H 5,35; N 5,55.

Example 49.

3-/1-/3-/4- (1-Ethoxyethyl)-2 - methoxyphenoxy/-propyl/ -4-piperidinyl/ -6-fluoro-1,2-benzisoxazole hydrochloride.

To the mixture 4-/3-/4-(6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl/- propoxy/-3-methoxy --methylbenzonitrile (3.8 g, 0,089 mol) in pyridine (25 ml) was added acetic anhydride (5 ml). The mixture was briefly heated on the steam bath to accelerate the dissolution and then the mixture was left at room temperature for 16 hours the Greater part of pyridine is evaporated under reduced pressure and the resulting oil was diluted with water. The aqueous solution was podslushivaet dilute sodium hydroxide and then extracted with ethyl acetate. The organic extract was washed with water, dried with magnesium sulfate, the solvent was concentrated and obtained 3.7 g of O-acetyl derivative as a colorless oil. The compound was dissolved in diethyl ether and the ether chloride-hydrogen acid was added to the precipitated precipitate retinoid chloride-hydrogen salt, which when processed by phlegm ethyl acetate gave 3.4 g of crystalline salt, the melting point 143-145oC. Attempt crystallization of salt from a mixture of ethanol - diethyl ether led to the substitution of acetate in favor of aidrelated 3-/1-/3-/4- (1-ethoxyethyl) -2-methoxyphenoxy)-propyl/ -4-piperidinyl/-6-fluoro-1,2-benzisoxazole, the melting point 139-141oC.

Elemental analysis for C26H33FN2O4HCl:

calculated (%): C 63,34; H 6,95; N 5,68;

found (%): C 63,06; H to 6.80; N 5,63.

Example 50.

Fumarate 3-/1-/3-/4- (1-acetoxyethyl)-2-methoxyphenoxy/-propyl/-4 - piperidinyl/-6-fluoro-1,2-benzisoxazole.

The mixture 4-/3-/4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl/- propoxy/-3-methoxy-methylbenzonitrile (4.8 g, to 0.011 mol) in pyridine (45 ml) was briefly heated to accelerate the formation of the solution and then added acetic anhydride (6.3 ml). The reaction mixture was stirred at ambient temperature for 16 h, concentrated in vacuo and the remaining colorless oil was dissolved in water. The aqueous solution was podslushivaet saturated potassium carbonate solution and the mixture was extracted with diethyl ether. The extract was washed with water, dried with magnesium sulfate, concentrated and received a 5.2 g of a viscous colorless oil. Oil (4.8 g) was dissolved in anhydrous diethyl ether was added fumaric acid (1.2 g, 0.01 mol). The mixture was stirred at ambient temperature for 4 h and then kept at the same temperature for 16 hours Obtained white fumarate 3-/1-/3-/4-(1-acetoxyethyl) -2-methoxyphenoxy/ -propyl/-4 - piperidinyl/-6-fluoro-1,2-be the acid (0.3 g) and were collected at 0.9 g fumarata 3-/1-/3-/4- (1-acetoxyethyl)-2-methoxyphenoxy/ -propyl/-4 - piperidinyl/-6-fluoro-1,2-benzisoxazole. Two downloads were combined and were led from acetonitrile (twice) and was obtained 2.3 g (43%) of acetate, melting point 150-152oC.

Elemental analysis for C26H31FN2O3C4H4O4:

calculated (%): C 61,43; H 6,01; N 4,78;

found (%): C 61,06; H by 5.87; N 4,73.

Example 51.

1-/4-/3-/4-(6-Fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl/- propoxy/-3-methoxyphenyl/ -pentanon.

A mixture of 6-fluoro-3-(4-piperidinyl) -1,2-benzisoxazole (2.9 g, 0.01 mol), potassium carbonate (3.0 g), 1-/4-(3-bromopropane)-3-methoxyphenyl)-pentanone (3.7 g, 0,0113 mol) in acetonitrile (140 ml) was heated under reflux for four hours. Upon completion of the reaction the mixture was cooled and filtered. The filtrate was concentrated to oil. Purification was performed by rapid chromatography on a column of silica gel (silica, 55 g, suirable mixture of 1% methanol in dichloromethane, 600 ml, 3% methanol - 97% dichloromethane, 400 ml). Fractions containing pure product were collected, concentrated and obtained 4.3 g (91%). By recrystallization from ethanol (10 ml) was obtained powder 1-/4-/3-/4- (6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl/- propoxy/-3-methoxyphenyl)- pentanone (3,22 g), point square 79-80oC.

Elemental analysis for C27H33FN2O4:

A mixture of 6-fluoro-3-(4-piperidinyl) -1,2-benzisoxazole (2.5 g, 0,0114 mol), potassium carbonate (1.8 g, 0,0130 mol), 4-(3-chloropropoxy)-2-methylaminophenol (2.4 g, 0,0120 mol) and acetonitrile (100 ml) was heated under reflux for 18 hours, the Reaction mixture was cooled to ambient temperature and poured into water. The aqueous mixture was extracted with ethyl acetate and an ethyl acetate extract was washed with water, dried with magnesium sulfate, concentrated and obtained 4.1 g of brown oil. The oil was purified preparative high performance liquid chromatography (Waters Associates Prep LC/System 500, using two columns with silica gel and elwira a mixture of 4% methanol - methylene chloride). Concentration of the appropriate fractions were received of 2.45 g of oil color beige. The product was dissolved in ethyl acetate (50 ml) was added fumaric acid (0,78 g). The mixture was stirred at moderate boiling under reflux for 45 minutes and then at room temperature for 1.5 hours the Product was isolated by vacuum filtration and received 2.5 g solid pale yellow color. By recrystallization from ethanol was obtained 2.0 g(40%) 2-/3-/4-(6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl/ -propoxy/-N methylbenzenamine, profumata in the form of a beige color crystals, melting point 180-182o
found (%): C 65,08; H 6,35; N 9,45.

Example 53.

3-/1-/3-(4-Bromo-2-methoxyphenoxy)-propyl/ -4-piperidinyl/- 6-fluoro-1,2-benzisoxazol.

A mixture of 6-fluoro-3-(4-piperidinyl) -1,2-benzisoxazole (2.6 g, to 0.0117 mol), potassium carbonate (2.0 g, 0,0144 mol), 4-(3-chloropropoxy) -3-methoxypropanol (3.6 g, 0,0129 mol), acetonitrile (100 ml) and a few crystals of potassium iodide was stirred at reflux under nitrogen atmosphere for 18 h the Cooled reaction mixture was poured into water and the aqueous mixture was extracted with ethyl acetate. An ethyl acetate extract was washed with water, dried with magnesium sulfate, concentrated and received 5.0 g of a green oil. The sample was purified preparative high performance liquid chromatography (Waters Associates Prep LC/System 500, using two columns with silica gel and a mixture of 4% methanol - methylene chloride as eluent). Concentration of the appropriate fractions were obtained 3,15 g solids reddish-brown color. The connection twice recrystallized from ethanol and obtained 2.0 g(37%) 3-/1-/3-(4-bromo-2-methoxyphenoxy)-propyl/ -4-piperidinyl/-6-fluoro-1,2-benzisoxazole in a solid beige color, melting point 88-90oC.

Elemental analysis on the Sabbath.">

Example 54.

1-/4-/3-/4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl/- propoxy/-3-methoxyphenyl/ -propanone.

A mixture of 6-fluoro-3-(4-piperidinyl) -1,2-benzisoxazole (2.8 g, of 15.2 mmol), potassium carbonate (3.0 g), 1-/4-(3-bromopropane) -3-methoxyphenyl/-propanone (4.6 g, 18.2 mmol) in acetonitrile (100 ml) was heated under reflux for 2 hours after the reaction mixture was filtered, the solvent was concentrated and the residue was extracted into dichloromethane (300 ml). Dichloromethane was again filtered and concentrated. The crude material (6.4 g) was purified by rapid chromatography on a column of silica gel (silica, 50 g, was suirable dichloromethane, 700 ml, a mixture of 1% methanol - dichloromethane, 1.4 l). Thus purified material (2,87 g, 51%) was recrystallized from ethanol (25 ml) and received 2,13 g 1-/4-/3-/4-(6-Fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl/- propoxy/-3-methoxyphenyl/ -propanone in the form of crystals, painted beige, the melting point of 118-119oC.

Elemental analysis for C25H29FN2O4:

calculated (%): C 68,16; H 6,64; N 6,36;

found (%): C 68,32; H 6,63; N 6,29.

Example 55.

4-/3-/4-(6-Fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl/- propoxy/-3-methoxybenzamide.

A mixture of 6-fluoro-3-(4-piperidyl) in acetonitrile (80 ml) was heated under reflux 5 hours Upon completion of the reaction, the solvent is evaporated. The residue was extracted into dichloromethane. Inorganic insoluble fraction was filtered. Dichloromethane was again concentrated. The crude residue was purified by rapid chromatography through a column of silica gel (55 g of silicon dioxide were suirable mixture of 1% methanol in dichloromethane, 1.0 l, 2% methanol in dichloromethane, 1.0 l). The resulting material is weighed with 2.93 g (84%) and consisted of white crystals. Recrystallization from hot ethanol (60 ml) gave 2.2 g 4-/3-/4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl/- propoxy/-3-methoxybenzamide in the form of white crystals, melting point 163-164oC.

Elemental analysis for C23H26FN3O4:

calculated (%): C 64,62; H 6,13; N 9,83;

found (%): C 64,20; H the 6.06; N 9,71.

Example 56.

1-/4-/3-/4-(6-Fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl/- propoxy/-3-(methylamino) -phenyl/-Etalon.

A mixture of 6-fluoro-3-(4-piperidinyl) -1,2-benzisoxazole (2.3 g, 0,0103 mol), potassium carbonate (1.4 g mol 0,0103), 1-/4-(3-chloropropoxy) -3-(methylamino)-phenyl/-ethanone (2.5 g, 0,010 mol), potassium iodide (0.10 g) and acetonitrile (100 ml) was stirred at reflux under nitrogen atmosphere for 23 hours, the Reaction mixture was cooled to temperature is vital washed with water, was dried over magnesium sulfate, concentrated and received 4.8 g wet brown solid. The compound was isolated by preparative high performance liquid chromatography (Waters Associates Prep LC/System 500, using two columns with silica gel and a mixture of 4% methanol in methylene chloride as eluent). Concentration of the appropriate fractions were obtained 2.4 g of product. By recrystallization from ethanol was obtained 2.1 g 1-/4-/3-/4-(6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl/- propoxy/-3-(methylamino) -phenyl/-ethanone in a solid beige

the colors, the melting point of 151-153oC.

Elemental analysis for C24H28FN3O3:

calculated (%): C 67,76; H 6,63; N 9,88;

found (%): C 67,83; H 6,76; N 9,90.

Example 57.

1-/4-/3-/4-(6-Fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl/- propoxy/-3-ethoxyphenyl/ -Etalon.

A suspension of sodium hydride (0.28 g of a 50% oil dispersion, 0,0059 mol) in dimethylformamide (20 ml) was cooled to 4oC in an ice bath. To the suspension was added dropwise 1-/4-/3-/4-(6-fluoro-1,2-benzoxazol-3-yl) -1-piperidinyl/- propoxy/-3 oksifenil/ -Etalon (2.3 g, 0,0056 mol) dissolved in dimethylformamide (40 ml). After you add the whole number and the mixture was stirred in an atmosphere of Azatan (1.3 g, 0,0018 mol). Stirring in an atmosphere of nitrogen was continued for three hours, allowing the temperature of the mixture to rise slowly to ambient temperature. The reaction mixture was cooled in an ice bath, was added water and the aqueous mixture was extracted with ethyl acetate. An ethyl acetate extract was washed with water, dried with magnesium sulfate, concentrated to obtain 3.9 g of the wet solid color beige. The solid is triturated with diethyl ether, filtered and given 1.5, They were combined with an additional sample (3.5 g) and recrystallization from ethanol was obtained 3.0 g (57%) of brilliant crystals beige connections 1-/4-/3-/4-(6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl/- propoxy/-3-ethoxyphenyl/-ethanone, the melting point of 112-114oC.

Elemental analysis for C25H29FN2O4:

calculated (%): C 68,16; H 6,64; N 6,36;

found (%): C 68,10; H 7,03; N 6,35.

Example 58.

1-/4-(3-Bromopropane) -3-(methylmercapto)-phenyl/ -Etalon.

A mixture of 1-/4-hydroxy-3-(methylmercapto) -phenyl/-ethanone (5.4 g, 0.03 mol), potassium carbonate (4,2 g), 1,3-dibromopropane (8.0 g, 0,039 mol) in acetonitrile (150 ml) was heated under reflux for 3 h and left overnight under stirring at room temperature. Acetonitrile. The dichloromethane solution was concentrated. The crude product was purified on a column of silica gel (silica 100 g, was suirable a mixture of hexane - dichloromethane in the ratio of 1:1, 1.6 l). The compound crystallized upon concentration and the product (3.5 g, 39%) was recrystallized from ethanol (40 ml) and received 2.0 g 1-/4-(3-bromopropane) -3-(methylmercapto)-phenyl/ -ethanone in the form of white needles, melting point 120-122oC.

Elemental analysis for C12H15BrO2S:

calculated (%): C 47,53; H 4,99;

found (%): C 47,74; H 4,91.

Example 59.

4-(3-Bromopropane) -3-methoxybenzonitrile.

A mixture of 4-hydroxy-3-methoxybenzonitrile (7.5 g, 50 mmol), potassium carbonate (12.5 g) and 1,3-dibromopropane (15 g, 75 mmol) in acetonitrile (100 ml) was heated under reflux for 3 h and left overnight at room temperature. The solvent of the reaction mixture was removed on a rotary evaporator and the crude solid was extracted into methylene chloride (500 ml). Insoluble substances were filtered off. The dichloromethane solution was concentrated and the material was purified column chromatography (silica, 105 g, suirable a mixture of dichloromethane - hexane in the ratio 2:3 and then dichloromethane). The desired product is 3-bromopropane) -3-methoxybenzonitrile, the melting point 99-101oC.

Elemental analysis for C4H12BrNO2:

calculated (%): C 48,91; H 4,48; N 5,19;

found (%): C 49,49; H 4,47; N to 5.21.

Example 60.

1-/4-(3-Bromopropane) -3-methoxyphenyl/-Etalon.

A mixture of 4-hydroxy-3-methylacetophenone (14.5 g, 96 mmol), potassium carbonate (17.5 g, 144 mmol) and 1,3-dibromopropane (30 g, 144 mmol) in acetonitrile (400 ml) was heated under reflux for 6 hours By the end of the reaction the solvent was removed on a rotary evaporator and the crude solid was extracted into dichloromethane (750 ml). Insoluble inorganic substance was filtered. The dichloromethane solution was again concentrated to a crude oil (34,5 g). Purification was performed by rapid chromatography on a column of silica gel (silicon dioxide, 150 g, elwira a mixture of hexane - dichloromethane in the ratio 7: 3, 2 l, and dichloromethane, 2 l). Thus purified material weighed 14.6 g (56%) and was recrystallized from ethanol. Recrystallization again from ethanol gave pure for analysis of 1-/4-(3-bromopropane) -3-were/-Etalon, melting point 59-61oC.

Elemental analysis for C12H15BrO2:

calculated (%): C 53,15; H 5,58;

found (%): C 53,35; H 5,52.

Example 61.

oC.

Elemental analysis for C17H17BrO3:

calculated (%): C 58,47; H 4,91;

found (%): C 59,03; H 4,87.

The present invention thus provides compounds that can cause antipsychotic action and may be able to influence the negative symptoms of schizophrenia in a positive way. In addition, many compounds can also reduce the tendency to cause extrapyramidal side phenomena in mammals.

1. The derived N-(aryloxyalkyl)-heteroarylboronic and heterotrimer the volume of chlorine, bromine or fluorine;

R2- benzoyl;

Z represents-CH - or

< / BR>
n = 2, 3, 4 or 5;

R is hydrogen, alkyl with 1 to 6 carbon atoms, alkoxy with 1 to 6 carbon atoms, hydroxyl, bromine atom, alkylamino, alkylthio, TRIFLUOROACETYL, aminocarbonyl, -CO-alkyl, -COO-alkyl, -CO-Ph, -CH(or SIG3)alkyl, where alkyl is lower alkyl, R3is hydrogen, lower alkyl;

m = 1, 2, 3, provided that Z is not a group

< / BR>
when X represents-S -, and R is hydrogen,

or their pharmaceutically acceptable salts.

2. Connection on p. 1, where X represents-O-, -S - or-NH-.

3. Connection on p. 1, where n = 2, 3, 4, Y is hydrogen or chlorine atom or a fluorine atom at the 6th position and p = 1.

4. Connection on p. 1, where R is hydrogen, bromine atom, alkyl with 1 to 6 carbon atoms, WITH1- C6-alkylthio, -CO-phenyl, or C1- C6the alkyl CH(or SIG3)-, where R3is hydrogen or C1- C6-alkyl and m = 2 or 3.

5. Connection on p. 1, where n = 3 or 4, R is-och3and-CO-CH3m = 2.

6. Connection on p. 1, representing 1-/4-/3-/4-(1H-indazol-3-yl)-1-piperazinil/propoxy/-3-methoxyphenyl/alanon or its pharmaceutically acceptable acid additive salt.

7. Connection on p. 1, Brestsky acceptable acid additive salt.

8. Connection on p. 1, representing 1-/4-/3-/4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl/propoxy/-3-methoxyphenyl/alanon or its pharmaceutically acceptable acid additive salt.

9. Connection on p. 1, representing 1-/4-/4-/4-(1,2-benzisoxazol-3-yl)-1-piperidinyl/butoxy/-3-methoxyphenyl/alanon or its pharmaceutically acceptable acid additive salt.

10. Connection on p. 1, representing 1-/4-/4-/4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl/butoxy/-3-methoxyphenyl/alanon or its pharmaceutically acceptable acid additive salt.

11. Pharmaceutical composition having anti-psychotic and/or analgesic activity, characterized in that it contains an effective amount of the compounds under item 1 in combination with a pharmaceutically acceptable carrier.

12. Connection on p. 1, which is 1-/4-/2-/4-(1,2-benzisoxazol-3-yl)1-piperidinyl/amoxi/-3-methoxyphenyl/-alanon or its pharmaceutically acceptable salt accession acid.

13. Connection on p. 1, which is 1-/4-/4-/4-(1H-indazol-3-yl)1-piperazinil/butoxy/-3-methoxyphenyl/alanon or its pharmaceutically acceptable salt accession acid.

14. Connection p what about the pharmaceutically acceptable salt accession acid.

15. Connection on p. 1, which is 4-/3-/4-(6-fluoro-1,2-benzisoxazol-3-yl)1-piperidinyl/propoxy/-3-methoxy-alpha-methylbenzylamine or its pharmaceutically acceptable salt accession acid.

16. Connection on p. 1, which is 1-/4-/3-/4-(1,2-benzisothiazol-3-yl)1-piperidinyl/propoxy/-3-methoxyphenyl/-alanon or its pharmaceutically acceptable salt accession acid.

17. Connection on p. 1, which is 1-/4-/3-/4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidyl/propoxy/-3-hydroxyphenyl/alanon or its pharmaceutically acceptable salt accession acid.

18. Connection on p. 1, which is 1-/4-/3-/4-(6-fluoro-1H-indazol-3-yl)-1-piperazinil/propoxy/-3-methoxyphenyl/alanon or its pharmaceutically acceptable salt accession acid.

19. Connection on p. 1, which is 1-/4-/4-/4-(6-fluoro-1H-indazol-3-yl)-1-piperazinil/butoxy/-3-methoxyphenyl/alanon or its pharmaceutically acceptable salt accession acid.

20. Connection on p. 1, which is 1-/4-/3-/4-(1H-indazol-3-yl)-1-piperidinyl/propoxy/-3-methoxyphenyl/alanon or its pharmaceutically acceptable salt accession acid.

21. Connection on p. 1, which is Raplamaa salt accession acid.

22. Connection on p. 1, which is 1-/4-/4-/4-(6-chloro-1,2-benzisoxazol-3-yl)-1-piperidinyl/butoxy/-3-methoxyphenyl/alanon or its pharmaceutically acceptable salt accession acid.

23. Connection on p. 1, which is 1-/4-/3-/4-(5-chloro-1,2-benzisoxazol-3-yl)-1-piperidinyl/propoxy/-3-methoxyphenyl/alanon or its pharmaceutically acceptable salt accession acid.

24. Connection on p. 1, which is 6-fluoro-3-/1-/3-(2-methoxyphenoxy)propyl/-4-piperidinyl/-1,2-benzisoxazol or its pharmaceutically acceptable salt accession acid.

25. Connection on p. 1, which is 1-/3-/4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl/propoxy/4-methoxyphenyl/-phenylmethane or its pharmaceutically acceptable salt accession acid.

26. Connection on p. 1, which is 1-/4-/4-/4-(1H-indazol-3-yl)-1-piperidinyl/butoxy/-3-methoxyphenyl/-alanon or its pharmaceutically acceptable salt accession acid.

27. Connection on p. 1, which is 1-/4-/2-/4-(6-chloro-1,2-benzisoxazol-3-yl)-1-piperidinyl/amoxi/3-methoxyphenyl/-alanon or its pharmaceutically acceptable salt accession acid.

28. Connection on p. 1, which is what I Sol accession acid.

29. Connection on p. 1, which is 1-/4-/3-/4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl-propoxy/-2-were/-alanon or its pharmaceutically acceptable salt accession acid.

30. Connection on p. 1, which is 1-/3-/3-/4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl/propoxy/-5-were/-alanon or its pharmaceutically acceptable salt accession acid.

31. Connection on p. 1, which is N-/3-/3-/4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl/propoxy/-4-were/-ndimethylacetamide or its pharmaceutically acceptable salt accession acid.

32. Connection on p. 1, which is 1-/4-/3-/4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl/propoxy/-3-were/-alanon or its pharmaceutically acceptable salt accession acid.

33. Connection on p. 1, which is 1-/4-/3-/4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl/propoxy/-3-were/-alanon or its pharmaceutically acceptable salt accession acid.

34. Connection on p. 1, which is 1-/4-/3-/4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl/propoxy/phenyl/-alanon or its pharmaceutically acceptable salt accession acid.

35. Connection on p. 1, which presima salt accession acid.

36. Connection on p. 1, which is 1-/4-/4-/4-(1,2-benzisothiazol-3-yl)-1-piperazinil/butoxy/-3-methoxyphenyl/-alanon or its pharmaceutically acceptable salt accession acid.

37. Connection on p. 1, which is 4-/3-/4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl/propoxy/-3-methoxybenzonitrile or its pharmaceutically acceptable salt accession acid.

38. Connection on p. 1, which is 1-/4-/4-/4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl/butoxy/-3 - methoxyphenyl/-alanon or its pharmaceutically acceptable salt accession acid.

39. Connection on p. 1, which is 1-/4-/3-/4-(1-benzoyl-6-fluoro-1H-indazol-3-yl)-1-piperazinil/propoxy/-3-methoxyphenyl/-alanon or its pharmaceutically acceptable salt accession acid.

40. Connection on p. 1, which is 1-/4-/4-/4-(6-chloro-1H-indazol-3-yl)-1-piperazinil-1 butoxy/-3-methoxyphenyl/-alanon or its pharmaceutically acceptable salt accession acid.

41. Connection on p. 1, which is 1-/4-/3-/4-(1,2-benzisothiazol-3-yl)-1-piperazinil/propoxy/-3-methoxyphenyl/-alanon or its pharmaceutically acceptable salt accession acid.

42. Connection on p. 1, which represents Jemima salt accession acid.

43. Connection on p. 1, which is 1-/4-/2-/4-(1,2-benzisothiazol-3-yl)-1-piperazinil/amoxi/-3-methoxyphenyl/-alanon or its pharmaceutically acceptable salt accession acid.

44. Connection on p. 1, which is 6-fluoro-3-/1-(3-phenoxypropan)-4-piperidinyl/-1,2-benzisoxazol or its pharmaceutically acceptable salt accession acid.

45. Connection on p. 1, which is 1-/4-/2-/4-(6-chloro-1H-indazol-3-yl)-piperazinil/amoxi/-3-methoxyphenyl/-alanon or its pharmaceutically acceptable salt accession acid.

46. Connection on p. 1, which is 1-/4-/3-/4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl/propoxy-3-methoxyphenyl/-2,2,2-triptoreline or its pharmaceutically acceptable salt accession acid.

47. Connection on p. 1, which is 1-/4-/3-/4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl/propoxy/-3-methylmercaptopurine/-alanon or its pharmaceutically acceptable salt accession acid.

48. Connection on p. 1, which is 1-/4-/4-/4-(1,2-benzisothiazol-3-yl)-1-piperidinyl/butoxy/-3-methoxyphenyl/-alanon or its pharmaceutically acceptable salt accession acid.

49. Connection on p. 1, which is /are acceptable salt accession acid.

50. Connection on p. 1, which is 1-/3-bromo-4-/3-/4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl/propoxy/-phenyl/-alanon or its pharmaceutically acceptable salt accession acid.

51. Connection on p. 1, which is 3-/1-/3-/4-(1-ethoxyethyl)-2-methoxyphenoxy/propyl-4-piperidinyl/-6-fluoro-1,2-benzisoxazol or its pharmaceutically acceptable salt accession acid.

52. Connection on p. 1, which is 3-/1-/3-/4-(1-acetoxyethyl)-2-methoxyphenoxy/propyl-4-piperidinyl/-6-fluoro-1,2-benzisoxazol or its pharmaceutically acceptable salt accession acid.

53. Connection on p. 1, which is 1-/4-/3-/4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl/-propoxy/-3-methoxyphenyl/pentane or its pharmaceutically acceptable salt accession acid.

54. Connection on p. 1, which is 2-/3-/4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl/propoxy/-N-methylbenzenamine or its pharmaceutically acceptable salt accession acid.

55. Connection on p. 1, which is 3-/1-/3-(4-bromo-2-methoxyphenoxy/propyl-4-piperidinyl/-6-fluoro-1,2-benzisoxazol or its pharmaceutically acceptable salt accession acid.

56. Connection on p. 1, pharmaceutically acceptable salt accession acid.

57. Connection on p. 1, which is 4-/3-/4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl/propoxy/-3-methoxybenzamide or its pharmaceutically acceptable salt accession acid.

58. Connection on p. 1, which is 1-/4-/3-/4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl/propoxy/-3-(methylamino)phenyl/alanon or its pharmaceutically acceptable salt accession acid.

59. Connection on p. 1, which is 1-/4-/3-/4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl/propoxy/-3-ethoxyphenyl/alanon or its pharmaceutically acceptable salt accession acid.

60. The pharmaceutical composition according to p. 11, characterized in that it comprises as active ingredient a compound according to any one of paragraphs.28 - 41, 43 - 46, 48 - 59, and an acceptable carrier.

Priority points:

19.05.89 on PP.1 to 10;

29.12.89 on PP.1 - 5, 12 - 59.

 

Same patents:

The invention relates to new substituted pyrrole General formula I

< / BR>
where R is hydrogen, hydroxyl;

R1and R2- together group of the formula -(CH2)nand R7is hydrogen, or R1and R7- together group of the formula -(CH2)nand R2is hydrogen;

R3is phenyl, naphthyl which may be substituted with halogen, C1-C7- alkoxy, CF3or benzofuranyl, benzo(b)thienyl, indolyl, substituted by 1-3 substituents selected from the group comprising halogen, C1-C7-alkyl, C1-C7-alkoxy; R4, R5and R6is hydrogen, halogen, C1-C4-alkoxy, C1-C7-alkyl,

R8a group of the formula -(CH2)p-R9or -(CH2)q-R100;

R9is hydrogen, C1-C7-alkylsulphonyl, C1-C7-alkylsulfonyl, aminocarbonyl;

R10is hydroxyl, amino, C1-C7-alkylamino, di(C1-C7)-alkylamino, three(C1-C7)-alkylamino, azido, C1-C7-alkoxy-carbylamine, isothiocyanate, C1-C7-alkylcarboxylic, C1-C7-alkylsulfonate, 6-membered nitrogen-containing saturated gets the SUB>2; W is amino; one of X and Y - O-atom, and the other is O or (H,H);

Z - group-CH - or N-atom;

m, p and q is a number from 0 to 5, n is a number from 1 to 5, provided that m and q represent the number from 2 to 5 when Z Is N-atom, and their pharmaceutically acceptable salts

The invention relates to new derivatives of benzimidazole with valuable properties, in particular a derivative of benzimidazole of General formula (I)

< / BR>
where R1is methyl,

R2- benzimidazole-2-yl, unsubstituted or substituted in position 1 by the stands, imidazol-4-yl substituted in position 1 by alkyl with 1 to 3 carbon atoms, substituted in position 2 by morpholinopropan, 5,6,7,8-tetrahydro-imidazo[1,2 - a]pyridine-2-yl or propanesultone-1-Il,

R3- nonbranched alkyl with 2 to 4 carbon atoms,

R4- amino group, sulfonyl substituted by a residue from the group consisting of dimethylaminopropylamine, cycloalkylcarbonyl, benzylaminocarbonyl in which cycloalkyl part contains 5 or 6 carbon atoms and the phenyl portion may be substituted methoxy group, triptorelin, tert

The invention relates to new derivatives of 5-arylindole formula I, where R1matter referred to in the description, A, B, C, and D each represent a carbon or one of them represents a nitrogen; R2, R3, R4, R5each independently represents hydrogen, C1- C6-alkyl, phenyl, halogen, cyano,- (CH2)mNR14R15, -(CH2)mOR9, -(CH2)mNR14COR9, -(CH2)mNR14CONHR9, -CO2R9; R6represents hydrogen, -OR10; R7, R8, R14, R15each independently represents hydrogen, C1- C6-alkyl, (CH2)xOR11; R9represents hydrogen, C1- C6-alkyl, phenyl; R10is1- C10-alkyl; R11is1- C6-alkyl; n = 0,1 or 2; m = 0, 1, 2 or 3; x = 2 or 3; the dotted line indicates the optional single bond or their pharmaceutically acceptable salts

The invention relates to new chemical compounds with valuable biological properties, in particular to derive hinolan and naphthyridinone acids with antibacterial activity, as well as to the isoindole derivative as starting compounds for obtaining the derivatives hinolan and naphthyridinone acid

The invention relates to new derivatives of erythromycin, method of production thereof, to pharmaceutical compositions based on them and to intermediate compounds

The invention relates to new aryl-substituted derivatives of piperidine, which has antagonistic activity to the receptor NK3person, to a method for their production and to their use in pharmaceutical compositions

The invention relates to a piperidine derivative of General formula (I) where Z represents the group -(CH2)m-CH(OR3) or a carbonyl group, R1is hydrogen or (C1- C3)alkyl, R2- (C1- C3)alkyl, or R1and R2together form a chain -(CH2)n, where n is the number of 3 - 5, or -(CH2)2-O-(CH2)2-, m = 0 - 1, n = 1 - 2, R3- hydrogen or-COCH3and R4- hydrogen, -CH3, -OH or-OCH3provided that when Z represents a carbonyl group, h = 2, or their pharmaceutically acceptable salts
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