Heteroarylboronic and pharmaceutical composition based on them

 

(57) Abstract:

Heiroartrology formula 1, where X-, -O-, -S-, R2- lower alkyl, aryl(lower alkyl), aryl, cycloalkyl, aroyl, alkanoyl or phenylsulfonyl; p = 1 or 2; Y is hydrogen, lower alkyl, hydroxyl, chlorine, fluorine, bromine, iodine, alkoxy, trifluoromethyl, nitro or amino, when p = 1; or Y is lower alkoxy, hydroxyl or halogen when p = 2 and X is-O-; Q is a residue of formula (a-b), Z is-CH - or Y2- the residue of formula (C), the values of other radicals see paragraph 1 of the claims. The compounds of formula 1 possess antipsychotic activity.

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7C. and 92 C.p. f-crystals, 2 tab.

The present invention relates to heteroarylboronic, pyrrolidines and piperazines. In particular, the present invention relates to heteroarylboronic, pyrrolidines and piperazines having antipsychotic activity, as well as to the use of these compounds as antipsychotic drugs.

Currently widely used therapeutic treatment of patients with schizophrenia by administration of neuroleptics, such as chlorpromazine, haloperidol, sulpiride, and very similar in chemical structure of the compounds. Although these cartonage recovery of patients with mental illness, and after discontinuation of treatment in these patients almost always observed the recurrence of the disease. Therefore, the need for antipsychotic drugs for the treatment of psychosis is still relevant.

Moreover, some of the known antipsychotic drugs have undesirable side effects. For example, many psychotropic drugs have side effects, as the so-called extrapyramidal disorders, for example, rigidity, tremor, hyperkinesia and late dyskinesia, which causes facial grimaces and involuntary movements of the muscles of the face and extremities. Often also observed orthostatic hypotension. In accordance with this it is obvious that it is necessary to develop such antipsychotics, which would have fewer side effects, or if antipsychotics have the above characteristic side effects, it is desirable that these side effects were expressed, possibly weaker.

In addition, you must obtain these drugs, which would have other biological actions. For example, research on pain senile aspiration led to NaturalNews means is underway at the present time.

The present invention is directed to meet the above needs and relates to the compound of the formula

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where X represents-O-, -S-,

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R2choose from the following groups: lower alkyl, aryl (lower alkyl), aryl, cycloalkyl, alkanoyl, and phenylsulfonyl;

p = 1 or 2;

Y represents hydrogen, lower alkyl, hydroxy, chlorine, fluorine, bromine, iodine, lower alkoxy, trifloromethyl, nitro, or amino, when p = 1;

Y represents lower alkoxy, hydroxy and halogen when p = 2, and X represents-O-;

Q is chosen from the following groups:

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where Z represents a-CH or

Y2choose from a group that includes

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in which R1is -(CH2)-, where n= 2, 3, 4, or 5; or-CH2-CH=CH-CH2-, -CH2-CH=CH-CH2-CH2-, -CH2-CH2-CH=CH-CH2- or

where-CH=CH-bond is CIS or TRANS; and R and m are defined above;

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where R3is H or-OCH3and n has the values defined above;

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where R4represents hydrogen, lower alkyl, lower alkyl, lower alkoxy, amino, mono - or dialkylamino, C1-C3-acylamino, C1-C6-alkanoyl, trifloromethyl, chlorine, fluorine, Brasil, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamines, lower dialkylamino, nitro, cyano, trifluoromethyl, triptoreline;

n has the values defined above;

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where n and R4defined above;

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where one of Xyand Xzis

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and the other is CH2-R'5is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, or bromine;

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where n and R4have the meanings defined above;

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where n and R4have the meanings defined above;

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where n and R4have the meanings defined above;

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where Q2is S, NH, or-CH2-;

R6has the same meaning as R1in case, if Q2is S or NH; and if Q2is-CH2-, R6selected from-CH2-CH2-, -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-CH2-, -CH2-CH=CH2-CH2-, -CH2-CH2-CH=CH-, -CH2-CH= CH-CH2-, -CH2-CH2-CH= CH-, -CH2-CH= CH-CH2-CH2-, -CH2-CH2-CH=CH-CH2-, -CH2-CH2-CH2-CH=CH-, -CH2-CH=CH-CH2-CH2-, -CH2-CH2-CH=CH-CH2-, -CH2-CH2-CH2-CH= CH-,

at the same time-CH=CH-bond is CIS or ISSI mono - or dialkylamino, nitro, lower alkylthio, trifluromethane, cyano, acylamino, trifloromethyl, triptorelin, aminocarbonyl, dialkylaminoalkyl, formyl,

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when the alkyl is lower alkyl, and aryl is as defined above; heteroaryl is a

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Q3is-O-, -S-, -CH=N;

W is CH2or CHR8or N-R9;

R7is hydrogen, lower alkyl, or acyl;

R8is lower alkyl;

R9is hydroxy, lower alkoxy, or-other10;

R10is hydrogen, lower alkyl, C1-C3-acyl, aryl,

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where aryl and heteroaryl are the same as defined above;

m = 1, 2, or 3;

either present invention relates to pharmaceutically acceptable acid additive salts of the above compounds.

The present invention also relates to the compound of the formula

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where X represents-O-, -S-,

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R2choose from the following groups: lower alkyl, aryl(lower) alkyl, aryl, cycloalkyl, aroyl, alkanoyl, and phenylsulfonyl;

p = 1 or 2;

Y is hydrogen, lower alkyl, hydroxy, chlorine, fluorine, bromine, iodine, lower alkoxy, triforium from the group includes

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where Z is

Y2selected from the group consisting of

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in which R1) is an R20, R21or R22where R20is -(CH2)n-, where n = 2, 3, 4 or 5; R21is-CH2-CH=CH-CH2-, -CH2-C=C-CH2-, -CH2-CH= CH-CH2-CH2-, -CH2-CH2-CH=CH-CH2-, -CH2C=C-CH2-CH2- or-CH2-CH2-C= C-CH2-, and-CH= CH-bond is CIS or TRANS, R22is R20or R21where one or more carbon atoms in R20or R21are substituted by at least one linear C1-C6is an alkyl group, phenyl group, or a part

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where Z1- lower alkyl, -OH, lower alkoxy, -CF3, -NO2, -NH2or halogen;

R and m are defined below;

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where R1defined above;

R3is hydrogen or-OCH3;

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where R1defined above;

R4is hydrogen, lower alkyl, lower alkoxy, hydroxy, amino, mono - or dialkylamino, C1-C3-acylamino, C1-C6-alkanol, trifloromethyl, chlorine, fluorine, bromine,

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or C-aryl, where the aryl is phenyl or

but, lower dialkylamino, nitro, cyano, trifluromethane;

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where R1and R4are the same as defined above;

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where one of Xyand Xzis

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and the other is-CH2-;

R'5is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, or bromine;

R1is the same as it was defined above;

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where R1and R4defined above;

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where q = 1, 2, 3 or 4;

R1and R4defined above;

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where R1defined above;

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where R1defined above;

Q2is S, NH, or-CH2-;

R and is defined below;

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where R1defined above;

(12) -R1-O-R12,

where R12selected from the group comprising hydrogen,

where R13selected from the group consisting of hydrogen and (C1-C12)alkyl groups, R14selected from hydrogen and (C1-C12)alkyl groups; NR15R16taken together form a ring structure selected from piperidinyl, morpholinyl and piperazinil; R17selected from lower alkyl and aryl groups;

(12) -R,-NR18R19< / BR>
where R18and R19independently selected from the group including asout ring structure, selected from piperidinyl, morpholinyl and piperazinil;

(13) -R1-S-R12< / BR>
where R1and R12defined above;

R is hydrogen, lower alkyl, lower alkoxy, hydroxyl, carboxyl, chlorine, fluorine, bromine, iodine, amino, lower mono - or dialkylamino, nitro, lower alkylthio, trifluromethane, cenro, acylamino, trifloromethyl, triptorelin, aminocarbonyl, monoalkylamines, formyl,

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< / BR>
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where the alkyl is lower alkyl, aryl is as defined above; heteroaryl is

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where Q3is-O-, -S-, -CH=N-;

is CH2or CHR8or N-R9;

R7is hydrogen, lower alkyl, or acyl;

R8is lower alkyl;

R9is hydroxy, lower alkoxy, or-other10;

R10is hydrogen, lower alkyl, C1-C3-acyl, aryl,

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where aryl and heteroaryl are the same as defined above;

m = 1, 2, or 3,

provided that in formula (9), Z is not if X is-S-, Q2is-CH2-, Y is hydrogen, lower alkyl, lower alkoxy, halogen, hydroxy, or trifloromethyl, and p = 1 or 2;

provided that in f hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, or trifloromethyl, and p = 1 or 2;

provided that in formula (9), Z is not if X is Y is hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, or trifloromethyl, and Q2is-CH2-;

provided that in formula (9), Z is not if X is-O-, Q2is-CH2-, Y is hydrogen, lower alkyl, lower alkoxy, or halogen, and p = 1 or 2;

provided that in formula (9), Z is not if X is-S-, Q2is-CH2-, Y is hydrogen, halogen, lower alkyl, lower alkoxy or hydroxy, p = 1 or 2, R is hydrogen, and m = 1;

provided that in formula (9), Z is not if X is-NR2, Q2is-CH2-, R is chlorine, fluorine, bromine, iodine, lower alkyl, lower alkoxy, lower alkylthio, lower mono - or dialkylamino, amino, cyano, hydroxy, trifloromethyl; R2is aryl; Y is hydrogen, halogen, lower alkyl, lower alkoxy or hydroxy, p = 1 or 2;

provided that in formula (9), Z is not if X is-NH - or-NR2where R2represents lower alkyl, aryl(lower alkyl) or phenylsulfonyl, Y represent the>;

provided that Y2is not part of the formula (8) when Z is-CH-, X is 0, p = 1, and Y is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, bromine, iodine or a hydroxyl group;

provided that in the formula (1), Z is not if X is O or S, Y is hydrogen, R represents hydrogen, C1-C4-alkyl, chlorine, fluorine, bromine, iodine, cyano, C1-C4-alkoxy, aryl, -COOR23where R23is C1-C4-alkyl;

provided that in the formula (1), Z is not if X is-S-, R1is R20R is H, and m = 1;

provided that in formula (7), R4is not hydrogen when Y is 6-F, X is-O-, Z is and n = 2, 3, or 4;

provided that in formula (11), R12is not H when Z is X is where R2represents lower alkyl, aryl(lower alkyl), or phenylsulfonyl, Y represents hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, bromine, iodine or a hydroxyl group, and p = 1 or 2;

provided that in formula (11), R12is not H when X is where R2is phenyl, Z is and Y is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, bromine, iodine or hydroxyl which is where R2is aryl and Y is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, bromine, iodine or a hydroxyl group;

provided that in formula (12) if X is-O-, Z is a and Y is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, bromine, iodine or a hydroxyl group, R18and R19are not lower alkyl;

provided that in formula (12), R18and R19are not hydrogen if R1is R20Z is-CH-, X is-O-, and Y is 6-F;

moreover, the scope of the present invention includes all geometric, optical and stereoisomers of the above compounds, or their pharmaceutically acceptable acid additive salt.

The present invention also relates to a pharmaceutical composition that includes a compound of the present invention and a pharmaceutically acceptable carrier. In one of the embodiments of the present invention, the mentioned pharmaceutical composition is an antipsychotic composition comprising the compound of the present invention in a quantity sufficient to produce an antipsychotic effect.

In addition, the present invention apply is soedineniya of the present invention.

Finally, the present invention relates to a method of reducing pain by injecting the patient connection of the present invention in amounts effective for relief of pain.

Compounds of the present invention can be used as a neuroleptic and analgeziruushim funds. Compounds of the present invention may have several different substituents and chemical groups. The term "lower" used in this description when defining a specific group means that this group contains from 1 to 6 carbon atoms.

The term "alkyl" used in the present description, means a straight or branched hydrocarbon group containing no unsaturation, such as methyl, ethyl, isopropyl, 2-butyl, neopentyl, or n-hexyl.

The term "alkoxy" used in the present description, means a monovalent Deputy comprising alkyl group attached through an oxygen atom of the ether residue, and having its svobodovaflat communication through the specified oxygen atom; in this case, as an example, the alkoxy groups can serve as methoxy, ethoxy-, propoxy-, butoxy-, or intoxi group.

The term "allyssa alkyl group, having valence bonds on two terminal carbon atoms, ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), or isopropylene (-CH2CHCH2-).

The term "cycloalkyl" means a saturated hydrocarbon group possessing at least one carbocyclic ring containing from 3 to 10 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclodecyl etc.

The term "alkanoyl" means a radical formed by removal of the hydroxyl functional groups of alanovoy acid. In particular, used in the present description, the term "alkanoyl" refers to alkylcarboxylic part, containing from 2 to 11 carbon atoms, for example,

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and other Examples alkanoyl groups can serve as formyl, acetyl, propionyl, 2,2-dimethylethyl, hexanoyl, octanoyl, decanoyl, etc.

The term "albanova acid" refers to a compound formed by combining the 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, etc.

The term "lower alkylthio" refers to monovalent Deputy, having the formula lower alkyl-S-.

The term "phenylsulfonyl" refers to monovalent Deputy, having the formula: phenyl-SO2-.

The term "acyl" refers to the Deputy, having the formula

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The term "lower monoalkylamines" refers to the monosubstituted derivative of ammonia, where the hydrogen of the ammonia substituted lower alkyl group.

The term "lower dialkylamino" refers to a disubstituted derivative of ammonia, where the two hydrogen atoms of ammonia are replaced by alkyl groups.

The term "acylamino" refers to a primary or secondary amine, in which hydrogen is substituted by an acyl group, as defined above.

The term "dialkylaminoalkyl" refers to a derivative of the acid, the hydroxyl group of which is substituted lower dialkylamino group.

The term "aroyl" refers to a disubstituted the carbonyl, in which at least one Deputy is an aryl group defined above.

If these are not specifically used in the present description, the term "halogen" refers to a member of cemetery, represented by chemical formulas and names of compounds include all geometric, optical and stereoisomers of these compounds, if any.

A. Compounds of the present invention.

Compounds of the present invention can be represented by the following formula

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where X represents-O-, -S-, NH - or-N-R2;

R2choose from the following groups: lower alkyl, aryl(lower alkyl), aryl, cycloalkyl, aroyl, alkanoyl, and phenylsulfonyl;

p = 1 or 2;

Y is hydrogen, lower alkyl, hydroxy, chlorine, fluorine, bromine, iodine, lower alkoxy, trifloromethyl, nitro, or amino, when p = 1 and Y is lower alkoxy, hydroxy and halogen when p = 2, and X is-O-;

Q1choose from a group that includes

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where Z is a

Y2choose from a group that includes

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in which R1is R20, R21or R22where R20is -(CH2)nwhere n = 2, 3, 4 or 5; R21represents-CH2-CH=CH-CH2-, -CH2-CH=CH-CH2-CH2-, -CH2-CH2-CH=CH-CH2- or where-CH=CH-bond is CIS or TRANS; R22is R20or R21where one or more atoms by piropos, phenyl group, or a group:

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where Z1- lower alkyl, -OH, lower alkoxy, -CH3, -NO2, -NH2or halogen;

R and m are defined below;

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where R1defined above;

R3- hydrogen or-CHO3;

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where R1defined above;

R4is hydrogen, lower alkyl, lower alkoxy, hydroxy, amino, mono - or dialkylamino, C1-C3-acylamino, C1-C6-alkanoyl, trifloromethyl, chlorine, fluorine, bromine,

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where aryl is phenyl or

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where R5is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamines, lower dialkylamino, nitro, cyano, trifluromethyl, trifluromethane;

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where R1and R4defined above;

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where one of Yyand Xzrepresents a

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and the other represents-CH2-;

R5is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, or bromine;

R1defined above;

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where R1and R4defined above;

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where q = 1, 2, 3 or 4;

where R1and R4defined above;

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where R1defined above;

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where R1defined above;

Q2is S, NH, and

where R12selected from the group comprising hydrogen;

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where R13selected from hydrogen and (C1-C12)alkyl groups, R14selected from hydrogen and (C1-C12)alkyl groups, NR15R16taken together form a ring structure selected from piperidinyl, morpholinyl, and piperazinil; R17selected from lower alkyl and aryl groups;

(12) -R1-NR18R19< / BR>
where R18and R19independently selected from the group comprising hydrogen; (C1-C12-straight or branched alkyl);

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NR18R19taken together form a ring structure selected from piperidinyl, morpholinyl, and piperazinyl;

(13) -R1-S-R12< / BR>
where R1and R12defined above;

R is hydrogen, lower alkyl, lower alkoxy, hydroxyl, carboxyl, chlorine, fluorine, bromine, iodine, amino, lower mono - or dialkylamino, nitro, lower alkylthio, trifluromethane, cyano, acylamino, trifloromethyl, triptorelin, aminocarbonyl, monoalkylamines, dialkylaminoalkyl, formyl,

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< / BR>
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where the alkyl is lower alkyl, aryl is as defined above; heteroaryl feedlabsm a hydrogen, lower alkyl, or acyl; R8represents lower alkyl; R9represents hydroxy, lower alkoxy, or-other10; R10represents hydrogen, lower alkyl, C1-C3-acyl, aryl,

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where aryl and heteroaryl are as defined above; m = 1, 2, or 3;

provided that in formula (9), Z is not if X is-S-; Q2is-CH2-, Y is hydrogen, lower alkyl, lower alkoxy, halogen, hydroxy, or trifluromethyl; and p = 1 or 2;

provided that in the formula (4), R4is not H, if R1is R20That Z is not X is-S-S-, Y is hydrogen, halogen lower alkyl, lower alkoxy, hydroxy or trifloromethyl, and p = 1 or 2;

provided that in formula (9), Z is not if X is Y is hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, or trifloromethyl, and Q2is-CH2-;

provided that in formula (9), Z is not if X is-O-, Q2is-CH2Y is hydrogen, lower alkyl, lower alkoxy, hydroxy, or halogen, and p = 1 or 2;

provided that in formula (9), Z is not if X is-S-, Q2is-CH2, Y is bogoslovii, in the formula (9), Z is not if X is Q2is-CH2, R is chlorine, fluorine, bromine, iodine, lower alkyl, lower alkoxy; lower alkylthio, lower mono - or dialkylamino, amino, cyano, hydroxy, trifluoromethyl; R2is aryl; Y is hydrogen, halogen, lower alkyl, lower alkoxy or hydroxy; p = 1 or 2;

provided that in formula (9), Z is not if X is lower alkyl, aryl(lower alkyl) or phenylsulfonyl; Y is hydrogen, halogen, lower alkyl, lower alkoxy or hydroxy, p = 1 or 2 and Q2is-CH2-;

provided that Y2is not part of the formula (8), if Z is X is O, p = 1; and Y represents hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, bromine, iodine or a hydroxyl group;

provided that in the formula (1), Z is not if X is O or S; Y is hydrogen; R is hydrogen, C1-C4-alkyl, chlorine, fluorine, bromine, iodine, cyano, C1-C4-alkoxy, - aryl, -COOR23where R23is C1-C4-alkyl;

provided that in the formula (1), Z is not if X is-S-; R1is R20; R is H, and m = 1;

provided that in formula (7), Rthe ule (11), R12is not hydrogen when Z is X is where R2represents lower alkyl, aryl(lower alkyl), or phenylsulfonyl; Y represents hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, bromine, iodine or a hydroxyl group; and p = 1 or 2;

provided that in formula (11), R12is not hydrogen if X is where R2is phenyl, Z is and Y is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, bromine, iodine or a hydroxyl group;

provided that in formula (12), R18and R19are not alkyl when Z is X is where R2is aryl and Y is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, bromine, iodine or a hydroxyl group;

provided that in formula (12), R18and R19are not lower alkyl when X is-O-, Z is-CH-; and Y represents hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, bromine, iodine or a hydroxyl group;

provided that in formula (12), R18and R19are not hydrogen if R1is R20Z is X is-O-, and Y is 6-F;

in addition, the scope of the present invention includes all geometric, optical and stereos the means of the present invention can be represented by the following formula:

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where the Deputy X is chosen from-O-, -S-, -NH-or-N-R2. If the Deputy X is-O-, the compound of the present invention contains 1,2-benzoxazolinone the core; and when X is-S-, the compound of the present invention contains 1,2-benzisothiazolinone the core. If X is-NH - or-N-R2then the connection of the present invention contains indazol the kernel.

If in the formula (1) p = 1, then Deputy Y is selected from hydrogen, lower alkyl, hydroxyl, halogen, lower alkoxy, -CF3, -NO2and-NH2. Preferably, if the Deputy Y is a 5 - or 6-position of the nucleus. In a preferred embodiment of the present invention, Deputy Y represents hydrogen, chlorine, bromine, or fluorine, particularly preferably, when Y is fluorine, for example, in the 6-position of the nucleus.

If in the formula (1), p = 2, and X is-O-, Deputy Y may be independently selected from a lower alkoxy group, hydroxy group or halogen group, and preferably, if Y is a methoxy group.

If the Deputy Y2has the formula (b) (1)

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and R1has unsaturation, R1preferably has the formula-CH2-CH= CH-CH2-.

If cover is1-C6alkylcarboxylic, and n = 3.

If the Deputy Y2has the formula (b) (4):

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the substituent R4is preferably hydrogen or

< / BR>
and n preferably is 1 or 2.

If the Deputy Y2has the formula (b) (5):

< / BR>
the substituent R'5preferably is-OCH3and preferably n is 3.

If the substituent R4has the formula (b) (6):

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the substituent R4is preferably

< / BR>
and preferably n is 3.

If the Deputy Y2has the formula (b) (7):

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the substituent R4is preferably hydrogen, and n is preferably 3 or 4.

If the Deputy Y2has the formula (b) (8):

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then n is preferably 3 or 4.

If the Deputy Y2has the formula (b) (9)

< / BR>
the substituent R6preferably a is-CH2-CH=CH2-CH2in that case, if R6has unsaturation.

If the substituent R is

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Deputy Q3is preferably-CH=N, and Deputy preferably W is CH2; the substituent R8in CHR8is the site shall sing, or NH2and the substituent R10in other10is preferably hydrogen.

In the above formulas, n may be equal to 2, 3, 4 or 5, and preferably 2, 3 or 4. In particularly preferred compounds, n = 3.

If in the compounds of the present invention, X is

< / BR>
the substituent R2choose from the following groups: lower alkyl, aryl(lower alkyl), aryl, cycloalkyl, aroyl, alkanoyl, and phenylsulfonyl.

If the compound of the present invention is a derivative of heteroarylboronic, Deputy Z can represent and if the connection of the present invention is derived heteroarylboronic, then Z can be If the Deputy Q1has the formula

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the connection of the present invention is heteroarylboronic. Preferred compounds of the present invention are heteroarylboronic, i.e., compounds in which Z is-CH-.

Compounds of the present invention may contain 1, 2 or 3 R-substituent. The substituent R may be a lower alkyl, C1-C6-Alcoi, hydroxyl, carboxyl, Cl, F, Br, I, amino, C1-C6-mono - or dialkylamino, -NO2
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< / BR>
or

< / BR>
< / BR>
where the alkyl is lower alkyl; aryl is phenyl or

< / BR>
(where R5represents hydrogen, lower alkyl, C1-C6-alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, C1-C6-alkylamino, -NO2-, -CN, -CF3, -OCF3); heteroaryl is

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

W is CH2or CHR8or N-R9;

R7is hydrogen, lower alkyl, or acyl;

R8is lower alkyl;

R9is a hydroxy group, a lower alkoxy group, or-other10;

R10represents hydrogen, lower alkyl, C1-C3-acyl, aryl,

< / BR>
where aryl and heteroaryl are the same as defined above; and m = 1, 2, or 3.

If the compounds of the present invention contain two or three R-substituent, then each R-Deputy may be independently selected from the substituents mentioned above. Preferably, if each of the R substituents chosen from hydrogen, C1-C3-alkyl, C1-C3-alkoxy, hydroxyl, -COCF3C1-C6alkanoyl, Cl, F, Br, I, C1-C3-alkylamino, -NO2, -CF3, -OCF3,

< / BR>
< / BR>
Getting the e number of m, n and p are as defined above.

B. Obtaining the compounds of the present invention.

Compounds of the present invention can be obtained by reaction of the piperidine or piperazine of the formula

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or pyrrolidine formula

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in the conditions of alkylation with a compound of the formula

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where HAL is chlorine, bromine or iodine.

These procedures can be used to obtain piperidines, piperazines, and pyrrolidines, and alkylating agents identified by the above formula, and their detailed description is provided below.

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

Compounds of the formula

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used for synthesis indazol-substituted piperazines of the present invention, can be obtained as follows.

Substituted complex arrowy ether of the formula (7)

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where R11is lower alkyl;

HaL is a halogen selected from chlorine, bromine, and iodine,

subjected to reaction with hydrazine, H2NNH2in standard conditions, usually used to obtain hydrazine. Typically, this reaction is carried out in an inert solvent, such, ka is orites, during the period of time from 4 to 16 hours; and the result of this reaction have the hydrazide of formula (8)

< / BR>
The hydrazide of formula (8) is subjected to reaction with phenylsulfonylacetate formula

< / BR>
where HaL is a halogen selected from chlorine and bromine;

and the result of this reaction obtain the connection formula

< / BR>
This reaction is mainly carried out in a basic solvent such as pyridine or kallidin, at a temperature of from 0oC to 30oC for 2-16 hours.

The compound of formula (10), in turn, is subjected to reaction with thionyl chloride at a temperature of from 50oC to 79oC (temperature distillation) for 2-16 hours, resulting in a receive connection formulas

< / BR>
The compound (11) is subjected to reaction with the compound of the formula

< / BR>
where R11is lower alkyl,

under standard conditions the reaction of nucleophilic substitution, for example, in an inert solvent, such as tetrahydrofuran (THF), toluene, or diethyl ether; at a temperature of from 5oC to 50oC and over a period of time from 1 to 16 hours; however, as a result of the reaction obtain the connection formula

< / BR>
Then connected the formula (13) is subjected to reaction with condensing, or tetramethylrhodamine, at a temperature of from 120oC to 177oC, and during the period of time from 1 to 16 hours, resulting in a gain piperazine-substituted phenylsulfonyl formula

< / BR>
Then the compound of formula (14) is subjected to reaction with a standard cyanation agent, such as halogenation, for example, Enrichment or ClCN, under standard conditions, usually used in the reaction of cyanide, for example in an inert solvent, such as dimethylsulfoxide (DMSO) or CHCl3at room temperature, over a period of time from 2 to 16 hours, and the result of this reaction receive cyano-substituted piperazinylcarbonyl formula

< / BR>
After that, the connection formula (15) is subjected to reduction reaction of using a metal hydride, such as alumalite lithium (LiAlH4). Typically, the reduction is carried out in standard conditions of recovery, for example, in a solvent such as tetrahydrofuran or diethyl ether, at a temperature 35-67oC for 6-16 hours, and the result of this reaction obtain the connection formula

< / BR>
The compound of formula (16) can be obtained in an alternative way, for example, first by reaction of compounds of formulas is led sodium, or KOH in tetrahydrofuran, resulting in a receive connection formulas

< / BR>
This reaction is usually carried out in a polar solvent, such as, for example, CH3OH or C2H5OH, at a temperature of from room temperature to 50oC for 1-16 hours.

Alternatively, the compound of formula (17) can be obtained by reduction reaction of (14) using LiAlH4and in the conditions described above.

The compound of formula (17), in turn, can be subjected to reaction with a cyanation agent described above, with the formation of the cyano-substituted piperazineethanol formula

< / BR>
which may be subjected to reduction reaction of using a metal hydride, as described above, and obtaining the compounds of formula (16).

In an alternative embodiment of the present invention, the compound of formula (18) can be subjected to reaction with an aqueous solution of mineral acid, for example, H2SO4or HCl, at a temperature of from 50oC to 120oC for 2-16 hours, the result can be obtained compound of the formula (16).

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

Connection procedure described in J. Med. Chem. 1986, 29:359. The compounds of formula (19) can be used to synthesize benzisoxazol-substituted piperazines of the present invention.

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

The compounds of formula

< / BR>
used for synthesis benzisothiazol-substituted piperazines of the present invention, can be obtained in accordance with the standard technique described in J. Med. Chem. 1986, 29:359 and in the patent of great Britain (GB) N 2163432 A.

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

The compounds of formula

< / BR>
< / BR>
used for synthesis indazol-substituted piperidine of the present invention can be obtained by standard methods. For example, suitable for this purpose methods are described in detail in U.S. patent 4 710 573.

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

The connection formulas

< / BR>
can be obtained by methods described in the following sources. For example, in U.S. patent 4 355 037-described compounds of formula (23) and methods for their preparation. In addition, methods of producing compounds of the formula (23) is described in U.S. patent No. 4 327 103, and in the work Strupczewski and other J. Med. Chem. 28: 761-769 (1985). Bretania.

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

Some 3-(4-piperidinyl)-1,2-benzisothiazole can be used in the synthesis of N-(aryloxyalkyl)heteroarylboronic of the present invention. In particular, benzisothiazol formula

< / BR>
may be subjected to reaction with an alkylating agent, described above, to obtain N-(aryloxyalkyl)heteroarylboronic of the present invention. The compounds of formula (24) and methods for their preparation are described in detail in U.S. patent 4 458 076.

7. Receiving alkylating agents.

Compounds described in Parts 1-6 (see above), can be subjected to reaction with alkylating agents of the formula

< / BR>
obtaining N-(aryloxyalkyl)heteroarylboronic, piperazines and pyrrolidines of the present invention. Alkylating agents of the formula (4) and methods for their preparation are described in U.S. patent No. 4 366 162. Furthermore, the description of alkylating agents and methods of their preparation are given in the publication South Africa EA 86 14522. In addition, the methods of obtaining the alkylating agents described in the Examples below. These methods can be used to obtain other alkylating agents intended for the purposes of the present invention.

retene.

Heteroarylboronic, piperazines, and pyrrolidine described above in paragraphs 1-6, may be subjected to reaction under the conditions of alkylation with alkylating agents described in 7 o'clock, in order to obtain the compounds of the present invention. This reaction can be carried out by dissolving the reagents in an inert solvent, such as dimethylformamide, acetonitrile, or butanol, followed by reaction of these reagents at a temperature of from 50oC to the temperature of distillation of the solvent in the presence of an acid acceptor, such as a ground. Examples of suitable bases are alkali metal carbonates such as potassium carbonate, sodium carbonate, or sodium bicarbonate. This reaction can be carried out in the absence or in the presence of catalytic amounts of alkali metal iodide such as sodium iodide or sodium iodide, in a period of time sufficient to obtain the compounds of formula (1) of the present invention. Typically, the alkylation reaction is conducted for from about 4 to about 16 hours, depending on the reactivity of the reagents. The reaction temperature can vary from about 50oC to about 120oC. the compounds Obtained can be isolated by elevayta with water; washing; drying; and concentrating the organic solvent to obtain the free base; and if necessary, with subsequent conversion of the obtained compound in its acid additive salt using standard procedures.

The above procedure can be used to obtain, for example, the following typical compounds of the present invention:

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-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] propoxy]-3-methoxyphenyl]Etalon;

1-[4-[4-[4-(1,2-benzisoxazol-4-yl)-1-piperidinyl]butoxy]-3 - methoxyphenyl]Etalon;

1-[4-[4-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] butoxy]-3-methoxyphenyl]Etalon;

1-[4-[2-[4-(1,2-benzisoxazol-3-yl)-1-piperidinyl] ethoxy]-3 - methoxyphenyl]ethanone fumarate;

1-[4-[4-[4-(1H-indazol-3-yl)-1-piperidinyl]butoxy]-3 - methoxyphenyl]ethanone fumarate;

1-[4-[4-[2-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] ethoxy]-3-methoxyphenyl]Etalon;

4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] propoxy]-3-methoxy - methylbenzylamino;

1-[4-[3-[4-(1,2-benzisoxazol-3-yl)-1-piperidinyl] propoxy]-n;

1-[4-[3-[4-(6-the fluorescent-1H-indazol-3-yl)-1-piperazinil] propoxy] -3-hydroxyphenyl]Etalon;

1-[4-[4-[4-(6-the fluorescent-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;

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

1-[4-[3-[4-(5-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] propoxy]-3-methoxyphenyl]Etalon;

6-fluorescent-3-[1-[3-(2-methoxyphenoxy)propyl] -4-piperidinyl] - 1,2-benzisoxazole fumarate;

4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] propoxy] -3-methoxyphenyl]phenylmethanone;

1-[4-[4-[4-(1H-indazol-3-yl)-1-piperidinyl]butoxy] -3-methoxyphenyl]Etalon;

1-[4-[2-[4-(6-chloro-1,2-benzisoxazol-3-yl)-1-piperidinyl] ethoxy]-3-methoxyphenyl]Etalon;

1-[3-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] propoxy]phenyl]ethanone fumarate;

1-[4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] propoxy]-2-were]Etalon;

1-[2-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] propoxy]-5-were]Etalon;

N-[4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] propoxy]-3-methoxyphenyl]ndimethylacetamide hemifumarate;
]Etalon;

1-[4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] propoxy]-3-methoxyphenyl]ethanone hemifumarate;

1-[4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] propoxy]phenyl]Etalon;

1-[4-[3-[4-(6-chloro-1H-indazol-3-yl)-1-piperidinyl] propoxy]-3-methoxyphenyl]Etalon;

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

4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] propoxy] -3-methoxybenzonitrile;

1-[4-[4-[4-(6-the fluorescent-1H-indazol-3-yl)-1-piperidinyl] butoxy]-3-methoxyphenyl]Etalon;

1-[4-[3-[4-(1-benzoyl-6-fluorescent-1H-indazol-3-yl)-1-piperidinyl] propoxy] -3-methoxyphenyl]ethanone sesquifumarate;

1-[4-[4-(6-chloro-1H-indazol-3-yl)-1-piperidinyl] butoxy]-3-methoxyphenyl Etalon;

1-[4-[3-[4-(1,2-benzisothiazol-3-yl)-1-piperidinyl] propoxy]-3-methoxyphenyl]ethanone hemifumarate;

1-[3,5-dibromo-4-[3-[4-(6-the fluorescent-1,2-benzisothiazol-3-yl)-1 - piperidinyl] propoxy]phenyl]Etalon;

1-[4-[2-(1,2-benzisothiazol-3-yl)-1-piperidinyl] ethoxy]-3-methoxyphenyl] Etalon;

6-fluorescent-3-[1-(3-phenoxypropan)-4-piperidinyl]-1,2-benzisoxazol;

1-[4-[2-[4-(6-chloro-1H-indazol-3-yl)-1-piperidinyl] ethoxy]-3-methoxyphenyl]Etalon;

1-[4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] propoxy]-3-methylmercaptopurine]Etalon;

1-[4-[4-[4-(1,2-bensiz the yl] propoxy]-3-methoxyphenyl]phenylmethanone;

1-[3-bromo-4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl]propoxy]phenyl]Etalon;

3-[1-[3-[4-(1-ethoxyethyl)-2-methoxyphenoxy)propyl] -4 - piperidinyl]-6-fluorescent-1,2-benzisoxazole]hydrochloride;

3-[1-[3-[4-(1-acetoxyethyl)-2-methoxyphenoxy)propyl] -4 - piperidinyl]-6-fluorescent-1,2-benzisoxazole fumarate;

1-[4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl] propoxy]-3-methoxyphenyl]pentanone;

2-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] - propoxy- -methylbenzenamine hemifumarate;

3-[1-[3-(4-bromo-2-methoxyphenoxy)propyl] -4-piperidinyl]-6 - fluorescent-1,2-benzisoxazol;

1-[4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] - propoxy]-3-methoxyphenyl]propanone;

4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] - propoxy]-3-methoxybenzamide;

1-[4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] - propoxy]-3-(methylamino)phenyl]Etalon;

1-[4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] - propoxy]-3-ethoxyphenyl]Etalon;

N-[2-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] - propoxy] phenyl]ndimethylacetamide;

1-[4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] - propoxy]-3-dimethylaminophenyl]Etalon;

1-[4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] - propoxy]-2-methoxyphenyl]ethanone hydrochloride;

1-[4-[3-[4-(�antisocial-3-yl)-1-piperidinyl] - propoxy]-3-hydroxy-methoxybenzylamine;

2-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] - propoxy]the aniline dihydrochloride;

N-[5-acetyl-2-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl]propoxy]phenyl]ndimethylacetamide;

3-[1-[3-(4-ethyl-3-methoxyphenoxy] propyl] -4-piperidinyl)- 6-fluorescent-1,2-benzisoxazole hydrochloride;

1-[3,5-dimethoxy-4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)- 1-piperidinyl]propoxy]phenyl]Etalon;

N-[3-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)- 1-piperidinyl]propoxy]phenyl]ndimethylacetamide hemifumarate;

3-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)- 1-piperidinyl]propoxy]aniline;

3-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)- 1-piperidinyl]propoxy]-4-methoxyaniline;

1-[4-[3-[4-(6-the fluorescent-1,2-benzisothiazol-3-yl)- 1-piperidinyl] propoxy]-3-methylaminophenol]ethanone]fumarate;

N-[3-[3-[4-(6-the fluorescent-1,2-benzisothiazol-3-yl)- 1-piperidinyl] propoxy]-4-methoxyphenyl]ndimethylacetamide;

1-[4-[3-[4-(6-the fluorescent-1,2-benzisothiazol-3-yl)- 1-piperidinyl] propoxy]-3-methoxyphenyl]ethanone hydrochloride;

N,N-dimethyl-4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)- 1-piperidinyl]propoxy]-3-methoxybenzamide;

1-[4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)- 1-piperidinyl] propoxy]-3-methoxyphenyl]ethanone the oxime;

1-[4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)- 1-piperidinyl]propoxy]-methoxybiphenyl]ethanone hydrazone;

6-fluorescent-3-[1-[3-[2-methoxy-4-(1-methylethenyl)phenoxy] propyl]-4-piperidinyl]-1,2-benzisoxazole hydrochloride;

(Z)-1-[4-[(4-chloro-2-butenyl)oxy]-3-methoxyphenyl]Etalon;

(Z)-1-[4-[[(4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] -2 - butenyl]oxy]-3-methoxyphenyl]Etalon;

(E)-1-[3-[[-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] -2 - butenyl]oxy]-4-hydroxyphenyl]ethanone hydrochloride;

(E)-1-[3-[[4-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl] -2-butenyl]oxy]-4-benzyloxyphenyl]Etalon;

6-(3-chloropropoxy)-5-methoxyindol;

6-fluorescent-3-[1-[3-[[(5-methoxy-1H-indol-6-yl)oxy] propyl]- 4-piperidinyl] -1,2-benzisoxazol;

6-fluorescent-3-[1-[3-[(1H-indol-7-yl)oxy] propyl] - 4-piperidinyl]-1,2-benzisoxazole hemifumarate;

6-fluorescent-3-[1-(3-hydroxypropyl)-4-piperidinyl] - 1.2 benzisoxazol;

6-fluorescent-3-[1-(2-pyrimidinone)propyl] -4-piperidinyl]-1,2 benzisoxazole fumarate;

6 Aceto-2-[4-(6-fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] methyl-1,4-benzodioxan;

2-[4-(6-fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] methyl - 1,4-benzodioxan;

2-[4-(6-fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] ethyl - 1,4-benzodioxan;

6-(3-chloropropoxy)-7-methoxy-1-tetralone;

6-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] propoxy] 7-methoxy-1-tetralone;

N-(3-chloropropyl the 1-piperidinyl] propyl] 6-acetyl-2-benzoxazolinone;

N-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl] phthalimide;

1-(3-aminopropyl)-4-(6-fluorescent-1,2-benzisoxazol-3-yl)- piperidine the dihydrochloride;

CIS-2-(3-(4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl propyl]-hexahydro-1H-isoindole-1,3-dione hydrochloride;

N-[4-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] butyl]phthalimide;

1-(4-aminobutyl)-4-(6-fluorescent-1,2-benzisoxazol-3-yl)piperidine, the dihydrochloride;

CIS-2-(4-(4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl) butyl)-hexahydro-1H-isoindole-1,3-dione hydrochloride;

1-[4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] propyl]thio] -3-methoxyphenyl Etalon;

4-(6-fluorescent-1,2-benzisoxazol-3-yl)-1-(2'-methoxyphenyl)- butylpiperazine maleate;

4-(4-bromobutyl)-1-(1,3-dition-2-yl)ethylbenzene;

1-[4-(1,3-dition-2-yl)ethylphenyl - 4-(6-fluorescent-1,2-benzisoxazol-3-yl)butylpiperazine;

1-[4-(4'-acetogenin)butyl - 4-(6-fluorescent-1,2-benzisoxazol-3-yl)piperidine;

1-[4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] propylamino] -3-methoxyphenyl]Etalon;

(2,4-defloriani)-1-[1-(phenylmethyl)-3-pyrrolidinyl]-methanone oxalate;

6-fluorescent-3-[1-phenylmethyl)-3-pyrrolidinyl]-1,2-benzisoxazole fumarate;

(E)-1-[4-[(4-bromo-2-butenyl)oxy]-3-methoxyphenyl]Etalon;

4-(3-chloropropoxy)-3-methoxybenzo is)-1-piperidinyl] propylamino] -3-hydroxyphenyl]Etalon;

1-[3-acetylamino-4-(3-chloropropoxy)phenyl]Etalon;

N-[2-(3-hydroxypropoxy)phenyl]ndimethylacetamide;

4-(3-chloropropoxy)-3-methoxybenzaldehyde;

()-1-[4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl]-2-methylpropoxy]-3-methoxyphenyl]Etalon;

(S)-(+)-1-[4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl]-2-methylpropoxy]-3-methoxyphenyl]Etalon;

(R)-(-)-1-[4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl]-2-methylpropoxy]-3-methoxyphenyl]Etalon;

1-[4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl] -2,2-DIMETHYLPROPANE]-3-methoxyphenyl]Etalon;

(+)-1-[4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl]-2-phenylpropoxy]-3-methoxyphenyl]Etalon;

()-1-[4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl] -2-(3-course)propoxy]-3-methoxyphenyl]Etalon;

()-1-[4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl] -2-(phenylmethyl)propoxy]-3-methoxyphenyl]Etalon;

()-1-[4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl]-1-methylpropyl]-3-methoxyphenyl]Etalon;

()-1-[4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl]-3-methylpropoxy]-3-methoxyphenyl]Etalon;

()-1-[4-[4-[4-(1,2-benzisoxazol-3-yl)-1 - piperidinyl]-3-methylbutoxy] -3-methoxyphenyl]Etalon;

()-1-[4-[4-[4-(1,2-benzisoxazol-3-yl)-1 - piperidinyl]-3-phenylmethoxy] -3-methoxyphenyl]ethane[4-(6-fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl]-1-methylethoxy]-3-methoxyphenyl]Etalon;

(E)-1-[4-[[4-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl]-1-methyl-2-butenyl]oxy]-3-methoxyphenyl]Etalon;

(Z)-1-[4-[[4-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl]-3-methyl-2-butenyl]oxy]-3-methoxyphenyl]Etalon;

()-1-[4-[[4-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl]-1-propyl-2-butenyl]oxy]-3-methoxyphenyl]Etalon;

(S)-(+)-1-[4-[3-[4-(6-the fluorescent-1H-indazol-3-yl)-1 - piperidinyl] -2-methylpropoxy]-3-methoxyphenyl]Etalon;

(R)-(-)-1-[4-[3-[4-(6-the fluorescent-1H-indazol-3-yl)-1 - piperidinyl] -2-methylpropoxy]-3-methoxyphenyl]Etalon;

()-1-[4-[[4-[4-(1,2-benzisothiazol-3-yl)-1 - piperidinyl]-3-methylbutoxy] -3-methoxyphenyl]Etalon;

()-1-[4-[4-[4-(1,2-the fluorescent-6-benzisoxazol-3-yl)-1 - piperidinyl] -2-phenylpropoxy]-3-methoxyphenyl]Etalon; and

()-6-fluorescent-3-[1-[3-(2-methyl-(2-methoxyphenoxy)propyl] - 4-piperidinyl] -1,2-benzisoxazol.

Compounds of the present invention can be used for the treatment of psychosis, since these compounds have the ability to call in mammals antipsychotic response. Antipsychotic (or neuroleptic) activity was determined by the method of analysis climbing out mice, similar to the method described by P. Protais et al. Psychopharmacol., 50 : 1 (1976) B. Costall, Eur. J. Pharmacol. 50 : 39 (1978).

Of male mice (SC-1 (23-27 grams) divided bolotnoe mesh (4" to 10") and left for one hour to adapt to the new conditions. After that, the animals were injected subcutaneously injected apomorphine dose of 1.5 mg/kg, i.e., the dose that causes rearing all mice within 30 minutes. Compounds analyzed for antipsychotic activity, were intraperitoneally injected with (i. p. or introduced in the form of oral doses at different time intervals (for example, 30 minutes, 60 minutes, etc. until provocative injection of apomorphine) and different doses of 10-60 mg/kg

To assess clamber after injection of apomorphine, animal behavior was evaluated 3 times: 10, 20 and 30 minutes after injection of apomorphine, according to the following rating scale:

The behavior of climbing mice - Score

4 paws on the bottom of the cells (climbing missing) - 0

2 paws on the wall of the cage (vertical column) - 1

4 paws on the wall of the cage (rearing) - 2

Mice that are constantly clambered over the walls of the cells before injection of apomorphine, were excluded from the experiment.

When behavior is measured as the full scale, the animals still "hung" on the walls of the cells over an extended period of time. Conversely, weak rearing was only estimated as increased motility in the behavior of the animal, continuing in just a few seconds.50
with confidence limits of 95% were calculated using linear regression analysis. ED50-values for some compounds of the present invention, as well as to standard neuroleptic drugs are presented in Table 1.

Antipsychotic response is achieved with the introduction of the compounds of the present invention to an individual in need of such introduction, effective oral, parenteral or intravenous dose comprising from 0.01 to 50 mg per kg of body weight per day. However, it should be noted that the specific dose will vary for each individual, and depending on the needs of the body they can be adjusted by a specialist. In addition, it should be noted that in the present description of the dose is purely illustrative and should not be construed as a limitation of the present invention.

Due to its ability to pain in mammals, some compounds of the present invention can be used as analgesics. The compounds of this is consistent convulsions in mice that is the standard test for analgesia (see Proc. Soc. Exptl. Biol. Med. 95: 729 (1957)). For example, in this analysis introduction subcutaneous (s.c.) doses of the test compounds to mice has produced in them a response, which was assessed (see Table 2) as the amount of approximately 50% inhibition (ED50) seizures in mice.

Analgesia can be achieved by introducing compounds of the present invention to an individual in need of such introduction, as an effective oral, parenteral or intravenous dose comprising from 0.01 to 100 mg/kg of body weight per day.

However, it should be noted that the specific dose for each individual can vary depending on the needs of the body, these doses can be adjusted by a specialist. In addition, it should be noted that in the present description of the dose is purely illustrative and should not be construed as a limitation of the present invention.

Effective amounts of compounds of the present invention can be introduced individuals in several ways, for example, orally as capsules or tablets; parenterally in the form of sterile solutions or suspensions, and in some who are themselves effective, can be obtained and introduced in the form of their pharmaceutically acceptable additive salts, which give the songs stability, improve its crystallochemistry and solubility, etc., the Preferred pharmaceutically acceptable additive salts are salts of mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, etc.; salt uniaxial carboxylic acids, such as acetic acid, propionic acid, etc., salt dvuhosnovnyj carboxylic acids, such as maleic acid, fumaric acid and so forth; and salt trekhosnovnykh carboxylic acids, such as carboxyesterase acid, citric acid, etc.

Effective amounts of compounds of the present invention can be administered orally, for example, in combination with an inert diluent or excipient suitable for human consumption. These compounds can be incorporated in gelatin capsules or compressed into tablets. For oral therapeutic administration, the compounds of the present invention together with an appropriate filler can be used as compositions made in the form of tablets, lozenges, capsules, elixirs, suspensions, syrups, wafers, chewing resinco amount of this compound can vary depending on the form enter the composition, and can be, mainly, from 4% to about 70% by weight of the dosage form. The number of active connections in this composition must conform to the desired dose. In accordance with the present invention, the compositions and preparations are made so that a single oral dosage form contains from 1.0 to 300 mg/active compounds of the present invention.

These tablets, pills, capsules, lozenges, etc. can also contain the following ingredients: a binder, such as microcrystalline cellulose, tragacanth gum, or gelatin; an excipient such as starch or lactose; disintegrity agent, such as alginic acid, primogel, corn starch, etc.; a lubricant such as magnesium stearate or Sterotes; additives that reduce friction, such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; fragrances such as peppermint, methyl salicylate, or orange flavoring. If the composition of the present invention is made in the form of capsules, in addition to the above ingredients, it may contain a liquid carrier such as fatty oil. Other dosage forms can also include I. So, for example, tablets or pills may be coated with sugar, shellac or other intersolubility coatings. Compositions in the form of syrups, in addition to the active ingredient may also contain sweetening agent such as sucrose, some additives, such as, for example, preservatives, dyes, tinted agents and flavouring agents. The materials used for the manufacture of such compositions should be pharmaceutically pure and used in quantities which are not toxic.

The active compound of the present invention, intended for parenteral therapeutic administration, can be incorporated into solutions or suspensions. These preparations should contain at least 0.1% of active compound, however, can vary from 0.5 to about 50% by weight of the composition. The number of active compound in these compositions should be such that it produces a medicinal product with the desired dose. In a preferred embodiment of the present invention, the compositions and preparations are made so that one parenteral dosage form contains from 0.5 to 100 mg of active soedinenii diluent, such as water for injection, saline solution, fatty 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 agents, such as ethylenediaminetetraacetate acid; buffers such as acetates, citrates or phosphates; and toning agents, such as sodium chloride or dextrose. These parenteral compositions can be introduced into ampoules, disposable syringes or containers intended for repeated administration of doses and made of glass or plastic.

The examples below are only for illustrative purposes and should not be construed as a limitation of the present invention. In these examples, if it is not specified particularly, all temperatures are given in degrees Celsius (oC).

Example 1. Getting 1-[4-[3-[4-(1H-indazol-3-yl)-1-piperazinil] propoxy]-3-methoxyphenyl]ethanone.

(A) Synthesis of 2-vinylsulfonylacetamido 2-bromobenzoic acid

To a solution of hydrazide 2-bromobenzoic acid (132 g) in pyridine (1.2 l) was cooled to about 10ooC)

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

The mixture phenylsulfonylacetate 2-bromobenzoic acid (125 g, 0.35 M) and thionyl chloride (265 ml) was stirred and heated under reflux for 2 hours. Approximately 15 minutes after heating under reflux, the solid was placed in the solution. The reaction mixture was left to cool and then poured into hexane. The obtained solid white collected and received 124 g - chloro-2-bromobenzaldehyde of phenylsulfonylacetate (so pl. 120-122oC).

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

To a stirred solution (under nitrogen atmosphere) - chloro-2-bromobenzaldehyde of phenylsulfonylacetate (271,1 g, 0,72 M) in tetrahydrofuran (2 l) was added one drop of N-methylpiperazine (159,7 g, 1.6 M). The resulting reaction mixture was stirred at room temperature for 3 hours and then left at totaline formed piperazine hydrochloride. The filtrate was concentrated and received a brown resin. This resin triturated with hot acetonitrile and the resulting mixture was cooled in an ice bath, and, when cooled, it was filtered to remove unwanted by-products. The filtrate was concentrated and received 392,9 g of the crude 1-[[(phenylsulfonyl)hydrazono]-2-(2-bromophenyl)methyl]-4-methylpiperazine in the form of a brown resin.

(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 M), copper bronze (3.1 g) K2CO3(11.5g) and dimethylformamide (500 ml) was stirred and heated under reflux for 1.5 hours. After the reaction mixture was poured into water and the aqueous suspension was vigorously stirred with ethyl acetate. The two-phase mixture was filtered through celite, and then the layers were separated. Then the aqueous portion was extracted with another portion of ethyl acetate, then the combined extracts were washed with water and dried with magnesium sulfate. After concentration of the extract, was formed solid substance was pereirae with ether and got to 19.7 g of solid substance. The obtained solid substance was recrystallized from isoprop isopropanol (coal processing) received analytical sample as colorless crystals indazole, 3-(4-methyl-1-piperazinil)-1-phenylsulfonyl-1H-indole (so pl. 160-161oC).

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 M), K2CO3(102 g, 0.74 M) and dimethyl sulfoxide (DMSO) (200 ml), under nitrogen atmosphere, was added brazian (72 g, 0.68 M) dissolved in DMSO (525 ml). The reaction mixture was stirred at room temperature for 5.5 hours, and then poured in H2O (7 l). The solid is formed from solution, was collected by filtration and thoroughly washed with water, resulting in a received 168 g (68%) of the desired product. Sample (5,2 g) was recrystallized twice from ethanol-H2O and obtained 4.0 g of 4-[1-(phenylsulfonyl)-1H-indazol-3-yl]-1-piperidinecarbonitrile (so pl. 178-180oC).

Analysis for C18H17N5O2S:

Calculated: C 58,85%; H 4,66%; 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 solution of 4-[1-(phenylsulfonyl)-1H-indazol-3-yl]-1-piperidinecarbonitrile (163 g, 0 tetrahydrofuran). After complete addition, the reaction mixture was heated under reflux and stirred for 6 hours and then stirred at room temperature for 1 hour, and left over night at room temperature for sedimentation. The reaction was suppressed by careful add (drop) of water. After the termination of the oxygen evolution reaction mixture was filtered, and the precipitate on the filter in the form of lithium salts were washed thoroughly with tetrahydrofuran. This filtrate was combined with the filtrate of another party (all inputs taken together, amounted to 300 g, i.e. 0,82 M), and the combined filtrates were concentrated and received 372 g of yellow solid, suspended in water. An attempt was made to distribute the product between water and dichloromethane, but this product was slightly soluble in dichloromethane. Therefore, this two-phase slurry product was filtered through a funnel fused glass, and the collected white product was dried off and got 121 g of the desired product. Two phases of the filtrate were separated, and the water was again extracted with dichloromethane. Then all of dichloromethane phases were combined, washed twice with water, dried with magnesium sulfate and concentrated in resli, as a result, we obtained 10 g of solid beige color (so pl. 139-150 C). NMR and MS spectra confirmed the structure of the obtained product. 10 g of the obtained product was recrystallized from toluene and received 7.5 g of 3-(1-piperazinil)-1H-indazole (so pl. 153 to 155oC).

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

The stirred mixture of 3-(4-methyl-1-piperazinil)-1-phenyl-sulfonyl - 1H-indazole (13.5 g, 0,038 M), methanol (150 ml) and 25% CH3ONa in methanol (15.3 ml) was stirred and heated under reflux for 2.5 hours. The reaction mixture was concentrated to about 1/10 of its volume, and then to this mixture was added water and got a red solution. The resulting solution was extracted with dichloromethane, the extract was washed with water, dried with magnesium sulfate, and the solvent was concentrated, resulting in a received 6.6 g solid pink color. After two recrystallization from toluene/hexane, obtained 4.3 g (52%) of 3-(4-methyl-1-piperazinil)-1H-indazole in the form of a whitish solid (so pl. 111-113oC).

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 mixed CME is sinil)-1H-indazol (11,0 g, 0,051 M), dissolved in dimethyl sulfoxide (60 ml). The resulting reaction mixture was stirred at room temperature for 1 hour and then poured into water. The aqueous suspension was extracted with ethyl acetate, then ethyl acetate, washed with water, dried with magnesium sulfate and concentrated, resulting in a received 7,8 g (67%) yellow solid. This sample was combined with another image, and twice recrystallized from toluene, which was obtained analytically pure 4-(1H-indazol-3-yl)-1-piperidinecarbonitrile in the form of a white solid (so pl. 120-122oC).

Analysis for C12H13N5(%):

Calculated: C 63,42; H 5,76.

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 M) and 25% solution of sulfuric acid (100 ml) was stirred at reflux for 4.5 hours. Then the reaction mixture was cooled in an ice bath and was podslushivaet by adding (drop by drop) 50% NaOH solution. The resulting alkaline solution was extracted with ethyl acetate. The ethyl acetate was washed with water, dried with magnesium sulfate and concentrated, resulting in a received 5,2 g is C toluene and received 3.0 g of 3-(1-piperazinil)-1H-indazole (so pl. 153 to 155oC).

Analysis for C11H14N4(%):

Calculated: C 65,32; H 6,98; N 27,70.

Found: C 65,21; H 6,99; N 27,80.

(J). 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 M), K2CO3(3.0 g, 0,022 M), 1-[4-(3-chloropropoxy)-3 - methoxyphenyl]ethanone (5,3 g, 0.22 M), several crystals of KI and dimethylformamide (60 ml) was stirred for 5 hours at 90oC. the Reaction mixture was poured into water and the aqueous mixture was extracted with ethyl acetate. The extract obtained was washed with saline, dried with magnesium sulfate, and the solvent was concentrated, resulting in the obtained white solid, which was then triturated with diethyl ether and collected. The result of this procedure was obtained 7.0 g of the desired product. After that, the product is twice recrystallized from absolute ethyl alcohol, resulting in received of 5.3 g (64%) of analytically pure 1-[4-[3-[4-(1H-indazol-3-yl)-1-piperazinil] propoxy]-3-methoxyphenyl] ethanone (so pl. 155-157oC).

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-Benzisoxazole (4.8 g, 0.02 M), K2CO3(of 5.2 g, 0.04 M), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (5.3g, of 0.022 M), several crystals of KI and dimethylformamide (60 ml) was stirred for 16 hours at 90oC. the Reaction mixture was poured into water and the aqueous mixture was extracted with ethyl acetate. The extract obtained was washed with water, dried with magnesium sulfate and concentrated, resulting in the obtained brown oily substance. The obtained oily substance was chromatographically on a Waters Prep. 500, using a column of silica gel (eluent: ethyl acetate/diethylamine, 2%). After concentration of appropriate fractions, received a 3.9 g of the product in the form of a whitish solid. The resulting material was recrystallized 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 in the form of colorless needle-like crystals (so pl. 102-104 C).

Analysis for C24H28N2O4(%):

Calculated: C 70,56; H 6,91; N 6,86.

Found: C 70,73; H 6,93; N 6,85.

Example 3. 1-[4-[3-[4-(6-the Fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl]-propoxy]-3-methoxyphenyl]alanon.

The stirred mixture of 6-fluorescent-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (5.1 g, 0.02 M), KoC. the Reaction mixture was poured into water and the aqueous mixture was extracted with ethyl acetate. Then the ethyl acetate was washed with water, dried with magnesium sulfate and concentrated, resulting in the obtained wet solid. The resulting material is twice recrystallized from ethanol and obtained 5.0 g(58%) 1-[4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidine] propoxy] -3 - methoxyphenyl] ethanone in a solid beige color (so pl. 118-120oC).

Analysis for C24H27FN2O4(%):

Calculated: C 67,70; 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]alanon.

A mixture of 3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (4.3 g, 0,018 M), K2CO3(5.5 g, 0.04 M), 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone (5.5 g, 0,018 M) and dimethylformamide (60 ml) was stirred and heated at 75oC for 16 hours. Then the reaction mixture was poured into water and was extracted with ethyl acetate. The ethyl acetate was washed with water, dried with magnesium sulfate, and the solvent was concentrated, the result of which was obtained 7.2 g solid beige color. The resulting product was twice recrystallize from ethanol and P CLASS="ptx2">

Analysis for C25H30N2O4: (%)

Calculated: C 71,11; H 7,16; N 6,63.

Found: C 70,76; H 7,24; N 6,58.

Example 5. 1-[4-[4-[4-(6-the Fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl] butoxy]-3-methoxyphenyl]alanon.

The stirred mixture of 6-fluorescent-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (5.1 g, 0.02 M), K2CO3(of 5.2 g, 0.04 M), 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone (6.6 g, of 0.022 M) and dimethylformamide (60 ml) was heated for 5 hours at 75oC. 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, resulting in the received first an oily substance, which was then utverjdali when defending. The obtained solid substance was puretravel with hexane and collected, resulting in received of 7.7 g of waxy solid product. The product was chromatographically on a Waters Prep. 500, using a column with silica gel (eluent: dichloromethane/methanol, 5%). After concentration of appropriate fractions, got 5,1 g 1-[4-[4-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl]butoxy] -3 - methoxyphenyl]ethanone in the form of a whitish solid, which is then recrystallized from E.

Analysis for C25H29FN2O4S (%):

Calculated: C 68,16; H 6,64; N 6,36.

Found: C 67,96; H Of 6.49; N 6,29.

Example 6. Fumarate 1-[4-[2-[4-(1,2-benzisoxazol-3-yl)-1 - piperidinyl]ethoxy]-3-methoxyphenyl]ethanone

A mixture of 3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (4.8 g, 0.02 M), K2CO3(of 5.2 g, 0.04 M), 1-[4-(2-chloroethoxy)-3-methoxyphenyl]ethanone (5.0 g, of 0.022 M) and dimethylformamide (90 ml) was heated for 16 hours at 90oC. 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, resulting in the obtained oily substance, which was utverjdali after settling, and received solid beige color. Then the crude solid product was recrystallized twice from ethanol and obtained 5.9 g of whitish solid. The obtained solid substance was dissolved in ethyl acetate and was added fumaric acid (1.2 g, 1.1 EQ. ). The resulting mixture was rapidly heated on the steam bath and then was stirred at room temperature for 2 hours. Green oily substance was deposited, and supernatant solution decantation. Then to decantate is anola-ether and was obtained 1.7 g(17%) 1-[4-[2-[4-(1,2-benzisoxazol-3-yl)-1-piperidinyl] ethoxy] -3 - methoxyphenyl]ethanone fumarata (so pl. 127-129oC).

Analysis for C23H26N2O4C4H4O4:

Calculated: C 63,32%; H Of 5.92%; N 5,49%.

Found: C 63,00%; H 5.87 Per Cent; N 5,42%.

Example 7. Fumarate 1-[4-[4-[4-(1H-indazol-3-yl)-1-piperazinyl] butoxy] -3-methoxyphenyl]ethanone.

The stirred mixture of 3-(1-piperazinil)-1H-indazole (4.0 g, 0.02 M), K2CO3(5,3 g, 0.04 M), 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone (6.6 g, of 0.022 M) and dimethylformamide (60 ml) was heated for 6 hours at 75oC. the reaction mixture was poured into water and the white solid was precipitated from solution. The obtained solid was collected and dried, resulting in a received 7.2 g of the crude product. Then the crude solid is recrystallized from ethanol and obtained 4.1 g of free base, which was converted into fumaric salt by adding fumaric acid (1.1 g) to the compound, dissolved in acetone, heated under reflux. Received fumaric salt (5.0 g) was recrystallized from ethanol and obtained 3.8 g (35%) fumarata 1-[4-[4-[4-(1H-indazol-3-yl)-1-piperazinyl] butoxy] -3 - methoxyphenyl]ethanone in the form of a white solid (so pl. 163-165oC).

Analysis for C24H

Example 8. 1-[4-[2-[4-(6-the Fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl] ethoxy]-3-methoxyphenyl]alanon.

The stirred mixture of 6-fluorescent-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (5.1 g, 0.02 M), K2CO3(5,2 g), 1-4-(2-chloroethoxy)-3-methoxyphenyl of ethanone (5.0 g, 1,022 M) and dimethylformamide (90 ml) was heated for 16 hours at 90oC. 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, resulting in received of 7.4 g of yellow solid. The obtained solid substance was chromatographically on a Waters Prep. LC 500, elwira dichloromethane/methanol (4%). After concentration of appropriate fractions were obtained 4.0 g of a yellow solid. The obtained solid was recrystallized from ethanol and obtained 3.1 g(38%) 1-[4-[2-[4-(6-the fluorescent-1,2 - benzisoxazol-3-yl)-1-piperidinyl] ethoxy] -3-methoxyphenyl]ethanone in the form of light-yellow flakes. so pl. 132-134oC.

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-the Fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl]propoxy]-3-methoxy-methylbenzylamino.

oC.

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-Benzisothiazol-3-yl)-1-piperidinyl] propoxy] -3-methoxyphenyl]alanon.

A mixture of 3-(4-piperidinyl)-1,2-benzisothiazole (3.0 g, 0,0137 M), potassium carbonate (2.3 g, M 0,0165), 1-[4-(3-chloropropoxy)-3-met the refrigerator for 24 hours in an atmosphere of N2. The cooled reaction mixture was filtered, and the precipitate on the filter was thoroughly washed with acetonitrile. The filtrate was concentrated to obtain an oily residue, which was then distributed between water and ethyl acetate. An ethyl acetate extract was thoroughly washed with water, dried with magnesium sulfate and concentrated, resulting in received of 6.1 g of the oily substance beige color, which was utverjdali when defending. The obtained product was pereirae with diethyl ether and filtered, resulting in a received 4,2 g solid beige color. The resulting material was recrystallized from ethanol and obtained 3.5 g of the product, and then again recrystallized from ethanol (discolored by processing, coal) and received 2.4 g(41%) 1-[4-[3-[4-(1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy]-3 - methoxyphenyl]ethanone (so pl. 93-95oC).

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-the Fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl] -propoxy]-3-hydroxyphenyl]alanon.

(A) Synthesis of 1-[4-(3-chloropropoxy)-3-hydroxyphenyl]ethanone.

To mix rest the chem ice/methanol), was added drop by drop to 1 mol of tribromide boron in methylene chloride (123 ml, 0.12 M). The temperature of the mixture was maintained at -40oC - 50oC. After complete addition, the reaction mixture was cooled to -30oC, and analyzed by TLC (approximately 15 minutes after the final addition of tribromide boron). After this was added one drop of a saturated solution of NaHCO3so that the temperature did not exceed 0oC during the addition. Once added to the alkaline solution of a sufficient amount of NaHCO3, the organic layer was collected. Then this layer was washed with saline, dried with magnesium sulfate and concentrated, resulting in received of 8.1 g of a dark brown oily substance, which was utverjdali when defending. Then the resulting material was chromatographically on a Waters Prep 500 LC, using 2 columns with silica gel (eluent: 2% methanol/methylene chloride). After concentration of appropriate fractions, obtained 5.8 g of a brown sticky solid. This product precrystallization from isopropyl ether (when decanting supernatant yellow isopropyl ether from the dark brown oily residue) and received first 2.5 g of yellow solid. � 1-[4-[3-[4-(6-Fluoro-1,2-benzoxazol-3-yl)-1-piperidinyl]propoxy]-3 - hydroxyphenyl]ethanone.

The stirred mixture of 6-fluorescent-3-(4-piperidinyl)-1,2-benzisoxazole (2.8 g, of 0.013 M), NaHCO3(1.1 g), several crystals of KI, 1-[4-(3-chloropropoxy)-3-hydroxyphenyl] -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 with water, dried with magnesium sulfate, and the solvent was concentrated, resulting in a yellow oily substance. The resulting substance was chromatographically on Wanter Prep 500 LC (silica gel; methanol/methylene chloride, 7%). After concentration of appropriate fractions were obtained yellow oily substance, which was then left to defend, and received 3.5 g of the compound as a pale yellow solid product. The resulting product was recrystallized from ethanol and obtained 2.7 g(50%) 1-[4-[3-[4-(6-the fluorescent-1,2-benzoxazol-3-yl)-1-piperidinyl] -propoxy] -3 - hydroxyphenyl]ethanone in the form of a pale yellow solid (so pl. 122-124oC).

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. 1-[4-[3-[4-(6-the Fluorescent-1H-indazol-3-yl)-1-piperazinil]propoxy] -3 - netoxygen the-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (2.8 g, to 0.011 MM), several crystals of KI and dimethylformamide (60 ml) was heated for 16 hours at 90oC. 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 and concentrated, resulting in a received 5.0 g of a yellow oily substance. The obtained oily substance was chromatographically on a Waters Prep column using silica gel (eluent: methylene chloride/methanol (7%)). After concentration of the desired fractions were obtained 2.0 g (46% off-white solid product. Then the sample was combined with 1.0 g of the previous sample, and after recrystallization from toluene, was obtained 2.6 g 1-[4-[3-[4-(6-the fluorescent-1H-indazol-3-yl)-1-piperazinil] propoxy]-3 - methoxyphenyl]ethanone in the form of a white solid (so pl. 135-137oC).

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-the Fluorescent-1H-indazol-3-yl)-1-piperazinil]butoxy] -3 - methoxyphenyl]alanon.

The stirred mixture of 6-fluorescent-3-(1-piperazinil)-1H-indazole hydrochloride (5.0 g, 0,019 ml), K2CO3(5.8 g) and 1-[4-(4-bromobutoxy)-3-methoxyphenyl] ethanone (6.3 g, 0,021 M) and dimethylformamide (80 ml) was heated at 75 waty a solid residue. Then the solid precipitate was collected and dried, resulting in a received 4.5 g of the crude product. The product was recrystallized 3 times from ethanol and obtained 3.0 g of whitish solid. This substance was chromatographically on a Waters Prep 500 using columns with silica gel and using as eluent methylene chloride/methanol (7%). After concentration of appropriate fractions were obtained 2.3 g of whitish solids, which is then recrystallized from ethanol, resulting in a received 1.9 grams (26%) of analytically pure 1-[4-[4-[4-(6-the fluorescent-1H-indazol-3-yl)-1-piperazinil] butoxy] -3 - methoxyphenyl] ethanone (so pl. 156-158oC).

Analysis for C24H29FN4O3(%):

Calculated: C 65,44; H 6,64; N 12,72.

Found: C, Compared With 65.38; H Of 6.49; N 12,60.

Example 14. 1-[4-[3-[4-(1H-indazol-3-yl)-1-piperazinil]propoxy]-3 - methoxyphenyl]alanon.

A mixture of 3-(4-piperidinyl)-1H-indazole (3.0 g, 0.015 g M), K2CP3(1.6 g), 1-[4-(3-chloropropoxy)-3-methoxyphenyl] ethanone (5.3g, of 0.022 M), several crystals of KI and acetonitrile (100 ml) was stirred and heated under reflux for 16 hours. The reaction mixture was poured into water, which formed a white solid precipitate. Then, this precipitate is PoE was subjected to chromatography using preparative HPLC (silica gel; methylene chloride/methanol 9:1) and obtained 3.0 g (49% off-white solid. The resulting material was recrystallized from ethanol and obtained analytically pure 1-[4-[3-[4-(1H-indazol-3-yl)-1-piperidinyl] propoxy] -3 - methoxyphenyl]Etalon in the form of a white solid (so pl. 171-173oC).

Analysis for C24H29N3O3(%):

Calculated: C 70,74; H 7,17; N 10,31.

Found: C 70,52; H 7,27; N 10,42.

Example 15. 1-[4-[3-[4-(6-Chloro-1,2-benzisoxazol-3-yl)-1-piperidinyl] propoxy]-3 - methoxyphenyl]alanon.

The stirred mixture of 6-chloro-3-(4-piperidinyl)-1,2-benzoxazole (4.7 g, 0.02 M), 1-[4-(3-chloropropoxy)-3-methoxyphenyl] ethanone (4.8 g, 0.02 M), K2CO3(2.8 g), several crystals of KI and acetonitrile (120 ml) was heated under reflux for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated, resulting received a mixture of solid and oily substances. The obtained residue was chromatographically on a Waters Prep 500 using a column with silica gel (eluent: methylene chloride/methanol (5%). After concentration of the desired fractions were obtained 3.2 g of a solid substance beige color, which is then recrystallized from ethanol and obtained 2.7 g(31%) 1-[4-[3-[4-(6-chloro-1,2-benzisoxazol-3-.

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)-1-piperidinyl]butoxy]-3 - methoxyphenyl]ethanone.

The stirred mixture of 6-chloro-3-(4-piperidinyl)-1,2-benzisoxazole (4.7 g, 0.02 M), 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanol (6.0 g, 0.02), K2CO3(2.8 g) and acetonitrile (120 ml) was heated under reflux for 16 hours. The reaction mixture was left to cool, filtered and then the filtrate was concentrated and got to 9.9 g of a brown oily substance. The resulting substance was chromatographically on a Waters Prep 500 (silica gel; methylene chloride/methanol (5%). The appropriate fractions were concentrated and obtained 2.3 g of whitish solid. This solid substance was dissolved in ethanol and added to 0.62 g (1.1 EQ.) fumaric acid. After concentration of the ethanol crude brown solid was collected and dissolved in acetone, heated under reflux. After cooling, the white solid was led from the solution and was obtained 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 UB>O4(%):

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-the Fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] propoxy]-3 - methoxyphenyl]alanon.

A mixture of 5-fluorescent-3-(4-piperidinyl)-1,2-benzisoxazole (2.2 g, 0.01 M), 1-[4-(3-chloropropoxy)-3-methoxyphenyl] ethanone (2.4 g, 0.01 M), K2CO3(1.4 g), several crystals of KI and acetonitrile (100 ml) was stirred and heated under reflux for 8 hours. The reaction mixture was poured into water and the aqueous mixture was extracted with ethyl acetate. An ethyl acetate extract was washed with saline, dried with magnesium sulfate and were extracted, resulting in the obtained 4.0 g of a white solid. The resulting substance was chromatographically on a Waters Prep 500 (HPLC) using a column with silica gel (eluent: methylene chloride/methanol (5%)). After concentration of appropriate fractions were obtained 2.0 g(47%) 1-[4-[3-[4-(5-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] propoxy] -3-methoxyphenyl] ethanone in the form of a white crystalline solid (so pl. 103-105oC).

Analysis for C24H27FN2O4(%):

Calculated: C 67,59; H 6,38; N 6,57.

Found: C 67,50; H 6,47; N 6,53.

Example 18. Fumarate 6-fluorescent-3-[1-[3-(2-methoxyphenoxy (2,45 g, 11,1 MM), K2CO3(2.0 g) and 3-(2-methoxyphenoxy) propylchloride (3.5 g, 17.4 mm) in acetonitrile (40 ml) was heated for 4 hours at 90oC. After completion of the reaction, the solvent was removed, and the solids were dissolved in dichloromethane (100 ml). Then the solution was washed with water and brine and then was dried with magnesium sulfate. The crude material from solution was combined with 1.2 g of the crude material obtained in the same way (using 0.5 g of starting material). After that, the combined material was purified using flash chromatography on silica gel (49 g, eluent: 0.5% diethylamine, 1% methanol and 98.5% with dichloromethane (1 l)). The fractions containing pure product were combined and concentrated to obtain a light oily substance (3,68 g). Then this oily substance was treated to 1.14 grams (9.8 mm) of fumaric acid in ethanol (13 ml). The result of this procedure was given to 4.01 g (60%) fumarata 6-fluorescent-3-[1-[3-(2-methoxyphenoxy)- propyl]-4-piperidinyl]-1,2-benzisoxazole, so pl. 169-170oC.

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-[3-[4-(6-the Fluorescent-1,2-benzisoxazol-3-yl)-1 - pipe (2,01 g, 9,13 mm), K2CO3(2.0 g), 1-[3-(3-chloropropoxy)-4-methoxyphenyl]phenylmethanone (3,93 g of 11.3 mm) and acetonitrile (50 ml) was heated under reflux for 4 hours. After completion of the reaction the solvent is evaporated and the residue was distributed between water (150 ml) and dichloromethane (400 ml). Then the dichloromethane solution was washed with water, brine (100 ml), dried with magnesium sulfate and concentrated to obtain an oily substance. The resulting material was purified using flash chromatography on silica gel (SiO2, 40 g; eluent: 300 ml dichloromethane and 850 ml of 1% methanol in dichloromethane). Thus obtained material in the form of colorless oily substance was utverjdali when defending. After recrystallization from ethanol was obtained of 3.07 g(63%) 1-[3-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl] propoxy] -4-methoxyphenyl]phenylmethanone in the form of white crystals, so pl. 140-141oC.

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]alanon.

A mixture of 3-(4-piperidinyl)-1H-indazole (3.2 g, 0,016 M), 1-[4-(4-bromobutoxy)-3-methoxyphenyl] ethanone (5.0 g, 0,016 M) KoC.

Analysis for C25H31N3O3(%):

Calculated: C 71,123; 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-1,02-benzisoxazol-3-yl)-1-piperidinyl] -ethoxy-3 - methoxyphenyl]alanon.

The stirred mixture of 6-chloro-3-(4-piperidinyl)-1,2 - benzisoxazole (4.6 g, 0,019 M), 1-[4-(2-chloroethoxy)-3-methoxyphenyl] ethanone (4.3 g, 0,019 M), K2CO3(2.8 g), several crystals of KI and acetonitrile (120 ml) was heated under reflux for 16 hours. The reaction mixture was filtered and the filtrate was concentrated, which was obtained 8.0 g of a yellow solid. Then, this solid was chromatographically on a Waters Prep 500 LC (silica gel; eluent: methylene chloride/methanol, 5%). After concentration of appropriate fractions were obtained 3.2 g of light yellow solid, which paracrystalline]ethanone in the form of a pale yellow solid, so pl. 133-135oC.

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 mm) in dimethylformamide (35 ml) was treated for 20 minutes (0oC) sodium hydride (600 mg, 25 mm) and then was added in one portion 1,3-dibromopropane (5 g, 24,7 mm). The resulting mixture was heated for 1 hour at 90oC, and then stirred at room temperature for 2 hours. After completion of the reaction the mixture was poured into water (500 ml) and was extracted with ethyl acetate (400 ml). Then an ethyl acetate solution was washed with water, brine, and then dried with anhydrous solution of magnesium sulfate. The solvent was removed and the crude oily substance was purified using flash chromatography on silica gel (85 g SiO2; eluent: 1.6 liters of hexane/dichloromethane (3:1), 1.4 l of hexane/dichloromethane, 3: 7). The result of this procedure was given of 4.67 g (66%) of pure product as an oily substance. Then this substance is recrystallized twice from isopropyl ether, resulting in the received 2,42 g (500 ml) of analytically pure 3-(3-bromoprop is R> Calculated: C 58,47; H 4,91.

Found: C, 58, 63; H 4,82.

Example 23. Fumarate 1-[3-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)- 1-piperidyl]propoxy]phenyl]ethanone.

A mixture of 6-fluorescent-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (4,53 mg, 20.5 mm), K2CO3(4.5 mg), 1-[3-(3-chloropropoxy)phenyl]ethanone (6.4 g, 29 mm) in acetonitrile (60 ml) was heated under reflux for 5 hours. After completion of the reaction the solvent was removed and the residue was extracted with dichloromethane (300 ml). Inorganic insoluble substances were filtered off. Thereafter, the dichloromethane solution was concentrated to small volume (10 ml) and was purified using flash chromatography on silica gel (75 g SiO2; eluent: 900 ml of dichloromethane and 800 ml of 2% methanol in dichloromethane). The fractions containing pure product were combined and concentrated to obtain an oily substance (2,87 g, 35%). After this oily substance was dissolved in ethanol and treated with a solution of fumaric acid (841 mg). After two precrystallization from ethanol received 2,53 g 1-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] -propoxy phenyl] ethanone fumarata in the form of white crystals, so pl. 172-174oC.

Analysis for C22H25FN2O4(%):

The stirred mixture of 6-Fleurieu-3-(4-piperidinyl)-1,2 - benzisoxazole hydrochloride (5.5 g, 21.6 mm), K2CO3(3.5 g), 1-[4-)3-bromopropane)-2-were] ethanone (4.83 g, 17,8 mm) in dimethylformamide (25 ml) and acetonitrile (75 ml) was heated for 5 hours at 120oC. After completion 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. The result of this procedure was obtained the crude oily substance, which was purified using flash chromatography on silica gel (80 g; eluent: 1 l of dichloromethane, 1.2 l of 1% methanol/-dichloromethane and 1.2 l of 2% methanol/dichloromethane). The most pure fractions were combined and received only 2.91 g of solid, which is then recrystallized from dichloromethane and ethanol, resulting in a received 2,42 g 1-[4-[3-[4-[(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy] 2-were]ethanone in the form of whitish crystals, so pl. 113-114oC.

Analysis for C24H27FN2O3(%):

Calculated: C 70,22; H 6,63; N 6,82.

Found: C 70,13; H 6,63; N 6,77.

Example 25. 1-[2-[3-[4-(6-the Fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl] -propoxy-5-were]alanon.

A mixture of 6-f is ethylphenyl]ethanone (3,74 g, 13,8 mm) in dimethylformamide (10 ml) and acetonitrile (50 ml) was heated for 6 hours at 95oC. After completion of 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 with magnesium sulfate and concentrated. The result of this procedure was obtained the crude oily substance, which was purified using flash chromatography on silica gel (60 g SiO2; eluent: 1.2 l of 1% CH3OH/-dichloromethane, 600 ml of a mixture of 3% CH3OH/dichloromethane). The resulting material was led from a small volume of ether and hexane, resulting in received 2,13 mg (46%) whitish 1-[2-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl] propoxy] -5-were] ethanone, so pl. 92-93oC.

Analysis for C24H27FN2O3(%):

Calculated: C 70,22; H 6,63; N 6,82.

Found: C 70,21; H 6,69; N For 6.81.

Example 26. Hemifumarate N-[3-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl]propoxy-4-methoxyphenyl]ndimethylacetamide.

A mixture of 6-fluorescent-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (3.94 g, 15.4 mm), K2CO3(3,67 g of 26.6 mm), N-[3-(3-bromopropane)-4-methoxyphenyl] ndimethylacetamide (5,56 g, 18.6 mm) in dimethylformamide (75 ml) and acetonitrile (g were extracted in dichloromethane (500 ml). The organic solution was washed with water (500 ml) and brine (400 ml) and then dried and concentrated. The result of this procedure was obtained the crude oily substance, which was then purified using flash chromatography on silica gel (65 g SiO2; eluent: 1.2 l of 1% CH3OH/-dichloromethane and 500 ml of a mixture of 3% CH3OH/dichloromethane) and received 2,33 g (34,3%) of the desired product as an oily substance. The resulting substance was dissolved in ethanol and treated 661 milligrams solution of fumaric acid in ethanol. The result of this procedure received 2,17 mg N-[3-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl] propoxy] -4-methoxyphenyl of ndimethylacetamide of hemifumarate in the form of whitish crystals with so pl. 205-206oC.

Analysis for C24H28FN3O30.5 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. 6-Chloro-3-(1-piperazinil)-1H-indazol.

To a stirred suspension of 4-(6-chloro-1-phenylsulfonyl-1H-indazol-3-yl)-1-piperidinecarbonitrile (192.5 kg g 0,479 M) in dry tetrahydrofuran (3.5 l), in an atmosphere of N2added drop by drop LiAlH4(958 ml of a 1.0 M solution of lithium aluminum hydride in tetrahydrofuran; 0,958 M). After time to relax. the donkey that the reaction mixture was cooled to 4oC in an ice/salt bath and the excess lithium aluminum hydride was neutralized by careful (drop by drop) add water. The mixture is then vigorously stirred for another 30 minutes, after which the mixture was filtered through a funnel of coarse sintered glass. The precipitate on the filter was thoroughly washed with tetrahydrofuran (3 500 ml) and then methanol (2 500 ml) and the filtrate was concentrated. The result of this procedure received 151,0 g resin beige color, which was then pereirae with diethyl ether and obtained a solid product. After that, the product was collected and dried, resulting in a received 75,0 g (66% of the desired indazole, 4.0 g sample precrystallization of toluene and was obtained 3.2 g of product, which again precrystallization from toluene (utilizing discolored coal), which was obtained 2.1 g (35%) 6-chloro-3-(1-piperazinil)-1H-indazole in a solid beige color, so pl. 135-137oC.

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-the Fluorescent-1H-indazol-3-yl)-1 - piperidinyl]propoxy] -3-methoxyphenyl]alanon.

The stirred mixture of 6-fluorescent-3-(4-piperidinyl) the sludge (90 ml) was heated under reflux for 16 hours. The reaction mixture was poured into water, which formed a white solid precipitate. Then, this precipitate was collected and obtained 5.5 g of the desired product. This product is recrystallized twice from dimethylformamide, resulting in received 3.0 g(44%) 1-[4-[3-[4-(6-the fluorescent-1H-indazol-3-yl)-1-piperidinyl] propoxy] -3-methoxy - phenyl]-ethanone in the form of a white solid substance, so pl. 202-204oC.

Analysis for C24H28FN3O3(%):

Calculated: C 67,75; H 6,63; N 9,88.

Found: C 67,59; H Is 6.61; N 9,96.

Example 29. Hemifumarate 1-[4-[3-[4-(6-the fluorescent-1,2-benzisoxazol - 3-yl)-1-piperidinyl]propoxy]-3-were]ethanone.

The stirred mixture of 6-fluorescent-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (3.0 g, 11.7 mm), K2CO3(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 for 4 hours. After the reaction, the solvent was concentrated to a volume of about 30 ml, and then distributed between water (200 ml) and dichloromethane (300 ml). The dichloromethane solution was separated and washed with water and brine, and then dried with magnesium sulfate. The crude product from the evaporated solution was purified using flash-HRO is e) and received 2,07 g (43%) of product as a pale yellow oily substance. The resulting substance was dissolved in ethanol and treated with a solution of fumaric acid (585 mg) in ethanol. After cooling at 0oC, formed crystals hemifumarate 1-[4-[3-[4-(6-the fluorescent-1,2-benzisoxazol - 3-yl)-1-piperidinyl]propoxy]-3-were]ethanone. Then the obtained crystals were collected and received 1.5 g of the target product, so pl. 185-187oC.

Analysis for C24H27FN2O3C4H4O4(%):

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-the Fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl] -propoxy]phenyl]alanon.

A mixture of 6-fluorescent-3-(4-piperidinyl)-1,2-benzisoxazole (3,27 g, 14,8 mm), K2CO3(3 g), 1-[4-(3-bromopropane)phenyl]-ethanone (4.5 g, 17.5 mm) in acetonitrile (60 ml) was heated under reflux for 4 hours. The solvent was removed. The residue was dissolved in dichloromethane (300 ml), washed with water and brine and then was dried with magnesium sulfate. The crude product from the evaporated solution was purified using flash chromatography (SiO2, 60 g; eluent: 1 l of 1% methanol in dichloromethane). After that, the most pure fractions were combined, resulting in a 2.8 g(48%) 1-[4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidine is R> Calculated: C 69,68; H 6,36; N 7,07.

Found: C 69,80; H 6,38; N 7,07.

Example 31. 1-[4-[3-[4-(6-Chloro-1H-indazol-3-yl)-1 - piperazinil] -propoxy]-3-methoxyphenyl]alanon.

A mixture of 6-chloro-3-(1-piperazinil)-1H-indazole (3.4 g, of 0.014 M), K2CO3(2.5 g, 0,018 M), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (3.8 g, 0,016 M), KI (200 mg) and acetonitrile (125 ml) was stirred at reflux (in nitrogen atmosphere) for 30 hours. After sedimentation at room temperature for 40 hours, the reaction mixture was filtered and then the filter cake was thoroughly washed with acetonitrile. The filtrate was concentrated to obtain an oily solid residue, which was distributed between water and ethyl acetate. Then an ethyl acetate extract was washed with water, dried with magnesium sulfate and concentrated. The result of this procedure was given to 6.9 g of a dark oily substance, which was aterials after keeping for 2 days under vacuum. The resulting product was purified using preparative HPLC (Waters Associated Prep. LC/ system 500, using 2 columns with silica gel of 4.2 g of the product. Then this product was recrystallized from ethanol and obtained 3.4 g 1-[4-[3-[4-(6-chloro-1H-indazol-3-yl)-1-piperazinil] propoxy] -3 - methoxyphenyl/SUB>ClN4O3(%):

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]alanon.

The stirred mixture of 3-(1-piperazinil)-1,2-benzisothiazole (4.0 g, M 0,0182), 1-[4-(4-bromobutoxy)-3-methoxyphenyl] ethanone (6.0 g, 0,0200 M), K2CO3(3.0 g, 0,0218 M), KI (200 kg) and acetonitrile (125 ml) was heated under reflux (in nitrogen atmosphere) for 5 hours. A large part of the solvent was removed in vacuum and the obtained residue in the form of the resin was distributed between ethyl acetate and water. Then the organic extract was washed with water, dried with magnesium sulfate and concentrated to obtain 7.8 g of the product. The resulting product was purified using preparative HPLC (Waters Associated Prep. LC/ System 500, using 2 columns with silica gel (eluent: 4% methanol/methylene chloride) was obtained 6.5 g of crude whitish solid product. This product is twice recrystallized from toluene and obtained 3.1 g(39%) 1-[4-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinil] butoxy] -3 - methoxyphenyl] ethanone in the form of a white solid substance, so pl. 114-116oC.

Analysis for C24H29N3O3S (%):

Calculated: C 65,58; H Of 6.65; N 9,56.

Found: C 65,74; H 6,66; N 9,54.

2CO3(2.8 g), 4-(3-bromopropane)-3-methoxybenzonitrile (4.0 mg, 14,8 mm) in acetonitrile (70 ml) was heated under reflux for 3 hours. After completion 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. Thereafter, the dichloromethane solution was concentrated to obtain the crude oily product. The resulting product was purified using flash chromatography on silica gel (55 mg SiO2; eluent: 600 ml of dichloromethane and 60 ml of 1% methanol in dichloromethane). Thus obtained material was led from the small amount of dichloromethane. After recrystallization from ethanol (25 ml) were 3.8 mg(68%) 4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] propoxy] -3 - methoxybenzonitrile in the form of white crystals, so pl. 107-108oC.

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-the fluorescent-1H-indazol-3-yl)-1-piperidinyl] butoxy] -3-methoxyphenyl]alanon.

The stirred mixture of 6-fluorescent-3-(4-piperidinyl)-1H-indazole (1,9 g, M 0,0086), 1-[4-(4-bromobutoxy)-3-methoxyphenyl] ethanone (2.6 g, 0,0086 M), KoC.

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. 1-[4-[3-[4-(1-Benzoyl-6-fluorescent-1H-indazol-3-yl)-1-piperazinil] propoxy]-3-methoxyphenyl]ethanone sesquifumarate.

The mixture 1-[4-[3-[4-(6-the fluorescent-1H-indazol-3-yl)-1-piperazinil] propoxy]-3-methoxyphenyl]ethanone (3.2 g, 0,0075 M) and benzoyl chloride (15 ml) was heated on the steam bath for 15 minutes. Then the reaction mixture was cooled and was added ether. Insoluble whitish compound were collected and obtained 4.4 g of product in the form of cleaners containing hydrochloride salt. This salt was converted to free base by adding an aqueous solution of ammonium hydroxide, and provided 3.0 g (after extraction with methylene chloride) of free base as a white solid. The obtained free base was dissolved in ethyl acetate and was added fumaric acid (0,72 g, 1,1 is based temperature 2.0 g of whitish fumaric salt was collected, and the filtrate was concentrated, resulting in the received 1.0 g of salt. The obtained salt was recrystallized first from ethyl acetate and then from ethanol. The result of this procedure was obtained 1.4 g (26%) of sesquifumarate 1-[4-[3-[4-(1-benzoyl-6-fluorescent-1H-indazol-3-yl)-1-piperazinil] propoxy] -3-methoxyphenyl] ethanone, so pl. 138-140oC.

Analysis for C30H31FN4O41,5 C4H4O4(%)

Calculated: C 61,35; H of 5.29; N OF 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]alanon.

A mixture of 6-chloro-[3-(1-piperazinil] )-1H-indazole (4.0 g, is 0.017 M), K2CO3(2.8 g, 0,020 M), 1-[] 4-(4-bromobutoxy)-3-methoxyphenyl]ethanone (5.7 g, 0,019 M), KI (100 mg) and acetonitrile (125 ml) was stirred at reflux (in nitrogen atmosphere) for 18 hours. Then the cooled reaction mixture was poured into water and the resulting whitish solid was collected by filtration, dried off and got to 7.0 g of the product. After that, the product is twice recrystallized from toluene and obtained 6.2 g of product, which was purified using preparative HPLC (Waters Associates Prep LC/System 500, using 2 columns with silica gel (this is obtained crystals 4 times recrystallized from toluene and obtained 3.1 g of white solid. Then, after recrystallization from dimethylformamide was obtained 2.5 g (32%) of analytically pure 1-[4-[4-(6-chloro-1H-indazol-3-yl)-1-piperazinil] butoxy]-3 - methoxyphenyl] ethanone in the form of a whitish powder-like substances, so pl. 189-191oC.

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. Hemifumarate 1-[4-[3-[4-(1,2-benzisoxazol-3-yl)-1-piperazinil]propoxy]-3 - methoxyphenyl]ethanone.

A mixture of 3-(1-piperazinil)-1,2-benzisothiazole (4.0 g, 0,0182 M), K2CO3(3.0 g, 0,0218 M), KI (200 mg), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (5.3g, 0,0222 M), and acetonitrile (125 ml) was stirred at reflux (in nitrogen atmosphere) for 26 hours. The cooled reaction mixture was filtered and the filter cake was thoroughly washed with acetonitrile. The filtrate was concentrated to obtain 10.7 g of oily residue, which was then extracted with ethyl acetate. Then an ethyl acetate extract was washed with water, dried with magnesium sulfate and concentrated to obtain 8.0 g of a dark oily substance. The obtained oily substance was purified using preparative HPLC (Waters Associates Prep LC/System 500, using 2 coali 4.6 g of a red oily substance, which was utverjdali when defending 3.4 g of sample was dissolved in ethyl acetate (100 ml) was added fumaric acid (0.95 g). The resulting mixture was stirred at reflux for 1 hour and then at room temperature for 1.5 hours. The resulting solid beige color was collected by filtration and dried off. The result of this procedure were obtained 4.0 g of product. Then the obtained product is recrystallized twice from ethanol, resulting in the obtained 2.7 g (27%) hemifumarate 1-[4-[3-[4-(1,2-benzisothiazol-3-yl)-1-piperazinil] propoxy]-3 - methoxyphenyl]ethanone in the form of a powder beige color, so pl. 186-188oC.

Analysis for C23H27N3O30.5 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. 1-[3,5-Dibromo-4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl]propoxy]phenyl]alanon.

The stirred mixture of 6-fluorescent-3-(4-piperidinyl)-1,2-benzisoxazole (2.0 g, 9.0 mm), K2CO3(11.3 g), 1-[4-(3-bromopropane)-3,5-dibromophenyl]ethanone (2.65 g, 9.0 mm) and acetonitrile (50 ml) was heated under reflux for 3 hours. After completion of the reaction, the solvent evaporated and the residue was extracted by the receiving oily substance. The resulting substance was purified using flash chromatography on silica gel (SiO247 g; eluent: 300 ml of dichloromethane and 600 ml of 1% methanol in dichloromethane). Thus purified material, in the form of a colorless oily substance was utverjdali when defending, and then, as a result of recrystallization from ethanol, was received with 2.93 g (57%) of 1-[3,5-dibromo-4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl] propoxy] phenyl] ethanone in the form of white crystals, so pl. 102-103oC.

Analysis for C23H23BN2FN2O3(%):

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] ethoxy]-3-methoxyphenyl]alanon.

A mixture of 3-(1-piperazinil)-1,2-benzisothiazole (4.0 g, M 0,0182), 1-[4-(2-chloroethoxy)-3-methoxyphenyl] ethanone (4.3 g, 0,0200 M), K2CO3(3.0 g, 0,0218 M), acetonitrile (125 ml) and catalytic amount of KI was heated under reflux and stirred (in nitrogen atmosphere) for 24 hours. At this stage the reaction mixture was added 1.0 g (0,0072 M) K2CO3and almyroudis agent (0.4 g, 0,0017 M), and the mixture was heated under reflux for 24 hours. Then the reaction mixture was cooled to room tempera oily substance. The resulting material was extracted with methylene chloride and the organic extract washed with water, dried with magnesium sulfate and concentrated. The result of this procedure was given to 9.2 g of oily product. Then the product was purified using preparative HPLC (Waters Associates Prep LC/System 500, using 2 columns with silica gel (eluent: 3% methanol/methylene chloride), which was obtained 3.8 g soft resinous substance beige color, which was utverjdali when defending. After this substance was recrystallized from ethanol (twice) and was obtained 2.1 g(28%) 1-[4-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinil] ethoxy] -3 - methoxyphenyl] -ethanone in the form of a solid beige color. so pl. 98-100oC.

Analysis for C22H25N3O3S (%):

Calculated: C 64,21; H 6,12; N Of 10.21.

Found: C 64,05; H 6,09; N 10,12.

Example 40. 6-Fluorescent-3-[1-(3-phenoxypropan)-4-piperidinyl] -1,2 - benzisoxazol.

A mixture of 6-fluorescent-3-(4-piperidinyl)-1,2-benzisoxazole (4.0 g, 0,0182 M), K2CO3(3.0 g, 0,0218 M), KI (100 mg), 3-chlorpromazine (3.4 g, 0,0200 M) and acetonitrile was stirred at reflux (in nitrogen atmosphere) for 30 hours. The reaction mixture was poured into water and the aqueous mixture was extracted with etilize is litate this procedure was obtained 6.2 g of crude solid beige color. Then the resulting material is twice recrystallized from ethanol, resulting in the received 6-fluorescent-3-[1-(3-phenoxypropan)-4-piperidinyl] -1,2-benzisoxazol (47%) as a light solid beige color, so pl. 78-80oC.

Analysis for C21H23N2O2(%):

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)-1 - piperazinil]ethoxy] [-3-methoxyphenyl]alanon.

A mixture of 6-chloro-[3-(1-piperazinil)] -1H-indazole (2.1 g, 0,0089 M), K2CO3(1.5 g, 0,0107 M), KI (100 mg), 1-[4-(2-chloroethoxy)-3-methoxyphenyl]ethanone (2.2 g, 0,0098 M) and acetonitrile (70 ml) was stirred at reflux (in nitrogen atmosphere) within 48 hours. Then 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 and concentrated to obtain 6.0 g of a light yellow oily substance. The resulting substance was purified using preparative HPLC (Waters Assocites Prep LC/System 500, using 2 columns with silica gel (eluent: 5,5% methanol/methylene chloride). After concentration of later fractions were obtained 1.6 g of whitish solid. Then what was alocale 2.1 g(23%) 1-[4-[2-[4-(6-chloro-1H-indazol-3-yl)-1 - piperazinil] ethoxy] -3-methoxyphenyl] ethanone in the form of a whitish solid, so pl. 154-156oC.

Analysis 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-the Fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl] propoxy]-3-methoxyphenyl]-2,2,2-trichoroethane.

A mixture of 6-fluorescent-3-(4-piperidinyl)-1,2-benzisoxazole (1.5 g, M 0,0067), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]-2,2,2 - trichoroethane (2.0 g, 0,0067 M), K2CO3(0,088 g), KI (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. Then an ethyl acetate extract was washed with water and dried with magnesium sulfate, and the solvent was concentrated to obtain an oily substance, which was subjected to high vacuum and obtained 3.2 g of a solid waxy substance. Then this substance was chromatographically using preparative LC (silica gel; eluent: 3% methanol/dichloromethane). After concentration of appropriate fractions were obtained 1.8 g(56%) 1-[4-[3-[4-(6-the fluorescent-1,2-benzisoxazol - 3-yl)-1-piperidinyl] propoxy] -3-methoxyphenyl]-2,2,2-trichoroethane in the form of a solid substance, so pl. 94-96oC.

Analysis for C24H<

Example 43. 1-[4-[3-[4-(6-the Fluorescent-1,2-benzisoxazol-3-yl-1-piperidinyl] propoxy]-3 - methylmercaptopurine]alanon.

The stirred mixture of 6-fluorescent-3-(4-piperidinyl)-1,2-benzisoxazole (1.88 g, 8.5 mm), K2CO3(1.8 g) and 1-[4-(3-bromopropane)-3-methylmercaptopurine]ethanone (2.3 g, 7.6 mm) in acetonitrile (100 ml) was heated under reflux for 4 hours. After completion of the reaction, the solvent was concentrated, and then diluted with dichloromethane (250 ml). The insoluble substance was filtered and the dichloromethane solution was concentrated to dryness and received an oily substance. The resulting material was purified using flash chromatography on silica gel (54 g SiO2; eluent: 500 ml dichloromethane and 1.1 l of 1% methanol/dichloromethane). The most pure fractions were combined and obtained colorless oily substance, which was utverjdali when defending. The result of this procedure was a 2.4 g of a whitish solid, which was recrystallized from ethanol (100 ml) and received 2.15 g 1-[4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl-1-piperidinyl] propoxy] -3-methylmercaptopurine] ethanone in the form of whitish needle-shaped crystals, so pl. 150-152oC.

Analysis for C24H27FN2O3S (%):

Calculated: C 65,14; H x 6.15; N, 6.3 mixture of 3-bromo-4-hydroxyacetophenone (4.5 g, 21,2 mm), K2CO3(4 g) and 1,3-dibromopropane (7.6 g) in acetonitrile (200 ml) was heated under reflux for 2 hours. After completion of the reaction the solvent was removed and the residue was dissolved in dichloromethane (400 ml) and then filtered. The dichloromethane solution was concentrated to obtain an oily substance, which was then added to isopropyl ether and was stirred for recrystallization from isopropyl ether, resulting in a 3.5 g of 1-[4-(3-bromopropane)-3-bromophenyl] ethanone in the form of brilliant crystals, so pl. 83-84oC.

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]alanon.

The stirred mixture of 3,5-dibromo-4-hydroxyacetophenone (3.0 g, 1,01 mm), K2CI3(2.8 g, 20.3 mm), 1,3-dibromopropane (4.0 g, 19,8 mm) in acetonitrile (100 ml) was heated under reflux for 5 hours. After that, the solvent was removed. The crude product was extracted in dichloromethane (150 ml) and the insoluble inorganic substance was filtered, and the solution was again concentrated to dryness. After that, the obtained product was subjected to flash chromatograph g) twice precrystallization of isopropyl ether and was obtained analytically pure 1-[4-(3-bromopropane)-3,5-dibromophenyl]alanon, so pl. 87-88oC.

Analysis for C11H11Br3O2(%):

Calculated: 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]alanon.

The stirred mixture of 3-(4-piperidinyl)-1,2-benzisothiazole (2.6 g, M 0,0119), 1-[4-(4-bromobutoxy)-3-methoxyphenyl] ethanone (3,9 g, 0,0131 M), K2CO3(2.0 g, 0,0143 M), KI (200 mg) and acetonitrile (125 ml) was stirred at reflux (in nitrogen atmosphere) for 18 hours. The reaction mixture was cooled to room temperature and filtered. The precipitate on the filter was thoroughly washed with fresh acetonitrile and then 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 oily substance. Then the resulting material was purified using preparative HPLC (Waters Associates Prep. LS/System 500, using 2 columns with silica gel (eluent: 5% methanol/methylene chloride), which was obtained 4.5 g of solid product beige color. The sample (3.1 g, 0,0071 M) was dissolved the fridge on a steam bath for 45 minutes, and then was stirred at room temperature for 1 hour. After that, the resulting suspension was diluted with anhydrous ether (150 ml) and stirred 5 minutes. The result of this procedure were obtained solid substance, which is then collected and drained. Thus was obtained 3.1 g bright solid beige color. After this salt was recrystallized from ethanol and obtained 2.8 g of product. This product is again transformed into the free base by adding 50% NaOH, resulting in a 2.4 g of the product, which was recrystallized from ethanol and obtained 1.5 g(29%) 1-[4-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperidinyl] butoxy] -3 - methoxyphenyl]ethanone in the form of a powder beige color, so pl. 78-80oC.

Analysis for C25H30N2O3(%)

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-the Fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl]-propoxy-3 - methoxyphenyl]phenylmethanone.

A mixture of 6-fluorescent-3-(4-piperidinyl)-1,2-benzisoxazole (2.2 g, 10 mm), K2CO3(2.3 g) and 1-[4-(3-bromopropane)-3-methoxyphenyl]phenylmethanone (3,47 g, 10 mm) in acetonitrile (100 ml) was heated under reflux for 3 hours. After completion of the reaction, the acetonitrile conical evaporated, the result that was obtained oily substance. The resulting material was purified using flash chromatography on silica gel (50 g SiO2; eluent: 600 ml dichloromethane; 600 ml of 1% methanol/-dichloromethane; 600 ml of 2% methanol/dichloromethane). The fractions containing pure product were combined and concentrated to obtain 4,24 g (87%) whitish solid. After recrystallization of the obtained substances from ethanol (75 ml) was received 3,96 g 1-[4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]- 3-methoxyphenyl]phenylmethanone in the form of whitish crystals, so pl. 128-130oC.

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-[4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl] -propoxy]-3-bromophenyl]alanon.

A mixture of 6-fluorescent-3-(4-piperidinyl)-1,2-benzisoxazole (2.1 g, 9.5 mm), K2CO3(2.0 g), 1-[3-bromo-4-(3-bromopropane)phenyl]ethanone (3.1 g, 9.2 mm) in acetonitrile (100 ml) was heated under reflux for 3 hours. After completion of the reaction the solvent was concentrated and the mixture was extracted into dichloromethane (200 ml). Insoluble substances were filtered off and the dichloromethane solution was again concentrated. PEFC is smetana, 600 ml of 1% methanol/dichloromethane and 600 ml of 3% methanol /97%/ dichloromethane). Thus obtained material (3,26 g, 72%) was recrystallized from ethanol (40 ml) and received 3.0 g 1-[4-[3-[4-(6-the fluorescent-1,2 - benzisoxazol-3-yl)-1-piperidinyl] propoxy] -3-bromophenyl] -ethanone in the form of light yellow crystals, so pl. 126-128oC.

Analysis for X23H24BrFN2O3(%):

Calculated: C 58,12; H 5,09; N Of 5.89.

Found: C 57,64; H 5,35; N 5,55.

Example 49. Hydrochloride 3-[1-[3-[4-(1-ethoxyethyl)-2-methoxyphenoxy]propyl]-4-piperidinyl]-6 - fluorescent-1,2-benzisoxazole.

To the mixture 4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] propoxy]-3-methoxy-methylbenzonitrile (3.8 g, 0,089 M) in pyridine (25 ml) was added acetic anhydride (5 ml). The resulting mixture was rapidly heated on a steam bath to obtain a solution, and then the reaction mixture was left at room temperature for 16 hours. A large part of pyridine is evaporated under reduced pressure, and the obtained oily substance was diluted with water. The aqueous solution was podslushivaet by adding dilute NaOH and then the solution was extracted with ethyl acetate. The organic extract was washed with water, dried with magnesium sulfate, and the solvent kontsentrirovanii in diethyl ether, and ether/HCl was added to the precipitated resinous cleaners containing hydrochloride salt, which was treated with boiling ethyl acetate, which was obtained 3.4 g of crystalline salts with so pl. 143-145oC. Attempt to recrystallized salt from a mixture of ethanol and diethyl ether showed that acetate may be replaced by ethyl ether. Salt of this product (2.8 g) was recrystallized from a mixture of ethanol and diethyl ether, which was obtained 2.1 g (48%) of the hydrochloride 3-[1-[4-(1-ethoxyethyl)-2-methoxyphenoxy] propyl] -4 - piperidinyl]-6-fluorescent-1,2-benzisoxazole, so pl. 139-141oC.

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 - fluorescent-1,2-benzisoxazole.

The mixture 4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl]-3 - methoxy-methylbenzonitrile (4.8 g, to 0.011 M) in pyridine (45 ml) was rapidly heated to obtain a solution, and was added acetic anhydride (6.3 ml). Then the reaction mixture was left at room temperature for 16 hours, concentrated in vacuo and the resulting colorless oily substance was dissolved in water. An aqueous solution of podsolic the obtained extract was washed with water, was dried by magnesium sulfate and concentrated to obtain 5.2 g of a viscous colorless oily substance. Then the obtained compound (4.8 g) was dissolved in anhydrous diethyl ether was added fumaric acid (1.2 g, 0.01 M). After that, the mixture was stirred at room temperature for 4 hours and then left at room temperature for 16 hours. The resulting white product, namely fumarate 3-[1-[3-[4-(1-acetoxyethyl)-2-methoxyphenoxy] propyl] -4-piperidinyl] -6 - fluorescent-1,2-benzisoxazole, collected and received 3.0 g of product. The filtrate was treated with an additional quantity of fumaric acid (0.3 g) and were collected at 0.9 g fumarata 3-[3-[4-(1-acetoxyethyl)-2-methoxyphenoxy] propyl] -4-piperidinyl]-6 - fluorescent-1,2-benzisoxazole. Then received two substances were combined and recrystallized twice from acetonitrile, which was obtained 2.3 g (43%) of the acetate with so pl. 150-152oC.

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-the Fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl] -propoxy]-3-methoxyphenyl]pentanone.

A mixture of 6-fluorescent-3-(4-piperidinyl)-1,2-benzisoxazole (2.2 g, 0.01 M), K2ATiM refrigerator for 4 hours. After completion of the reaction the mixture was cooled and filtered. The obtained filtrate was concentrated to obtain an oily substance. Then the resulting material was purified using flash chromatography on silica gel (55 g SiO2; eluent: 600 ml of 1% methanol in dichloromethane and 400 ml of 3% methanol and 97% dichloromethane). The fractions containing pure product were collected and concentrated to obtain a solid (4.3 g, 91%). Then the solid substance was recrystallized from ethanol (10 ml) and received 3,22 g 1-[4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] propoxy - 3-methoxy-phenyl]pentanone in the form of powdered solids with so pl. 79-80oC.

Analysis for C27H33FN2O4(%):

Calculated: C 69,21; H 7,10; N 5,98

Found: C 69,00; H 6,94; N 6,39

Example 52. Hemifumarate 2-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy -- methylbenzenamine.

A mixture of 6-fluorescent-3-(4-piperidinyl)-1,2-benzisoxazole (2.5 g, 0,0114 M), K2CO3(1.8 g, 0,0130 M), 4-(3-chloropropoxy)-2-methylaminophenol (2.4 g, 0,0120 M) and acetonitrile (100 ml) was stirred at reflux for 18 hours. Then the reaction mixture was cooled to room temperature and poured into water. Then water (Mus) who has demonstrated obtaining 4.1 g of a brown oily substance. The resulting material was purified using preparative HPLC (Waters Associates Prep LC/System 500, using 2 columns with silica gel (eluent: 4% methanol/methylene chloride). After concentration of appropriate fractions were received of 2.45 g of the oily substance beige color. The obtained product was dissolved in ethyl acetate (50 ml) and added to 0.78 g of fumaric acid. Then the mixture was stirred for 45 minutes at reflux, and then for 1.5 hours at room temperature. After that, the product was isolated by vacuum filtration and received 2.5 g of pale yellow solid. The obtained solid was recrystallized from ethanol and obtained 2.0 g(40%) 2-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] propoxy -- methyleneindoline hemifumarate in the form of beige crystals, so pl. 180-182oC.

Analysis for C22H26FN3O20.5 C4H4O4(%):

Calculated: C 65,08; H 6,40; N 9,52.

Found: C 65,08; H 6,35; N 9,45.

Example 53. 1-[4-[3-[4-(6-the Fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl]-propoxy]- 3-methoxyphenyl]propanone.

A mixture of 6-fluorescent-3-(4-piperidinyl)-1,2-benzisoxazole (2.8 g, 15,2 mm), K2CO3(3 g) and 1-[4-(4-bromopropane)-3-methoxyphenyl]propanone the mixture was filtered, the solvent was concentrated and the residue was extracted into dichloromethane (300 ml). Thereafter, the dichloromethane extract was filtered and again concentrated. The crude material (6.4 g) was purified using flash chromatography on silica gel (50 g SiO2; 700 ml of dichloromethane and 1.4 l of 1% methanol in dichloromethane). Thus purified material (weight: 2,87 g, 51%) precrystallization from ethanol (25 ml), resulting in a received 2,13 g 1-[4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] propoxy] - 3-methoxyphenyl] propanol in the form of beige crystals, so pl. 118-119oC.

Analysis for C25H29FN2O4(%):

Calculated: C 68,16; H 6,64; N 6,36.

Found: C 68,32; H 6,63; N 6,29.

Example 54. 4-[3-[4-(6-the Fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] -propoxy]-3 - methoxybenzamide.

A mixture of 6-fluorescent-3-(4-piperidinyl)-1,2-benzisoxazole (2.2 g, 10.0 mm), K2CO3(2.0 g) and 4-(3-bromopropane)-3-methoxybenzamide (2,32 g, 8.0 mm) in acetonitrile (80 ml) was heated under reflux for 5 hours. After completion of the reaction the solvent is evaporated and the residue was extracted in dichloromethane. Inorganic insoluble substance was filtered and dichloromethane was concentrated again. Patanol in dichloromethane and 1 l of 2% methanol in dichloromethane). The result of this procedure was received with 2.93 g (84%) of product as white crystals. After precrystallization from hot ethanol (60 ml) was received 4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl]-propoxy]-3 - methoxybenzamide in the form of white crystals, so pl. 163-164oC.

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 55. 1-[4-[3-[4-(6-the Fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] propoxy]-3- (methylamino)phenyl]alanon.

A mixture of 6-fluorescent-3-(4-piperidinyl)-1,2-benzisoxazole (2.3 g, 0,0103 M), K2CO3(1.4 g, M 0,0103), 1-[4-(3-chloropropoxy)-3-(methylamino)phenyl]ethanone (2.5 g, 0,0103 M), KI (0.10 g), and acetonitrile (100 ml) was stirred at reflux, under nitrogen atmosphere, for 23 hours. Then the reaction mixture was cooled to room temperature, poured into water and the aqueous mixture was extracted with ethyl acetate. An ethyl acetate extract is washed twice with water, dried with magnesium sulfate and concentrated to obtain 4.8 g of moistened brown solid. The resulting substance was isolated using preparative HPLC (Waters Associates Prep. LS/System 500, using 2 columns with silica gel and elwira 4% methanol and methylthio from ethanol, resulting received 1-[4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] propoxy] -3- (methylamino)phenyl] ethanone in a solid beige color. So pl. 151-153oC.

Analysis for C24H28FN3O3(%):

Calculated: C 67,75; H 6,63; N 9,88.

Found: C 67,83; H 6,76; N 9,90.

Example 56. 1-[4-[3-[4-(6-the Fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl]-propoxy]-3 - ethoxyphenyl]alanon.

A suspension of NaH (0.28 g of a 50% oil suspension, 0,0059 M) in dimethylformamide (20 ml) was cooled to 4oC in an ice bath. Then to this suspension drop was added 2.3 g (0,0056 M) 1-[4-[32[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] -propoxy] -3 - hydroxyphenyl]ethanone dissolved in dimethylformamide (40 ml). After complete addition, the mixture was stirred for 1 hour in nitrogen atmosphere, maintaining the temperature below 10oC. thereafter, to the reaction mixture drop by drop solution was added ethylbromide (1.3 g, 0,0118 M) dissolved in dimethylformamide (15 ml) and the resulting mixture was stirred for 3 hours in nitrogen atmosphere. The temperature during the procedure was slowly raised to room, and then the reaction mixture was cooled in an ice bath, was added water and the aqueous mixture was extracted with ethyl acetate. Ethylacetate substances beige color. Then the solid is triturated with diethyl ether and filtered, resulting in a received 1.5 g of product. Then this product was combined with an additional sample (3.5 g), and recrystallized from ethanol, resulting in a received 3.0 g(57%) 1-[4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] -propoxy - 3-ethoxyphenyl] ethanone in the form of brilliant crystals beige color, so pl. 112-114oC.

Analysis for C25H29FN2O4(%):

Calculated: C 68,16; H 6,64; N 6,36.

Found: C 68,10; H 7,03; N 6,35.

Example 57. 1-[4-(3-Bromopropane)-3-(methylmercapto)phenyl]alanon.

A mixture of 1-[4-hydroxy-3-(methylmercapto)phenyl] ethanone (5.4 g, 0.03 M), K2CO3(4,2 g), and 1,3-dibromopropane (8 g, 0,039 M) in acetonitrile (150 ml) was heated under reflux for 3 hours and stirred at room temperature overnight. The acetonitrile was removed under reduced pressure and the residue was extracted into dichloromethane (250 ml). Insoluble substances were filtered off and the dichloromethane solution was concentrated. The crude product was purified using flash chromatography on silica gel (100 g SiO2; eluent: 1.6 liters of a mixture of hexane and diamantane, 3:2). After concentration of this is, the resulting received 2.0 g 1-4-(3=-bromopropane)-3-(methylmercapto)phenyl of ethanone in the form of white needle crystals. So pl. 120-122oC.

Analysis for C12H15BrO2S (%):

Calculated: C 47,53; H 5,99.

Found: C 47,74; H 4,91.

Example 58. 4-(3-Bromopropane)-3-methoxybenzonitrile.

A mixture of 4-hydroxy-3-methoxybenzonitrile (7.5 g, 50 mm), K2CO3(12.5 g), and 1,3-dibromopropane (15 g, 75 mm) in acetonitrile (100 ml) was heated under reflux for 3 hours and left at room temperature over night. Then the solvent was removed on a rotary evaporator, and the crude solid product was extracted in methylene chloride (500 ml). Insoluble substances were filtered off and the dichloromethane solution was concentrated. The resulting material was purified using flash chromatography on silica gel (105 g SiO2%; eluent: a mixture of dichloromethane and hexane, 2:3, and then dichloromethane). The result of this procedure has been purified desired product (7,74 g, 52%), which is then twice recrystallized from ethanol and obtained analytically pure 4-(3-bromopropane)-3-methoxybenzonitrile, so pl. 99-101oC.

Analysis for C11H12BrNO2(%):

Calculated: C 48,91; H 4,">

A mixture of 4-hydroxy-3-methylacetophenone (14.5 g, 96 mm), K2CO3(17.5 g, 144 mm) and 1,3-dibromopropane (30 g, 144 mm) in acetonitrile (400 ml) was heated under reflux for 6 hours. After completion of the reaction, the solvent was removed on a rotary evaporator, and the crude solid product was extracted in dichloromethane (750 ml). Thereafter, insoluble inorganic substances were filtered off and the dichloromethane solution was again concentrated to obtain the crude oily substance (34,5 g). Then this substance was purified using flash chromatography on silica gel (150 g SiO2; eluent: 2 l of hexane/dichloromethane, 7: 3; 2 l dichloromethane). The result of this procedure has been purified material (14.6 g, 56%), which is then recrystallized from ethanol. After re-precrystallization from ethanol was obtained analytically pure 1-[4-(4-bromopropane)-3-were] alanon. So pl. 59-61oC.

Analysis for C12H15BrO2S (%):

Calculated: C 53,15; H 5,58.

Found: C 53,35; H 5,52.

Example 60. 1-[4-(3-Bromopropane)-3-methoxyphenyl]phenylmethanone.

A mixture of 1-(4-hydroxy-3-methoxyphenyl)phenylmethanone (14 g, 61,4 mm), K2CO3(13 g, to 92.1 mm) and 1,3-dibromopropane (28 g, 86 mm) in ACE OSU TLC. After completion of the reaction, the inorganic substance was filtered and the solvent evaporated on a rotary evaporator. The residue was purified using flash chromatography on silica gel (140 g SiO2; eluent: 1.2 l of hexane and dichloromethane, 4:1), resulting in a received 15,44 g (72%) of the partially cured material. This material is twice recrystallized from ethanol and obtained 2,84 g of 1-[4-(3-bromopropane)-3-methoxyphenyl] phenylmethanone in the form of white crystals, so pl. 88-89oC.

Analysis for C17H17BrO3(%):

Calculated: C 58,47; H 4,91.

Found: C 59,03; H 4,87.

Example 61. N-[2-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl] -propoxy]phenyl]ndimethylacetamide.

(A) N-[2-(3-phenylsulfonylacetate)phenyl]ndimethylacetamide.

To a cooled to 0oC to a solution of N-[2-(3-hydroxypropoxy)-phenyl]ndimethylacetamide (Example 113) (7.5 g, 0.036 M) in pyridine (90 ml) was added p-toluensulfonate (13,6 g 0,056 M). After placing taillored in solution, the reaction mixture was left for 16 hours in 5oC. Then the reaction mixture was poured into ice water, the result of which was deposited a brown oily product. Water supernatant solution decantation from the oily substances and obtained mcme saline. The organic layer was washed with magnesium sulfate, and concentrated to obtain 5.3 g of a viscous brown oily substance.

(B) N-[2-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] propoxy] phenyl]ndimethylacetamide.

A mixture of 6-fluorescent-3-(4-piperidinyl)-1,2-benzisoxazole (3.4 g, 0,016 M), N-[2-(3-phenylsulfonylacetate)phenyl] -ndimethylacetamide (5,3 g, 0.16 M), K2CO3(2.2 g) and acetonitrile (50 ml) was stirred and heated under reflux for 5 hours. The reaction mixture was poured into water and the aqueous suspension was extracted with ethyl acetate. An ethyl acetate extract was washed (water and brine), dried with magnesium sulfate and the solvent was concentrated to obtain 6.0 g of a brown oily substance. Then this substance was chromatographically on a Waters Prep 500 LC, using silica gel. After concentration of appropriate fractions were obtained 3,0 solid beige color, which is then precrystallization of ethyl acetate and after concentrating the mother liquor was obtained 2.2 g (33%) N-[2-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] - propoxy]phenyl]ndimethylacetamide in a solid beige color, so pl. 118-120oC.

Analysis for C23H26FN3O3(%):
Sasol-3-yl)-1 - piperidinyl] -propoxy]-3-dimethylaminophenyl]alanon.

(A) 1-[4-(4-Chloropropoxy)-3-dimethylaminophenyl]alanon.

To a suspension of sodium hydride (2.3 g, 0,0485 M 50% oil dispersion) in dimethylformamide (75 ml), cooled to 3oC in an ice-salt bath and the flow of nitrogen drop was added 1-(4-hydroxy-3-dimethylaminophenyl)alanon (8.7 g, 0,0485 M) dissolved in dimethylformamide (150 ml), so that the temperature did not exceed 7oC. After complete addition, the bath was removed and the reaction mixture was stirred at room temperature for 45 minutes. Then used the ice bath, and to the mixture drop by drop solution was added 1-bromo-3-chloropropane (8,4 g, 0,0534 M) in dimethylformamide (25 ml). After the addition, the reaction mixture was stirred 18 hours at room temperature (under nitrogen atmosphere). After that, the obtained reaction mixture was cooled to 7oC in an ice bath and carefully added 200 ml of water. After 5 min stirring, the aqueous mixture was extracted with ethyl acetate (5 200 ml). An ethyl acetate extract was washed with water (2 50 ml), dried with magnesium sulfate and concentrated to obtain of 22.2 g of a black oily liquid. The obtained liquid was purified by HPLC (Prep), the appropriate fractions were combined and received 5.0 g brown makeovers is the Thanon beach.

A mixture of 1-[4-(3-chloropropoxy)-3-dimethylaminophenyl]ethanone (2.9 g, 0,0113 M), 6-fluorescent-3-(4-piperidinyl)-1,2-benzisoxazole (2.5 g, 0,0013 M), K2CO3(1.7 g, 0,0122 M), KI (200 mg) and acetonitrile (125 ml) was stirred at reflux for 18 hours. 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 and concentrated to obtain 5.3 g of the oily substance amber color. Then this substance was purified using preparative HPLC (Waters Associates Prep LS/System 500, using 2 columns with silica gel. After concentration of appropriate fractions, obtained 1.65 g (33%) of product. After merging with two additional samples obtained product (3.4 g, 7,74 mm), was dissolved in ethyl acetate and added to 0.90 g (7,75 mm) fumaric acid. Then the resulting mixture was stirred for 30 minutes at reflux, and then for 1 hour at room temperature. The reaction mixture was left overnight and filtered to obtain 3.6 g of product. This product twice precrystallization from ethanol and obtained 2.3 g of material, and then once from acetonitrile, the h is the suspension of this salt in dilute NaOH and was extracted with dichloromethane. After washing dichloromethane extract with water and drying with magnesium sulfate the solvent was removed in vacuum and obtained 1.4 g(14%) 1-[4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] propoxy]- 3-dimethylaminophenyl]ethanone in a solid beige color, so pl. 94-96oC.

Analysis for C25H30FN3O3:

Calculated: C 68,32%; H 6,88; N 9,56%.

Found: C 67,74%; H 6,74%; N 9,40%.

Example 63. 1-[4-[3-[4-(6-the Fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl] propoxy]-2-methoxyphenyl]ethanone hydrochloride.

A mixture of 6-fluorescent-2-(4-piperidinyl)-1,2-benzisoxazole (4.4 g, 0.02 M), 1-[4-(3-chloropropoxy)-2-methoxyphenyl] ethanone (4.8 g, 0.02 M), K2CO3(2.8 g), KI (200 ml) and acetonitrile (110 ml) was stirred and heated under reflux for 16 hours. The reaction mixture was filtered and the filtrate was concentrated to obtain 9.0 g of a brown oily substance. Then this substance was dissolved in acetone and was added fumaric acid (2.5 g, 0,0022 M). After that, the mixture was heated under reflux and stirred at room temperature for one hour. Received fumaric salt (7.0 g) was collected and converted into the free base using aqueous sodium hydroxide, in rezultatai on silica gel (eluent: a mixture of dichloromethane and methanol, (10%) and after concentration of appropriate fractions, obtained 3.6 g of whitish solid. Then this solid is dissolved in anhydrous ether and ethereal hydrochloric acid was added to the precipitated (3.3 grams) cleaners containing hydrochloride salt. The salt was recrystallized from ethanol and obtained a 3.3 g of the product. Occluded alcohol was removed and was obtained 2.8 g (29%) hydrochloride 1-[4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl]propoxy]-2-methoxyphenyl]-ethanone, so pl. 193-195oC.

Analysis for C24H28ClFN2O4(%):

Calculated: C 62,27; H 6,10; N 6,05.

Found: C 61,88; H 5,90; N 5,96.

Example 64. 1-[4-(3-Chloropropoxy)-3-methoxyphenyl]-2,2,2 - trichoroethane.

(A) 4-(3-Chloropropoxy)-3-methoxybenzoic acid.

In nitrogen atmosphere, to a stirred suspension of sodium hydride (6.4 g, 0,13 M, a mixture of about 50% oil dispersion, washed with ether) in tetrahydrofuran (220 ml), was added drop by drop pyrazole (4.4 g, is 0.06 M) in tetrahydrofuran (60 ml). After complete addition, the reaction mixture was stirred for about 15 minutes and then were added 4-(3-chloropropoxy)-3-benzaldehyde (24.5 g, 0,107 M). The flow of nitrogen was stopped, and after the reactor was purged of air for 3 hours. Then the reaction mixture is about is about added water, the reaction mixture was cooled in an ice bath and one drop was added 25 ml of concentrated hydrochloric acid. Then again added water, and the resulting yellow solid product was collected and obtained 16.2 g of product. The filtrate was extracted with ethyl acetate and got another 9.3 g of the product. The samples were combined and recrystallized from acetonitrile, resulting in received of 12.6 g of light yellow solid, so pl. 154-156oC. thereafter, 4.0 g sample was recrystallized from acetonitrile and obtained 2.6 g of a yellow solid. The resulting material was combined with 0.4 grams of another sample and again recrystallized from acetonitrile (coal processing), resulting in a received 2.0 g of 4-(3-chloropropoxy)-3-methoxybenzoic acid in the form of a yellow solid, so pl. 157-159oC.

Analysis for C11H13ClO3(%):

Calculated: C 54,00; H 5,35.

Found: C 54,65; H 5,34.

(B) 4-(3-Chloropropoxy)-3-methoxybenzoate.

To a mixture of 4-(3-chloropropoxy)-3-methoxybenzoic acid (2.4 g, 0.01 M) in dichloromethane (5 ml) was added thionyl chloride (0.9 ml, 0,012 M) dissolved in dichloromethane (5 ml). The reaction mixture was stirred and heated under reflux for 1 casho oily substance was washed with hexane, and the resulting solid was collected, scraping off with a glass rod. The result of this procedure was obtained 1.6 g of 4-(3-chloropropoxy)-3-methoxybenzonitrile, so pl. 60-63oC.

(C) 1-[4-(3-Chloropropoxy)-3-methoxyphenyl]-2,2,2-trichoroethane.

To a stirred mixture of 4-(3-chloropropoxy)-3-methoxybenzaldehyde (10.0 g, 0,038 M) in methylene chloride (55 ml) cooled to -70oC... (obviously in the text pass - Approx. trans.) ... are condensed in the reaction BROMOTRIFLUOROMETHANE (70 g 0,047 M). Then this mixture was added to the reaction triamide of hexamethylphosphoric (9.4 g, 0,041 M) dissolved in dichloromethane (7 ml). The first 90% of the mixture was added quickly, and the rest more slowly. After complete addition, the reaction mixture was stirred for another 1 hour at a temperature of from -70oC to -65oC. thereafter, the temperature of the reaction mixture was raised to room. Then added an equal volume of hexane, and the layers were separated. The bottom layer was extracted with hexane, and then diethyl ether. The extracts were combined and concentrated to obtain 5.6 g of a viscous colorless oily substance. The resulting substance was chromatographically on a Waters Prep 500 LC, using 2 columns with silica gel and elwira 20% ethyl acetate/hexane. After kontali by high vacuum. The result of this procedure was obtained 2.4 g of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]-2,2,2-trichoroethane in the form of a white waxy solid.

Example 65. 4-[3-[-4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl]-propoxy]-3-hydroxy-methylbenzylamino.

(A) 1-[4-(3-Chloropropoxy)-3-hydroxyphenyl]alanon.

A mixture of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone and concentrated sulfuric acid (50 ml) was stirred for 23 hours at 65oC. Then, the cooled reaction mixture was poured into 250 g of ice water and vigorously stirred for 10 minutes. The aqueous mixture was extracted with dichloromethane (CH2Cl2) and the dichloromethane extract was thoroughly washed with 5% sodium hydroxide. The alkaline phase was combined and washed with dichloromethane. After this aqueous mixture was cooled in an ice bath was added concentrated hydrochloric acid until then, until a precipitate. After that, the product was isolated by filtration and dried, resulting in the obtained 3.1 g of light brown solid. Then this substance was combined with an additional image (a total of 5.0 g) and, after two precrystallization of toluene were obtained 3.4 g(22%) 1-[4-(3-chloropropoxy)-3-hydroxyphenyl]etano is B>(%):

Calculated: C 57,78; H 5,73.

Found: C 58,17; H 5,66.

(B) 4-(3-chloropropoxy)-3-hydroxy-methylbenzylamino.

In a flask loaded with sodium borohydride (1.5 g, 0,0394 M) under nitrogen atmosphere, and cooled to 10oC, was slowly added a solution of 1-[4-(3-chloropropoxy)-3-hydroxyphenyl] ethanone (6.0 g, 0,0262 M) dissolved in ethanol/tetrahydrofuran (120 ml, 2:1). After complete addition, the ice bath was removed and the reaction mixture was stirred at room temperature for 3 hours. Then carefully added 0.2 g (0,0053 M) of sodium borohydride. After an hour of stirring at room temperature, the solvent was removed in vacuum. The obtained solid residue was diluted with water (100 ml) and left overnight. Then the product was isolated by vacuum filtration and was obtained 3.8 g of product which is then recrystallized twice from toluene. The result of this procedure was given to 3.3 g (55%) of 4-(3-chloropropoxy)-3-hydroxy-methylbenzimidazole in the form of a light brown solid, so pl. 107-109oC.

Analysis for C11H15ClO3(%):

Calculated: C 57,27; H 6,55.

Found: C 57,60; H To 6.43.

(C) 4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] propoxy]-3-propoxy)-3-hydroxy-methylbenzonitrile (4.5 g, 0,0195 M), KI (200 mg), NaHCO3(1.8 g, 0,0215 M) and CH3CN (125 ml) was stirred at reflux (in nitrogen atmosphere) for 24 hours. Then the cooled reaction mixture was filtered and the filter cake was washed CH3CN. Thereafter, the filtrate was concentrated to obtain an oily residue, which was distributed between water and ethyl acetate. An ethyl acetate extract was washed with water, dried with magnesium sulfate and concentrated. The result of this procedure was obtained 8.6 g of a dark oily substance, which was purified using preparative HPLC (Waters Associates Prep LC/System 500), and received 5.0 g of product. The obtained product is recrystallized twice from ethanol, resulting in a received 3,9 g(49%) 4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] propoxy] -3 - hydroxy-methylbenzimidazole in the form of a light beige solid. So pl. 142-144oC.

Analysis for C23H27FN2O (%):

Calculated: C 66,65; H To 6.57; N 6,76.

Found: C 66,68; H 6,335; N 6,72.

Example 66. 2-[3-[4-(6-the Fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy] the aniline dihydrochloride.

(A) 2-(3-Chloropropoxy)aniline.

To a stirred suspension of sodium hydride (11,0 g 0,23 M 50% oil WM is dimethylformamide (125 ml). After complete addition, the reaction mixture was stirred 1 hour at room temperature and then was cooled to 5oC (ice bath). Then to the mixture drop by drop) was added 3-chloro-1-bromopropane (36,2 g to 0.23 M) in dimethylformamide (50 ml), so that the temperature did not exceed 8oC. Then the reaction mixture was stirred for 4 hours and left for 16 hours at room temperature. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate extract was washed with water, dried with magnesium sulfate, and the solvent was concentrated to obtain 25.4 g reddish oily product. About 12.0 g of oily product were chromatographically on HPLC. After concentration of the major fractions were obtained of 5.4 g of 2-(3-chloropropoxy)aniline in the form of an oily substance.

(B) Dihydrochloride 2-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl]propoxy]aniline.

A mixture of 6-fluorescent-3-(4-piperidinyl)-1,2-benzisoxazole (4.8 g, of 0.022 M), 2-(3-chloropropoxy)aniline (4.0 g, of 0.022 M), K2CO3(4.1 g, of 0.022 M), KI (0.2 g) and acetonitrile (100 ml) was stirred and heated under reflux for 10 hours. The reaction mixture was poured into water and the aqueous mixture was extracted with etracesystem 9.0 g of red solid. This solid is triturated with diethyl ether and was obtained 3.0 g solid beige color. This sample was combined with a sample (1.1 g) from another party, and cleaners containing hydrochloride salt was obtained by dissolving the free base in ethanol and then by adding ethereal hydrochloric acid. The obtained salt (3.5 g) is recrystallized twice from methanol/diethyl ether and was obtained 2.6 g (22%) dihydrochloride 2-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-piperidinyl]propoxy]aniline as a brown solid substance, so pl. 253-255oC.

Analysis for C21H24FN3O22HCl (%):

Calculated: C 57,02; H Of 5.92; N 9,50.

Found: C 56,68; H 5,71; N 9,35.

Example 67. N-[5-Acetyl-2-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]ndimethylacetamide.

(A) Obtaining 1-[3-acetylamino-4-(3-chloropropoxy)phenyl]- ethanone.

The stirred mixture of 1-[3-acetylamino-4-hydroxyphenyl] -ethanone (7.7 g, 0.04 M), K2CO3(5.7 g), 3-chloro-1-bromopropane (8,9 g 0,056 M) and acetone (100 ml) was heated under reflux for 16 hours. Then the reaction mixture was cooled to room temperature and filtered. After concentration of the filtrate was obtained 8.5 g of a white solid. This is also solid. Sample (3,3 g) of this material was subjected to flash chromatography on silica gel, elwira with ethyl acetate. After concentration of appropriate fractions were obtained 2.8 g of solid product which is then recrystallized from toluene and then from ethanol/water, which was obtained 2.2 g (51%) of a solid substance, so pl. 124-126oC.

Analysis for C13H16ClNO3(%):

Calculated: C 57,89; H 5,98; N 5,19.

Found: C 57,08; H Of 5.85; N 5,13.

(B) N-[5-Acetyl-2-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl] propoxy]phenyl]ndimethylacetamide.

A mixture of 6-fluorescent-3-(4-piperidinyl)-1,2-benzisoxazole (4.4 g, 0.02 M), 1-[3-atsetamino-4-(3-chloropropoxy)phenyl]-ethanone (5.5 g, 0,0205 M), K2CO3(2.8 g) and acetonitrile (70 ml) was stirred and heated under reflux for 16 hours. The 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 and concentrated to obtain 9.5 g of a brown oily product. This oily substance was dissolved in ethyl acetate and was added an ethereal solution of hydrochloric acid until then, until the reaction mixture becomes acidic. The crude brown product (ghidrah is the query result which he received of 5.4 g of compound as a brown oily product. Then this compound was chromatographically using preparative HPLC (Waters Prep) using a column with silica gel. After concentration of appropriate fractions were obtained 3.5 g of N-[5-acetyl-2-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] propoxy] -phenyl] ndimethylacetamide in the form of a white solid substance, so pl. 108-110oC.

Analysis for C25H28FN3O4(%):

Calculated: C 66,21; H 6,22; N 9,27.

Found: C 66,12; H 6,25; N 9,27.

Example 68. Hydrochloride 3-[1-[3-(4-ethyl-3-methoxyphenoxy]-4 - piperidinyl] -6-fluorescent-1,2-benzisoxazole.

(A) 4-Ethyl-2-methoxyphenol.

To 1.5 g of 5% palladium charcoal was added acetovanillone (Aldrich, of 11.0 g of 0.066 M), dissolved in absolute ethanol (200 ml). Then added a few drops of concentrated hydrochloric acid and the resulting mixture was hydrogenosomal on a shaker at 42 psi (2,953 kg/cm2). The reaction mixture was filtered through celite and the filtrate was concentrated to obtain 10.3 g of the liquid Golden. Then, this liquid was diluted with water, was extracted with diethyl ether, and the organic phase is washed with water and sodium bicarbonate. The solvent was dried with magnesium sulfate and concentrated, resulting in a received 9.3 g of svetol (9.0 g, 0,059 M), 3-chloro-1-bromopropane (13,0 g, 0,083 M), K2CO3(6.2 g) and acetone (200 ml) was stirred and heated under reflux for 16 hours. The reaction mixture was cooled, and then filtered. The filtrate was concentrated to obtain a transparent liquid. This liquid was diluted with dilute aqueous NaOH and the alkaline mixture was extracted with diethyl ether. Diethyl ether was washed with water, dried with magnesium sulfate and the solvent was concentrated to obtain 11.9 g of a Golden liquid. After that, the liquid was subjected to flash chromatography and was received with 9.9 g of 4-ethyl-2-methoxy-4-(3-chloropropoxy)benzene as a colorless liquid.

(C) Hydrochloride 3-[1-[3-(4-ethyl-2-methoxyphenoxy)propyl] -4 - piperidinyl-6-fluorescent-1,2-benzisoxazole.

The stirred mixture of 6-fluorescent-3-(4-piperidinyl)-1,2-benzisoxazole (4.0 g, 0,018 M), KI (0.4 g), K2CO3(2.5 g), 4-ethyl-2-methoxy-4-(3-chloropropoxy)benzene (4.4 g, 0,018 M) and acetonitrile was heated under reflux for 8 hours. The reaction mixture was poured into water and the aqueous suspension was extracted with ethyl acetate. An ethyl acetate extract was washed with water, dried with magnesium sulfate and the solvent was concentrated to obtain 7.0 g of a brown oily substance. Then this prophetic the f concentration of the appropriate fractions, received 4.4 g of a viscous oily product, which was utverjdali when defending. The obtained solid substance was dissolved in ethyl acetate and precipitated white cleaners containing hydrochloride salt (4.5 g) was added an ethereal solution of hydrochloric acid. After recrystallization from acetone, was obtained 3.0 g (29%) hydrochloride 3-[1-[3-(4-ethyl-2-methoxyphenoxy)propyl[-4-piperidinyl-6-fluorescent-1,2 - benzisoxazole, so pl. 150-152oC.

Analysis for C24H29FN2O3HCl (%):

Calculated: C 64,21; H 6,74; N 6,24

Found: C 64,39; H 6,84; N 6,14.

Example 69. 1-[3,5-Dimethoxy-4-[3-[4-(6-the fluorescent-1,2-benzisoxazol - 3-yl)-1-piperidinyl]propoxy]phenyl]alanon.

(A) 3,5-Dimethoxy-4-(3-bromopropane)acetophenone.

To 3,5-dimethoxy-4-hydroxyacetophenone (5,2 g) in dimethylformamide (50 ml) at 0oC and under nitrogen atmosphere, was added sodium hydride (700 mg, 1.1 EQ., 98%). Then the resulting mixture was stirred for 10 minutes, until, until gas evolution ceased. After this was added potassium carbonate (4 g), and then 1,3-dibromopropane. The mixture was heated at 60oC for one hour. After completion of the reaction, the mixture was poured into a mixture of water and ice and the resulting solution was extracted with ethyl acetate. (600 ml). An ethyl acetate extract was washed with water by means of chromatography on silica gel and obtained 7.6 g of 3,5-dimethoxy-4-(3-bromopropane)acetophenone in the form of a light oily product.

(B) 1-[3,5-Dimethoxy-4-[3-[4-(6-the fluorescent-1,2-benzisoxazol - 3-yl)-1-piperidinyl]propoxy]phenyl]alanon.

The stirred mixture of 6-fluorescent-3-(4-piperidinyl)-1,2-benzisoxazole (3.0 g, 13,6 mm), K2CO3(2.1 g, 15 mm) and 3,5-dimethoxy-4-(3-bromopropane)acetophenone (4.4 g, 13,8 mm) in acetonitrile (50 ml) was heated under reflux for 3 hours. After completion of the reaction, the mixture was diluted with dichloromethane (200 ml). Insoluble substances were filtered off and the solution was concentrated to obtain approximately 10 g of oily substance. Then the resulting material was purified using flash chromatography on silicalite and received a colorless oily substance (of 3.85 g, 61%), which was led from ethanol (400 ml). The result of this procedure was given to 2.94 g of 1-[3,5-dimethoxy-4-[3-[4- (6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] propoxy]phenyl]ethanone in the form of clean crystals, so pl. 107-108oC.

Analysis for C25H29FN2O5(%):

Calculated: C 65,78; H 6,40; N 6,14.

Found: C 65,84; H 6,44; N 6,15.

Example 70. Hemifumarate N-3-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy] phenyl]ndimethylacetamide.

(A) 3-(3-acetamidophenol)propyl bromide.

To 3-acetamidophenol (15.1 g) in dry dexatrim refrigerator for 6 hours, and then over night at room temperature. After another 24 hours, the reaction was completed, the solid was filtered from the reaction mixture and the resulting solution was concentrated. The result of this procedure was obtained oily substance was purified and got to 13.2 g of 3-(3-acetamidophenol)propyl bromide.

(B) N Hemifumarate-[3-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)- 1-piperidinyl]propoxy]phenyl]ndimethylacetamide.

The stirred mixture of 6-fluorescent-3-(4-piperidinyl)-1,2-benzisoxazole (9,25 g, 42 mm), K2CO3(8 g, 58 mm) and 3-(3-acetamidophenol)propyl bromide (11.4 g, 42 mm) in acetonitrile (350 ml) was heated under reflux for 3 hours. After the reaction, the reaction mixture was cooled, filtered and the solids washed with dichloromethane (100 ml). The organic solvent was removed on a rotary evaporator, resulting in the formed crude oily substance ( 18 g), which was then purified using flash chromatography on silica gel. The result of this procedure was obtained 12.2 g (70%) of the pure product as an oily substance. Analytically pure sample was obtained by dissolving 3 g of the free base in ethanol and treatment with a solution of fumaric acid in ethanol (foil] ndimethylacetamide in the form of crystals (2,73 g, so pl. 184-186oC).

Analysis for C23H26FN3O30.5 C4H4O4(%):

Calculated: C 63,95; H 6,01; N 8,94.

Found: C 63,46; H 5,94; N 8,78.

Example 71. 3-[3-[4-(6-the Fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] -propoxy]analyn.

The stirred mixture of N-[3-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] propoxy] phenyl]ndimethylacetamide (of 9.2 g, 22 mm) (obtained as described in the previous example) in 110 ml of 15% hydrochloric acid, was heated at 100oC for 2.5 hours, until then, until the solution became homogeneous. Then the reaction mixture was cooled to 0oC in an ice bath and was podslushivaet 50% NaOH. The product was extracted with ethyl acetate (3 200 ml). Then an ethyl acetate solution was washed with water, brine and then was dried with sodium sulfate, then the solvent was removed. The crude product was purified using flash chromatography and obtained solid (6.6 g, 80%). Then this substance was recrystallized from hot ethanol (50 ml) and received of 3.46 g 3-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] propoxy] - aniline in the form of whitish crystals, so pl. 115-117oC.

Analysis for C21H24FN3O2(%):

Calculated: C 68,27; H 6,55; N 11,37.

The mixture 3-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]- 4-methoxyphenylacetamide (4,2 g, 9.5 mm), (obtained as described above in Example 26) in 60 ml of 15% NaOH was heated under reflux for 2 hours ( 110oC). After completion of the reaction, the solution was cooled to 0oC, and then podslushivaet by addition of 25% NaOH (to pH 10). The product was extracted in ethyl acetate (300 ml). An ethyl acetate solution was washed with water and brine, then dried with sodium sulfate. The solvent was removed under reduced pressure and the crude oily substance was purified using flash chromatography on silica gel, which was obtained 2.6 g of purified oily substance. Then this substance was led from 5 ml of ethanol and 3 ml of petroleum ether, resulting in the received 1.2 g 3-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] propoxy] -4-methoxyaniline in the form of small crystals. So pl. 94-95oC.

Analysis for C22H26FN3O3(%):

Calculated: C 66,15; H 6,56; N 10,52.

Found: C 66,16; H Is 6.54; N 10,44.

Example 73. Fumarate 1-[4-[3-[4-(6-the fluorescent-1,2-benzisothiazol-3-yl) -1-piperidinyl]propoxy]-3-methylaminophenol]ethanone.

(A) 1-[(3-N-Acetyl-N-methylamino)-4-g is 10-15oC, and slowly, drop by drop solution was added to acetylchloride cases (33.8 g, 0,43 M) dissolved in dichloroethane (50 ml). After the additions were added 100 ml of dichloroethane. Then the reaction mixture was cooled to 0oC and within 45 minutes was added to 72.3 g (0.54 M) of aluminum chloride so that the temperature did not exceed 10oC. After complete addition, the reaction mixture was heated under reflux and stirred 18 hours (under nitrogen atmosphere). Then the reaction mixture was cooled and poured into ice-cold water. The resulting aqueous phase was extracted with dichloromethane and the combined extracts were washed with water, dried with magnesium sulfate and concentrated. The result of this procedure received 32,0 g (1-[(3-N-acetyl-N-methylamino)-4-hydroxyphenyl of ethanone in the form of a brown solid, so pl. 168-171oC.

(B) 1-(4-Hydroxy-3-methylaminophenol)Etalon.

A mixture of 1-[3-N-acetyl-N-methylamino)-4-hydroxyphenyl] -ethanone (15.0 g, 0,0724 M) and concentrated hydrochloric acid (150 ml) was stirred at reflux for 3 hours. Then heating was stopped and the reaction mixture was left over night. After the reaction mixture was transferred into a 1-liter flask and gladeana 2 and the resulting aqueous mixture was left over night. The reaction mixture was podslushivaet by adding solid sodium bicarbonate. After the pH was equal to 8, the reaction mixture was extracted with ethyl acetate. An ethyl acetate extract was washed with 200 ml-aliquot of water and then filtered through a layer of celite. After washing the precipitate on the filter with fresh ethyl acetate, the phases were separated. An ethyl acetate extract several times washed with water, dried with magnesium sulfate and concentrated, resulting in received of 10.5 g (1-(4-hydroxy-3-methylaminophenol)ethanone as a dark solid.

(C) 1-[4-(3-Chloropropoxy)-3-methylaminophenol]alanon.

In nitrogen atmosphere, to a stirred suspension of sodium hydride (0,57 g, 0,0182 M 50% oil dispersion) in dimethylformamide (25 ml), cooled to 0oC in an ice-salt bath, a drop of solution was added 1-(4-hydroxy-3-methylaminophenol)-ethanone (3.0 g, 0,0182 M) dissolved in dimethylformamide (55 ml), so that the temperature did not exceed 3oC. After complete addition, the reaction mixture was stirred for 80 minutes at room temperature. Then the reaction mixture was cooled to 5oC and one drop of solution was added 1-bromo-3-chloropropane (3.1 g, 0,0120 M) in dimethylformamide (20 ml). After this dobavlennogo was added water (75 ml) and the mixture vigorously stirred for 5 minutes, and then this mixture was left over night. The resulting aqueous mixture was extracted with ethyl acetate, and an ethyl acetate extract was washed with water, dried with magnesium sulfate and concentrated to obtain 3.9 g of a dark solid product. The resulting product was purified using preparative HPLC and was obtained 2.4 g solid beige color. After that, the obtained substance was combined with an additional sample (a total of 3.8 g) and after two precrystallization from ethanol was obtained 2.1 g(31%) 1-[4-(3-chloropropoxy)-3-methylaminophenol] ethanone in the form of solid flakes beige color, so pl. 115-117oC.

Analysis for C12H16ClNO2(%):

Calculated: C 59,63; H 6,67; N 5,79.

Found: C 59,49; H 6,64' N 5,79.

(D) Fumarate 1-[4-[3-[4-(6-the fluorescent-1,2-benzisothiazol-3-yl)-1 - piperidinyl] propoxy]-3-methylaminophenol]ethanone.

The stirred mixture of 6-fluorescent-3-(4-piperidinyl)-1,2-benzisothiazole (1,9 g, 0.079 in M), 1-[4-(3-chloropropoxy)-3-methylaminophenol]ethanone (1,9 g, 0.079 in M), K2CO3(1.1 g), KI (0.1 g) and acetonitrile (95 ml) was heated under reflux for 16 hours. Then the reaction mixture was poured into water and the aqueous suspension was extracted with ethyl acetate. An ethyl acetate extract was washed (water and brine), what about the substance. Then the resulting material was chromatographically on a Waters Prep 500 LC, using a column with silica gel. After concentration of appropriate fractions were obtained 1.5 g of a brown oily substance. This substance was dissolved in acetone and was added 0.4 g (0,003 M) fumaric acid, and then the white fumaric salt (1.9 g) was collected and recrystallized from dimethylformamide, which was obtained 1.1 g (25%) fumarata 1-[4-[4-(6-the fluorescent-1,2-benzisothiazol-3-yl)-1-piperidinyl] propoxy-3 - methylaminophenol] -ethanone in the form of a white solid with so pl. 198-200oC.

Analysis for C28H32FN3P6S:

Calculated: C 60,31%; H 5,78%; N Rate Of 7.54%.

Found: C 60,02%; H 5.88 Per Cent; N, 7.68 Per Cent.

Example 74. N-[3-[3-[4-(6-the Fluorescent-1,2-benzisothiazol-3-yl)-1-piperidinyl] propoxy]- 4-methoxyphenyl]ndimethylacetamide.

(A) N-[3-[3-(3-Chloropropoxy)-4-methoxyphenyl]ndimethylacetamide.

To a stirred suspension of (in nitrogen atmosphere) of sodium hydride (1.8 g, 0,038 M) in dimethylformamide (60 ml), one drop was added N-(3-hydroxy-4-methoxy)ndimethylacetamide (6,1 g 0,034 M) dissolved in dimethylformamide (23 ml). After complete addition, the reaction mixture was stirred at room temperature for half an hour, and then drop by drop) was added 3-chloro-1-bromoalkanes temperature, and then poured into water and the aqueous mixture was extracted with ethyl acetate. An ethyl acetate extract was washed with water, dried with magnesium sulfate, and the solvent was concentrated to obtain solid purple color. This solid is triturated with diethyl ether and collected, resulting in a 2.8 g of purple solid product. This sample was combined with 1.2 g sample of another party and twice recrystallized from toluene, which was obtained 2.9 g of a whitish solid. This solid was subjected to flash chromatography on 200 g of silica gel, elwira with ethyl acetate. After concentration of appropriate fractions were obtained 2.4 g of a white solid. Then this substance was recrystallized from toluene and obtained 2.2 g (17%) of N-[3-(3-chloropropoxy-4-methoxyphenyl]ndimethylacetamide, so pl. 112-114oC.

Analysis for C12H16ClNO3(%):

Calculated: C 55,93; H Of 6.26; N, 5,44.

Found: C 56,25; H Of 6.29; N, 5,44.

(B) N-[3-[3-[4-(6-the fluorescent-1,2-benzisothiazol-2-yl)-1-piperidinyl] propoxy] -4-methoxyphenyl]ndimethylacetamide.

The stirred mixture of 6-fluorescent-3-(4-piperidinyl)-1,2-benzisothiazole (4.0 g, is 0.017 M), N-[3-[2-chloropropoxy)-4-methoxyphenyl]ndimethylacetamide (4.3 g, is 0.017 M), K2CO3(2.3 g), KI (0.2 g)travali and the filtrate was concentrated to obtain a dark oily substance. Then this substance was dissolved in acetone and to the resulting yellow cleaners containing hydrochloride salt (5.7 g) was added an ethereal solution of hydrochloric acid. Then salt again transformed into the free base and the obtained oily substance (5,2 g) was chromatographically on a Waters Associates Prep LC, using a column with silica gel. After concentration of appropriate fractions were obtained 4.7 g of oily product, which was then turned into cleaners containing hydrochloride salt. Then this salt was again converted into the free base (2.8 g) as a brown oily substance. After this matter vigorously stirred with ether, which was obtained 1.4 g (18%) N-[3-[3-[4-(6-the fluorescent-1,2-benzisothiazol-3-yl)-1-piperidinyl] propoxy] -4-methoxyphenyl] -ndimethylacetamide in the form of a white solid substance, so pl. 109-111oC.

Analysis for C24H28FN3O3S (%):

Calculated: C 63,00; H 6,17; N 9,18.

Found: C 62,80; H 6,17; N 8,86.

Example 75. Hydrochloride 1-[4-[3-[4-(6-the fluorescent-1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy]-3 - methoxyphenyl]ethanone.

The stirred mixture of 6-fluorescent-3-(4-piperidinyl)-1,2-benzisothiazole (4.0 g, is 0.017 M), 1-4-(3-chloropropoxy)-3-methoxyphenyl of ethanone (4.1 g, is 0.017 M), K2CO3(2.3 g), KI (0.2 g) and acetonitrile (100 ml) naked who was regionali with ethyl acetate. An ethyl acetate extract was washed with water, dried with magnesium sulfate and the solvent was concentrated to obtain 8.0 g of a brown oily substance. The resulting substance was chromatographically on a Waters Prep 500 using a column with silica gel. After concentration of appropriate fractions were obtained resinous residue which is triturated with isopropyl ether and was obtained 1.9 g of a white solid. The obtained solid substance was dissolved in absolute ethanol, and precipitated cleaners containing hydrochloride salt (1.7 g) was added an ethereal solution of hydrochloric acid. After concentration of the filtrate of isopropyl ether and treatment of the residue with isopropyl ether were given 0.5 g of salt. The samples were combined and recrystallized from absolute ethanol, the result of which was obtained 1.7 g (21%) hydrochloride 1-[4-[3-[4-(6-the fluorescent-1,2-benzisothiazol-3-yl)-1-piperidinyl] propoxy] -3-methoxyphenyl]-ethanone in the form of a white solid substance, so pl. 221-223oC.

Analysis for C24H27FN2O3HCl (%):

Calculated: C 60,18; H Of 5.89; N 5,85.

Found: C 60,01; H 5,97; N 5,79.

Example 76. N,N-Dimethyl- 4-[3-[4-(6-the fluorescent-1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy]-3 - methoxybenzamide.

(A) N,N-Dimethyl-4-bromo ml) was added potassium carbonate (7.9 g), and then 1,3-dibromopropane (11.6 g). The resulting reaction mixture was heated under reflux for 3 hours and stirred at room temperature for 12 hours. Then the mixture was filtered and concentrated to obtain an oily substance. After purification of this material with the help of column chromatography were obtained 7.6 g of N, N-dimethyl-4-bromopropane-3-methoxybenzamide in the form of a colorless oily substance.

(B) N,N-Dimethyl-4-[3-[4-(6-the fluorescent-1,2-benzisothiazol-3-yl)-1-piperidinyl] propoxy]-3-methoxybenzamide.

The stirred mixture of 6-fluorescent-3(4-piperidinyl)-1,2-benzisoxazole (3,9 g, 17.7 mm), N,N-dimethyl-4-bromopropane-3-methoxybenzamide (5,54 g, 17.5 mm), and K2CO3(3 g) in acetonitrile (250 ml) was heated under reflux for one hour. When you are finished adding the insoluble substance was filtered and washed with dichloromethane. The solvent was removed on a rotary evaporator. The residue was purified by flash chromatography on silica gel and obtained 7 g of the product. This product has led from hot ethanol (45 ml), which was obtained analytically pure N,N-dimethyl-4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] propoxy] -3-methoxybenzamide (of 3.95 g, 50%) as light-jellys 65,92; H 6,64; N WHICH 9.22.

Found: C 65,76; H 6,64; N 9,14.

Example 77. The oxime 1-[4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] propoxy]-3-methoxyphenyl]ethanone

The mixture 1-[4-3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-piperidinyl]propoxy] -3-methoxyphenyl] ethanone (4.3 g, 0.01 M) (obtained as described above in Example 3), hydroxylamine hydrochloride (1.3 g, 0,018 M), ammonium acetate (1.7 g, of 0.022 M) and ethanol/H2O was stirred and heated under reflux for 16 hours. Then the reaction mixture was poured into water and the mixture was cooled in an ice bath for 2 hours. The obtained white solid was collected, washed with water and dried, resulting in a received 4.6 g cleaners containing hydrochloride salt of the oxime, so pl. 216-218oC. the compound Obtained was dispersible in water was added ammonium hydroxide until then, until the suspension became primary. Then this suspension was again extracted with dichloromethane, and after washing with water, drying with magnesium sulfate and concentrating the obtained extract was collected 3.0 g of white solid product with so pl. 168-170oC. This product was recrystallized from dimethylformamide and obtained 2.3 g (52%) oksima 1-[4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3 - methoxyphenyl]alanon is (%):

Calculated: C 65,29; H To 6.39; N 9,52.

Found: C 65,27; H 6,44; N 9,46.

Example 78. O-Methyl ether oksima 1-[4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy] methoxyphenyl]ethanone.

The solution 1-[4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] propoxy] methoxyphenyl]ethanone (4.3 g, 0.01 M) (obtained as described in Example 3), hydrochloride methoxylamine (0,93 g, 0.01 M) in a mixture of pyridine (75 ml) and ethanol (75 ml) was heated under reflux for 16 hours. A large part of the solvent is evaporated under reduced pressure and the residue was diluted with water, resulting in the formed white solid (1.6 g) with so pl. 200-201oC. the Aqueous filtrate obtained after deposition of another collection of white crystals, gave 1.2 g of a pale-yellow solid with so pl. 70-72oC. Initial collection of crystals was converted into its free base by adding aqueous NaOH. After extraction with ethyl acetate, was obtained 1.2 g of free base. These two samples were combined and precrystallization from isopropyl ether, resulting in the received 2.0 g (44%) O-methyl ester oksima 1-[4-[3-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] propoxy] methoxyphenyl of ethanone in the form of colorless crystals with so pl. 97-99Found: C 65,89; H 6,86; N 9,15.

Example 79. Hydrazone 1-[4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy] -3-methoxyphenyl]ethanone.

The stirred mixture 1-[4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy] -3-methoxyphenyl]ethanone (4.3 g, 0.01 M), (obtained as described above in Example 3), hydrazine (0.8 g, 0,0025 M), and ethanol (40 ml) was heated under reflux for 16 hours. The cooled solution was concentrated to obtain an oily residue. This residue was pereirae with water, the obtained solid substance was collected and received to 4.2 g of hydrazine 1-[4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] propoxy] -3-methoxyphenyl] ethanone in the form of a yellow solid. This substance is recrystallized from isopropanol and then from toluene and received 1.7 g (39%) of the desired product with so pl. 106-108oC.

Analysis for C24H29FN4O3(%):

Calculated: C 65,44; H 6,64; N 12,72.

Found: C, Compared With 65.38; H 6,55; N 12,55.

Example 80. Hydrochloride 6-fluorescent-3-[1-[3-[2-methoxy-4-(1-methylethenyl)phenoxy]propyl]-4 - piperidinyl]-1,2-benzisoxazole.

The solution of utility (4,7 ml of a 2.3 M solution in hexane, 0,0107 M) in tetrahydrofuran (65 ml) was stirred under nitrogen atmosphere and cooled to -70ooC for one hour, and then gradually heated to room temperature, then stirred for another 3.5 hours. Then the reaction mixture was cooled to 0oC and drop by drop over 30 minutes, the solution was added 1-[4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] propoxy] -3-methoxyphenyl] ethanone (obtained as described in Example 3) (4.7 g, 0,01100 M) dissolved in tetrahydrofuran (50 ml). After complete addition, the reaction mixture was stirred at room temperature for 19 hours. Then the reaction mixture was poured into water and the aqueous mixture was extracted with diethyl ether. Diethyleneamine extract washed several times with water, dried with magnesium sulfate and concentrated to obtain 7.0 g of a light orange solid. This solid is recrystallized from toluene-hexane and was obtained 1.4 g of triphenylphosphine oxide, and after concentrating the filtrate, obtained 5.5 g of glassy solid beige color. Then this product was combined with another sample (a total of 6.5 g) and purified using preparative HPLC (Waters Associates Prep LC/System 500), resulting in a received 5,2 g solid beige color, kotalanol (5 drops), and then was added an ethereal solution of hydrochloric acid, which was obtained 4.0 g of sediment in the form of a pale white solid, so pl. 192-194oC.

Analysis for C25H30ClFN2O3(%):

Calculated: C 65,14; H 6,56; N Between 6.08.

Found: C 64,95; H 6,62; N 6,04.

Example 81. (E)-1-[[4-[4-(6-the Fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl] -2-butenyl]oxy]-3-methoxyphenyl]alanon.

A mixture of 6-fluorescent-3-(4-piperidinyl)-1,2-benzisoxazole (2.2 g, 10 mm), K2CO3(22 d) and (E)-4-[(4-bromo-2-butenyl)-oxy]-3 - methoxyacetophenone (4.0 g, 1.3 EQ.) in acetonitrile (100 ml) was heated under reflux for 2 hours. After completion of the reaction, the solvent was removed on a rotary evaporator. The residue was extracted into dichloromethane (300 ml). Then the insoluble substance was filtered and dichloromethane was concentrated. The resulting crude product was purified using flash chromatography and after elution, obtained oily substance (2,87 g, 64%). After recrystallization of this substance from a mixture of ethanol and hexane (20 ml: 5 ml) was obtained (E)-1-[[4-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl] -2-butenyl] oxy]-3-methoxyphenyl]ethanone in the form of whitish crystals (2,46 g) so pl. 91-93oC.

Analysis for C25

The stirred mixture of 4-hydroxy-3-methoxyacetophenone (16.6 g, 0.1 M), K2CO3(14 g, 0.10 M) and CIS-1,4-sodium dichloro-2-butene (Aldrich, 15 g, 0.12 M) in acetonitrile (250 ml) was heated under reflux for 2.5 hours. Then the mixture was filtered and concentrated to obtain an oily substance. The resulting substance was purified using flash chromatography. The fractions containing the most pure product were combined and concentrated to obtain 7.7 g of the product as white crystals (30%). Then this product was recrystallized from ether, which was obtained analytically pure (Z)-1-[4-[(4-chloro-2-butenyl)-oxy]-3-methoxyphenyl]alanon (2,72 g) so pl. 64-66oC.

Analysis for C13H15ClO3(%):

Calculated: C 61,30; H 5,94.

Found: C 61,28; H 5,94.

Example 83. (Z)-1-[4-[[4-[4-(6-the Fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2 - butenyl]oxy]-3-methoxyphenyl]alanon.

The stirred mixture of 6-fluorescent-3-(4-piperidinyl)-1,2-benzisoxazole (2.2 g, 10 mm), K2CO3(1.8 g, 12 mm) and (Z)-1-[4-[(4-chloro-2-butenyl)-oxy]-3-methoxyphenyl]ethanone (3,43 g, 9.7 mm) in acetonitrile (100 ml) was heated under reflux for one and a half hours. For the methane (250 ml). Thereafter, the dichloromethane solvent was again removed and the crude oily substance was purified using flash chromatography (2 columns), resulting in a received 2,78 g of a colorless oily substance. Then this substance was utverjdali by energetic drying using a vacuum pump. After recrystallization from ethanol (10 ml) and hexane (2 ml) was obtained analytically pure (1,83 g) (Z)-1-[4-[[4-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] - 2-butenyl] oxy]-3-methoxyphenyl]ethanone, so pl. 57-59oC.

Analysis for C25H27FN2O4(%):

Calculated: C 68,48; H 6,21; N 6,39.

Found: C 687,26; H 6,18; N 6,32.

Example 84. Hydrochloride (E)- 1-[3-[[4-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl]- 2-butenyl]oxy]-4-hydroxyphenyl]ethanone.

A mixture of (E)-1-[3-[[4-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] - 2-butenyl]oxy]-4-benzyloxyphenyl]ethanone (5.5 g, 10,7 mm), acetic acid (50 ml) and hydrochloric acid (6 ml) was heated for 2 hours at 75oC. After completion of the reaction, the solvent was concentrated to a volume of about 20 ml on a rotary evaporator. Then the solution was poured into ice water (350 ml) and was extracted with dichloromethane (3 250 ml). The dichloromethane solution which was harvested by filtration, the result that was obtained 3.4 g of product. Then this product was recrystallized from hot methanol (40 ml), resulting in a received 1,82 g (37.5%) of the hydrochloride (E)-1-[3-[[4-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] - 2-butenyl] oxy]-4-hydroxyphenyl]ethanone in the form of white crystals with so pl. 208-210oC.

Analysis for C24H25FN2O4HCl (%):

Calculated: C 62,54; H 5,69; N Between 6.08.

Found: C 62,40; H Ceiling Of 5.60; N 6,04.

Example 85. (E)-1-[3-[[4-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl]-2-butenyl]oxy]-4-benzyloxyphenyl]alanon.

(A) (E)-3-[(4-Bromo-2-butenyl)oxy]-4-benzyloxyacetophenone.

To 4-benzyloxy-3-hydroxyacetophenone (17.6 g) in acetonitrile (200 ml) was added 10 g of potassium carbonate, and then 19 g of (E)-1,4-dibromobutane. The mixture was concentrated, were extracted in dichloromethane and potassium salt was removed by filtration. After removal of solvent, the resulting material was purified using flash-chromatography, and got to 20.5 g (E)-3-[(4-bromo-2-butenyl)oxy]-4-benzyloxyacetophenone in the form of white crystals.

(B) (E)-1-[3-[[4-[4-(6-the Fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl]-2-butenyl]oxy]-4-benzyloxyphenyl]alanon.

A mixture of 6-fluorescent-3-(4-piperidinyl)-1,2-benzisoxazole (5,62 g, 25,5 is 125 ml) was heated under reflux for 3.5 hours. Then the mixture was cooled and concentrated to obtain crude solid. The residue was extracted into dichloromethane (300 ml) and the insoluble substance was filtered. The crude material from dichloromethane solution was purified using flash chromatography and obtained the purified product as a pale white solid (8 g). Then this substance was recrystallized from hot ethanol and received 7,11 g (E)-1-[3-[[4-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl]-2-butenyl] oxy] -4-benzyloxyphenyl] ethanone in the form of whitish crystals with so pl. 124-125oC.

Analysis for C31H31FN2O4(%):

Calculated: C 72,36; H 6,07; N, 5,44.

Found: C 72,23; H 6,04; N 5,04.

Example 86. 6-Fluorescent-3-[1-[3-[(5-methoxy-1H-indol-6-yl)oxy] propyl]-4-piperidinyl]-1,2-benzisoxazol.

(A) 6-(3-Chloropropoxy)-5-methoxyindol.

To a stirred suspension of sodium hydride (0,94 g, 19,6 mm 50% oil dispersion)in dimethylformamide (20 ml), cooled to -5oC (under nitrogen atmosphere), one drop was added 5-methoxy-6-hydroxyindole (3.2 g, 19,6 mm) dissolved in dimethylformamide (60 ml), so that the temperature of the mixture did not exceed -2oC. After complete addition, the reaction mixture is), dissolved in dimethylformamide (15 ml) while maintaining the temperature of the reaction mixture from -5oC and 0oC. then the mixture was stirred at room temperature (under nitrogen atmosphere) for 21 hours. Then the reaction mixture was cooled in an ice bath and to remove excess sodium hydride was added water and the resulting aqueous mixture was extracted with ethyl acetate. An ethyl acetate extract was washed with water, dried with magnesium sulfate and concentrated to obtain 5.3 g of a dark oily liquid. Then, this liquid was combined with another sample (a total of 10.0 g) and purified using preparative HPLC (Waters Associates Prep LC/System 500), resulting in received of 5.1 g of a brown solid product. 2.5 g sample was recrystallized from isopropyl alcohol and obtained 1.1 g (30%) 6-(3-chloropropoxy)-5-methoxyindole in the form of beige crystals, so pl. 73-75oC.

Analysis for C12H14ClNO2(%):

Calculated: C 60,13; H Of 5.89; N Of 5.84.

Found: C 60,26; H 5,86; N 5,77.

(B) 6-Fluorescent-3-[1-[3-[(5-methoxy-1H-indol-6-yl)oxy]propyl]-4 - piperidinyl]-1,2-benzisoxazol.

A mixture of 6-fluorescent-3-(4-piperidinyl)-1,2-benzisoxazole (2.5 g, 11.5 mm), 6-(3-chloropropoxy)-5-methoxyindole (2.5 g, 10,4 mm), K2CO3(PTA) for 40 hours. Then the cooled reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate extract was washed with water, brine, dried with magnesium sulfate and concentrated to obtain 4.0 g of a solid substance. The resulting material was recrystallized from ethanol and obtained a 3.3 g of the product. After repeated recrystallization from ethanol (coal processing) was obtained 2.9 g (66%) 6-fluorescent-3-[1-[3-[(5-methoxy-1H-indol-6-yl)oxy]propyl]-4 - piperidinyl]-1,2-benzisoxazole in a solid beige color, so pl. 156-158oC.

Analysis for C24H26FN3O3(%):

Calculated: C 68,07; H 6,10; N 9,92.

Found: C 67,89; H 6,07; N To 9.91.

Example 87. Hemifumarate 6-fluorescent-3-[1-[3-[(1H-indol-7-yl)oxy]propyl]-4 - piperidinyl]-1,2-benzisoxazole.

(A) 7-(3-Chloropropoxy)indole.

In nitrogen atmosphere, to a stirred suspension of sodium hydride (0.8 g, is 0.017 M 50% oil dispersion) in dimethylformamide (20 ml) drop by drop) was added 7-hydroxyindole (2.1 g, 0,0157 M) in dimethylformamide (20 ml). After complete addition, the reaction mixture was stirred at room temperature for 0.5 hour and then was cooled to 15oC. To this cooled solution drop by drop) was added 1-bromo-3-chloro-proparacaine 16 hours, and then poured into water and the aqueous suspension was extracted with ethyl acetate. An ethyl acetate extract was washed with water, dried with magnesium sulfate and the solvent was concentrated to obtain a dark brown oily substance. Then this substance was subjected to flash chromatography on silica gel, resulting in a received 1.0 g of 7-(3-chloropropoxy)indole as a colorless oily substance.

Analysis for C11H12ClNO (percent):

Calculated: C 63,01; H 5,77; N 6,68.

Found: C 63,25; H 5,61; N Of 6.65.

(B) Hemifumarate 6-fluorescent-3-[1-[3-[(1H-indol-7-yl)oxy]-propyl]-4 - piperidinyl]-1,2-benzisoxazole.

The stirred mixture of 7-(3-chloropropoxy)-1H-indole (3.5 g, is 0.017 M), 6-fluorescent-3-(4-piperidinyl)-1,2-benzisoxazole (3.5 g, is 0.017 M), K2CO3(2.3 g) and acetonitrile (60 ml) was heated under reflux for 11 hours. After the reaction mixture was poured into water and the aqueous mixture was extracted with ethyl acetate. An ethyl acetate extract was washed with water and dried with magnesium sulfate, and the solvent was concentrated to obtain a dark oily substance. This substance was subjected to flash chromatography on silica gel. After concentration of appropriate fractions were obtained 3.0 g of a white foamy the model the resulting mixture was rapidly heated under reflux, and then was stirred at room temperature for 1.5 hours. The obtained insoluble white fumaric salt collected and received to 4.2 g of the product. Then the salt was recrystallized from dimethylformamide and obtained 3.1 g (36%) of hemifumarate 6-fluorescent-3-[1-[3-[(1H-indol-7-yl)oxy] propyl] -4 - piperidinyl] -1,2-benzisoxazole in the form of a white solid with so pl. 213-215oC.

Analysis for C25H26FN3O4(%):

Calculated: C 66,50; H 5,80; N 9,31.

Found: C 66,23; H 6,14; N 9,39.

Example 88. 6-Fluorescent-3-[1-(3-hydroxypropyl)-4-piperidinyl] -1,2-benzisoxazol.

The stirred mixture of 6-fluorescent-3-(4-piperidinyl)-1,2-benzisoxazole (10.0 g, 0,045 M), K2CO3(10.0 g), 4-bromo-1-propanol (7,3 g 0,046 M) and acetonitrile (200 ml) was heated under reflux for 3 hours. The reaction mixture was poured into water and collected 7,1 g solid beige color. The filtrate was extracted with dichloromethane and, after concentration, were collected at 6.7 g of crude solid. The obtained solids were combined and pereirae with boiling ethyl acetate, which was obtained 8.0 g of 6-fluorescent-3-[1-(3-hydroxypropyl)-4-piperidinyl] -1,2-benzisoxazole in the form of a whitish solid. A sample (4.0 g) as the TBA with so pl. 140-142oC.

Analysis for C15H19FN2O2(%):

Calculated: C 64,73; H 6,88; N 10,06.

Found: C 64,79; H 6,97; N There Is A 10.03.

Example 89. Fumarate 7-fluorescent-3-[1-(2-pyrimidinone)propyl]-4 - piperidinyl-1,2-benzisoxazole.

To a stirred suspension of 6-fluorescent-3-[1-(3-hydroxypropyl)-4-piperidinyl] -1,2-benzisoxazole (3,63 g of 0.013 M) in tetrahydrofuran (50 ml), was added drop by drop bestremembered potassium (2.6 g, 0,013 M) dissolved in tetrahydrofuran (20 ml). After complete addition, the reaction mixture was stirred for 5 minutes at room temperature, and then was added 2-chloropyrimidine (1.6 g, of 0.014 M). The reaction mixture was stirred at room temperature for 4 hours and at this stage, TLC indicated that the reaction is not complete. Then to the reaction mixture were added 0.5 g of the base, and then the mixture was left at room temperature for another 14 hours to continue the reaction. After the reaction mixture was poured into water and the aqueous mixture was extracted with dichloromethane. The dichloromethane extract was washed with water, dried with potassium carbonate and the solvent was concentrated to obtain a wet solid. Then the solid was pereirae with diethyl e and 3.8 g of waxy yellow solid. This material was combined with 2.6 g of sample from another party and the obtained sample was subjected to flash chromatography on silica gel, elwira first ethyl acetate and then a mixture of 8% diethylamine and ethyl acetate. After concentration of appropriate fractions were obtained 3.0 g of the desired compound as a yellow solid product. This solid product was converted into fumaric salt by adding fumaric acid in acetone, and then was converted into its free base. This base was combined with another sample and the sample obtained (3,88) was chromatographically by HPLC on silica gel (eluent: 4.5% methanol/dichloromethane). After concentration of appropriate fractions were obtained 1.6 g of yellow solids, and then received fumaric salt in the form of fumarata 6-fluorescent-3-[(2-pyrimidinone)propyl]-4-piperidinyl]-1,2-benzisoxazole (2.1 g 16%) with T. pl. 184-186oC.

Analysis for C23H25FN4O6(%):

Calculated: C 58,47; H 5,33; N UP 11,86

Found: C 58,52; H Of 5.34; N 11,80.

Example 90. 6 Aceto-2-[4-fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl]methyl-1,4-benzodioxan.

(A) 6 Aceto-2-methyloxime-1,4-benzodioxan.

6 Aceto-2-hydroxymethyl-1,4-benzodioxan (3,39 g, 16,3 mm) was dissolved in trichlorethylene at room temperature for 2 hours. The mixture is then diluted, washed with 150 milliliters of a mixture of ice and dilute hydrochloric acid, sodium bicarbonate and brine, then were dried with magnesium sulfate and concentrated to obtain 5.6 g of the product. After chromatography was carried out on a column of silica gel, received of 3.64 g (yield 78%) 6 Aceto-2-metaloxides-1,4-benzodioxane.

(B) 6 Aceto-2-[4-fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl] methyl-1,4-benzodioxan.

The stirred mixture of 6-fluorescent-3-(4-piperidinyl)-1,2-benzisoxazole (3.0 g, 13,6 mm), K2CO3(2 g, 14.5 mm) and 6-Aceto-2-methyloxime-1,4-benzodioxane (3.5 g, 12 mm) in acetonitrile (100 ml) was heated under reflux for 3 hours. After completion of the reaction the solvent was removed on a rotary evaporator. The residue was extracted in dichloromethane (350 ml), and insoluble substances were filtered off. Then the dichloromethane solution was concentrated to obtain the crude oily product, which was purified using flash chromatography and got to 3.38 g (59%) of product. This product was recrystallized from ethanol and obtained 3.2 g of 6-Aceto-2-[4-(6-fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] methyl - 1,4-benzodioxane in the form of light yellow crystals, so pl. 122-123oC.

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Example 91. 2-[4-(6-the Fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl]methyl-1,4 - benzodioxan.

The stirred mixture of 6-fluorescent-3-(4-piperidinyl)-1,2-benzisoxazole (3.0 g, 13,6 mm), K2CO3(of 2.45 g, 17.7 mm) and 2-methanesulfonylaminoethyl-1,4-benzodioxane (3,35 g of 13.7 mm) in acetonitrile (100 ml) was heated under reflux for 12 hours. After the reaction, the insoluble substance was filtered and washed with dichloromethane. The organic solution was concentrated. Thus obtained crude oily substance was purified using flash chromatography on silica gel. The fractions containing pure product were combined and concentrated to obtain a light yellow oily substance (3.94 g, 74%). Then this substance was led from ethanol and petroleum ether, resulting in the received 2,22 g of 2-[4-(6-fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] methyl-1,4 - benzodioxane in the form of whitish crystals, so pl. 86-87oC.

Analysis for C21H21FN2O3(%):

Calculated: C 68,47; H Of 5.75; N 7,60.

Found: C 68,33; H Of 5.75; N 7,51.

Example 92. 2-[4-(6-the Fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl-1,4 - benzodioxan.

(A) 2-Methylacetate-1,4-benzodioxan.

Connection 2-Hypo drop added methylchloride (9.2 grams) and the reaction mixture was stirred for one hour at room temperature. After completion of the reaction the solution was washed with water, brine and concentrated to obtain an oily substance, which was then purified by chromatography on silica gel and got 17,08 g 2-methylacetate-1,4-benzodioxane.

(B) 2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl] ethyl-1,4 - benzodioxan.

A mixture of 6-fluorescent-3-(4-piperidinyl)-1,2-benzisoxazole (4.7 g, 21 mm), K2CO3(3.5 g, 25.4 mm) and 2-methylacetate-1,4-benzodioxane (5.5 g, 21.3 mm) in acetonitrile (250 ml) was heated under reflux for 3.5 hours. After completion of the reaction, insoluble matter was filtered. The obtained solid was washed with dichloromethane (200 ml). The solutions were combined and evaporated, resulting in the obtained oily substance. Then, this crude oily substance was purified using flash chromatography on a column of silica gel. Thus obtained material was led from ethanol. Crystals of 2-[4-(6-fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl-1,4 - benzodioxane collected and obtained 3.8 g (48%) of the target product, so pl. 112-113oC.

Analysis for C22H23FN2O3(%):

Calculated: C 69,09; H the 6.06; N 7,32

Found: C 69,17; H Of 6.02; N 7,31.

Example 9)-7-methoxy-1-tetralone.

A mixture of 6-hydroxy-7-methoxy-1-tetralone (J. Org. Chem. 1985, 50, 4937) (1.5 g, 7.8 mm), K2CO3(1.7 g, 12.3 mm) and acetone (30 ml) was stirred at reflux for 45 minutes (in nitrogen atmosphere). Then the reaction mixture was cooled to room temperature and to this mixture one drop of solution was added 1-bromo-3-chloropropane (1.9 grams, 12,1 mm) dissolved in 8 ml of acetone. After complete addition, the reaction mixture was heated to a temperature of distillation and then mixed (in nitrogen atmosphere) for 21 hours. Then the reaction mixture was cooled to room temperature and filtered. The filter cake was thoroughly washed with acetone, and the filtrate was concentrated. The result of this procedure was obtained 2.0 g of 6-(3-chloropropoxy)-7-methoxy-1-tetralone in the form of oily substance amber color.

(B) 6-[3-[4-(6-the Fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] propoxy-7 - methoxy-1-tetralone.

A mixture of 6-fluorescent-3-(4-piperidinyl)-1,2-benzisoxazole (0,78 g, 3.6 mm), K2CO3(to 0.060 g, 4.1 mm), KI (100 mg), 6-(3-chloropropoxy)-7-methoxy-1-tetralone (0.87 g, 3.2 mm) and acetonitrile (50 ml) was stirred at reflux for 17 hours (under nitrogen atmosphere). Then the cooled reaction mixture valorem, was dried by magnesium sulfate, and concentrated to obtain 1.7 g of a brown oily substance. The resulting material was purified using preparative HPLC (Watets Associates Prep LC/System 500), which received 1.0 g of light brown solid. After that the substance was combined with another sample (a total of 2.3 g) and recrystallized from ethanol, resulting in a received 1.7 g of product. Then this product again recrystallized from ethanol and received 1,25 g(36%) 6-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] propoxy] -7 - methoxy-1-tetralone in the form of powder beige color, so pl. 129-131oC.

Analysis for C26H29FN2O4(%):

Calculated: C 69,01; H 6,46; N Is 6.19.

Found: C 68,77; H To 6.43; N 6,16.

Example 94. N- [3-[4-(6-the Fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] propyl]-6-acetyl - 2-benzoxazolinone.

(A) N-(3-Chloropropyl)-2-benzoxazolinone.

To a stirred suspension of sodium hydride (7.8 g, 0.16 M, rinsed with ether) in dimethylformamide (75 ml) drop by drop, in an atmosphere of nitrogen, was added 2-benzoxazolinone (20,0 g, 0.15 M) dissolved in dimethylformamide (150 ml). After complete addition, the reaction mixture was stirred at room temperature in the ordinary temperature did not exceed 0oC) a solution of 3-chloro-1-bromopropane (46.6 g, 0.30 M) in dimethylformamide (50 ml). The reaction mixture was left for reaction at room temperature and under stirring for 16 hours. Then the 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 and concentrated to obtain of 21.9 g of brown solid. This substance was recrystallized from a mixture of toluene and hexane, resulting in received 15.6 g of N-(3-chloropropyl)-2-benzoxazolinone in the form of large needle-shaped crystals, so pl. = 263-266oC.

(B) N-(3-Chloropropyl)-6-acetyl-2-benzoxazolinone.

A mixture of N-(3-chloropropyl)-2-benzoxazolinone (8.5 g, 0.04 M), polyphosphoric acid (100 g), and acetic acid (2.4 g, 2.3 ml, 0.04 M) was stirred and heated at 100oC for 2 hours. The hot solution was poured into ice water, resulting in the deposited yellow substance in the form of a gum. The resulting mixture was extracted, and any insoluble matter was filtered. The dichloromethane extract was washed with water, dried with potassium carbonate (K2CO3) and concentrated, resulting in a received 6.4g slightly greenish solid. After recrystallization of this matter, so pl. 100-103oC.

(C) N-[3-[4-(6-the Fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] propyl]-6-acetyl-2-benzoxazolinone.

A mixture of 6-fluorescent-3-(4-piperidinyl)-1,2-benzisoxazole (2.0 g, 0,009 M), N-(3-chloropropyl)-6-acetyl-2-benzoxazolinone (2.4 g, 0,009 M), K2CO3(3.6 g), several crystals of KI and acetonitrile (50 ml) was stirred at reflux for 13 hours. Then the reaction mixture was poured into water and released a dark brown solid product (3.3 g) was collected. This product has chromatographically using HPLC (Waters Prep 500). After concentration of appropriate fractions were obtained 2.3 g of a yellow solid, after recrystallization which was obtained 1.2 g (31%) N-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] propyl] -6 - acetyl-2-benzoxazolinone, so pl. = 152-154oC.

Analysis:

Calculated for C24H24FN3O4: C 65,89%, H OF 5.53%, N BEING 9.61%.

Found: C 65,67%, H 5,48%, N 9,52%.

Example 95. N-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl]propyl]-phthalimide.

A mixture of 6-fluorescent-3-(4-piperidinyl)-1,2-benzisoxazole (6,44 g, 239,1 mm), K2CO3(6.4 g, 46 mm), N-(3-bromopropyl)phthalimide (8,4 g, 31 mm) in acetonitrile (150 ml) was heated under reflux for 3.5 if using column chromatography on silica gel, resulting in a received N-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] propyl] phthalimide in the form of a white solid. After recrystallization of this material from the ethanol was obtained 9.8 g (8%) white crystals, so pl. = 129-130oC.

Analysis for C23H22FN3O3(%):

Calculated: C 67,89; H 5,44; N 10,31

Found: C 67,49; H 5,38; N 10,13.

Example 96. 1-(3-Aminopropyl)-4-6-fluorescent-1,2-benzisoxazol-3-yl)piperidine hydrochloride.

A mixture of N-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] propyl] phthalimide (8.5 g, 21 mm), hydrazine monohydrate (1.5 g, 30 mm) in methanol (60 ml) was heated under reflux for 3 hours. Upon completion of the reaction, the solvent was removed and received a crude solid. This substance was added water (60 ml) and the resulting mixture was acidified by adding HCl (to pH 1). Any insoluble solids were filtered through a layer of celite. The aqueous solution was podslushivaet 50% NaOH (pH 13), and then was extracted with dichloromethane. The combined dichloromethane solution was washed with saline, dried off and got a colorless oily substance (4.5 g). An analytical sample (1.5 g) was obtained by processing the obtained oily substance HCl in ethanol at 0 the form of white crystals, so pl. = 231-234oC.

Analysis for C15H20FN3O 2HCl (%):

Calculated: C 51,44; H 6,33; N 12,00.

Found: C 51,35; H Of 6.49; N 11,90.

Example 97. CIS-2-[3-[4- (6-the Fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] propyl]-hexahydro-1H - isoindole-1,3-dione hydrochloride.

A mixture of 1-(3-aminopropyl)-4-(6-fluorescent-1,2-benzisoxazol-3-yl) piperidine (3,01 g, 10.8 mm) and anhydride CIS-1,2-cyclohexanedicarboxylic acid (1.9 g, 12.3 mm) in dry pyridine (30 ml) was heated under reflux for 16 hours. The dark brown solution was concentrated to dryness on a rotary evaporator. The crude residue was purified twice using flash chromatography on a column of silica gel. The result was obtained 2.5 g (67%) of pure product. This product was made in cleaners containing hydrochloride salt by treatment with HCl in ethanol (50 ml). Thus was obtained 3.0 g of crystals of the hydrochloride CIS-2-[3-[4-fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl]propyl]-hexahydro-1H-isoindole-1,3-dione, so pl. = 242-245oC.

Analysis for C23H28FN3O3HCl (%)

Calculated: C 61,14; H 6,50; N 9,34.

Found: C 61,32; H 6,32; N 9,27.

Example 98. N-[4-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl]butyl] phthalimide.

A mixture of 6-fluorescent-3-(4-piperidinyl)-1,2-b (100 ml) was heated under reflux for 3 hours. After completion of the reaction, the mixture was filtered. Any insoluble matter was washed with dichloromethane (200 ml). The organic solution was concentrated gradually to the formation of crystals. The crude crystals (5.9 g) was collected. The mother liquor was concentrated and obtained 5.5 g of solid, which was purified using flash chromatography on a column of silica gel. The purified product (3.8 g) was recrystallized from ethanol (70 ml) and received 2,48 g N-[4-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] butyl] phthalimide in the form of white crystals, so pl. = 144-146oC.

Analysis for C24H24FN3O3(%):

Calculated: C 68,39; H 5,74; N Becomes 9.97.

Found: C 68,34; H 5,74; N 9,84.

Example 99. 1-(4-Aminobutyl)-4-(6-fluorescent-1,2-benzisoxazol-3-yl)- piperidine the dihydrochloride.

A mixture of N-[4-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)piperidinyl] butyl] phthalimide (6,9 g, 16.4 mm) and hydrazine monohydrate (1.64 g, 32,8 mm) in methanol (70 ml) was heated under reflux for 3 hours. After completion of the reaction, methanol was removed and was obtained as crude product. This product was dissolved in water and acidified by adding HCl (to pH 2). Any insoluble matter was filtered. The aqueous solution was podslushivaet by adding 50% NaO is drained magnesium sulfate. After removal of the solvent was obtained colorless oily product (4,48 g). This product was treated with 2.5 equivalents of HCl in ethanol. The formed solid substance was collected. After recrystallization from ethanol (65 ml) and methanol (20 ml) was obtained 2.0 g of the dihydrochloride of 1-(4-aminobutyl)-4-(6-fluorescent-1,2-benzisoxazol-3-yl)-piperidine in the form of white crystals, so pl. = 234-237oC.

Analysis for C16H22FN3O 2HCl (%):

Calculated: C 52,75; H 6,64; N 11,53.

Found: C 52,37; H 6,59; N 11,07.

Example 100. CIS-2-[4-[4-(6-the Fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl] -butyl]-hexahydro-1H-isoindole-1,3-dione hydrochloride.

A mixture of 1-(4-aminobutyl)-4-(6-fluorescent-1,2-benzisoxazol-3-yl) piperidine (4.7 g, 16,1 mm) and anhydride CIS-1,2-cyclohexanedicarboxylic acid (3,23 g, 21 mm) in pyridine 945 ml) was heated under reflux for 8 hours. After completion of the reaction, the pyridine was removed to dryness. The crude product was purified on a column of silica gel. The result has been 3,18 g of material (45%) as a transparent oily product. This product was dissolved in ethanol (15 ml) and then was treated with HCl in ethanol (45 ml). After cooling, the product crystallized. These crystals were collected and obtained 3.2 g of the desired product, N 9,06.

Found: C 61,79; H Of 6.68; N 8,92.

Example 101. 1-[4-[3-[4-(6-the Fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl] -propyl]thio-3-methoxyphenyl]alanon.

(A) 1-[4-[3-(3-[chloropropyl)thio]-3-methoxyphenyl]alanon

A mixture of 1-(4-thio-3-methoxyphenyl of ethanone (10.0 g, 0,0549 M), potassium carbonate (9.0 g, 0,651 M), and acetone (100 ml) was stirred at reflux for 30 minutes. The reaction mixture was cooled to room temperature and the mixture drop by drop solution was added 1-bromo-3-chloropropane (6.5 ml, 9.5 g, 0,0604 M) in acetone (25 ml). After complete addition, the reaction mixture was heated under reflux and stirred under nitrogen atmosphere for 17 hours. After the reaction was fully completed, the mixture was filtered, and the residue obtained filtrate, washed with acetone. The filtrate was concentrated and obtained oily product amber color. A small sample of this product was utverjdali by trituration with hot cyclohexane and received in the result of 11.7 g of 1-[4-[(3-chloropropyl)thio]-3-methoxyphenyl]ethanone in the form of a yellow solid, so pl. 53-55oC.

(B) 1-[4-[[3-[4-(6-the Fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl]propyl] thio]-3-methoxyphenyl]alanon.

A mixture of 6-fluorescent-3-(4-piperidinyl)-1,2-Benidorm) and CH3CN (100 ml) stirred under reflux in an atmosphere of nitrogen for 7.5 hours, and then left for reaction at 65 hours at room temperature. After the reaction mixture was poured into water and the aqueous mixture was extracted with ethyl acetate. Atrocity extract was washed twice with water, once with brine, and was dried with magnesium sulfate. The solvent was removed in vacuum and obtained 6.8 g of light brown oily substance. The sample was purified using flash chromatography. After concentration of appropriate fractions were obtained 3.0 g of product. This product precrystallization from ethanol and obtained 2.4 g(41%) 1-[4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] propyl] thio - 3-methoxyphenyl] ethanone in a solid beige color, so pl. = 93-95oC.

Analysis for C24H27FN2O3(%):

Calculated: C 65,14; H X 6.15; N 6,33.

Found: C 64,66; H 6,17; N 6,26.

Example 102. 4-(6-Fluorescent-1,2-benzisoxazol-3-yl)1-(2'-methoxyphenyl)butyl - piperidine maleate

(A) 2-(4-Bromobutyl)anisole.

2-Bromoanisole (2.0 g, 1,07 mm) in tetrahydrofuran (20 ml) was cooled to -78oC in nitrogen atmosphere and the resulting solution for 2 hours was added to the fluorine-utility (1.3 EQ. ). Restlessly with ethyl acetate, washed with water and brine and concentrated to obtain an oily product. After chromatography on a column of silica was obtained 2.4 g of 2-(4-bromobutyl)anisole.

(B) 4-(6-Fluorescent-1,2-benzisoxazol-3-yl)-1-(2'-methoxyphenyl)- butylpiperazine maleate.

A mixture of 6-fluorescent-3-(4-piperidine)-1,2-benzisoxazole (2,36 g, 10,7 mm), K2CO3(2 g, 14.5 mm) and 2-(4-bromobutyl)anisole (2.4 g, 10 mm) in acetonitrile (100 ml) was heated under reflux for 2.5 hours. After completion of the reaction, the solvent was removed. The residue was extracted into dichloromethane (200 ml) and filtered. The dichloromethane solution was concentrated. The crude oily product was purified using flash column-chromatography. The purified material was a light yellow oily substance (2,73 g, 53%). This substance was dissolved in ethanol and was treated with maleic acid (607 mg, 1.0 EQ.) in ethanol. After concentration and subsequent cooling to 0oC was obtained 4-(6-fluorescent-1,2-benzisoxazol-3-yl)-1-(2'-methoxyphenyl)butylpiperazine maleate in the form of crystals. These crystals were collected and dried, resulting in a received 2,05 g of the product, so pl. = 132-133oC.

Analysis for C23H27FN

Example 103. 1-[4-(1,3-Dition-2-yl)ethyl]phenyl-4-(6-fluorescent-1,2 - benzisoxazol-3-yl)butylpiperazine.

(A) 4-Bromo-1-(1,3-dition-2-yl)ethylbenzene.

To connect p-bromoacetophenone (eur36, 85 g, 0,185 M) trichlormethine (300 ml) was added 1,3-propanedithiol (25 g, 0,23 M) and etherate of boron TRIFLUORIDE (3 ml). The resulting mixture was stirred at room temperature for 48 hours. Then the mixture was diluted with dichloromethane (500 ml), twice washed with 10% sodium hydroxide (200 ml), water, and brine, and then dried with sodium sulfate. After concentration was obtained an oily product. Part of this product is stirred with ether (100 ml), resulting in the formed crystalline product. This product was isolated by filtration and purified by recrystallization, resulting in a received 4-bromo-1-(1,3-dition-2-yl)ethylbenzene.

(B) 4-(4-Bromobutyl)-1-(1,3-dition-2-yl)ethylbenzene.

To a solution of 4-bromo-1-(1,3-dition-2-yl)ethylbenzene (27,2 g, 94 mm) in tetrahydrofuran (200 ml) at -78oC in nitrogen atmosphere for one drop was added to the fluorine-utility (99 ml, 1.3 M in cyclohexane, of 0.13 M). The mixture is stirred at room temperature for 1.5 hours, and then extinguished 1,4-dibromobutane (42 g, 0.2 M). After 3 hours stirring, the MCA is whether sodium sulfate and concentrated to obtain an oily product. This product was purified using flash chromatography on a column of silica gel. The result was obtained 4-(4-bromobutyl)-1-(1,3-dition-2-yl)ethylbenzene in the form of purified transparent oily substance (22,3 g).

Analysis for C15H21BrS2(%):

Calculated: C 52,17; H 6,13;

Found: C 52,60; H 6,25.

(C) 1-4-(1,3-Dition-2-yl)ethylphenyl-4-(6-fluorescent-1,2-benzisoxazol-3-yl) butylpiperazine.

A mixture of 6-fluorescent-3-(4-piperidinyl)-1,2-benzisoxazole (5,4 g of 24.5 mm), K2CO3(to 4.2 g, 30 mm), 4-(4-bromobutyl)-1-(1,3-dition-2-yl)ethylbenzene (8.5 g, 24.6 mm) in acetonitrile (200 ml) was heated under reflux for 2.5 hours. After the reaction, the mixture was filtered, and the solvent was concentrated. The crude residue (13 g) was purified using flash chromatography on a column of silica gel. The purified material was precrystallization from ethanol (50 ml) and hexane (100 ml) and was obtained 6.6 g of 1-[4-(1,3-dition-2-yl)ethyl] phenyl-4-(6-fluorescent-1,2-benzisoxazol - 3-yl)butylpiperazine in the form of light yellow crystals, so pl. = 108-110oC

Analysis: calculated C 66,91%; H 6,86%; N 5.78 percent.

found: C 66,72%; H 6,76%; N 5,71%.

Example 104. 1-[4-(4-Acetogenin)butyl]-4-(6-fluorescent-1,2 - benzisoxazol-3-yl)-piperidine.

A solution of 1-[4-(1,3-dition-2-yl)atababaevoi precharacterization mercury (11) (5 g, 1.1 EQ.) at room temperature. After 30 minutes the reaction was completed. The solids were filtered, and the solvent was removed on a rotary evaporator. The crude product was dissolved in ethyl acetate (500 ml) and washed with water and brine, and then dried with sodium sulfate. The solvent was removed and received the crude oily product. After purification of this product by flash chromatography on a column of silica gel obtained oily product (2.67 g, 50%) was combined with 1.1 grams of oily product obtained in a similar way. This combined material was recrystallized from ethanol (10 ml) and hexane (20 ml) and received 2,32 g of 1-[4-(4'-acetogenin)butyl]-4-(6-fluorescent-1,2-benzisoxazol-3-yl) piperidine in the form of whitish crystals, so pl. = 85-86oC.

Analysis for C24H27FN2O2(%):

Calculated: C 73,07; H 6,90; N 7,10.

Found: C 72,68; H 7,05; N 7,09.

Example 105. 1-[4-[3-[4-(6-the Fluorescent-1,2-benzoxazol-3-yl)-1 - piperidinyl] propylamino]-3-methoxyphenyl]alanon.

To a stirred suspension of sodium hydride (0,37 g 0,007 M 50% oil suspension) in dimethylformamide (20 ml) was added drop by drop 1-[4-[3-[4-(6-the fluorescent-1,2-benzoxazol-3-yl)-1 - piperidinyl] propylamino] -3-hydroxyvalerate for 15 minutes, and then cooled in an ice bath to about 5oC, then drop by drop added methyliodide (1.0 g, 0,007 M) in dimethylformamide (1 ml). The reaction mixture was stirred at room temperature for 30 minutes and then added water. The resulting aqueous mixture was extracted with ethyl acetate, the extract washed with water, dried with magnesium sulfate, and the solvent was concentrated, the result of which was obtained 4.9 g of a brown oily product, which was utverjdala after settling. The solid product was subjected to flash chromatography on silica gel. The appropriate fractions were concentrated and obtained 2.7 g of a yellow solid product. After recrystallization of this product from a mixture of toluene and hexane were obtained 2.0 g (67% analytically pure 1-[4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] propylamino] - 3-methoxyphenyl] ethanone in the form of a yellow solid substance, so pl. = 96-98oC.

Analysis for C24H28FN3O3(%):

Calculated: C 67,75; H 6,63; N 9,88.

Found: C 67,93; H 6,72; N 9,80.

Example 106. (2,4-Defloriani)-[1-(phenylmethyl)-3-pyrrolidinyl] methanone oxalate.

A solution of ethyl-N-benzyl-3-pyrrolidine carboxylate (21.8 g, 11.7 mm) in 140 ml of 6 N. HCl was heated in a 1-liter round-bottom flask with a return pump. The residue was treated with thionyl chloride (100 ml) for 16 hours at room temperature. After completion of the reaction, the excess thionyl chloride was subjected to vacuum evaporation to dryness (60oC, 4 hours. ). To the residue in the flask, at room temperature, was added 1,3-differental (30 g, 26 mm), and then aluminum chloride (25 g, 18,7) in parts. When the mixture became homogeneous (approximately 10 minutes), it was heated at 55oC for 1 hour. After completion of the reaction, the excess 1,3-diferente was removed under reduced pressure. The residue was distributed between ice/water and dichloromethane (700 ml) and podslushivaet to pH 10 by adding 50% NaOH solution. The dichloromethane solution was washed with water and brine, and then dried with anhydrous magnesium sulfate. The solvent is evaporated and the oily residue (31 g) was purified using flash chromatography on a column of silica gel. The result obtained 26 g (74%) of the pure product as a yellow oily substance. An analytical sample was obtained by dissolution of 4.2 g of the oily substance in ethanol followed by treatment of an ethanol solution of oxalic acid (1,33 g, 14,8 mm). For crystallization, to the mixture drop by drop was added ether. After recrystallization of the metal, so pl. = 114-116oC.

Analysis for C20H19FNO5(%):

Calculated: C 61,38; H 4,89; N To 3.58.

Found: C 61,16; H 4,80; N 3,60.

Example 107. 6-Fluorescent-3-[1-(phenylmethyl)-3-pyrrolidinyl]-1,2 - benzisoxazole.

(A) (2,4-Deformity)[1-(phenylmethyl)-3-pyrrolidinyl]metrorock.

To the compound (2,4-differenl)-1-(phenylmethyl)-3-pyrrolidinyl methanone (22 g) in 95% ethanol (350 ml) and water (100 ml) was added NH2OH HCl (10.1 g) and ammonium acetate (12.7 g, 2.1 EQ.). The resulting mixture was heated under reflux for 3.5 hours. Then the mixture was left stirred for 24 hours at room temperature. The reaction mixture was concentrated to remove ethanol, poured into water and was extracted with dichloromethane (500 ml). Then, the extract was washed with water and brine and was dried with magnesium sulfate. The obtained product was concentrated and the oily residue was purified by column chromatography, resulting in received 12 g of (2,4-defloriani)[1-(phenylmethyl)-3 - pyrrolidinyl]methanosarcina.

(B) 6-fluorescent-3-[1-(phenylmethyl)-3-pyrrolidinyl]-1,2 - benzisoxazole.

A mixture of (2,4-defloriani)1-(phenylmethyl)-3-pyrrolidinyl - methanosarcina (10.8 g, 34,2 mm), potassium hydroxide (10 g), water (100 majdali, and the ethanol was removed on a rotary evaporator. The aqueous mixture was diluted with water (100 ml) and then was extracted with dichloromethane (500 ml). The organic solution was washed with saline, and was dried with anhydrous magnesium sulfate. After concentrating the resulting solution was obtained oily product (9.8 g). This product was purified using flash chromatography on a column of silica gel and was received as the result of 4.46 g (44%) of a light yellow oily substance. This substance was dissolved in ethanol, and then treated with a solution of fumaric acid (1.73 g, 1.0 EQ.) in ethanol. After addition of isopropyl ether, the product slowly crystallized. After recrystallization from ethanol (15 ml) was obtained 4.6 g of 6-fluorescent-3-[1-(phenylmethyl)-3-pyrrolidinyl] -1,2 - benzisoxazole in the form of white crystals, so pl. = 142-144oC.

Analysis for C22H21FN2O5(%):

Calculated: C 64,07; H 5,13; N For 6.81.

Found: C 64,11; H Of 5.05; N 6,89.

Example 108. (E)-1-[4-[(4-Bromo-2-butenyl)oxy]-3-methoxyphenyl] alanon.

A mixture of 4-hydroxy-3-methoxyacetophenone (10 g, 69 mm), K2CO3(10 g, 1.2 g) and 1,4-dibromo-2-butene ( > 95% TRANS, Aldrich, 18 g, 1.2 EQ.) in acetone (500 ml) was heated at 55oC for 3 hours. After reactve was filtered; then the solution was again concentrated to obtain an oily product. This product was purified on a column of silica gel (SiO2that was 100 suirable dichloromethane) and got to 7.25 g (40%) of a white solid. After recrystallization from ether was obtained analytically pure (E)-1-[4-[(4-bromo-2-butenyl)oxo]-3-methoxyphenyl]alanon (3,91 g), so pl. = 71-72oC.

Analysis for C13H15BrO3(%):

Calculated: C 52,19; H 5,50.

Found: C 52,12; H 4,94.

Example 109. 4-(3-Chloropropoxy)-3-methoxybenzaldehyde.

A mixture of vanillin (a 30.4 g, 0.2 M), K2CO3(27,6 g) and acetone (150 ml) was stirred at reflux for 0.5 hours. Then heating was stopped and one drop was added 1-bromo-3-chloropropane (40,8 g, 0,26 M). The reaction mixture was heated, with stirring, under reflux for 16 hours and then poured into water. The aqueous mixture was extracted with diethyl ether, the extract was dried with magnesium sulfate, and the solution was concentrated to obtain an oily residue, which after degassing was utverjdala with the formation of a white solid (50.2 g), 8.0 g of sample was subjected to flash chromatography on silica gel, elwira a mixture of 50% ethyl acetate and hexane. Povaloka solids, so pl. = 53-55oC.

Analysis for C11H13ClO3(%):

Calculated: C 57,78; H 5,73

Found: C 57,21; H 5,52.

Example 110. 6-Fluorescent-3-(3-pyrrolidinyl)-1,2-benzisoxazole hydrochloride.

A mixture of 3-(6-fluorescent-1,2-benzisoxazol-3-yl)-1-pyrrolidinyl - carboxylic acid Atanasova of ester (5.1 g, 18,4 mm), hydrochloric acid (5 ml) and isopropyl alcohol (50 ml) was heated under reflux for 3.5 hours. After the reaction, the solvent was concentrated to about volume 30 ml on a rotary evaporator, and the mixture was cooled to 0oC for 2 hours. The crystals were collected by filtration and washed with cold isopropyl alcohol. The result has been to 3.09 g (69%) 6-fluorescent-3-(3-pyrrolidinyl)-1,2 - benzisoxazole hydrochloride, T. pl. = 225-227oC.

Analysis for C11H11FN2O HCl (%)

Calculated: C 54,44; H 4,99; N 11,54

Found: C 54,35; H 4,99; N 11,38.

Example 111. 1-[4-[3-[4-(6-the Fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl] -propylamino]-4-hydroxyphenyl]alanon.

A mixture of N-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] propyl-6-acetyl-2-benzoxazolinone (6.0 g, of 0.014 M) and 10% aqueous sodium hydroxide (50 ml) was stirred and heated under reflux for 40 minutes. CO3added as long as you do not stop the gas. The aqueous mixture was extracted with dichloromethane. The dichloromethane extract was washed (water), dried (potassium carbonate) and concentrated, resulting in received of 2.6 g of a sticky solid. The crude solid was treated with saturated NaHCO3and were extracted in dichloromethane. Dichloromethane was washed (brine and then with water and was dried with magnesium sulfate. After that, the organic extract was concentrated and received 2.4 g of a brown solid, which was combined with another sample (just received 5 g). This sample was subjected to flash chromatography on silica gel. A small sample (0.25 g) was recrystallized from toluene and was obtained 0.15 g 1-[4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] propylamino] -3-hydroxyphenyl] ethanone in the form of a brown solid substance, so pl. = 150-152oC.

Analysis for C23H26FN3O3(%):

Calculated: C 67,14; H 6,37; N Of 10.21.

Found: C 67,54; H To 6.58; N 9,95.

Example 112. 1-3-Acetylamino-4-(3-chloropropoxy phenyl, alanon.

Stirred mixture of 1-[3-acetylamino-4-hydroxyphenyl]-ethanone (7.7 g, 0.04 M), K2CO3(5.7 g), 3-chloro-1-bromoprop is left to cool to ambient temperature and filtered. After concentration of the filtrate was obtained 8.5 g of white solid product. This solid product was recrystallized from toluene and then from ethanol, resulting in received of 6.5 g of a whitish solid. 3,3 g of the obtained material was subjected to flash chromatography on silica gel. After concentration of appropriate fractions were obtained 2.8 g of a white solid. After recrystallization of this substance from toluene and then from a mixture of ethanol and water was obtained 2.2 g (51%) of 1-[3-acetylamino-4-(3-chloropropoxy)phenyl]ethanone in the form of a white solid product. So pl. = 124-126oC.

Analysis for C13H16ClNO3(%):

Calculated: C 57,89; H 5,98; N 5,19.

Found: C 57,08; H Of 5.85; N 5,13.

Example 113. N-[2-(3-Hydroxypropoxy[phenyl]ndimethylacetamide.

Stirred mixture of 2-hydroxyphenylacetamide (10.0 g, of 0.066 M), K2CO3(6,9 g), 3-bromopropane (12.8 g, a 0.012 M) and acetone (250 ml) was heated under reflux for 16 hours. Then the reaction mixture was left to cool and then filtered. The filtrate was concentrated to obtain 19,0 g of a thick brown oily substance. This substance was subjected to distillation on a Kugelrohr apparatus, and collected 11.2 g (82%) of a viscous oily which was alocale by recrystallization from ethyl acetate in the form of a whitish solid alcohol, so pl. = 78-80.

Analysis for C11H15NO3(%):

Calculated: C 63,14; H Of 7.23; N 6,69.

Found: C 63,10; H 7,32; N 6,64.

Example 114. 4-[4-(6-the Fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl]butyl] bromide.

A mixture of 6-fluorescent-3-(4-piperidinyl)-1,2-benzisoxazole (12 g, 55 mm), K2CO3(13 g) and 1,4-dibromobutane (20 g, 9.3 mm, 1.7 EQ.) in acetonitrile (300 ml) stirred over night at room temperature. The solution was concentrated to a volume of about 80 ml, after which the crystals were dissolved. Then the product was filtered and received 14,16 g (73%), so pl. = 243-245oC.

Analysis for C16H20BrFN2O (%):

Calculated: C 54,09; H 5,67; N 7,89.

Found: C 54,13; H 5,52; N 7,83.

Example 115. 2-[4-(6-the Fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl]etilatsetatom.

A mixture of 6-fluorescent-3-(4-piperidinyl)-1,2-benzisoxazole (3.0 g, 13,6 mm), K2CO3(3.5 g, 25 mm), 2-bromoacetate (4 g, 26.5 mm) in acetonitrile (50 ml) was heated under reflux for 4 hours After cooling to room temperature, the inorganic salts were filtered, and washed with dichloromethane (DHM) (50 ml). The organic solvent was removed on a rotary evaporator and received an oily product. The oily product was purified with poroduct. This oily product was dissolved in ethanol and treated with a solution of fumaric acid (1.2 g) in ethanol. After recrystallization of the salt at room temperature received 3,44 g (57%), so pl. 154-155oC.

Analysis for C16H19FN2O3C4H4O4(%):

Calculated: C 56,86; H 5,49; N 6,63.

Found: C 56,75; H 5,41; N 6,54.

Example 116. N-[2-[-(6-Fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl]ethyl] -morpholine.

A mixture of 6-fluorescent-3-(4-piperidinyl)-1,2-benzisoxazole (3.0 g, 13,6 mm), 2-chloroethylamine hydrochloride (4,46 g, and 29.7 mm) and K2CO3(3 g, 2.2 EQ.) in acetonitrile (60 ml) was heated under reflux for 24 hours. The crude mixture was diluted with dichloromethane and filtered. The solvent was concentrated to obtain an oily residue (about 7.1 g). After purification on a column of silica gel (55 g, SiO2, eluent MeOH: DHM) received 4 g of solid product. After recrystallization from hot ethanol was obtained 2.1 g (48%), so pl. 131-132oC.

Analysis for C18H24FN3O2(%):

Calculated: C 64,84; H 7,26; N 12,60

Found: C 64,80; H to 7.09; N 12,77

Example 117. N-[2-[-(6-Fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl]ethyl] phthalimide.

A mixture of 6-fluorescent-acetonitrile (250 ml) was heated under reflux for 3.5 hours. The solids and solvent were removed. The residue was purified using flash chromatography (SiO2, 110 g, eluent: 2-;% CH3OH: DCM) and received a 7.8 g (84%) of product. Part of this product was recrystallized and got to 2.35 g of the product in the form of whitish crystals, so pl. 148-149oC.

Analysis for C22H20FN3O3(%):

Calculated: C 67,17; H 5,12; N IS 10.68,

Found: C 67,01; H 5,20; N 10,76.

Example 118. Fumarate 2-[4-(6-fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl]-ethyl ester.

A mixture of 6-fluorescent-3-(4-piperidinyl)-1,2-benzisoxazole (3.75 g, 17 mm), K2CO3(3 g, 21,7 mm) and bromoethylamine ether (2,84 g, 20,4 mm) in acetonitrile (150 ml) was heated under reflux for 3.5 hours. The reaction mixture was cooled. Inorganic substances were filtered and washed with DCM. The organic solution was concentrated to obtain an oily substance (7 g). After purification of this substance using flash chromatography (SiO2- 45 mg; eluent: methanol/-DHM) received the product (4 g, 87%) as a pale yellow oily substance. This oily substance was dissolved in ethanol and treated with a solution of fumaric acid (1,67 g) in ethanol (20 ml), resulting in a collected product (5,15 g) as white crystals, so chileno: C 57,86; H 5,88; N 7,10.

Found: C 57,53; H 5,94; N 6,94.

Example 119. Fumarate 4-[4-(6-fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl]-butyl acetate.

A mixture of 6-fluorescent-3-(4-piperidinyl)-1,2-benzisoxazole (9.5 g, 41 mm), K2CO3(7.2 g, 51 mm) and 4-bromobutyrate (10 g, 51 mm) in acetonitrile (200 ml) was heated under reflux for 3.5 hours. After completion of the reaction the solution was cooled and filtered. Inorganic salt was washed DHM (50 ml). The organic solvent was removed. The residue was purified using flash chromatography on a column Packed with silica gel Sorbsil 1C30; 100 g, eluent: DHM-1 liter, with increasing amount of methanol from 2 to 4;, of 2.51) and got cleaned material (12,92 g, 89%). A small sample (1,67 g) was dissolved in ethanol and treated with 1 equivalent of fumaric acid (580 mg) in ethanol, resulting in a received 1.8 g of product as white crystals, so pl. 142-143oC.

Analysis for C18H23FN2O3C4H4O4(%):

Calculated: C 58,66; H 6,04; N 6,22.

Found: C 58,56; H Of 6.02; N 6,13.

Example 120. Fumarate 4-[4-(6-fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl]butanol.

A mixture of 4-[4-(6-fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] butyl acetate (11.5g, 34,4 mm), 15% NaOH (100 Emperature base was neutralized by adding hydrochloric acid, to pH 7. The solution was concentrated to small volume ( 50 ml) and was extracted with dichloromethane. Then the dichloromethane solution was washed with saline and dried with magnesium sulfate. The solvent was concentrated to obtain the crude oily substance ( 10 g). This substance was purified using flash chromatography (Sorbsil C-30,; 100 mg; eluent: a mixture of MeOH and DHM, 3 l), resulting in received of 9.8 g of white solid. The sample for analysis was obtained by treating the free base (2.0 g) with fumaric acid (780 mg, 1.0 equiv. ) in ethanol. The obtained crystals were collected and dried, resulting in a received 1.5 mg of product, so pl. 131-132oC.

Analysis for C16H21FN2O2C4H4O4(%):

Calculated: C 58,82; H 6,17; N 6,86.

Found: C 58,81; H 6,37; N 6,66.

Example 121. 4-[4-(6-the Fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] buildagent fumarate

To a solution of 4-[4-(6-fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl]butanol (2.0 g, 6,84 mm) and triethylamine (1.0 g, 10 mm) in DHM (70 ml), drop by drop at room temperature was added decanolide (1.7 g, 8.9 mm). The resulting mixture was stirred 1 hour and then concentrated to obtain the crude solid. This solid axle using flash chromatography (Sorbsil C-30, 30 g; eluent: a mixture of MeOH in DHM) and received an oily substance (2.5 g, 81%). Thus obtained substance was converted into fumaric salt by adding fumaric acid (650 mg, 1.0 EQ.) in ethanol and collected the crystals of the target product (1.48 g, so pl. 109-110oC).

Analysis for C26H39FN2O3C4H4O4(%):

Calculated: C 64,04; H Of 7.70; N 4,98.

Found: C 64,30; H 7,86; N 4,78.

Example 122. 3-[4-(6-the Fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl - decanoate fumarate.

To a solution of 3-[4-(6-fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl]propanol (1,81 g, 6.5 mm) of triethylamine (0.9 g, 9.0 mm), DHM (45 ml) was added drop by drop decanolide (1.5 g, 7.8 mm) at room temperature. The resulting mixture was stirred 20 minutes and then concentrated to obtain the crude solid residue. This residue was extracted in EtOAc (20 ml), and any insoluble salt was filtered. EtOAc was removed. The oily substance was purified using flash chromatography (Sorbsil C-30, 30 g, eluent MeOH: DHM). Thus obtained oily substance was converted into fumaric salt using fumaric acid (670 mg) in ethanol. In the collected of 1.61 g of crystals, so pl. 100-102oC.

Analysis for C25

Example 123. N, N-Diethyl-4-[4-(6-fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl]BUTYLCARBAMATE fumarate.

To a mixture of 4-[4-(6-fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] butanol (1.55 g, 5.3 mm) and t-butoxide potassium (750 mg, 6.7 mm) in THF (100 ml) drop by drop) was added at room temperature, diethylcarbamoyl (900 mg, 6,63 mm). The resulting mixture was stirred for 2 hours, after which the solvent was removed. The residue was extracted in DHM. The dichloromethane solution was washed with saline and dried with magnesium sulfate. Then the solution was concentrated. The product was purified using flash column-chromatography (SiO214 g, eluent: 2% MeOH in DHM) and obtained 1.84 g of oily product. This product was dissolved in ethanol ( 5 ml) and treated with a solution of fumaric acid (850 mg, 1.0 EQ.) in ethanol. After crystallization stimulated by the addition of a small amount of isopropyl ether, received 2,09 g of the product, so pl. = 152-153oC.

Analysis for C21H30FN3O3C4O4(%):

Calculated: C 59,16; H Of 6.75; N 8,28.

Found: C 59,17; H 6,84; N 8,16.

Example 124. N-Methyl-4-[4-(6-fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl]BUTYLCARBAMATE fumarate.

To a mixture of 4-[4-(6-fluorescent-1,2-benzisoxazole and methyl isocyanate (448 mg, 7.7 mm and 360 mg, 6.2 mm). The resulting mixture was filtered and concentrated to obtain the crude oily product. After purification of this product by flash chromatography on a column (SiO2- 11 g, eluent: 2% CH3OH DHM) received 2,05 g (93%) of light yellow oily substance. This substance was dissolved in ethanol and treated with solution of fumaric acid (800 mg, 1.0 EQ.). After crystallization, stimulated with a few drops of isopropyl ether, received of 1.36 g of the product, so pl. 96-98oC.

Analysis for C18H24FN3O3C4O4(%):

Calculated: C 56,76; H The 6.06; N 9,02.

Found: C 56,27; H 6,03; N 8,86.

Example 125. Fumarate 2-[2-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-1,3-dioxane.

A mixture of 6-fluorescent--3-(4-piperidinyl)-1,2-benzisoxazole (2.0 g, 9.1 mm), K2CO3(1.5 g, 10,9 mm) and bromoethyl-1,3-dioxane (2.1 g, 10,7 mm) in acetonitrile (50 ml) was heated under reflux for 3 hours. After completion of the reaction, insoluble matter was filtered and washed with dichloromethane, after which the filtrate is evaporated. The crude mixture was purified using flash chromatography on a column of silica gel (Sorbsil C-30, 25 g; eluent: DHM and MeOH (1-3% in DHM). Faction, s was treated with a solution of fumaric acid (1.0 g) in ethanol and collected 3,98 g (77%) of product as crystals so pl. 161-162oC.

Analysis for C18H23FN2O3C4H4O4(%):

Calculated: C 58,66; H 6,04; N 6,22

Found: C 58,69; H 5,96; N 6,20

Example 126. Hemifumarate 2-[4-(6-fluorescent-1,2-benzisoxazol-3-yl-1-piperidinyl]ethanol.

(A) 2-[4-(6-fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl]-acetic acid ethyl ester.

2-[4-(6-fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl]-acetic acid ethyl ester was obtained according to the procedure described in Example 115.

(B) 2-[4-(6-fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl]-acetic acid ethyl ester

A mixture of 2-[4-[6-fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] -ethylacetate (of 10.58 g, 34,6 mm), 15% NaOH (100 ml) and ethanol (100 ml) was heated under reflux for 4 hours. The solution was cooled to approximately 5oC and neutralized by adding HCl to pH about 7. Then the ethanol was removed under reduced pressure. The aqueous solution was podslushivaet by adding NaHCO3and was extracted with dichloromethane (2 200 ml). The dichloromethane solution was washed with saline and dried with magnesium sulfate, and then evaporated, resulting received to 6.88 g (75%) of white solids. Sample (2,03 g) was dissolved in ethanol and was treated with fumaric acid (660 g, 1.0 EQ). After crystallization promoting">

Analysis for C14H17FN2O20.5 C4H4O4(%):

Calculated: C 59,62; H 5,94; N 8,69.

Found: C 59,55; H 5,95; N 8,53.

Example 127. 2-[4-(6-the Fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] acidcanada fumarate.

A mixture of 2-[4-(6-fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] ethanol (1.6 g, 5 mm) and triethylamine (800 mg, 8 mm) in chloroform (100 ml), at room temperature, one drop was treated with decanoylamino (1.3 g,7,2 mm). The resulting mixture was stirred for 4 hours. The solvent was removed, resulting in the formed crude solid. This solid was dissolved in a small amount DHM (15 ml) and then filtered. The resulting solution was concentrated.

After purification using flash chromatography on a column of silica gel (Sorbsil C-30, 30 g; eluent: MeOH: DHM), obtained oily substance (2,45 g, 95%). This purified substance was treated with a solution of fumaric acid (660 mg, 1.0 EQ) in ethanol (15 ml). After crystallization, stimulated with a few drops of ether, was obtained of 1.97 g of the product, so pl. 109-110oC.

Analysis for C24H35FN2O3C4H4O4(%):

Calculated: C 62,90; H 7,35; N 5,24.

Found: C 62,93.

To a mixture of 2-[4-(6-fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethanol (1.6 g, 6 mm) and t-butoxide potassium (850 mg, 7.6 mm) in THF (100 ml) drop by drop) was added (at room temperature) diethylcarbamoyl (of 1.03 g, 7.5 mm). The resulting mixture was stirred 4 Asa. Then the reaction mixture was concentrated to obtain the crude solid. This solid was dissolved in DHM and was purified using flash chromatographie in column (Sorbsil C-30, 27 mg; eluent: a mixture of MeOH and DHM). Thus purified product (2.2 g, 91%) as a light oily substance was dissolved in ethanol and treated with a solution of fumaric acid (690 mg, 1.0 EQ) in ethanol (15 ml). After crystallization by cooling, received 2.15 g of product as white crystals, so pl. 133-135oC.

Analysis for C19H26FN3O3C4H4O4(%):

Calculated: C 57,61; H Of 6.31; N 8,76.

Found: C 57,49; H 6,25; N 8,54.

Example 129. Hemifumarate 2-[4-(6-fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylamine.

(A) 2-[4-(6-fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl]Utilitaire.

2-[4-(6-fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] ethelfleda received in accordance with the procedure described in Example 117.

(B) the azole-3-yl)-1-piperidinyl]ethelfleda (4.6 g, 0 11.7 mm) and hydrazine monohydrate (1,17 g, 23,4 mm) in methanol (50 ml) was heated under reflux overnight. After completion of the reaction, the methanol was removed, resulting in the formed crude solid product. This product was stirred with water (150 ml) and acidified by adding HCl to pH 2. Insoluble substances were filtered. The aqueous solution was podslushivaet by adding 50% NaOH and then was extracted with dichloromethane (2 250 ml). The dichloromethane solution was washed with saline and dried with magnesium sulfate. After that, the solvent was removed to obtain a colorless oily substance (2,12 g). The obtained oily substance was treated with a solution of fumaric acid (935 mg, 1.0 EQ.) in ethanol. The obtained Sol was led and received 0,99 g, so pl. 203-205oC product, which is then collected and received a second collection of product (0.73 g, so pl. 198-200oC).

Analysis for C14H18FN3O 0.5 C4H4O4(%):

Calculated: C 59,80; H 6,27; N 13,07.

Found: C To 59.51; H 6,35; N 13,31.

Example 130. Fumarate 2-[4-(6-fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] -acidcanada.

To a mixture of 2-[4-(6-fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] ethylamine (1,49 g, 5.5 mm) and triethylamine who ü stirred at room temperature for 3 hours. The solvent is evaporated and obtained the crude mixture. Then this mixture was purified using flash chromatography on a column of silica gel (SiO2- 20 g; eluent: MeOH solution (0-3%) in DHM). The fractions containing pure product were combined and concentrated to obtain 2.3 g of the oily product. This oily product was converted into fumaric salt by treatment with fumaric acid (655 mg) in ethanol. The ethanol was concentrated to small volume and added 3 volumes of isopropyl ether. The resulting mixture was stirred over night for crystallization, and then collected to 1.83 g (60,5%) solid product with so pl. 108-110oC.

Analysis for C24H36FN3O2C4H4O4(%):

Calculated: C 63,02; H 7,56; N 7,87.

Found: C 62,42; H 7,58; N 7,66.

Example 131. Fumarate 2-[4-(6-fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] -ethylacetamide.

A mixture of 2-[4-(6-fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] -ethylamine (2,56 g, 9.7 mm) and triethylamine (1.45 g, 14.5 mm) in DHM (50 ml) was treated with (at room temperature) by adding one drop of acetylchloride (1.0 g, 12.7 mm). The resulting mixture was stirred for 4 hours at room temperature. Then the reaction mixture was diluted with dichloromethane and eojidanno oily substance. Then this substance was purified using flash chromatography on a column of silica gel (SiO2- 20 g; eluent: (0-2%) CH2OH DHM) and received 1,36 g (46%) of pure product. This product was converted into fumaric salt by treatment with fumaric acid (517 mg) in ethanol. After recrystallization from ethanol was obtained 1,53 g of the product as white crystals, so pl. 132-133oC.

Analysis for C16H20FN3O2C4H4O4(%):

Calculated: C 57,00; H 5,74; N BECOMES 9.97

Found: C 57,05; H of 5.85; N 9,95

Example 132. Fumarate 2-[[2-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]amino] ethyl acetate.

A mixture of 2-[4-(6-fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylamine (2.0 g, 7.6 mm), K2CO3(to 1.38 g, 10 mm) and bromoethylamine (1.40 g, 8.3 mm) in acetonitrile (50 ml) was heated under reflux for 4 hours. After completion of the reaction, insoluble matter was filtered and washed DHM. The solvent is evaporated. The crude mixture was purified using flash chromatography on a column of silica gel (Sorbsil C-30, 30 g; eluent: 2% CH3OH DHM, 800 ml). Then, the thus obtained oily substance was treated with a solution of fumaric acid (358 mg) in ethanol. After crystallization, stimulated the of C18H24FN3O3C4H4O4(%):

Calculated: C 56,77; H The 6.06; N 9,03.

Found: C 56,32; H 5,97; N 8,94.

Example 133. Fumarate, methyl 2-[4-(6-fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylcarbamate.

A mixture of 2-[4-(6-fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylamine (2.0 g, 7.6 mm) and triethylamine (1.0 g, 10 mm) in DHM (50 ml) was treated by adding drop by drop (at room temperature) of methylchloroform (860 mg, 9,12 mm). Then the mixture was stirred for one hour. The reaction mixture was diluted with dichloromethane and washed with saline. The organic solution was dried with magnesium sulfate and concentrated to obtain the crude oily substance. This product was purified using flash chromatography on a column of silica gel (28 g Sorbsil C-30, eluent: DHM and MeOH/DHM). Thus obtained pure product as an oily substance (2,34 g) was converted into fumaric salt by treatment with fumaric acid (840 mg, 1.0 EQ) in ethanol. After crystallization, stimulated by adding a few drops of isopropyl ether, received 2,31 g of the product, so pl. 163-165oC.

Analysis for C16H20FN3P3C4H4O4(%):

Calculated: C 54,92; H Of 5.53; N Being 9.61.

A mixture of 1-(2-amino-ethyl)-4-(6-fluorescent-1,2-benzisoxazol-3-yl)piperidine (3.77 g, 14,3 mm) and CIS-1,2-cyclohexane-dicarboxylic anhydride (2,82 g, 18.2 mm, 1.25 EQ) in dry pyridine (50 ml) was heated at 65oC for 48 hours. The obtained dark brown solution was concentrated to dryness on a rotary evaporator. The crude residue was twice purified using flash chromatography on a column of silica gel (SiO245 g, and 50 g; DHM and 1% CH3OH DHM). Thus obtained pure product (2.35 g, 41%) was converted into fumaric salt by treatment with fumaric acid (660 mg) in ethanol. After two precrystallization got to 1.37 g of product as crystals, so pl. 172-173oC.

Analysis for C22H26FN3O3C4H4O4(%):

Calculated: C 60,57; H By 5.87; N 8,15.

Found: C 60,40; H Of 5.55; N Of 7.82.

Example 135. Fumarate (S)-(+)-3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-piperidinyl]-2-methyl-1 - propanol.

A mixture of 4-(6-fluorescent-1,2-benzisoxazol-3-yl)-piperidine (7.2 g, 32,7 mm), (S)-(+)-3-bromo-2-methyl-1-propanol (5.0 g, 32,6 mm), K2CO3(7,19 g, 52 mm) in acetonitrile (250 ml) was heated under reflux overnight. Insoluble substances hoteltravel. The solvent was removed under reduced pressure and the crude the ATA which received the compound in the form of a whitish solid (8,83 g, 94%). Sample (1.7 g) was converted into fumaric salt by treatment with fumaric acid (710 mg) in ethanol. After recrystallization from ethanol, got 1,74 g of the product as white crystals, so pl. 119-121oC.

Analysis for C20H25FN2O6(%):

Calculated: C 58,82; H 6,17; N 6,86.

Found: C 58,81; H 6,24; N 6,76.

Example 136. 4-(6-Fluorescent-1,2-benzisoxazol-3-yl)-1-[3-(1- piperidinyl)-propyl]piperidine difumarat.

A mixture of 4-(6-fluorescent-1,2-benzisoxazol-3-yl)piperidine (3.0 g, 13,6 mm), N-(3-chloropropyl)piperidine hydrochloride (4,05 g, 20,4 mm), K2CO3(6 g, 43,4 mm) and tetrabutyl-ammonium bisulfate (interphase catalyst, 2.3 g) in acetonitrile (100 ml) and water (15 ml) was heated under reflux for 16 hours. The resulting mixture was washed with salt solution, and the layers were separated. The organic solution was concentrated. The crude product (6.4 g) was purified using flash chromatography on a column of silica gel (55 g Sorbsil C-30; eluent: 1.4 l of a mixture of 2% CH3OH, and 0.5% DEA in DHM). Thus purified product as an oily substance (4.5 g) was treated with fumaric acid (1.6 g) in ethanol. The result of this procedure was obtained 3.1 g of a solid substance, so pl. 178-181oC. Then it is a solid substance periklis for C20H24FN3O 2C4H4O4(%):

Calculated: C 58,22; H 6,28; N 7,27.

Found: C 58,39; H 6,36; N 7,34.

Example 137. 1-(3-Dimethylaminopropyl)- 4-(6-fluorescent-1,2-benzisoxazol-3-yl)piperidine difumarat.

A mixture of 6-fluorescent-3-(4-piperidinyl)-1,2-benzisoxazole (3,05 g, 13,8 mm), hydrochloride 3-dimethylaminopropylamine (3.4 g, 21 mm), K2CO3(6.2 g, 45 mm) and tetrabutylammonium bisulfate (interphase catalyst (1.5 g) in acetonitrile (100 ml) and water (50 ml) was heated at 60oC during the night. Then the aqueous phase was separated and the acetonitrile was removed under reduced pressure. The residue was extracted into dichloromethane. The organic solution was washed with water and brine, and then dried with magnesium sulfate. The solvent was removed, and the resulting crude product (4.3 g) was treated with fumaric acid (1,58 g, 1.0 EQ) diluted in ethanol, resulting in collected 2,53 g of crystals with so pl. 192-194oC. After recrystallization from ethanol was obtained of 2.08 g of the product as white crystals, so pl. 194-195oC.

Analysis for C17H24FN30,2 C4H4O4(%):

Calculated: C 55,86; H 6,00; N Of 7.82.

Found: C 56,11; H 5,94; N 7,86.

Example 138. (R)-(-)-3[4-(6-the Fluorescent-1,2-benzisoxazol is 5 g, 65 mm), K2CO3(10 g, 65,3 mm), (R)-(-)-3-bromo-2-methyl-1-propanol (10 g, 65,3 mm), tetrabutylammonium bisulfate (1.27 g, interfacial catalyst) in acetonitrile (300 ml) and water (5 ml) was heated under reflux for 6 hours. Then the mixture was cooled, and the solvent evaporated on a rotary evaporator. The residue was extracted into methylene chloride, and insoluble matter was filtered. After concentration of the extract, the crude product was purified using flash chromatography on a column of silica gel (SiO2- 150 g; eluent: 1 l DHM and 1.6 liters of 2% CH3OH DHM) and obtained 17 g of purified material (89%). Then, the sample for analysis was obtained by processing 2.28 g of sample fumaric acid (953 mg) in ethanol. After adding isopropyl ether, formed crystals, which are then collected and dried, resulting in a received 1.84 g of product, so pl. 114-115oC.

Elemental analysis for C16H21FN2O2C4H4O4(%):

Calculated: C 58,82; H 6,17; N 6,86.

Found: C 58,48; H Between 6.08; N 6,57.

Example 139. 3-[1-[3-[4-(1-Methoxyethyl)-2-hydroxyphenoxy]-propyl]-4-piperidinyl] -6-fluorescent-1,2-benzisoxazol.

In a nitrogen atmosphere, a mixture of 6-fluorescent-3-(4-piperidinyl)-1,2-gasoline the(200 mg) and CH3CN (150 ml) was stirred at reflux for 17 hours. TLC indicated trace amounts of alkylating the side chain, therefore, to the mixture was added 6-fluorescent-3-(4-piperidinyl)-1,2-benzisoxazol (0.6 g, 2.7 mm) and NaHCO3(0,22 g, 2.6 mm) and the reaction mixture was heated under reflux for 3 hours. After that, the cooled reaction mixture was concentrated and the residue was distributed between EtOAc and water. Then an ethyl acetate extract was washed with water, brine and after drying with magnesium sulfate, the extract was concentrated to obtain 11.9 g of the oily substance beige color. This sample was purified using preparative HPLC (Watersa Associates Prep LC/System 500), using a column with silica gel (eluent: 5% MeOH-CH2Cl2). After concentration of later fractions were obtained at 4.2 g 4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] propoxy]-3 - hydroxy-methylbenzimidazole. After concentrating the early fractions were obtained 4.0 g of a mixture of 4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] propoxy] -3 - hydroxy-methylbenzimidazole and 3-[1-[3-[4-(1-methoxyethyl)-2-hydroxyphenoxy] propyl] -4-piperidinyl]-6 - fluorescent-1,2-benzisoxazole (last connection was evidently formed by the reaction of pervogo (100 ml), then I added an ethereal solution of hydrochloric acid. After stirring for 1.5 hours, was added anhydrous Et2O, and the resulting solid is collected and dried, resulting in a received 2.9 g of a mixture of appropriate cleaners containing hydrochloride salts. Then the solid is suspended in H2O and acidified NH4OH. The aqueous mixture was extracted with methylene chloride and the extract was washed with water, dried with magnesium sulfate and concentrated to obtain 2.7 g of the oily product in a light beige color. This oily substance was purified using preparative HPLC (Waters Associates Prep LC/System 500, using 2 columns with silica gel (eluent: 3% MeOH/CH2Cl2). After concentration of later fractions was obtained 0.5 g 4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] propoxy] -3 - hydroxymethylbenzene. After concentrating the early fractions were obtained oily substance, which was then utverjdali when defending. The obtained product was pereirae with heptane and filtered to obtain 1.2 g of a white powdery substance. Then this compound was recrystallized from EtOH was obtained 1.1 g(10%) 3-[1-[4-(1-methoxyethyl)-2-hydroxyphenoxy] propyl] -4-piperidinyl]-6 - fluorescent-1,2-benzisoxazole as ocisenie: C 67,27; H 6,82; N 6,54.

Found: C 67,18; H 6,84; N 6,54.

Example 140. 6-Fluorescent-3-[1-[3-[(1H-indol-5-yl)oxy]propyl]-4 - piperidinyl] -1,2-benzisoxazol.

In nitrogen atmosphere, a mixture of 6-fluorescent-3-(4-piperidinyl)-1,2-benzisoxazole (2.6 g, 11.8 mm), K2CO3(1.6 g, 11.6 mm), KI (200 mg), 5-(3-chloropropoxy)indole (2.2 g, 10.5 mm) and CH3CN (100 ml) was stirred at reflux for 18 hours. Then the cooled reaction mixture was poured into water and the aqueous mixture was extracted with ethyl acetate. An ethyl acetate extract 2 times washed with water, 2 times with saline, and then after drying with magnesium sulfate, the solvent was removed in vacuum and got a 5.1 g of a dark oily product. This oily product was purified using preparative HPLC (Waters Associates Prep LC/System 500, using 2 columns with silica gel (eluent: 4% MeOH-CH2Cl2) and received 2.65 g (65%) solid beige color. After recrystallization from ethanol, was obtained 2.2 g (54%) powder beige color, so pl. 118-121oC.

Analysis for C23H24FN3O2(%):

Calculated: C 70,21; H X 6.15; N Is 10.68.

Found: C 69,80; H 6,21; N 10,78.

Example 141. Sesquifumarate 6-fluorescent-3-[1-[3-(1-isoquinoline-5-yl) oxy] propyl]- 0,013 M), 5-(3-chlorotoxin)isoquinoline (2.8 g, of 0.013 M), K2CO3(1.7 g) and CH3CN (50 ml) was heated under reflux for 16 hours. Then the reaction mixture was filtered and the filtrate was concentrated to obtain an oily substance. The filter cake was treated with water and the aqueous suspension was extracted with methylene chloride. The filtrate was extracted with methylene chloride and the extracts were combined, washed with water, dried with potassium carbonate and concentrated to obtain 5.4 g of a brown oily substance. This substance was purified by HPLC on a column of silica gel, elwira a mixture of CH2Cl2and MeOH (5%), which was obtained 2.3 g of a yellow oily substance. Then this substance was dissolved in EtOAc was added fumaric acid (0.66 g, 1 EQ.). The resulting mixture was rapidly heated to a temperature of distillation and then stirred at room temperature for 16 hours. The obtained white solid was collected and obtained 2.2 g of fumaric salt. This compound was recrystallized from DMF and was obtained 1.4 g (18,6%) of isoquinoline as sesquifumarate, so pl. 213-215oC.

Analysis for C30H30FN3O8(%):

Calculated: C 62,17; H 5,22; N 7,25.

CLASS="ptx2">

In nitrogen atmosphere, a mixture of 6-fluorescent-3-(4-piperidinyl)-1,2 - benzisoxazole (3.5 g, 16 mm), K2CO3(2.2 g, 16 mm), KI (200 mg), 4-chloropropoxy)indole (3.0 g, 14 mm) and CH3CN (100 ml) was stirred at reflux for 7 hours and then at room temperature for 68 hours. When TLC showed that the reaction is not yet complete, reflux was continued for another 6 hours. Then to the mixture was added K2CO3(0.5 g, 4 mm) and the reaction mixture was stirred at reflux for 17 hours. The cooled reaction mixture was poured into water and the aqueous mixture was extracted with ethyl acetate. The organic extract was washed with water and saturated sodium chloride, then dried with magnesium sulfate; the solvent was removed and received 5.7 g solid beige color. This product was purified using preparative HPLC (Waters Associates Prep LC/System 500, using 2 columns with silica gel (eluent: 4% MeOH/CH2Cl2) and received 3.04 from g (61%) solid beige color. This substance is recrystallized twice from EtOH, which was obtained 2.3 g (41%) of white powder, so pl. 129-131oC.

Analysis for C23H24FN3O2(%):[1-[3-(6-methoxy-1H-indol-5 - yl)oxy] propyl]-4-piperidinyl]-1,2-benzisoxazole.

In nitrogen atmosphere, a mixture of 6-fluorescent-3-(4-piperidinyl)-1,2-benzisoxazole (3.0 g, 14 mm), 5-(3-chloropropoxy)-6-methoxyindole (3.0 g, 13 mm), K2CO3(2.1 g, 14 mm), KI (200 mg) and CH3CN (150 ml) was stirred at reflux for 48 hours. 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 and brine, and then dried with magnesium sulfate. After removal of solvent in vacuo, was obtained 5.6 g of a dark oily substance. This substance was purified using preparative HPLC (Waters Associtates Prep LC/System 500, using 2 columns with silica gel (eluent: 2% EtNH/EtOAc), and was obtained 2.5 g (47%) solid beige color. After recrystallization from EtOH, was obtained 2.0 g of whitish powder. 1.8 g (4 mm) of the sample was dissolved in hot ethyl acetate and was added fumaric acid (0.5 g, 4 mm). The reaction mixture was stirred 30 minutes at approximately 40oC, and then gradually cooled to room temperature. Received hemifumarate salt was collected and dried to obtain 2.0 g of the product. This product was recrystallized from EtOH and received 1.5 g (25%) of a light beige powder with so pl. 186-188oC.

Analysis for C26H284. 1-[4-[3-[4-(6-the Fluorescent-1,2-benzisothiazol-3-yl)-1 - piperidinyl] -propoxy]-3-hydroxyphenyl]alanon.

In nitrogen atmosphere, a mixture of 6-fluorescent-3-(4-piperidinyl)(-1,2-benzisothiazole (2.4 g, 10.1 mm), 1-[4-(3-chloropropoxy)-3-hydroxyphenyl]ethanone (2.5 g, 11,1 mm), NaHCO3(0,94 g, 11,1 mm), KI (100 mg) and CH3CN (100 ml) was stirred at reflux for 65 hours. The cooled reaction mixture was poured into water and the aqueous mixture was extracted with ethyl acetate. An ethyl acetate extract was washed once with water, three times with saline, dried with magnesium sulfate and the solvent evaporated, resulting in received of 4.2 g of a dark solid. After three precrystallization of EtOH was obtained 2.1 g (48%) of brilliant crystals beige with so pl. 135-137oC.

Analysis for C23H25FN2O3S (%):

Calculated: C 64,47; H 5,88; N 6,54

Found: C 64,44; H 5,69; N 6,29.

Example 145. 4-[3-[4-(6-the Fluorescent-1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy]-3 - methoxy an methylbenzylamino.

In nitrogen atmosphere, to a mixed solution 1-[4-[3-[4-(6-the fluorescent-1,2-benzisothiazol-3-yl)-1-piperidinyl] propoxy]-3 - methoxyphenyl]ethanone (4.1 g, 9.3 mm) in 60 ml of MeOH-THF (1:1) at room temperature, portions were added NaBH4(0,386 g, 10,2 of white gums. This gum was washed with water (twice), and water fraction again decantation. Residual water was removed under high vacuum and received 5.0 g of white powder. This compound was dissolved in boiling toluene and the insoluble matter was again filtered. After concentrating the toluene filtrate was obtained 3.8 g of solid product beige color. Then, this solid was purified using preparative HPLC (Waters Associates Prep LC/System 500, using 2 columns with silica gel (eluent: 2% Et2NH-EtOAc), which was obtained 2.7 g of a light beige solid. Then this substance was recrystallized from EtOAc and was obtained 1.7 g (42%) of pure white powder with so pl. 113-115oC.

Analysis for C24H29FN2O3S (%):

Calculated: C 64,84; H To 6.58; N 6,30.

Found: C 64,85; H 6,44; N Is 6.19.

Example 146. Fumarate (R)-(-)-3-[4-(6-the fluorescent-1,2-benzisoxazol-3 - yl)-1-piperidinyl]-2-methyl-1-propyl.

To a mixture of (R)-(-)-3-[4-(6-the fluorescent-1,2-fluorescent-benzisoxazol-3-yl)-1-piperidinyl] -2 - methyl-1-propanol (3.2 g, 11 mm) and triethylamine (3.2 g, 11 mm) in DHM (100 ml), one drop was added (at 0oC) acetylchloride (890 mg, 11,3 mm). The resulting mixture was stirred at room temperature for 4.5 hours. After that, the solvent was removed on Resta DHM. The resulting crude product was dissolved in DHM and was purified using flash chromatography on a column of silica gel (SiO230 mg) eluent: DHM and 1% CH3OH DHM). The result of this procedure received 2,11 g (58%) purified oily substance. This oily substance was treated with a solution of fumaric acid (695 mg, 1.0 EQ) in ethanol and received fumaric salt. This salt is again recrystallized from ethanol and isopropyl ether, resulting in received of 2.09 g of the product as white crystals, so pl. 118-120oC.

Analysis for C18H23FN2O3C4H4O4(%):

Calculated: C 58,66; H 6,04; N 6,22.

Found: C 58,53; H 5,76; N 8,91.

Example 147. Fumarate of 1-(R)-(-)-[4-[3-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2 - methyl-1-propoxy]-3-methoxyphenyl]ethanone.

(A) 1-(R)-(-)-3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] -2 - methyl-1-propylaminosulfonyl.

To a mixture of (R)-(-)-3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1 - methyl-1-piperidinyl-2-methyl-1-propanol (7,26 g, 24.8 mm), and triethylamine (3 ml, 30 mm) in methylene chloride (DHM)120 ml) drop by drop) was added, at 0oC, methansulfonate (3.13 g, 27,3 mm). The resulting mixture was stirred at room temperature for one hour, and then the end is ispolzovaniem mixture DHM and ether as solvent. The obtained oily mixture was purified using flash chromatography on a column of silica gel (90 mg - SiO2, eluent: DHM). The result of this procedure received ester of methanesulfonate in the form of a colorless oily substance (6,48 g, 70%) which was used directly in the subsequent stage.

(B) Fumarate 1-(R)-(-)-[4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2 - methyl-propoxy]-3-methoxyphenyl]ethanone.

The solution above methanesulfonate (6,48 g, 175 mm) in DMF (5 ml) was added entirely to the seasoned (within half an hour) cold mixture of acetovanillone (4,13 g, 24,9 mm) and sodium hydride (670 mg, 26.5 mm) in DMF (40 ml) at 0oC. Then the mixture was rapidly heated to approximately the 50oC and was stirred at room temperature for 16 hours. After that, the mixture was extracted into dichloromethane (500 ml) and washed twice with water and then brine. The organic solution was dried with magnesium sulfate and concentrated to obtain an oily substance. This substance was twice purified using flash chromatography on a column of silica gel, resulting in received lower than the 5.37 g of purified material. Fumaric salt was obtained by treating the purified oily substances, low, so pl. 141-142oC.

Analysis for C25H29FN2O4C4H4O4(%):

Calculated: C 62,58; H 5,98; N 5,03.

Found: C Totals 62.52; H Of 5.75; N 4,96.

Example 148. Fumarate 3-[4-(6-fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl]-2,2-dimethyl-1-propanol.

A mixture of 4-(6-fluorescent-1,2-benzisoxazol-3-yl)piperidine (3 g, 13,6 mm), K2CO3(12.5 g, 17.5 mm), 3-bromo-2,2-dimethyl-1-propanol (3 g, 21 mm, 1.5 equiv.) and tetrabutylammonium bisulfate (interphase catalyst (1 g) in water (5 ml) and acetonitrile (150 ml) was heated under reflux for 43 days. TLC showed a small spot of the intended product. Then the mixture was diluted with ethyl acetate (400 ml) and washed with saline. The organic solution was dried and concentrated to obtain a dark brown mixture. This crude mixture was carefully purified using flash chromatography (SiO2; 95 g dried pure product; 260 mg (6%) of the oily substance) and received an oily substance, which was then converted into fumaric salt by treatment with fumaric acid (98,5 mg, 1 EQ) in ethanol. After recrystallization from ethanol/ether there was obtained 210 mg of product as white crystals, so pl. 114-145oC.

Analysis for C17H23.

Product 149. Fumarate of 1-(S)-(+)-[4-[3-[4-(6-the fluorescent-1,2 - benzisoxazol-3-yl)-1-piperidinyl]-2-methyl-1-propoxy]-3-methoxyphenyl] ethanone.

(S)-(+)-3-[4-(6-the Fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] -2 - methyl-1-propylaminosulfonyl.

To a mixture of (S)-(+)-3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2 - methyl-1-propanol (8.8 g, 30 mm) and triethylamine (3.2 g, 32 mm) in dichloromethane (150 ml), was added drop by drop at 0oC, for 10 minutes, methansulfonate (4 g, 35 mm). The resulting mixture was stirred at room temperature for one hour, and then concentrated. Triethylamine cleaners containing hydrochloride salt was filtered, using as solvent a small amount of dichloromethane. The crude oily substance was purified using flash chromatography on a column (SiO290 g; eluent: DHM) and received 5,28 g (47%) of purified colorless oily substance, which was used directly in the next stage.

(B) the Fumarate Of 1-(S)-(+)-[4-[3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl]-3 - methyl-propoxy]-3-methoxyphenyl]ethanone.

In nitrogen atmosphere, at 0oC, the solution (S)-(+)-3-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] -2 - methyl-1-propylmalonate (5,28 g, 14,27 mm) in dimethylformamide is rija (530 mg, 22 mm) in DMF (35 ml). The resulting reaction mixture was stirred overnight (16 hours) at room temperature. Then the mixture was diluted with ethyl acetate and 2 times washed with water and brine. The organic solution was dried and concentrated to obtain 9.4 g of oily substance. This substance was purified using flash chromatography (SiO2- 60 g) was obtained 4.3 g (68%) of purified oily substance. The resulting material was converted into fumaric salt by treatment with fumaric acid (1.13 g) in ethanol. After recrystallization from ethanol was obtained of 1.36 g of the product as white crystals, so pl. 163-165oC.

Analysis for C25H29FN2O4C4H4O4(%):

Calculated: C 62,58; H 5,98; N 5,03

Found: C 62,40; H Of 5.84; N 4,92.

Example 150. Fumarate 2-[4-(6-fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl]-ethyldiazoacetate.

To a mixed solution (at 0oC) triphenylphosphine (13.3 g, 0.05 M) in THF (150 ml) was added drop aminobutiramida-azodicarboxylate (10,2 ml, 0.05 M). After stirring at 0oC for 0.5 hours at the drop of solution was added 6-fluorescent-3-[1-(2-hydroxyethyl)-4-piperidinyl]-1,2-benzisoxazole (8.5 g, to 0.032 M) and teoksessa acid (10,2 ml of 0.14 M) in DMF (35 ml). Then SUP>C in vacuum, resulting received a red oily substance. The obtained oily substance was washed with water and subjected to flash chromatography on silica gel, elwira first methylene chloride and then with a mixture of 10% MeOH and CH2Cl2. The appropriate fractions were concentrated and got 16.5 g of oily substance. This oily substance was washed with Et2O and the resulting solid reaction by-products) was removed by filtration. The filtrate was treated with fumaric acid (4.3 g) was obtained the desired product (fumaric salt) in the form of a whitish solid. This salt was recrystallized from EtOAc and then twice recrystallized from EtOH, which was obtained 1.0 g (7.0 percent) thioacetate in the form of a whitish solid, so pl. 118-120oC.

Example 151. N-[2-[4-(6-the Fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl-4,5 - dichloromaleimide

A mixture of 2-[4-(6-fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] ethylamine (2.83 g, 10,7 mm) and 4,5-anhydride dichloromaleic acid (2,56 g, 11,93 mm, 1.1 equiv.) in methylene chloride (100 ml) was stirred for 2 hours, the white solid was deposited and TLC indicated absence of starting material. The solvent was removed and the crude solid is in the final stage of elution). The result of this procedure was received and 2.26 g of purified material in the form of white crystals. This material is twice recrystallized from a large volume of hot ethanol (400 ml) and received 1,057 g of the product as white shiny crystals, so pl. 132-134oC.

Analysis for C22H18Cl2FN3O3(%):

Calculated: C 57,16; H To 3.92; N Is 9.09.

Found: C 57,13; H 3,63; N 8,93.

Example 152. N-[2-[4-(6-the Fluorescent-1,2-benzisothiazol-3-yl)-1 - piperidinyl] ethyl]-3,6-dichlorphenamide.

The stirred mixture of 6-fluorescent-3-(3-(4-piperidinyl)-1,2 - benzisothiazole (4.72 in g, 0.02 M), potassium carbonate (4,14 g, 0.02 M) and N-(2-bromoethyl)phthalimide (6,35 g, 0.025 M) in 200 ml of acetonitrile was heated under reflux for 4 hours. Then the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel and got N-[2-[4-(6-the fluorescent-1,2-benzisothiazol-3-yl)-1-piperidinyl]ethyl]-phthalimide.

Example 153. N-[2-[4-(6-the Fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl]-ethyl]- 3,6-dichloromaleimide.

A mixture of 2-[4-(6-fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl ethylamine (2,44 g, 9,24 mm) and anhydride 3,6-dichloromaleic acid (2,01 g, 9,27 mm) in dichloromethane (50 ml) was stirred PAMINA. The solvent is evaporated and the white residue, which was poorly soluble in DHM, was loaded onto a flash chromatography column (SiO2- 30 g), which was suirable solution 1% CH3OH DHM. The result of this procedure was given to 2.29 g (54%) of the desired product. This product preregistration from hot ethanol and received 2.15 g of product as white crystals, so pl. 163-164oC.

Analysis for C22H18Cl2FN3O3(%):

Calculated: C 57,16; H To 3.92; N Is 9.09.

Found: C 57,16; H To 3.64; N 9,13.

Example 154. N-[2-[3-(6-the Fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl] - 4-chlorophthalic.

The stirred mixture of 2-[4-(6-fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl] ethylamine (2,63 g, 0.01 M) and anhydride 4-chlorophthalic acid (1,82 g, 0.01 M) in dichloromethane (100 ml) was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure and the residual material was purified using flash chromatography. The resulting product, in addition, was purified by precrystallization, resulting in a received N-[2-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-4 - chlorophthalic.

Example 155. N-[2-[4-(6-the Fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl]-ethyl]-3 - foroptimal.

Soiclalisation (DCC) (5.5 g, 26,7 mm, 2.6 EQ) in dichloromethane (250 ml) was stirred at room temperature for 18 hours. The solids were filtered off. The organic solution was concentrated. The residue was purified using flash chromatography column (SiO2- 50 g, eluent: 1.4 l 1% CH3OH/ 99 % DHM and 1 l 2-6% CH3OH/DHM). The result of this procedure received 2.64 g (71%) of the desired product in the form of a whitish solid. Then this substance was recrystallized from hot ethanol and received of 1.41 g of the substance in the form of white crystals, so pl. 142-143oC.

Analysis for C22H19F2N3O3:

Calculated: C 64,22; H Of 4.66; N Of 10.21.

Found: C 64,11; H 4,70; N 10,14.

Example 156. N-[2-[4-(6-the Fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl]-ethyl]-4-ferrofluid.

The stirred mixture of 2-[4-(6-fluorescent-1,2-benzisoxazol-3-yl)-1 - piperidinyl] ethylamine (2,63 g, 0.01 M) and anhydride 4-foropruebas acid (1,83 g to 0.011 M) in dichloromethane (100 ml) stirred at room temperature for 4 hours. Then the solvent was removed under reduced pressure and the residual product was purified by means of recrystallization and received N-[2-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-4 - foroptimal.

Example 157. N-[2-[4-(6-the Fluorescent-1,2-b is retinyl] ethylamine (2,44 g, 9,24 mm), anhydride 4-methylphthalic acid (1,76 g, 10.8 mm) and dicyclohexylcarbodiimide (2.1 g, 1.0 mm) in dichloromethane (100 ml) was stirred at room temperature for 2 hours. Insoluble substances were filtered off. The dichloromethane solution was concentrated to obtain the crude solid. This substance was purified using flash chromatography column (SiO2- 35 g, Sorbsil C-30; eluent: 1% CH3OH and 99% DHM) and got cleaned material (1.0 g, 26%) as a white solid. After recrystallization from hot ethanol received 665 mg of product as crystals, so pl. 138-140oC.

Analysis for C23H22FN3O3(%):

Calculated: C 67,80; H 5,44; N 10,31.

Found: C 67,67; H 5,48; N 10,30.

Example 158. N-[2-[4-(6-the Fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl]-ethyl]- 4-methoxyflavone.

The stirred mixture of 2-[4-(6-fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] -ethylamine (2,63 g, 0.01 M) and anhydride 4-methoxyflavone acid (1.78 g, 0.01 M) in dichloromethane (100 ml) stirred at room temperature for 3 hours. Then the solvent was removed under reduced pressure and the residue was purified using flash chromatography. This product, in addition, was purified using precrystallization and received the-benzisoxazol-3-yl)-1-piperidinyl]-ethyl]-4 - nitrophthalimide.

The stirred mixture of 2-[4-(6-fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] -ethylamine (2,63 g, 0.01 M) and anhydride 4-nitrophthalic acid (1.39 g, 0.01 M) in dichloromethane (200 ml) stirred at room temperature for 3 hours. Then the solvent was removed under reduced pressure and the residual material was purified using flash chromatography. Thus obtained product, in addition, was purified by recrystallization and received N-[2-[4-(6-the fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] -ethyl] -4 - nitrophthalimide.

Example 160. Fumarate 4-[4-(6-fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] -2-methyl-2 - hydroxybutane.

In a nitrogen atmosphere to a solution of ethyl 3-[4-(6-fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl] propionate (3,21 g, 10 mm) in tetrahydrofuran (100 ml) drop by drop at room temperature for 30 minutes was added methylmagnesium (10 ml, 30 mm, 3 M solution in ether). The resulting mixture was stirred 16 hours. The mixture is then slowly hydrolyzed in aqueous solution of NH4Cl. After that, THF-solution was diluted with ethyl acetate (300 ml) and then washed with water and brine. The organic solution was separated and dried with magnesium sulfate. After removal of solvent the crude product was purified using flash chromatography (SiOthe white crystals. Then this material was converted into fumaric salt by treatment with fumaric acid (895 g) in ethanol and after recrystallization from ethanol was obtained 2,417 g of the product as white crystals, so pl. 156-158oC.

Analysis for C17H23FN2O2C4H4O4(%):

Calculated: C 59,70; H 6,44; N 6,63.

Found: C 59,40; H 6,27; N 6,28.

Example 161. Fumarate, ethyl 3-[4-(6-fluorescent-1,2-benzisoxazol-3-yl)-1-piperidinyl]propionate.

A mixture of 4-(6-fluorescent-1,2-benzisoxazol-3-yl)piperidine (5 g, 22.7 mm), K2CO3(3.8 g, 27,5 mm) and ethylbromoacetate (5 g, 27,6 mm, 1.2 EQ.) in acetonitrile (200 ml) was heated under reflux for 16 hours. The mixture was cooled and filtered. The solvent was removed and the residue was purified using flash chromatography column (60 g, SiO2; eluent: DHM), resulting in a received purified material (7,27 g, 83%). Fumaric salt was obtained by treating the free base (2.17 g) fumaric acid (820 mg, 1 EQ.) in ethanol. After recrystallization from ethanol was obtained 2,49 g of the product as white crystals, so pl. 135-136oC.

Analysis for C17H21FN2O3C4H4O4(%):

Calculated: C 57,79; H 5,77; N, 6.42 Per.

1. Heteroarylboronic formula 1

< / BR>
where X represents-O-, -S-,

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

p = 1 or 2;

Y is hydrogen, lower alkyl, hydroxyl, chlorine, fluorine, bromine, iodine, lower alkoxy, trifluoromethyl, nitro or amino, when p = 1, or Y is lower alkoxy, hydroxyl or halogen when p = 2 and X is-O-;

Q1selected from the group including

< / BR>
and

< / BR>
where Z represents the

< / BR>
Y2selected from the group comprising the radicals of formulas

< / BR>
where (R1) is R20, R21or R22where R20- -(CH2)nwhere n = 2, 3, 4 or 5; R21represents-CH2-CH= CH-CH2-; -CH2-CC-CH2-; -CH2-CH=CH-CH2-CH2-;-CH2-CH2-CH=CH-CH2-; -CH2-CC-CH2-CH2- or-CH2-CH2CC-CH20
or R21substituted by at least one non-branched C1-C6is an alkyl group, phenyl group or

< / BR>
where Z1- lower alkyl, -OH, lower alkoxy, -CF3, -NO2, -NH2or halogen;

p same as defined above;

R and m such, as hereinafter defined,

< / BR>
where R1such as defined previously;

R3- hydrogen or-OCH3;

< / BR>
R1such as defined previously;

R4is hydrogen, lower alkyl, lower alkoxy, hydroxyl, amino, mono - or dialkylamino, C1-C3acylamino, C1-C6alkanoyl, trifluoromethyl, chlorine, fluorine, bromine,

< / BR>
or

where aryl is phenyl or

< / BR>
where R5is hydrogen, lower alkyl, lower alkoxy, hydroxyl, chlorine, fluorine, bromine, iodine, lower monoalkylamines, lower dialkylamino, nitro, cyano, trifluoromethyl or triptoreline;

< / BR>
where R1and R4such as previously defined, except that when R1is R20n = 1, 2, 3, 4 or 5;

< / BR>
where any one of Xyand Xzis

< / BR>
and the other is-CH2-;

R5'is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine or bromine;

R1such as the
R1and R4such as defined above;

< / BR>
where R1such as defined previously;

< / BR>
where R1such as defined previously;

Q2-S-, -NH - or-CH2-;

R and m such, as hereinafter defined,

< / BR>
where R1such as defined previously;

(11) - R1-O-R12,

where R12selected from the group including hydrogen,

< / BR>
< / BR>
< / BR>
and

< / BR>
where R13selected from the group comprising hydrogen and (straight or branched C1-C12) alkyl; R14selected from the group comprising hydrogen and (straight or branched C1-C12) alkyl; NR15R16taken together form a cyclic structure selected from the group comprising piperidinyl, morpholinyl and piperazinil; R17selected from the group comprising lower alkyl, and aryl group, where R1such as defined previously;

(12) -R1-NR18R19,

where R18and R19independently selected from the group comprising hydrogen, (straight or branched C1-C12) alkyl;

< / BR>
< / BR>
or NR18R19taken together form a cyclic structure selected from the group comprising piperidinyl, morpholinyl and piperazinil;

R
R is hydrogen, lower alkyl, lower alkoxy, hydroxyl, carboxyl, chlorine, fluorine, bromine, iodine, amino, lower mono - or dialkylamino, nitro, lower alkylthio, triptoreline, cyano, acylamino, trifluoromethyl, TRIFLUOROACETYL, aminocarbonyl, monoalkylamines, dialkylaminoalkyl, formyl,

< / BR>
< / BR>
< / BR>
< / BR>
heteroaryl is

< / BR>
where Q2-O-, -S-, or-CH=N; alkyl is lower alkyl; aryl such as that previously defined; W - R7is hydrogen, lower alkyl or acyl; R8is lower alkyl; R9is hydroxyl, lower alkoxy or-other10; R10is hydrogen, lower alkyl, C1-C3acyl, aryl,

< / BR>
where aryl and heteroaryl such as defined above;

m = 1, 2, or 3;

assuming: 1) that in the formula (1) R1cannot be R20when Q1represents (a) and R represents hydrogen, lower alkyl, lower alkoxy, hydroxyl, carboxyl, chlorine, fluorine, bromine, iodine, amino, lower mono - or dialkylamino, nitro, lower alkylthio, triptoreline, cyano, acylamino, trifluoromethyl, TRIFLUOROACETYL, aminocarbonyl,

< / BR>
< / BR>
< / BR>
heteroaryl such as defined previously, the alkyl is lower alkyl, aryl as defined above, R7is hydrogen, lower alkyl and the>
-C4-alkyl, chlorine, fluorine, bromine, iodine, cyano, C1-C4-alkoxy or-COOR23where R23represents C1-C4-alkyl;

3) in the formula (1) Z may not be when X represents-S-, R1- R20and R is H;

4) in the formula (4) Z cannot be-N, when X represents-S-, R1- R20, R4Is H and Y is hydrogen, lower alkyl, hydroxyl, halogen, lower alkoxy or trifluoromethyl;

5) in the formula (7) R4cannot be H when Y is 6-F, X is-O-, Z is R1is R20and n = 2, 3, or 4;

6) in the formula (7) R4cannot be H when Z is X is S, Y is H, OH, CN, lower alkyl, lower alkoxy, halogen or CF3, R1is R20and n = 2, 3, 4 or 5;

7) in the formula (8) Z may not be when X represents-O-, p = 1, and Y is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, bromine, iodine or a hydroxyl group;

8) in the formula (8) Z may not be when X represents-S -, and R1represents-CH2CH2CH2CH2-, -CH2CH=CHCH2or CH2C=CCH2-;

9) in the formula (9) Z may not be when X represents-O-,Q2represents-CH2and Y is hydrogen, lower alkyl, lower alley-CH2and Y is hydrogen, lower alkyl, lower alkoxy, hydroxyl or halogen, R is hydrogen and m = 1;

11) in the formula (9) Z may not be when Q2represents-CH2-, X is Y is hydrogen, lower alkyl, lower alkoxy, hydroxyl, halogen, NO2, NH2, trifluoromethyl;

12) that in the formula (9) Z may not be when Q2represents-CH2-, X is-S - and Y is hydrogen, lower alkyl, lower alkoxy, halogen, hydroxyl or trifluoromethyl;

13) in the formula (9) Z may not be when Q2represents-CH2-, and X represents where R2- lower alkyl, aryl(lower)alkyl or phenylsulfonyl;

14) that in the formula (9) Z may not be when Q2represents-CH2-, X is R2is aryl and R is hydrogen, chlorine, fluorine, bromine, iodine, lower alkyl, lower alkoxy, lower alkylthio, lower mono - or dialkylamino, amino, nitro, cyano, hydroxyl or trifluoromethyl;

15) that in the formula (11) R12cannot be H when Z represents X - where R2- lower alkyl, aryl, aryl(lower)alkyl or phenylsulfonyl;

16) that in the formula (12) R18and R19can't be both lower alkyl when X represents-O-, Z -, and Y is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, bromine, iodine or gidroksilnuyu>1
is R20and Y is 6-F;

18) that in the formula (12) R18and R19can't be both lower alkyl when Z - and X - where R2represents aryl;

19) in the formula (12), if any one of R18and R19represents hydrogen and the other represents hydrogen or straight or branched C1-C12)alkyl when Q1= (a) X cannot be-S-, when Y is hydrogen and R1is R20or R21;

20) that in the formula (12) when R18and R19both represent hydrogen and Q1= (a), R1cannot be R20or R21when X represents-O - and Y is hydrogen;

21) that in the formula (12) when R18represents a straight or branched C1-C12)alkyl and R19represents-C(=O) - (straight or branched C1-C12)alkyl or when R19is (straight or branched) alkyl and R18represents-C(=O) - (straight or branched C1-C12)alkyl, X cannot be-S-, where Z is-N-, Y is hydrogen and R1is R20;

the term "lower" when it is mentioned for any of the above groups, indicates that this group contains from 1 to 6 carbon atoms;

all geometric>/P>2. Connection on p. 1, where Q1is

< / BR>
3. Connection on p. 1, where Q1is

< / BR>
4. Connection on p. 1, where R1is R20.

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

6. Connection on p. 1, where Y is hydrogen, hydroxyl, chlorine, bromine or fluorine.

7. Connection on p. 1, where Z is

8. Connection on p. 1, where Z is

9. Connection on p. 1, where R1is R20and n = 2, 3, or 4.

10. Connection on p. 1, where X represents-O-.

11. Connection on p. 1, where X is-S-.

12. Connection on p. 1, where X is

13. Connection on p. 1, where X is

14. Connection on p. 1, where X represents-O-, -S - or-NH-; Y is H, OH, CL, F or-CF3; R is chosen from the group comprising hydrogen, C1-C3alkyl, C1-C3alkoxy, -OH, Cl, F, Br, I, C1-C3alkylamino, alkanoyl, acylamino, -NO2, -OCF3or-CF3; R1is R20and n = 2, 3, or 4.

15. Connection on p. 14, where the Deputy Y is a 5 - or 6-position.

16. Connection on p. 15, where m = 2.

17. Connection on p. 15, where n = 3.

18. Connection on p. 15, where p = 1.

19. Soede
is

< / BR>
where Y2has the formula (1).

22. The connection 21, which represents a N,N-dimethyl-4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl] propoxy] -3-methoxybenzamide or its pharmaceutically acceptable acid additive salt.

23. The connection 21, which represents an oxime 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl] propoxy]-3-methoxyphenyl]ethanone or its pharmaceutically acceptable acid additive salt.

24. The connection 21, which represents a hydrazone 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl] propoxy] -3-methoxyphenyl] ethanone or its pharmaceutically acceptable acid additive salt.

25. The connection 21, which represents 6-fluoro-3-[1-[3-[2-methoxy-4-(1-methylethenyl)phenoxy] propyl]-4-piperidinyl]-1,2-benzisoxazol or its pharmaceutically acceptable acid additive salt.

26. The connection 21, which represents a (Z)-1-[4-[[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-butenyl]oxy]-3-methoxyphenyl]alanon or its pharmaceutically acceptable acid additive salt.

27. The connection 21, which represents a 1-(R)-(-)-[4-[3-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl] -2">

28. The connection 21, which represents a 1-(S)-(+)-[4-[3-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl] -2-methyl-1-propoxy] -3-methoxyphenyl]alanon or its pharmaceutically acceptable acid additive salt.

29. Connection on p. 1, where Q1is

< / BR>
where Y2has the formula (1).

30. Connection on p. 29, which represents 6-fluoro-3[1-(phenylmethyl)-3-pyrrolidinyl] -1,2-benzisoxazol or its pharmaceutically acceptable acid additive salt.

31. Connection on p. 1, where Q1is

< / BR>
where Y2has the formula (2).

32. Connection on p. 31, which represents 6-fluoro-3-[1-[3-[(6-methoxy-1H-indol-5-yl)oxy] propyl]-4-piperidinyl]-1,2-benzisoxazol or its pharmaceutically acceptable acid additive salt.

33. Connection on p. 1, where Q1is

< / BR>
where Y2has the formula (3).

34. Connection on p. 33, which represents 6-fluoro-3-[1-(2-pyrimidinone)propyl]-4-piperidinyl]-1,2-benzisoxazol or its pharmaceutically acceptable acid additive salt.

35. Connection on p. 1, where Q1is

< / BR>
where Y2has the formula (4).

36. Connection on p. 35, kotorowski acceptable acid additive salt.

37. Connection on p. 1, where Q1is

< / BR>
where Y2has the formula (5).

38. Connection on p. 37, which is a 6-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-7-methoxy-1-tetralone or its pharmaceutically acceptable acid additive salt.

39. Connection on p. 1, where Q1is

< / BR>
where Y2has the formula (6).

40. Connection on p. 39, which is a N-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl]-6-acetyl-2-benzoxazolinone or its pharmaceutically acceptable acid additive salt.

41. Connection on p. 1, where Q1is

< / BR>
where Y2has the formula (7).

42. Connection on p. 41, which is a N-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-phthalimide or its pharmaceutically acceptable acid additive salt.

43. Connection on p. 41, which is a N-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl] ethyl] -3-fertilised or its pharmaceutically acceptable acid additive salt.

44. Connection on p. 41, which is a N-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl] ethyl] -4-fertilised or faboy pharmaceutically acceptable acid additive salt N-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-phthalimide.

46. Connection on p. 45 where the specified pharmaceutically acceptable acid additive salt is an acid additive salt of hydrochloric acid.

47. Connection on p. 1, where Q1is

< / BR>
where Y2has the formula (8).

48. Connection on p. 1, where Q1is

< / BR>
where Y2has the formula (9).

49. Connection on p. 48, which is 1-[4-(4'-acetogenin)butyl] -4-(6-fluoro-1,2-benzisoxazol-3-yl)-piperidine or pharmaceutically acceptable acid additive salt.

50. Connection on p. 48, which is a 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl] propylthio]-3-methoxyphenyl]alanon or its pharmaceutically acceptable acid additive salt.

51. Connection on p. 48, which is a 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propylamino]-3-methoxyphenyl]alanon or its pharmaceutically acceptable acid additive salt.

52. Connection on p. 48, which is a 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl] propylamino] -3-hydroxyphenyl] alanon or its pharmaceutically acceptable acid additive salt.

53. Connection on p. 1, where Q

55. Connection on p. 1, where Q1is

< / BR>
where Y2has the formula (11).

56. Connection on p. 55, which represents 6-fluoro-3-[1-(3-hydroxypropyl)-4-piperidinyl)-1,2-benzisoxazol or its pharmaceutically acceptable acid additive salt.

57. Connection on p. 55, which is 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl] acetic acid ethyl ester or its pharmaceutically acceptable acid additive salt.

58. Connection on p. 55, which is 4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butanol or its pharmaceutically acceptable acid additive salt.

59. Connection on p. 55, which is 3-[4-(6-fluoro-1,2-benzisoxazol-3-ml)-1-piperidinyl] Propellerhead or its pharmaceutically acceptable acid additive salt.

60. Connection on p. 55, which is an N-methyl-4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl] BUTYLCARBAMATE or its pharmaceutically acceptable acid additive salt.

61. Connection on p. 55, which is 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl] ethanol or its pharmaceutically acceptable acid additive salt.

62. Connection on p. viable acid additive salt.

63. Connection on p. 55, which is a S-(+)-3-[4-(6-fluoro-1,2-benzoxazol-3-yl)-1-piperidinyl] -2-methyl-1-propanol or its pharmaceutically acceptable acid additive salt.

64. Connection on p. 1, where Q1is

< / BR>
where Y2has the formula (12).

65. Connection on p. 64, which is 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl] atelecine or its pharmaceutically acceptable acid additive salt.

66. Connection on p. 64, which is 4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-[3-(1-piperidinyl] propyl] -piperidine or pharmaceutically acceptable acid additive salt.

67. Connection on p. 1, where Q1is

< / BR>
where Y2has the formula (13).

68. Connection on p. 67, which is 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl] ethylthiourea or its pharmaceutically acceptable acid additive salt.

69. Heteroarylboronic formula

< / BR>
where X represents-O-, -S-,

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

p = 1 or 2;

Y is hydrogen, lower alkyl, hydroxyl, CHL is, hydroxyl or halogen when p = 2 and X is-O-;

Z represents

R1is R20, R21or R22where R20represents -(CH2)n-, where n = 2, 3, 4 or 5; R21represents-CH2-CH=CH-CH2-, -CH2-CC-CH2-, -CH2-CH= CH-CH2-CH2-, -CH2-CH2-CH= CH2-, -CH2-CC-CH2-CH2- or-CH2-CH2CC-CH2-, and-CH= CH - is CIS - or TRANS-configuration; R22is R20or R21where one or more carbon atoms, R20or R21substituted by at least one straight line C1-C6is an alkyl group, phenyl group or

< / BR>
where Z1represents lower alkyl, -OH, lower alkoxy, -CF3, -NO2, -NH2or halogen and p is as defined above;

R is hydrogen, lower alkyl, lower alkoxy, hydroxyl, carboxyl, chlorine, fluorine, bromine, iodine, amino, lower mono - or dialkylamino, nitro, lower alkylthio, triptoreline, cyano, acylamino, trifluoromethyl, TRIFLUOROACETYL, aminocarbonyl, monoalkylamines, dialkylaminoalkyl, formyl,

< / BR>
< / BR>
< / BR>
< / BR>
heteroaryl is

< / BR>
Q3represents-O-, -S-, or-CH=N-;

alkyl represents either a hydroxyl, chlorine, fluorine, bromine, iodine, lower monoalkylamines, lower dialkylamino, nitro, cyano, trifluoromethyl or triptoreline;

W is

R7is hydrogen, lower alkyl or acyl;

R8is lower alkyl;

R9is hydroxy, lower alkoxy or-other10;

R10is hydrogen, lower alkyl, C1-C3acyl, aryl,

< / BR>
where aryl and heteroaryl such as defined above;

m = 1, 2, or 3,

with the proviso that R1cannot be R20when R represents hydrogen, lower alkyl, lower alkoxy, hydroxyl, carboxyl, chlorine, fluorine, bromine, iodine, amino, lower mono - or dialkylamino, nitro, lower alkylthio, triptoreline, cyano, acylamino, trifluoromethyl, TRIFLUOROACETYL, aminocarbonyl,

< / BR>
< / BR>
< / BR>
heteroaryl such as defined previously, the alkyl is lower alkyl, aryl as defined above, R7is hydrogen, lower alkyl or acyl and m = 1, 2, or 3;

provided that Z cannot be when X represents-O - or-S-, Y is hydrogen and R is hydrogen, C1-C4-alkyl, chlorine, fluorine, bromine, iodine, cyano, C1-C4-alkoxy or-COOR23where R23represents C1-C4-alkyl;

provided that Z cannot be when X represents-S-, R1the submitted what this group contains from 1 to 6 carbon atoms,

all geometric and optical isomers and stereoisomers, or its pharmaceutically acceptable acid additive salt.

70. Connection on p. 69, where Y is in position 5.

71. Connection on p. 69, where Y is in position 6.

72. Connection on p. 69, where Y is chosen from the group comprising hydrogen, hydroxyl, chlorine, bromine and fluorine.

73. Connection on p. 72, where Y is fluorine.

74. Connection on p. 73, where Y is in position 6.

75. Connection on p. 69, where p = 2, X is-O - and Y is chosen from the group comprising group, lower alkoxy, hydroxyl and halogen.

76. Connection on p. 75, where Y is a methoxy group.

77. Connection on p. 69, where R is chosen from the group comprising hydrogen, C1-C3-alkyl, C1-C3-alkoxy, hydroxyl, -OCF3C1-C6-alkanoyl, Cl, F, Br, I, C1-C3-alkylamino, -NO2, -CF3; -OCF3and

78. Heteroarylboronic formula

< / BR>
where X represents-O-, -S-,

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

p = 1 or 2;

Y is hydrogen, lower alkyl, hydroxyl, chlorine, fluorine, bromine, iodine, lower alkoxy, triptoreline

(R1) is R20, R21or R22where R20represents -(CH2)n-, where n = 2, 3, 4 or 5; R21represents-CH2-CH=CH-CH2-, -CH2-CC-CH2-, -CH2-CH= CH-CH2-CH2-, -CH2-CH2-CH= CH-CH2-, -CH2-CC-CH2-CH2- or-CH2-CH2-CC-CH2-, and-CH= CH - is CIS - or TRANS-configuration; R22is R20or R21where one or more carbon atoms, R20or R21substituted by at least one non-branched C1-C6is an alkyl group, phenyl group or

< / BR>
where Z1- lower alkyl, -OH, lower alkoxy, -CF3, -NO2, -NH2or halogen and p is as defined above;

R4is hydrogen, lower alkyl, lower alkoxy, hydroxy, amino, mono - or dialkylamino, C1-C3acylamino, C1-C3alkanoyl, trifluoromethyl, chlorine, fluorine, bromine,

< / BR>
or

where aryl represents phenyl or

< / BR>
where R5is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamines, lower dialkylamino, nitro, cyano, trifluoromethyl or triptoreline;

q = 1, 2, 3 or 4;

provided that R4can not be H, Koroviy, what R4cannot be H when Z represents X represents-S-, Y - H;

the term "lower" when it is mentioned for any of the above groups, indicates that this group contains from 1 to 6 carbon atoms;

all geometric and optical isomers and stereoisomers, or its pharmaceutically acceptable acid additive salt.

79. Connection on p. 78, where Y is in position 5.

80. Connection on p. 78, where Y is in position 6.

81. Connection on p. 78, where Y is chosen from the group comprising hydrogen, chlorine, bromine and fluorine.

82. Connection on p. 81, where Y is fluorine.

83. Connection on p. 82, where Y is in position 6.

84. Connection on p. 78, where X represents-O-.

85. Connection on p. 78, where Z is

86. Connection on p. 78, where R4- hydrogen.

87. Connection on p. 78, where R1- R20.

88. Connection 87, where n = 2, 3, or 4.

89. Heteroarylboronic formula

< / BR>
where X represents-O-, -S-,

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

p = 1 or 2;

Y is hydrogen, lower alkyl, hydroxy, chlorine, fluorine, bromine is a gene when p = 2 and X is-O-;

Z represents

(R1) is R20, R21or R22where R20represents -(CH2)n-, where n = 2, 3, 4 or 5; R21represents-CH2-CH=CH-CH2-, -CH2-CC-CH2-, -CH2-CH= CH-CH2-CH2-, -CH2-CH2-CH= CH-CH2-, -CH2-CC-CH2-CH2- or-CH2-CH2-CC-CH2-, and-CH= CH - is CIS - or TRANS-configuration; R22is R20or R21where one or more carbon atoms, R20or R21substituted by at least one non-branched C1-C6is an alkyl group, phenyl group or

< / BR>
where Z1- lower alkyl, -OH, lower alkoxy, -CF3, -NO2, -NH2or halogen and p is as defined above;

Q2is-S-, -NH - or-CH2-;

R is hydrogen, lower alkyl, lower alkoxy, hydroxyl, carboxyl, chlorine, fluorine, bromine, iodine, amino, lower mono - or dialkylamino, nitro, lower alkylthio, triptoreline, cyano, acylamino, trifluoromethyl, TRIFLUOROACETYL, aminocarbonyl, monoalkylamines, dialkylaminoalkyl, formyl,

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

< / BR>
SSI dialkylamino, nitro, cyano, trifluoromethyl or triptoreline;

heteroaryl is

< / BR>
where Q3represents-O-, -S-, or-CH=N-; W is

R7is hydrogen, lower alkyl or acyl;

R8is lower alkyl;

R9is hydroxy, lower alkoxy or-other10;

R10is hydrogen, lower alkyl, C1-C3acyl, aryl,

< / BR>
where aryl and heteroaryl such as defined above;

m = 1, 2, or 3,

provided that Z cannot be when X represents-O-, Q2represents-CH2and Y is hydrogen, lower alkyl, lower alkoxy, hydroxyl or halogen;

provided that Z cannot be when X represents-S-, Q2represents-CH2-, Y is hydrogen, lower alkyl, lower alkoxy, hydroxyl or halogen; R is hydrogen and m = 1;

provided that Z cannot be when Q2represents-CH2-, X is-NH - or-HR2and Y is hydrogen, lower alkyl, lower alkoxy, hydroxyl, halogen, NO2, NH2, trifluoromethyl;

provided that Z cannot be when Q2represents-CH2-, X is-S - and Y is hydrogen, lower alkyl, lower alkoxy, halogen, hydroxyl or trifluoromethyl; provided that Z cannot be when Q2the submitted the AI, that Z cannot be when Q2represents-CH2-, X is R2is aryl and R is hydrogen, chlorine, fluorine, bromine, iodine, lower alkyl, lower alkoxy, lower alkylthio, lower mono - or dialkylamino, amino, nitro, cyano, hydroxyl or trifluoromethyl,

the term "lower" when it is mentioned for any of the above groups, indicates that this group contains from 1 to 6 carbon atoms;

all geometric and optical isomers and stereoisomers, or its pharmaceutically acceptable acid additive salt.

90. Heteroarylboronic formula

< / BR>
where X represents-O-, -S-,

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

p = 1 or 2;

Y is hydrogen, lower alkyl, hydroxy, chlorine, fluorine, bromine, iodine, lower alkoxy, trifluoromethyl, nitro or amino, when p = 1, Y is lower alkoxy, hydroxy, or halogen when p = 2 and X is-O-;

Z represents

(R1) is R20, R21or R22where R20represents -(CH2)n-, where n = 2, 3, 4 or 5; R21represents-CH2-CH=CH-CH2-, -CH2-CC-CH2-, -CH2-CH= CH-CH2-CH2-, -CH2-CH2-CH= CH-CH222is R20or R21where one or more carbon atoms, R20or R21substituted by at least one non-branched C1-C6alkyl group, phenyl group or

< / BR>
where Z1- lower alkyl, -OH, lower alkoxy, -CF3, -NO2, -NH2or halogen and p is as defined above;

R12selected from the group including hydrogen,

< / BR>
< / BR>
< / BR>
where R13selected from the group comprising hydrogen and (straight or branched C1-C12) alkyl, R14selected from the group comprising hydrogen and (straight or branched C1-C12) alkyl, NR15R16taken together form a cyclic structure selected from the group comprising piperidinyl, morpholinyl and piperazinil, R17selected from the group comprising lower alkyl and aryl groups, provided that R12cannot be H when Z represents X represents-NH - or where R2- lower alkyl, aryl, aryl(lower)alkyl or phenylsulfonyl,

the term "lower" when it is mentioned for any of the above groups, indicates that this group contains from 1 to 6 carbon atoms;

all geometric and optical isomers and wiped the formula

< / BR>
where X represents-O-, -S-,

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

p = 1 or 2;

Y is hydrogen, lower alkyl, hydroxyl, chlorine, fluorine, bromine, iodine, lower alkoxy, trifluoromethyl, nitro or amino, when p = 1, Y represents lower alkoxy, hydroxy, or halogen when p = 2 and X is-O-;

Z represents

(R1) is R20, R21or R22where R20represents -(CH2)n-, where n = 2, 3, 4 or 5; R21represents-CH2-CH=CH-CH2-, -CH2-CC-CH2-, -CH2-CH= CH-CH2-CH2-, -CH2-CH2-CH= CH-CH2-, -CH2-CC-CH2-CH2- or-CH2-CH2-CC-CH2-, and-CH= CH - is CIS - or TRANS-configuration; R22is R20or R21where one or more carbon atoms, R20or R21substituted by at least one non-branched C1-C6is an alkyl group, phenyl group or

< / BR>
where Z1- lower alkyl, -OH, lower alkoxy, -CF3, -NO2, -NH2or halogen and p is as defined above;

R18and R19independently selected from the group comprising hydrogen, (straight and Klionsky structure, selected from the group comprising piperidinyl, morpholinyl and piperazinil, provided that R18and R19can't be both lower alkyl when X represents-O-, Z is-and Y is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, bromine, iodine or a hydroxyl group;

provided that R18and R19cannot be both hydrogen when Z is X is-O-, R1is R20and Y is 6-F;

provided that R18and R19can't be both lower alkyl when Z is and X represents where R2- aryl;

provided that if any one of R18and R19represents hydrogen and the other represents hydrogen or straight or branched C1-C12) alkyl, then X cannot be-S-, when Y is hydrogen and R1is R20or R21;

provided that when R18and R19are both hydrogen, R1cannot be R20or R21when X represents-O - and Y is hydrogen;

provided that when R18represents a straight or branched C1-C12) alkyl and R19represents-C(=O) - (straight or branched C1-C12) alkyl or when R19predst
) alkyl, X cannot be-S-, where Z is Y is hydrogen and R1is R20;

the term "lower" when it is mentioned for any of the above groups, indicates that this group contains from 1 to 6 carbon atoms;

all geometric and optical isomers and stereoisomers, or its pharmaceutically acceptable acid additive salt.

92. The compound according to any one of paragraphs.1 - 3, 21, 29, 31, 33, 35, 37, 39, 41, 47, 48, 53, 55, 64, 67, 69, 78, 89, 90 and 91, where the specified pharmaceutically acceptable acid additive salt is chosen from the group comprising salts of mineral acids, salts of monobasic, dibasic and trekhosnovnykh carboxylic acids.

93. Connection p. 92, where specified pharmaceutically acceptable acid additive salt is chosen from the group comprising salts of hydrochloric, sulfuric, nitric, acetic, propionic, maleic, fumaric, carboxytherapy and citric acid.

94. Connection on p. 93 where the specified pharmaceutically acceptable acid additive salt is a salt of hydrochloric acid.

95. Pharmaceutical composition comprising as an active ingredient the compound according to any one of paragraphs.1 - 3, 21, 29, 31, 33, 35, 37, 39, 41, 47, 48, 53, 55, 64, 67, 69, 78, 89, 90, redstavlyaya an antipsychotic pharmaceutical composition.

97. The composition according to p. 95, representing the analgesic pharmaceutical composition.

98. The compound according to any one of paragraphs.1 - 3, 21, 29, 31, 33, 35, 37, 39, 41, 47, 48, 53, 55, 64, 67, 69, 78, 89, 90, 91, 92, 93 or 94 for obtaining a medicinal product for the treatment of psychosis.

99. The compound according to any one of paragraphs. 1 - 3, 21, 29, 31, 33, 35, 37, 39, 41, 47, 48, 53, 55, 64, 67, 69, 78, 89, 90, 91, 92, 93 or 94 for receiving the drug for pain relief.

Priority points and features:

05.11.91 under item 1: all signs, except those listed below for the second priority, in PP.2 - 26, 29 - 31, 33 - 41, 47 - 52; in p. 69: all signs, except those listed below for the second priority, PP.70 - 77; p. 70: all signs, except those listed below for the second priority, PP.79 - 88; p. 89: all signs, except those listed below for the second priority, PP.92 - 99.

30.10.92 under item 1: if Y2corresponding to the radical of the formula (1), where R1is R22that takes all the values specified in paragraph 1 in the section on formulas (1); if Y2corresponding to the radical of the formula (3), R4- hydroxyl, -O-C(O) - (straight or branched C1-C12) alkyl; if a 1), (12) or (13); R - monoalkylamines, and all signs indicated under the conditions 1) - 21); PP.27, 28, 32, 42 - 46, 53 - 68; in p. 69: if R1representing R22where R22accepts all listed in paragraph 69 values, R - monoalkylamines, and on all grounds specified in section "C" of this paragraph; p. 78: if R1representing R22where R22accepts all listed in paragraph 78 of values, with R4- hydroxy, -O-C(O) - (straight or branched C1-C12) alkyl; q = 2, 3, or 4, and all of the grounds referred to in the section "subject" of this paragraph; p. 89: if R1representing R22where R22accepts all listed in paragraph 89 values, R - monoalkylamines, and on all grounds specified in the section "subject" of this paragraph, in points.90 and 91.

 

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< / BR>
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