Piperidinyloxy or hinkleyville-isoxazoline derivatives or their pharmaceutically acceptable salts, the composition having properties to reduce violations cognitive abilities

 

(57) Abstract:

Usage: in the chemistry of heterocyclic compounds with properties to reduce violations cognitive abilities. The inventive product-piperidinyloxy or giocodigitale derivatives of f-crystals 1, where R1-H, halogen or lower alkyl, R2-H, lower alkyl, phenyl, possibly substituted with halogen lower alkoxy or hydroxy, or R2- heterocyclic group containing 5 or 6 atoms in the cycle, one of which is nitrogen, or sulfur, or R1and R2together form a group-CR4=CR5-CR6=CR7- where R4, R5, R6and R7-H, lower alkyl or alkoxy, R3- piperideine group in which the atom may substituted lower alkyl. The proposed composition comprising an effective amount of compound f-ly 1. 2 S. p. f-crystals. 9 table.

The invention relates to a series of new piperidyl - occaisonally and khinuklidinilbenzilata derivatives that can be used in the treatment and prevention of various disorders, especially senile dementia / including disease of Alzheimer/. In accordance with the invention are also methods and HDMI is dei among the population has increased substantially and therefore increases the number of diseases and disorders, associated with old age, especially senile dementia, including disease of Alzheimer. Senile dementia is a serious and increasing problem in the modern world, which can cause discomfort and severe malaise not only suffering, but also for relatives and those responsible for them, therefore, considerable efforts have been made to facilitate or improve the situation of these people. In particular, the disease of Alzheimer in which senile dementia affects patient prematurely, is the cause of severe discomfort. Due to the fact that the causes of dementia and diseases of Alzheimer currently unknown, treatment is difficult and, in General, should only be a symptom profile.

It is known that the characteristics typical of patients suffering from senile dementia, is a decrease in cerebral microcirculation and decrease cerebrales metabolism, which together lead to dysfunction of cognitive abilities. In addition, early-stage dementia in the General case, accompanied by depression and weakening of this depression could lead wide scope of activities in the body, and disruption in its production and/or activity, as has been shown, leads to various disorders. It was found that patients suffering from senile dementia, including disease of Alzheimer, biosynthesis of acetylcholine in the brain is disturbed, however, even in these patients, the receptors for acetylcholine in the brain can be much less depressed and they can still function satisfactorily. Receptors for acetylcholine, located on presinapticheskih endings in the brain, are the M2receptors, whereas receptors on post-synaptic membranes in the brain, are the M1and M3the receptors. M2receptors are abundant in the pre - and post-synapses of the heart, then how many M1the receptors are located in the cerebral subcortical layer and the hippocampus of the brain, which play an important role in memory and cognition. Therefore, if M1receptors can be stimulated during the early stages of dementia, it would be possible to improve symptoms of dementia, and possibly prevent further deterioration. On the other hand, it is desirable that any agent designed to stimulate M

Currently, the applicant has developed a series of new piperidinecarboxylate and khinuklidinilbenzilata derivatives, which was found to bind selectively with M1- receptors, while communicating to a much lesser extent with M2c- receptors, and thus, as already mentioned above, are of value in the treatment and prevention of senile dementia, including diseases of Alzheimer.

In an unexpected way by the applicant, it was found that compounds which are the subject of the present invention, have also been associated with 5-HT3receptors and, thus, affect 5-HT3- activity. Since it is known that 5-HT3antagonists have overwhelming anxiety, anti-depressing and antipsychotic activities, it can be expected that the compounds that are the subject of the present invention are of value for a broader treatment of patients with disorders of consciousness, in particular, suffering from anxiety, depression and psychosis.

Several derivatives from which profilaktike variety of diseases and disorders, including diseases of the brain vessels, which act through the Central nervous system as muscle relaxants muscle system and as an antidepressant. They are described, for example, in concurrently filed patent application U.S. N 07/620 842, 30 November 1990 patent application U.S. N 07/537 517, filed June 13, 1990, and patent application U.S. N 07/585 828, filed September 20, 1990 Of them coming on the connection structure proposed in Patent application U.S. N 07/620 843 offering. Among others, compounds of the formula:

< / BR>
in which the symbols R each represents different groups and atoms, and the symbols R' may represent an organic group or together with the nitrogen atom to which they are attached, may represent a heterocyclic group, including piperidino group. These known compounds differ from the compounds of the present invention that piperidylamine group that is represented through NR'r R' compulsory attached to the remainder of the molecule via the nitrogen atom and, most importantly, the presence of the known compounds of the group of the formula:

< / BR>
which were hitherto considered as having essentially the target activity and which are completely absent in the compounds of the present is to offer a series of new compounds, which can be valuable in the treatment and prevention of senile dementia, including disease of Alzheimer.

Another objective of the present invention is to provide compounds, some of which have more widespread use in the treatment and prevention of disorders of consciousness.

Other objectives and advantages of the present invention will become apparent from the subsequent description.

The compounds of the present invention are the compounds of formula I:

< / BR>
in which R1represents a hydrogen atom, halogen atom or alkyl group containing from 1 to 4 carbon atoms;

R2represents a hydrogen atom, alkyl group containing from 1 to 4 carbon atoms, phenol group, which is unsubstituted or which is substituted by at least one of the substituents /a/, defined below, or a heterocyclic group containing 5 or 6 atoms in the cycle, of which one is a nitrogen atom or sulfur, with the above-mentioned heterocyclic group unsubstituted or substituted by at least one of the substituents /a/, defined below, or

R1and R2together form a group of the formula

CR4=CR5-CR6 is PPI, consisting of hydrogen atoms, halogen atoms, alkyl groups containing from 1 to 4 carbon atoms or alkoxygroup containing from 1 to 4 carbon atoms,

R3is piperidino group, substituted piperidino group in which the nitrogen atom is substituted by an alkyl group containing from 1 to 6 carbon atoms, or hinkleyville group;

Deputy /a/

the atoms of Halogens: alkoxy groups containing from 1 to 4 carbon atoms, and hydroxy groups, and acceptable from a pharmaceutical point of view of their salts.

In addition, in accordance with the invention features a pharmaceutical composition having properties to reduce violations cognitive abilities, for the treatment and prevention of disorders of consciousness, containing an effective amount of at least one active compound in a mixture with acceptable from a pharmaceutical point of view of a carrier or diluent, and an active compound selected from the group consisting of compounds of the formula I and their salts, as defined above.

Detailed description of the invention.

In the compounds of the invention in which R1represents a halogen atom, they can be an atom of fluorine, chlorine, bromine or IO>
represents an alkyl group containing from 1 to 4 carbon atoms, this may be a group with a linear or branched chain containing from 1 to 4 atoms, and examples include methyl, ethyl, sawn, ISO-propyl, boutelou, isobutylene, second-boutelou, tert-boutelou, pentelow, isopentanol, neopentylene, hexoloy and isohexyl group. Of them, preferred are alkyl groups containing from 1 to 4 carbon atoms, in a preferred embodiment, methyl, ethyl, sawn, ISO-propyl, bucilina and isobutylene groups, and in naibolee preferred embodiment a methyl group.

When R2represents a phenyl group, such group may be substituted, and unsubstituted groups. Substituted groups may be substituted by one or more substituents /a/, which have been defined above and examples below. If this group is substituted, there are no restrictions on the number of substituents, except those which may be imposed by the number of substitutable positions and possibly it is necessary to consider the steric restrictions, for example, up to 5 substituents for the phenyl group. However, in the General case of predpochtitel the ora, bromine and iodine;

alkoxy group containing from 1 to 4, and in the preferred embodiment 1 or 2, carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy group, in the preferred embodiment, methoxy group; and a hydroxy group.

If R2represents a heterocyclic group, it has 5 or 6 ring atoms. From one of these atoms is a hetero-atom selected from the group consisting of hetero-nitrogen atoms or sulfur.

Such groups can be unsubstituted or can be substituted by at least one (in the preferred embodiment, from 1 to 3) Deputy /a/, which is defined together with the examples above. Examples of such unsubstituted groups include furyl, thienyl, pyrrolyl, pyridyl, tetrahydrofuranyl, tetrahydrothieno, pyrrolidinyl, pyrrolidinyl, piperidinyl, pyridinyl and 2H-pyrrolyl. Such groups may be unsubstituted or they may have at least one Deputy, selected from the group consisting of substituents /a/, which were defined above, and examples have been already given.

Alternatively, R1and R2can form a group of the formula-CR4CR5-CR6CR7

If R4, R5, R6or R7represent a halogen atom, an alkyl group containing from 1 to 4 carbon atoms, alkoxy group containing from 1 to 4 carbon atoms. They can be groups, examples of which are given above in connection with the same groups that were included in alternates /a/.

R3may represent substituted or unsubstituted piperidino group or unsubstituted hinkleyville group, which in the preferred embodiment, attached to isoxazoline group through a carbon atom. If substituted piperidino group, the substituents are selected from the group consisting of alkyl groups containing from 1 to 6, in the preferred embodiment, from 1 to 4, carbon atoms, such examples have been given above in connection with R1and R2.

Preferred classes of compounds of the present invention include those compounds of formula I and their salts, in which:

A/ R1represents a hydrogen atom, halogen atom or alkyl group containing from 1 to 3 carbon atoms.

B/ R2represents a hydrogen atom, alkyl group containing from 1 to 3 carbon atoms, phenyl group , what do heterocyclic group which contains 5 or 6 ring atoms, one of which is nitrogen, or sulfur, and the above-mentioned group is unsubstituted or substituted by at least one of the substituents /a'/, defined below;

Deputy /a'/:

the halogen atoms, alkoxy groups containing from 1 to 4 carbon atoms, and hydroxy-group.

/C/ R1and R3together form a group of the formula:

-CR4CR5CR6CR7< / BR>
in which R4, R5, R6and R7independently selected from the group consisting of hydrogen atoms, halogen atoms, alkyl groups containing from 1 to 3 carbon atoms and alkoxygroup containing from 1 to 3 carbon atoms;

/D/ R3is piperidino group, substituted piperidino group in which the nitrogen atom is substituted by an alkyl group containing from 1 to 6 carbon atoms, or hinkleyville group.

Of them, preferred are those compounds of formula I and their salts, in which R1and R2was already defined in /A/ and /B/ or /C/, and R3was already defined in /D/ above.

More preferred classes of compounds of the invention include those compounds of formula I and their salts, in which:

Deputy /a"/:

the atoms of halogen, alkoxygroup containing from 1 to 4 carbon atoms, and hydroxy-group.

/G/ R1and R2together form a group of the formula

-CR4CR5-CR6CR7,

in which R4, R5, R6and R7independently selected from the group consisting of hydrogen atoms and halogen atoms.

/H/ R3is substituted piperidino group in which the nitrogen atom is substituted by an alkyl group containing from 1 to 6 carbon atoms, or hinkleyville group.

Of them, preferred are those compounds of formula I and their salts, in which R1and R2was already defined in /E/ and /F/ or /G/ and R3was already defined in /H/ above.

Examples of some compounds of the invention are represented by the following formulas /I-1/-/I-4 is L. 2 refers to a formula /I-2/ etc. In the table. 1, where benzyloxyresorufin can be attached to 2-3 or 4 positions piperidino rings, this is specified using the o-, m - or p respectively, so that, for example 2-isomer. 3-isomer to 18m, etc. Similar agreement used in the table. 3. In the tables use the following abbreviations:

Bu butyl

the iBu is isobutyl

sBu-sec-butyl

tBu tert-butyl

Et ethyl

Fur furyl

Hx hexyl

Me methyl

Ph phenyl

Ph Patil

Pr drunk

iPr isopropyl

Pyr pyridyl

Thi-thienyl

< / BR>
where Z is:

< / BR>
marked respectively as "p", "m" and "o"/, Z1is:

< / BR>
/marked, respectively, as "p" "m" / a "Quin" represents hinkleyville group.

Of the compounds listed above, the following are preferred: Compounds NN 1-1, 1-2, 1-4, 1-6, 1-8, 1-10, 1-12, 1-14, 1-16, 1-18, 1-22, 1-24, 1-28, 1-32, 1-33, 1-34, 1-33, 1-39, 1-40, 1-56, 1-89, 1-90, 1-91, 1-144, 1-145, 1-147, 2-1, 2-2, 2-10, 2-11, 2-12, 2-13, 2-16, 2-17, 2-20, 2-21, 2-22, 2-29, 2-30, 2-32, 2-39, 2-40, 2-42, 2-44, 2-45, 2-97, 2-98, 2-99, 2-100, 2-102, 2-103, 2-107, 3-2, 3-51, 3-87, 3-88, 3-144, 2-145, 3-169, 3-264, 3-265, 3-266, 3-267, 3-268 and 3-269, of which more preferred are compounds N 1-2, 2-1, 2-2, 2-10, 2-20, 2-21, 2-97, 2-98, 2-99, 2-100 and 2-107. The most preferred ablauts is codelocks/isoxazol isomers;

2-20. 4-chloro-3-/3-hinkleyville/isoxazol;

2-107. 4-chloro-3-/3-inulinase/-5-phenyloxazol; and acceptable from a pharmaceutical point of view salts, in particular chlorhydrate.

Compounds of the invention can be obtained using various methods well known in obtaining compounds of this type. For example, in the General case, they can be obtained through condensation of the compounds of formula (II):

< / BR>
Y-R3< / BR>
/in the above formulas, R1, R2and R3have already been defined above, and X and Y represent more substitutable groups under conditions which assure condensation.

For example, X can represent a halogen atom (for example, chlorine atom, bromine or iodine/, and Y may represent oxygraph or a group of the formula MO-where M represents a metal atom (for example, an alkali metal, especially sodium or potassium, or X and Y may both represent oxygraph, in this case, the reaction is carried out in the presence of a dehydrating agent. Then the connection can be, if necessary, converted into a salt to obtain its salt.

In more detail, one preferred method of preparing compounds of the present invention includes collaboration is rmula V:

R3OH

in which R3has already been defined above in the presence of a dehydrating agent to obtain a compound of the formula /I/, and then, if necessary, conversion to the salt of the resulting compound of the formula /I/.

There are no particular restrictions on the nature of the dehydrating agent used in this reaction, and it is possible to use any compound capable of participating in the condensation reaction, to remove the elements of water, as is well known in this field of technology, provided that it does not exert any adverse effects on the reagents. Especially preferred dehydrating agent that can be used in this reaction is a compound which is obtained by the interaction of diethyl azodicarboxylate with triphenylphosphine, namely

< / BR>
in which R2represents phenyl group, and Et represents ethyl group.

This reaction can be carried out using reaction Mitsunobu, as described in Bull. Chem. Soc. Gapan. so 40 p. 2380 /1967/.

In particular, the reaction in the preferred embodiment, is carried out in the presence of an organic solvent. Don't have any specific OGRA what about the effect on the reaction or the reagents, and that it can dissolve the reagents, at least to some extent. Examples of appropriate solvents include: aromatic hydrocarbons such as benzene or toluene; ethers, such as dioxane or tetrahydrofuran; nitrides such as acetonitrile; ketones such as acetone or methyl ethyl ketone; amides, in particular amides of fatty acids such as dimethylformamide or dimethylacetamide; and solitarii such as dimethyl sulphates.

There are no particular restrictions on the molar ratio of the two reagents in the preferred embodiment, is used by about ravnomernye amount or a slight excess of the compound of the formula /V/.

This reaction can take place in a wide range of temperatures and the precise reaction temperature is not critical to the present invention. In General, it was found that it is preferable to carry out the reaction at a temperature of from -20oC to +50oC and in practice, the preferred and most preferred at room temperature. The time required for the reaction may also vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents. However, when the conditions is the period from 5 to 48 h, in General suitable period of approximately 24 hours

The product of this reaction may be separated from the reaction mixture by known means. For example, one such procedure includes extraction of the mixture with a suitable organic solvent, such as ethyl acetate, removing the solvent from the extract, in the General case, using evaporation, and then, if this is necessary, the product is subjected to subsequent purification stages, for example, by recrystallization or one of chromatography techniques such as chromatography on a column or preparative thin layer chromatography.

An alternative preferred method of preparing compounds of the present invention and, in particular, those in which R1has already been defined above, and R2represents a possibly substituted phenyl group or heterocyclic group that contains the interaction halogen or alfaprostol or connection isoxazol or connection piperidyl or hinokitiol formula /VI/:

R3X' /VI/

with oxycontintear formula /YII/:

RB-OH /VII/

or with the corresponding metal connection formula /YIIa/:

RB-OM

in which X' represents at the and and in the most preferred embodiment, the sodium atom or potassium; and one of Raand Rbrepresents a group of the formula /VIII/:

< / BR>
and the other of Raand Rbrepresents a group R3as identified above. Preferred reaction involves the interplay of compounds of formula /1X/:

< / BR>
in which R1, R2and x /have already been defined above/ oxycontintear formula /X/:

HO-R3< / BR>
or with the corresponding metal connection formula /Xa/.

Mo-Ra< / BR>
/in which M and R3have already been defined above. In this reaction /X/ in a preferred embodiment, is a halogen atom, and in the most preferred embodiment, the chlorine atom.

There are no particular restrictions on the molar ratio of these two reagents, though, because the reaction requires equal amounts of each reagent, approximately molar equality is preferred. However, there is a molar excess of one component, though, because any such excess is reset, the excess in the preferred embodiment, minimize.

The reaction in General and in the preferred embodiment, is carried out in the presence of a nonaqueous solvent. There are no particular restrictions on the solvent nature, which when amout to dissolve the reagents, at least to some extent.

Examples of appropriate solvents include halogenated aliphatic hydrocarbons such as methylene chloride, 1, 2-dichloroethane, chloroform and carbon tetrachloride, ethers, such as simple diethyl ether, simple disutility ether, simple diisobutenyl ether, dioxane, tetrahydrofuran and ethylene glycol dimethyl simple ether; aromatic hydrocarbons such as benzene, toluene and xylene; esters such as ethyl acetate; amides such as dimethylformamide and gexametilmelamin; and mixtures of any two or more of these solvents.

The reaction can take place in a wide range of temperatures and the precise value of the reaction temperature are not critical to the invention. In General, it was found that it is preferable to carry out the reaction at a temperature in the range of 0oC to 100oC, and in the exercise area from 0 to 50oC is more preferable. The time required for the reaction may also vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents. However, provided that the reaction is carried out at predpochtite the 0 h is preferred.

After completion of the reaction, the target compound can be separated from the reaction mixture using any suitable extraction procedures. For example, one such procedure includes: the reaction mixture is poured into a mixture of ice-water; the mixture is extracted with water-immiscible organic solvent such as ethyl acetate; the solvent is removed from the extract, for example, by distillation; and then, if necessary, the product is subjected to subsequent purification stages, for example, by recrystallization or by using one of chromatographic techniques such as chromatographic column or preparative thin layer chromatography.

The connection formula /1X/, which is used as one of the starting materials can be obtained, for example as described in Chem. Ber. so 100 p. 3326-3330 /1967/ or using similar known methods.

Compounds of the invention can exist in the form of various optical isomers and diastereomers due to the existence of asymmetric carbon atoms in the molecule. The optical isomers can be separated using known techniques, optical separation, to obtain optically active compounds. This is the query result of the synthesis reaction, or by using the offset. If you require a separate isomers, they can be obtained from mixtures by known means, or they can be obtained by using stereospecific synthesis techniques that are well known to any expert in this field of technology.

Salts of compounds of formula (I) can be obtained using known methods of salt formation. For example, the compound of formula I is dissolved in a suitable, in the preferred embodiment, non-aqueous, solvent, and then add the required acid, optionally also dissolved in the solvent. Salt in General precipitated and the solvent or solvents in the preferred embodiment, so choose what he does/ and it can be removed by filtering or using similar techniques. There are no particular restrictions on the nature of the used solvent, provided that it does not adversely affect the reaction or on the reagents, and that it can dissolve the reagents, at least to some extent. Examples of appropriate solvents include alcohols such as methanol or ethanol; ethers, such as diethyl simple ether or tetrahydrofuran; and aromatic hydrocarbons t but about ravnomernye share or a slight excess of acid is preferred for example, from 1 to 1.2 equivalents of acid per equivalent of the compound of the formula /I/. The reaction takes place in a wide range of temperatures, and the precise value of the reaction temperature is not critical to the present invention. In General, it was found that it is preferable to carry out the reaction at a temperature in the range from -5oC to 30oC.

The nature of acid will depend, of course, from the salt, which is preferred, but examples of appropriate acids include salts with mineral acids, especially halogen acids /such as hydrofluoric acid, Hydrobromic acid, itestosterone acid or hydrochloric acid, nitric acid, carbonic acid, sulfuric acid or phosphoric acid; salts with lower alkyl/mono/sulfonic acids such as methane/mono/acid, triptorelin/mono/acid or ethane/mono/acid; salts with aryl/mono/sulfonic acids such as the benzene/mono/acid or para-toluene/mono/acid; salts with organic carboxylic acids such as acetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid ASS="ptx2">

After separation of the salt can be, if necessary, subjected to purification by recrystallization from an appropriate solvent, for example alcohol such as ethanol.

Biological activity.

As below is confirmed in the experiments, the compounds that are the subject of the present invention, contact is very specific with muscarinic receptors, which are distributed in the brain among the receptors for acetylcholine, which is neuroparalytic; in particular, they prefer to contact muscarinic 1/M1/ receptors located on the postsynaptic membrane. In addition, they have Intertechnology activity without antihistaminas activity, which is essential for use as an antidepressant. In addition, they possess antagonistic activity relative to 5-HT3-receptors. Because 5-HT3antagonists, as is well known, possess anti-fobia and antipsychotic activities, it can be expected that the compounds of the present invention may be useful in the treatment of the symptoms of patients with disorders of consciousness. As a result, properties, connection, which I type Alzheimer, senile dementia and horei Huntington, which apparently caused by a violation of the pathways of biosynthesis of acetylcholine, with negligible side effects on the heart and digestive tract.

In addition, since 5-HT3antagonists, as you know, useful as antibotic agents, and M1antagonists, as is well known, are acting on the Central nervous system non-narcotic pain-soothing activity, it can be expected that the compounds that are the subject of the present invention are also useful as antibotic and agents acting on the Central nervous system, non-narcotic analgesic agents.

It has also been found that the compounds that are the subject of the present invention, have a favorable effect on ischemia-induced increased blood viscosity and this activity, as you might expect, it also increases cerebral microcirculation in patients with disorders of consciousness, which also improves these symptoms.

In addition, and most importantly, the compounds that are the subject of the present invention has been found to have low toxicity.

Compounds of the present invention can be used to prepare the known pharmaceutical forms, which are well known to every expert in this field of technology. So connections can be applicable tematicheskie, for example, in the form of tablets, capsules, granules, powders, syrups or other well-known forms, or parenterally, for example by means of injections, suppositories, etc.

Such pharmaceutical compositions can be obtained using known means and they may contain known additives that are in General use in this area, for example, the media linking agents, disintegrator lubricating agents, "correction" agents, etc. depending on the upcoming use in the form of spooling. The dose will depend on the condition, age and body weight of the patient, and the type and extent of the disorder to be treated, but if tematicheskoe use adult patient person in the General case, the total daily dose should be 5 mg to 50 mg, which can be applied in the form of one or more doses, for example from one to three times a day.

Exposure of the present invention using the above-mentioned compounds is further illustrated using the following examples and compositions of these compounds in the form acceptable to termni then illustrated with the help of the subsequent experiments.

Example 1. 4-chloro-5-methyl-3-/3-hinkleyville/isoxazol.

The solution 7,86 g of triphenylphosphine in 100 ml of tetrahydrofuran was cooled to 5oC, and then was added dropwise with 5.22 g of diethyl azodicarboxylate to the cooled solution, and then of 4.00 g of 4-chloro-3-hydroxy-5-methylisoxazole. In the resulting mixture were then added 3,81 g 3-oxyhemoglobin, and the mixture was stirred at room temperature for 24 hours At the end of this time the solvent was removed from the mixture by distillation under reduced pressure. The resulting residue was subjected to purification using chromatographic column on silica gel, using ethyl acetate as eluent to obtain 4.72 in /output 64,8%). Connection header example in the form of a colourless powder, melting point 37-38oC.

Infrared absorption spectrum /KBr/maxcm-1: 1632, 1520, 1455.

Spectrum of nuclear magnetic resonance /CDCl3/ ppm: 1,34-2,00 /4H, multiplet/, 2,25-2,39/ 1H, multiplet/, 2,33/3H, singlet/, 2,68-3.04 from/5H, multiplet/, 3,26-3,35/1H, multiplet/, 4,71-4,78 /1H, multiplet/.

Example 2. 3-(3-hinkleyville)isoxazol.

The solution 9,18 g of triphenylphosphine in 100 ml of tetrahydrofuran, the cooling gap is whether 2,98 g 3-accesorize and 4.45 g of 3-oxyhemoglobin, and the resulting mixture was stirred at room temperature for 24 hours At the end of this time the solvent was removed by distillation under reduced pressure and the resulting residue was subjected to purification using chromatographic columns through silicagel, using ethyl acetate as eluent to obtain 5,18 g /exit 76,6% / connection header example in the form of a colourless powder with a melting point 80-81oC.

Infrared absorption spectrum /KBr/maxcm-1: 1581, 1486, 1465, 1423.

Spectrum of nuclear magnetic resonance /CDCl3/ ppm: 1,27-1,97 /4H, multiplet/, 2,24-2,30/1H, multiplet/, 2,68-3,01 /5H, multiplet/, 3.27 to 3,37/ 1H, multiplet/, 4,69-4,76/1H, multiplet/, 5,96/1H, doublet, J=1.97 Hz/, 8,12/1H, doublet, J=1.97 Hz/.

Example 3. Hydrochloride 4-chloro-5-methyl-3-/3-hinkleyville/isoxazol.

A solution of 2.30 g of 4-chloro-5-methyl-3-/3-hinkleyville/isoxazol obtained in example 1, in 30 ml of ethanol was cooled to 5oC. To the solution was added dropwise 2,50 ml 4 solution of hydrogen chloride in dioxane. The resulting mixture was stirred at the same temperature for 10 minutes At the end of this time the reaction RGALI recrystallization from isopropanol, to get 2,42 g (yield of 91.6%) of the compound from the header of the example as colorless powder having a melting point 195-198oC /decomposition/.

Infrared absorption spectrum /KBr/maxcm-1: 1633, 1521, 1461, 1425.

Spectrum of nuclear magnetic resonance /D2O/ ppm/: 1,87-2,36 /4H, multiplet/, 2,62-2,73 /1H, multiplet/, 2,38/3H, singlet/, 3,28-3,57/5H, multiplet/, 3,75-3,84/1H, multiplet/, 5,09-5,15/1H, multiplet/.

Example 4. Hydrochloride-3-/3-hinkleville/isoxazol.

A solution of 1.70 g of 3-/3-hinkleyville/isoxazol obtained in example 2 in 20 ml of ethanol was cooled to 5oC. To the solution was added dropwise 2.30 ml 4n. solution of hydrogen chloride in dioxane, and received the resulting mixture was stirred at the same temperature for 10 minutes At the end of this time the reaction mixture was concentrated by distillation under reduced pressure and the solid residue thus obtained was subjected to recrystallization from isopropanol, to get to 1.83 g /exit 91,0%/. Connection header example in the form of a colourless powder, melting point which was 221-223oC /decomposition/.

Infrared absorption spectrum /KBr/ maxthe, ultiple/, 2,64-2,70/ 1H/ multiplet/, 3,28-3,53/ 5H, multiplet/, 3,75-3,84/ 1H, multiplet/, of 5.05-5,11/1H, multiplet/, 6,24/1H, doublet, J= 1.97 Hz/, to 8.41 (1H, doublet, J=1.97 Hz/.

Example 5. R-/+/-3-/3-inulinase/isoxazol.

The solution 62,50 g of the monohydrate of 2,3-di-ParetoLogic-L-tartaric acid in 200 ml of methanol was added to a solution of 30.00 g 3-/3-hinkleyville/isoxazol obtained as described in example 2, 800 ml of methanol, and the resulting mixture was stirred over night at room temperature. The crystals which precipitated were collected by filtration and washed with 300 ml of ethanol to obtain 28,21 g (yield of 62.8%) of crude crystals of 2,3-di-paratroop-L-tartrate 3-/3-R-hinkleyville/isoxazol. The combination of these crude crystals and ethanol wash liquids used as starting material for the synthesis described in example 6.

Meanwhile, the crude crystals were subjected to recrystallization three times from methanol to obtain 16,32 grams of relatively pure 2,3-di-paratroop-L-tartrate 3-/3-R-hinkleyville/isoxazol as colorless columnar crystals, melting point 165-166oC/decomposition/ having a refractive index []2D4-48,7o/ c=and the resulting solution was cooled to 5oC. To the suspension was added 36 ml of 1N. an aqueous solution of hydrochloric acid, and the resulting mixture was stirred at the same temperature for 10 minutes At the end of the second period of time, the aqueous layer was separated and cooled to 5oC. it was then added 63 g of sodium carbonate and the mixture was extracted twice, each time using 200 ml of ethyl acetate. Next, the organic layer was dried over anhydrous magnesium sulfate and the drying agent was removed by filtration. Then the solvent was removed from the filtrate by distillation under reduced pressure. The resulting crystalline residue was led from diisopropylamido ether to obtain 5.10 g /exit 34,0%/ connections from the header of the example as colorless columnar crystals, melting point 69 70oC.

[]2D4+7,70 /c 1.0, ethanol/.

Infrared absorption spectrum /KBr/maxcm-1: 1577, 1473, 1424.

Spectrum of nuclear magnetic resonance /CDCl3/ ppm: 1,35 1,98 /4H. multiplet/, and 2.26 2,32 /1H, multiplet/, 2,70 3,03 /5H, multiplet/, 3,28 3,37 /1H, multiplet/, 4,71 4,77 /1H, multiplet/, 5,96 /1H, doublet, J 1,95 Hz/, 8,12 /1H, doublet, J 1,95 Hz/.

Example 6. S-/-/3-/3-hinkleyville/isoxazol.

[]2D4to-7.6o/c 1.0,ethanol/.

Infrared absorption spectrum /KBr/maxcm-1: 1577, 1473, 1423.

Spectrum of nuclear magnetic resonance /CDCl3/ ppm: of 1.35 to 1.98 (4H, multiplet/, 2,31 2,25 /1H, multiplet/, 2,66 3,02 /5H, multiplet/, 3,28 3,37 /1H, multiplet/, 4,70 4,76 /1H, multiplet/, 5,96 /1H, doublet, J 1,95 Hz/, 8,12 /1H, doublet, J 1,95 Hz/.

Example 7. Hydrochloride R -/ is example 5/ 50 ml isopropanol was cooled to 5oC and added 6,07 ml of 4n. solution of hydrogen chloride in dioxane. The mixture was stirred for 10 min, and then the crystals which precipitated were collected by filtration and subjected to recrystallization from methanol, to obtain 4,85 g /exit 9,0%/. Connection header example in the form of colorless needles, melting at 255 257oC /decomposition/.

[]2D4-29,70 /s 1,0, H2O/.

Infrared absorption spectrum /KBr/maxcm-1: 1579, 1485, 1477, 1456, 1430.

Spectrum of nuclear magnetic resonance /D20/ ppm: 1,86 2,33 /4H, multiplet/, 2,63 2,68 /1H, multiplet/, 3,30 3,53 /5H, multiplet/, 3,74 3,83 /1H, multiplet/, of 5.05 5,11 /1H, multiplet/, 3,24 /1H, doublet, J a 1.96 Hz/, to 8.41 /1H, doublet, J a 1.96 Hz/.

Example 8. Hydrochloride S-/+/-3-/3-hinkleyville/isoxazol.

The solution 5,95 g S-/-/-3-/3-hinkleyville/isoxazol /obtained in example 6/ in 60 ml of isopropanol was cooled to 5oC and it was added to 8.41 ml of 4n. solution of hydrogen chloride in dioxane. The mixture was stirred for 10 min, and then the crystals which precipitated were collected by filtration and subjected to recrystallization from ethanol to obtain 6,64 g /exit 94,0%/ connection header example in vid,8o/s 1,0 H2O/.

Infrared absorption spectrum /KBr/maxcm-1: 1579, 1484, 1477, 1456, 1430.

Spectrum of nuclear magnetic resonance /D20/ ppm: 1,86 2,34 /4H, multiplet/, 2,63 2,69 /1H, multiplet/, 3,30 to 3.58 /5H, multiplet/, 3,74 3,83 /1H, multiplet/, of 5.05 5,11 /1H, multiplet/, 6,241 H, doublet, J a 1.96 Hz/, to 8.41 /1H, doublet, I 1,96 Hz/.

Example 9. 4-Chloro-3-/3-hinkleyville/-5-phenylmethoxy.

The solution to 1.96 g of 3-hinokitiol in 30 ml of dimethylformamide was cooled to 5oC in nitrogen atmosphere. In cooling, the solution was added 67 g of sodium hydride /as 55% wt/wt dispersion in mineral oil/ and then the solution was stirred at room temperature for 30 minutes At the end of this time the reaction mixture was cooled to 5oC and was added 3.0 g of 3,4-dichloro-5-phenylisoxazole. The resulting mixture was then stirred at room temperature for 5 hours At the end of this period of time it was poured into 100 ml of a mixture of ice-water and was extracted twice, each time using 100 ml of ethyl acetate. An ethyl acetate extracts were combined and washed twice, each time using 100 ml of 10% wt/wt aqueous solution of sodium chloride then dried over anhydrous magnesium sulfate, then the drying is no. Thus obtained residue was subjected to purification using chromatographic column on silica gel using a mixture of 10:1 /volumes/ ethyl acetate and methanol as the eluent, to obtain 4,21 g /exit 98,7%/ connection header example in the form of a colorless and transparent oil. n2D81,5701.

Infrared absorption spectrum /CHC13/maxcm-1: 1625, 1520, 1460, 1375.

Spectrum of nuclear magnetic resonance /CDCl3/ ppm: 1,38 2,05 /5H, multiplet/, 2,31 3:40 /6H, multiplet/, 4,80 4,86 /1H, multiplet/, 7,44 7,54 /3H, multiplet/, 7,93 7,99 /2H, multiplet/.

Example 10. Hydrochloride 4-chloro-3-/3-hinkleyville/-5-phenylisoxazole.

A solution of 1.12 g of 4-chloro-3-/3-hinkleyville/-5-phenylisoxazole /obtained as described in example 9/ in 20 ml of ethanol was cooled to 5oC. Then the solution was added dropwise 2.1 ml 4n. solution of hydrogen chloride in dioxane and the resulting mixture was stirred at room temperature for 30 minutes At the end of this time the reaction mixture was concentrated by distillation under reduced pressure and the thus obtained solid residue was subjected to recrystallization from ethanol to obtain 2,>
C /decomposition/.

Infrared absorption spectrum /KBr/maxcm-1: 1627, 1522, 1450, 1421.

Spectrum of nuclear magnetic resonance /hexadecacarbonyl dimethyl sulphates/ ppm: 1,81 2,56 /5H, multiplet/, 3,16 3,79 /6H, multiplet/, 5,08 5,14 /1H, multiplet/, multiplet/, to 7.59 7,65 /3H, multiplet/, of 7.90 7,95 /2H, multiplet/.

Example 11. 5-Chloro-3-/1-methyl-4-piperidinyloxy/-1,2-benzisoxazol.

A solution of 1.53 g /13.3 mmol of 4-hydroxy-1-methylpiperidine in 25 ml of dimethylformamide was cooled to 5oC in nitrogen atmosphere. To the solution was added 0,58 g /13.3 mmol/ hydrate sodium /as 55% wt/wt dispersion in mineral oil/ and then the solution was stirred at room temperature for 30 minutes, the Reaction mixture was cooled to 5oC, and then it was added 2.50 g /13.3 mmol/ 3,5-dichloro-1,2-benzisoxazole; the resulting mixture was stirred at 5oC for 30 min and then at room temperature for 1 h In the end of this time the mixture was poured into 50 ml of a mixture of ice-water and then was extracted twice, each time using 50 ml of ethyl acetate. The ethyl acetate layer was separated and washed with 100 ml of 10% weight/volume aqueous solution of sodium chloride; it was then dried over anhydrous magnesium sulfate and sawlani. Received the residue was subjected to purification using chromatographic column on silica gel, using ethyl acetate as eluent to obtain 2.38 g /exit 67,00%/. Connection header example in the form of a colorless powder, melting at 55 56oC.

Infrared absorption spectrum /CHCl3/ cm-1; 1535, 1470, 1440, 1360, 1310.

Spectrum of nuclear magnetic resonance /CDCl3/ d ppm: 1,73 3,00 /8H, multiplet/, 2,32 /3H, singlet/, 4,92 /1H, double doublet of doublets, J is 13.5, 9.0 and 4.5 Hz/, 7,30 /7,76 /3H, multiplet/.

Example 12. Hydrochloride-5-chloro-3-/1-methyl-4-piperidinyloxy/-1,2-benzisoxazole.

A solution of 2.20 g /8,24 mmol/ 5-chloro-3-/1-methyl-4-piperidinyloxy/-1,2-benzisoxazole /obtained as described in example 11/ in 20 ml of ethanol was cooled to 5oC. the cooled solution was added dropwise 2.5 ml of 4n. solution of hydrogen chloride in dioxane, and the resulting mixture was stirred at room temperature for 30 minutes At the end of this time the solvent was removed from the reaction mixture by distillation under reduced pressure. The solid residue thus obtained was subjected to recrystallization from ethanol to obtain 2,47 g /wilpert 212 214oC /decomposition/.

Infrared absorption spectrum /KBr/maxcm-1; 1532, 1471, 1440, 1311.

Spectrum of nuclear magnetic resonance /hexadecacarbonyl dimethylsulphoxide/ ppm: 2.06 to 2,43 /4H, multiplet/, 5,16 /1H, multiplet/, 7,66 8,03 /3H, multiplet/.

Example 13-108. Following the procedure similar to that described in examples 1 to 12 were obtained the following compounds.

Examples 13. /+/-4-chloro-5-phenyl-3-/3-hinkleyville/isoxazol.

n2d41,6290

[]2D4+8,4o/c=1.0 in CHCl3/.

Example 14. /-/-4-chloro-5-phenyl-3-/3-hinkleyville/isoxazol.

n2D4= 1,6290

[]2D4-8,5o/c=1,0, CHCl3/.

Example 15. Hydrochloride /+/-4-chloro-5-phenyl-3-/3-hinkleyville/ isoxazol.

The melting point of 250 255oC /decomposition/. []2D4= +33,3o/c= 1,0, H2O/.

Example 16. Hydrochloride /-/-4-chloro-5-phenyl-3-/3-hinoksolinov/-isoxazol.

The melting point of 250 255oC /decomposition/. []2D4= -33,5o/c= 1,0, H2O/.

Example 17. Hydrochloride 5-chloro-3-/4-piperidinyloxy/-1,2-benzisoxazole.

The melting point 52 53oC.

Example 19. Hydrochloride 5-methyl-3-/3-hinkleyville/isoxazol.

The melting point 207 209oC /decomposition/.

Example 20. Hydrochloride 5-methyl-3-/4-piperidinyloxy/isoxazol.

The melting point 209 211oC /decomposition/.

Example 21. Hydrochloride 5-/3-pyridyl/-3-/3-hinkleyville/isoxazol.

The melting point of 250 253oC /decomposition.

Example 22. Hydrochloride 3-/1-methyl-4-piperidinyloxy/-5-/3-pyridyl/isoxazol.

The melting point 217 220oC /decomposition/.

Example 23. 4-Chloro-3-/1-methyl-3-piperidinyloxy/-5-phenylisoxazol.

n2D8= 1,5579.

Example 24. 4-Chloro-3-/1-methyl-4-piperidinyloxy/-5-phenylisoxazol.

The melting point 43 44oC.

Example 25. 5-Phenyl-3-/3-hinkleyville/isoxazol.

n2D8= 1,5712.

Example 26. 3-/1-Methyl-3-piperidinyloxy/-5-phenylisoxazol.

n2D8= 1,5612.

Example 27. 3-/1-Methyl-4-piperidinyloxy/-5-phenylisoxazol.

The melting point 70,5 71,5oC.

Example 28. 5-/Para-chlorine is 29. 5-/para-chlorophenyl/-3-/1-methyl-3-piperidinyloxy/isoxazol.

n2D8= 1,5645.

Example 30. 5-/para-chlorophenyl/-3-/1-methyl-4-piperidinyloxy/isoxazol.

The melting point 122 123oC

Example 31. Hydrochloride 4-chloro-3-/1-methyl-3-piperidinyloxy/-5-phenylisoxazole.

The melting point 101 102oC

Example 32. Hydrochloride 4-chloro-3-/1-methyl-4-piperidinyloxy/-5-phenylisoxazole.

The melting point 192 193oC /decomposition/.

Example 33. Hydrochloride 5-phenyl-3-/3-hinkleyville/isoxazol.

The melting point 238 240oC /decomposition/.

Example 34. Hydrochloride /1-methyl-3-piperidinyloxy/-5-phenylisoxazole.

The melting point 189 190oC.

Example 35. Hydrochloride /1-methyl-4-piperidinyloxy/-5-fendizoate.

The melting point 210 212oC /decomposition/.

Example 36. Hydrochloride 5-/para-chlorophenyl/-3-/3-hinkleyville/isoxazol.

The melting point 227 229oC /decomposition/.

Example 37. Hydrochloride 5-/para-chlorophenyl/-3-/1-methyl-1-piperidinyloxy/isoxazol.

The melting point 215 217oC /resopiratory the melting point 209-211oC /decomposition/.

Example 39. 4,5-Dimethyl-3-/3-hinkleyville/isoxazol.

n2D6= 1,5332.

Example 40. 4,5-Dimethyl-3-/1-methyl-4-piperidinyloxy/isoxazol.

n2D6= 1,5437.

Example 41. 5-Ethyl-3-/3-hinkleyville/isoxazol.

The melting point 71-72oC.

Example 42. 5-Ethyl-3-/1-methyl-4-piperidinyloxy/isoxazol.

n2D6=1,5612.

Example 43. 5-Isopropyl-3-/3-hinkleyville/isoxazol.

The temperature of the melting point of 75-76oC.

Example 44. 5-Isopropyl-3-/1-methyl-4-piperidinyloxy/isoxazol.

n2D4= 1,5634.

Example 45. 4-Chloro-5-ethyl-3-/1-methyl-4-piperidinyloxy/isoxazol.

The melting point 78-80oC.

Example 46. 4-Chloro-5-ethyl-3-/1-methyl-4-piperidinyloxy/isoxazol.

n2D4= 1,5802.

Example 47. 4-Chloro-5-isopropyl-3-/3-hinkleyville/isoxazol.

The melting point 82-83oC.

Example 48. 4-Chloro-5-isopropyl-3-/1-methyl-4-piperidinyloxy/isoxazol.

n2D4= 1,5724.

Example 49. 5-Methyl-3-/1-methyl-4-piperidinyloxy/seksdelisi/isoxazol.

The melting point 30-31oC.

Example 51. 3-/1-Methyl-4-piperidinyloxy/isoxazol.

The melting point 40-40,5oC.

Example 52. 4-Chloro-3-/1-methyl-4-piperidone/isoxazol.

n2D6= 1,6340.

Example 53. 4-Fluoro-5-methyl-3-/3-hinkleyville/isoxazol.

The melting point 40-41oC.

Example 54. Hydrochloride 4,5-dimethyl-3-/3-hinkleyville/isoxazol.

The melting point 212-214oC /decomposition/.

Example 55. Hydrochloride 4,5-dimethyl-3-/1-methyl-4-piperidinyloxy/isoxazol.

The melting point 219-222oC /decomposition/.

Example 56. Hydrochloride 5-ethyl-3-/3-hinkleyville/isoxazol.

The melting point 211 213oC /decomposition/.

Example 57. Hydrochloride 5-ethyl-3-/1-methyl-4-piperidinyloxy/isoxazol.

The melting point 184-186oC /decomposition/.

Example 58. Hydrochloride 5-isopropyl-3-/3-hinkleyville/isoxazol.

The melting point 210-212oC /decomposition/.

Example 59. Hydrochloride 5-isopropyl-3-/1-methyl - 4-piperidinyloxy/isoxazol.

Point temperature Ola.

The melting point 219-222oC /decomposition/.

Example 61. Hydrochloride 4-chloro-5-ethyl-3-/1-methyl-4-piperidinyloxy/isoxazol.

The melting point 211-214oC /decomposition/.

Example 62. Hydrochloride 4-chloro - 5-isopropyl-3-/3-hinkleyville/isoxazol.

The melting point 213-216oC /decomposition/.

Example 63. Hydrochloride 4-chloro-5 - isopropyl-3-/1-methyl-4-piperidinyloxy/isooctanol.

The melting point 209-212oWith /decomposition/.

Example 64. Hydrochloride 5-methyl-3-/1-methyl-4-piperidinyloxy/isoxazol.

The melting point 198-200oC /decomposition/.

Example 65. Hydrochloride 4-chloro-5-methyl-3-/1-methyl-4-piperidinyloxy/isoxazol.

The melting point 211-214oC /decomposition/.

Example 66. Fumarate 3-/1-methyl-4-piperidinyloxy/isoxazol.

The melting point 148-150oC /decomposition/.

Example 67. Hydrochloride 4-chloro-3-/1-methyl-4-piperidinyloxy/isoxazol.

The melting point 201-204oC /decomposition/.

Example 68. Hydrochloride 4-fluoro-5-methyl-3-/3-hinkleyville/isoxazol.

The melting point 200-203oC.

Example 70. 6-Chloro-3-/3-inulinase/-1,2-benzisoxazol.

The melting point of 73.5-74,5oC.

Example 71. 6-Chloro-3-/1-methyl-3-piperidinyloxy/-1,2-benzisoxazol.

The melting point 64-65oC.

Example 72. 6-Chloro-3-/1-methyl-4-piperidinyloxy/-1,2-benzisoxazol.

The melting point of 106.5-107,5oC.

Example 73. 7-Chloro-3-/3-chinuklidinyl/-1,2-benzisoxazol.

The melting point 63-64oC.

Example 74. 7-Chloro-3-/1-methyl-4-piperidinyloxy/-1,2-benzisoxazol.

The melting point 74-75oC.

Example 75. 5-Methoxy-3-/3-nucleinate/-1,2-benzisoxazol.

The temperature of the melting point of 85-86oC.

Example 76. 5-Methoxy-3-/1-methyl-4-piperidinyloxy/-1,2-benzisoxazol.

n2D6=1,5390

Example 77. 5-fluoro-3-/3-hinkleyville/-1,2-benzisoxazol.

The melting point 90-91oC.

Example 78. 5-fluoro-3-/1-methyl-4-piperidinyloxy/-1,2-benzisoxazol.

The melting point 83-84oC.

Example 79. 5-Chloro-3-/1-ethyl-4-piperidinyloxy/-1,2-benzisoxazol.

The melting point 62-63melting 71-72oC.

Example 81. 5-Chloro-3-/-isobutyl-4-piperidinyloxy/-1,2-benzisoxazol.

The melting point 76-77oC.

Example 82. 5-Methyl-3-/3-hinkleyville/-1,2-benzisoxazol.

The melting point 94-95oC.

Example 83. 5-Methyl-3-/1-methyl-4-piperidinyloxy/-1,2-benzisoxazol.

The melting point 87-99oC.

Example 84. 5-Chloro-3-/1-methyl-3-piperidinyloxy/-1,2-benzisoxazol.

The melting point 61-62oC.

Example 85. 5-Chloro-3-/3-hinkleyville/-1,2-benzisoxazol.

The melting point 69-70oc.

Example 86. 5-Chloro-3-/4-piperidinyloxy/-1,2-benzisoxazol.

The melting point 81-82oC.

Example 87. Hydrochloride 3-/1-methyl-4-piperidinyloxy/-1,2-benzoxazole.

Point temperature of Platania 197-199oC /decomposition/.

Example 88. The hydrochloride of 6-chloro-3-/3-inulinase/-1,2-benzisoxazole.

The melting point 237-239oC /decomposition/.

Example 89. The hydrochloride of 6-chloro-3-/1-methyl-3-piperidinyloxy/-1,2-benzisoxazole.

The melting point 213-215oC /decomposition/.

Example 90. Hydrochloride 6-begins/.

Example 91. The hydrochloride is 7-chloro-3-/3-hinkleyville/-1,2-benzisoxazole.

The melting point 251 253oC /decomposition/.

Example 92. The hydrochloride is 7-chloro-3-/1-methyl-4-piperidinyloxy/-1,2-benzisoxazole.

The melting point 238 240oC /decomposition/.

Example 93. Hydrochloride 5-methoxy-3-/3-hinkleyville/-1,2-benzisoxazole.

The melting point 245 247oC /decomposition/.

Example 94. Hydrochloride 5-methoxy-3-/1-methyl-4-piperidinyloxy/-1,2-benzisoxazole.

The melting point 225 227oC /decomposition/.

Example 95. Hydrochloride 5-fluoro-3-/3-hinkleyville/-1,2-benzisoxazole.

The melting point 231 233oC /decomposition/.

Example 96. Hydrochloride 5-fluoro-3-/1-methyl-4-piperidinyloxy/-1,2-benzisoxazole.

The melting point 234 236oC /decomposition/.

Example 97. Hydrochloride 5-chloro-3-/1-ethyl-4-piperidinyloxy/-1,2-benzisoxazole.

The melting point 186 188oC /decomposition/.

Example 98. Hydrochloride 5-chloro-3-/1-propyl-4-piperidinyloxy/-1,2-benzisoxazole.

The melting point 226 228oC /decomposition/.

Example 99. UP>o
C /decomposition/.

Example 100. Harkirat 5-methyl-3-/3-hinkleyville/-1,2-benzisoxazole.

The melting point 262 264oC /decomposition/.

Example 101. Hydrochloride 5-methyl-3-/1-methyl-4-piperidinyloxy/-1,2-benzisoxazole.

The melting point 223 235oC /decomposition/.

Example 102. Hydrochloride 5-chloro-3-/1-methyl-3-piperidinyloxy/-1,2-benzisoxazole.

The melting point 204 206oC /decomposition/.

Example 103. Hydrochloride 5-chloro-3-/3-hinkleyville/-1,2-benzisoxazole.

The melting point of 269 271oC /decomposition/.

Example 104. Hydrochloride 3-/1-methyl-3-/1-piperidinyloxy/-1,2-benzisoxazole.

The melting point 188 190oC /decomposition/.

Example 105. Hydrochloride 3-/3-hinkleyville/-1,2-benzisoxazole.

The melting point 248 250oC /decomposition/.

Example 106. Hydrochloride 4-chloro-5-phenyl-3-/3-piperidinyloxy/isoxazol.

The melting point 111 113oC.

Example 107. Hydrochloride 3-/3-hinkleyville/-5-/2-thienyl/isoxazol.

The melting point 240 242oC /decomposition/.

Example 108. Hydrochloride is e/.

Example 109. 4-Chloro-3-/3-hinkleyville/isoxazol/

of 6.99 g /40,2 mmol/ dietel of diazocarbonyl was added dropwise into the solution 10,54 g /40,2 mmol/ triphenyl in 150 ml of tetrahydrofuran, while cooling to 0 to 10oC, and the resulting mixture was stirred at the same temperature for 30 minutes At the end of this period of time was added 5.10 g /40,2 mmol/ 3-hinokitiol and the mixture was stirred at a temperature of 0 to 5oC for 30 min and then at room temperature for 24 hours At the end of this time the solvent was removed by distillation under reduced pressure and the resulting residue was then subjected to purification using chromatographic column on silica gel, using ethyl acetate as eluent to obtain 3,90 g /exit 50,9%/ connecting header example in the form of a colorless powder, melting at 68 69oC.

Elemental analysis:

Calculated for C10H13N2O2Cl C 52,52; H 5,73; N 12,5; Cl 15,51.

Found, C 52,28; H 5,610; N 12,21; Cl 15,49.

Infrared absorption spectrum /KBr/maxcm-11582, 1514, 1418.

Spectrum of nuclear magnetic resonance /CDCl3/, 270 MHz/ ppm: 1,36 2,00 /4H, multiplet/, 2,27 2,33 /iMER 110. Hydrochloride 4-chloro-3-/3-hinkleyville/isoxazol.

of 3.00 ml /12,00 mmol/ 4h. solution of hydrogen chloride in dioxane was added dropwise into the solution to 2.29 g /10.0 mmol of 4-chloro-3-/3-hinkleyville/isoxazol /obtained in example 109/ in 20 ml of ethanol, cooling up to 5oC, then the mixture was stirred at the same temperature for 10 minutes At the end of this time the solvent was removed by distillation under reduced pressure and the solid residue was subjected to recrystallization from isopropanol to obtain 2,40 g /exit 90,4%/ connection header example in the form of a colorless powder, melting at 235 238oC /decomposition/.

Elemental analysis:

Calculated for C10H14N2O2Cl C 45,30; H 5,32; N 10,57; Cl 26,74.

Found, C 44,55; H Lower Than The 5.37; N 10,44; Cl 26,45.

Infrared absorption spectrum /KBr/maxcm-1: 1590, 1513, 1484, 1455, 1422.

Spectrum of nuclear magnetic resonance /CDCl3, 270 MHz/ ppm: 1,87-2,39 4H, multiplet/, 2,68-2,75 /1H, multiplet, J 0,97 Hz/, 3,28-to 3.58 /5H, multiplet/, 3,76-3,86 /1H, multiplet/, 5,13-5,19 /1H, multiplet/, 8,56 /1H, singlet/.

Using a technique similar to that described in examples 1-12 were obtained the following compounds.

Example 112. 5-(m-methoxy)phenyl-3-(3-chinuklidinyl)isoxazol NMR CDCl3d ppm: 1,33-to 2.18 (5H, multiplet); 2,50-to 3.34 (6H, multiplet); is 3.82 (3H, singlet); 4,62-and 4.68 (1H, multiplet); at 6.84 (1H, singlet); 7.03 is 7,11 (1H, multiplet); 7,33 7,44 (3H, multiplet).

Example 113. 5-(o-methoxy)phenyl-3-(3-hinkleyville)isoxazol hydrochloride.

So pl. 252 253oC (Razlog.)

NMR (D2O) d ppm: 1.8V to 2.64 (5H, multiplet); 3,29 of 3.85 (6H, multiplet); 3,93 (3H, singlet); 4,98 free 5.01 (1H, multiplet); 6,47 (1H, singlet); 7,09 was 7.08 (4H, multiplet).

Example 114. 5-(m-matoki)phenyl-3-(3-chinuklidinyl)isoxazol hydrochloride.

So pl. 211 214oC (Razlog.)

NMR (D2O) d ppm: 1,92 of 2.68 (5H, multiplet); 3.33 and of 3.85 (6H, multiplet); the 3.89 (3H, singlet); 5,04 to 5.08 (1H, multiplet); 6,47 (1H, singlet); 7,11 to 7.15 (1H, multiplet); 7,31 to 7.50 (3H, multiplet).

Example 115. 5-(p-matoki)phenyl-3-(3-hinkleyville)isoxazol.

NMR (CDCl3) d ppm: 1,35 2,17 (5H, multiplet); 2.50 is of 3.43 (6H, multiplet); is 3.82 (3H, singlet); 4,62 the 4.65 (1H, multiplet); only 6.64 (1H, singlet); 7,07 (2H, doublet, J 8,58 Hz); 7,74 (2H, doublet, J 8,58 Hz).

Example 116. 5-(3,4-Dimethoxy)phenyl-3-(3-hinkleyville)isoxazol.

NMR (CDCl3) d ppm: 1,32 2, multiplet).

Example 117. 5-(p-methoxy)phenyl-3-(3-hinkleyville)isoxazol hydrochloride.

So pl. 235 238oC (Razlog.)

NMR (D2O) d ppm: 1,91 of 2.66 (5H, multiplet); 3,32 of 3.84 (6H, multiplet); the 3.89 (3H, singlet); 5,02 of 5.05 (1H, multiplet); 6,34 (1H, singlet); was 7.08 (2H, doublet, J 9,82 Hz); 8,72 (2H, doublet, J a 9.25 Hz).

Example 118. 5-(3,4-Dimethoxy)phenyl-3-(3-hinkleyville)isoxazol hydrochloride.

T. pl. 198 201o(With Razlog.)

NMR (D2O) d ppm: 1,93 of 2.66 (5H, multiplet); 3,32 of 3.85 (6H, multiplet); a 3.87 (3H, singlet); 4,89 (3H, singlet); 5,00 to 5.03 (1H, singlet); 6,28 (1H, singlet); 7,02 to 7.32 (8H, multiplet).

Example 119. 4-Chloro-5-(m-methoxy)phenyl-3-(3-hinkleyville)isoxazol.

NMR (CDCl3) d ppm: 1,36 to 2.42 (5H, multiplet); 2,79 3,44 (6H, multiplet); 3,86 (MN, singlet); 4.80 to a 4.86 (1H, multiplet);? 7.04 baby mortality for 7.12 (1H, multiplet); 7,32 of 7.48 (MN, multiplet).

Example 120. 5-(m-hydroxy)phenyl-3-(3-hinkleyville)isoxazol.

NMR (CDCl3)d ppm: 1,39 of 2.21 (5H, multiplet); 2,53 3,52 - (6H, multiplet); 4,67 4,70 (1H, multiplet); 6,74 (1H, singlet); 6.90 to - 6,93 (1H, multiplet); 7,19 7,37 (MN, multiplet).

Example 121. 4-Chloro-5-(m-methoxy)phenyl-3-hinkleyville)isoxazol hydrochloride.

So pl. 222 225o(With Razlog.)

NMR (D2O)d ppm: 1,94 of 2.66 (5H, multiplet); 3,34 a 3.83 (6H, the mule is includename)isoxazol hydrochloride.

So pl. 260 263oC (Razlog.)

NMR (D2O)d ppm: 1,91 to 2.67 (5H, multiplet); 3,32 of 3.84 (6H, multiplet); 5,01 of 5.05 (1H, multiplet); 6,44 (1H, singlet); 7,01 7,05 (1H, multiplet); 7,22 was 7.45 (3H, multiplet).

Example 123. 4-Chloro-5-(m-hydroxy)phenyl-3-(3-hinkleyville)isoxazol.

NMR (CDCl3)d ppm: 2,40 1,51 (5H, multiplet), 2,83 3,44 (6H, multiplet); 4,87 of 4.90 (1H, multiplet); 6,91 6,94 (1H, multiplet); 7,30 of 7.48 (3H, multiplet).

Example 124. 4-Chloro-5-(m-hydroxy)phenyl-3-(3-hinkleyville)isoxazol hydrochloride.

So pl. 246-250oC(Razlog).

NMR (D2O) d ppm: 1,93-2,69 (5H, multiplet); 3,32 of 3.85 (6H, multiplet); 5,10 5,07 (1H, multiplet); 7,03 was 7.08 (1H, multiplet); 7,37 7,52 (3H, multiplet).

Form 1.

Capsules mg:

Hydrochloride 5-chloro-3-/1-methyl-4-piperidinyloxy/-1,2-benzisoxazole 10,0

Lactose of 153.6 mg

Corn starch 100,0

Magnesium stearate 2,4

Just 280,0 mg.

Powders of the above compounds were mixed and passed through a sieve of 60 mesh /0,34 mm, standard Tyler/, and 280 mg of the resulting powder was Packed in a gelatin capsule No. 3.

Form 2.

The powders. The powder obtained in accordance with the description for the form 1, extruded, to obtain tablets each of apsule, mg:

Hydrochloride 3-/3-inulinase/isoxazol 10,0

Lactose 153,6

Corn starch 100,0

Magnesium stearate 1,4

Just 280,0 mg.

Powders of the above compounds were mixed and passed through a sieve of 60 mesh /0,34 mm, standard Tyler/ and 280 mg of the resulting powder was Packed in a gelatin capsule No. 3.

Form 4.

The powders. The powder obtained in accordance with the description for the form 3, extruded, to obtain tablets each containing 120 mg, using a well known tool for the manufacture of tablets.

Experiment 1.

Test for binding to muscarinic receptors.

The membrane fraction obtained from cerebral cortex of rats, was added to the test compound together with3H-oxotremorine-M to a final concentration of 3 nm/ mixture and gave the opportunity to interact with the 30oC for 60 minutes At the end of this time the mixture was filtered through filter paper. 3H-radioactivity associated with the membrane, which remains on the filter paper was determined using a liquid scintillation counter.

As the compound which binds to muscarinic receptorgamma compounds will be characterized less radioactivity in the membrane, remaining on the filter paper. The concentration of the compounds to be tested, which reduces 3H-radioactivity by 50% /lC50/, is taken as an indicator of the ability to link with masarykovy receptor test compounds; the figures obtained are given in table. 5.

Test for selective binding with M1- receptors.

The membrane fraction obtained from cerebral cortex of rats /where M1receptors are abundant/ added to test the connection with H-pirenzepinom to a final concentration of 1 nm/ mixture and gave the opportunity to interact at a temperature of 30oC for 60 minutes Meanwhile membrane fraction obtained from rat heart /where M2- receptors are the predominant/ added to test the connection with H-hinokitiol benzilate /which connects selectivity with M1and M2receptors, to a final concentration of 0.12 nm/, and the mixture was allowed to interact at a temperature of 30oC for 120 minutes In each case at the end of the reaction period, the preparation was filtered and the radioactivity remaining on the filter paper was determined using plants listed in the table. 5 the following symbols:

A1: Chlorhydric 5-chloro-3-/1-methyl-4-piperidinyloxy/-1,2-benzisoxazole /connection of the invention, obtained as described in example 12/;

B1: oxotremorine known M1agonist, which has the formula:

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B2: RS-86, which has the formula:

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B3: AF 102-B, which has the formula:

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B4: Arecoline, which has the formula:

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Table-oxo-M marks3H-oxotremorine, Pirenzp indicates3H-pirenzepine and QNB indicates3H-hinokitiol benzilate.

Experiment 2.

Antiresorptive action.

It seems that the sedative effect caused by the use of reserpine or tetrabenazine to mice or rats, similar in terms of symptoms of clinical depression. From various pharmacological effects caused by these compounds, ptosis (drooping upper eyelid) and the temperature reduction is most widely used as indicators of their activity, and it was found that any compound which inhibits or ptosis, or reduction of body temperature, is also active against symptoms of clinical depression. Thus, antiresorptive or antityrosinase effects widely and spymania, used to assess compounds that are the subject of the invention is antagonistic effects of the test compounds against reserpine-induced ptosis in mice.

Used in the test animals were adult male mouse family ddy at the age of 4 weeks and each weighing 22 to 27, the Animals were divided into groups, each of which consisted of 3 mice. The test compound was dissolved or suspended in an appropriate solvent /or physiological solution, or 0.5% CMC /carboxymethyl cellulose/ solution/ and used tematicheskim way the mice of the test group at the dose indicated in the table. 6. Mice from the control group was given only the solvent without any active connection, which was introduced in the same way. Immediately after applying the subcutaneous way each mouse was injected with 2 mg/kg of reserpine. After 90 min was determined as the lid is closed /the degree of ptosis/, for this purpose, mice were removed from their cages and observed the shape of the eye. Results of the "normal" mice, i.e. without ptosis and, therefore, with the normal round eye, evaluated 0 while mice that have been ptosis in the field 1/3 1/2, was evaluated 1, mice that have been ptosis 2/3 is presented in table. 6 7.

The labels on the vials containing solutions of samples to be tested, all had the form of ciphers, which were not known responsible for the application, and the application was carried out in random order, so that "evaluators did not know which treatment was applied and what the mouse. The obtained estimates of the degree of inhibition for each level of the dose was calculated from the following equation:

The degree of inhibition /%/

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In evaluating the degree of inhibition is not less than 71% from 41 to 70% and not more than 40% was considered as /+/, /+/ and/ -/, respectively.

Used in the test compounds were identified by the following codes:

A2: Hydrochloride 4-chloro-5-methyl-3-/3-hinkleyville/isoxazol /obtained according to example 3/;

A3: Hydrochloride 3-/3-hinkleyville/isoxazol /obtained in example 4/;

A4: Hydrochloride 5-methyl-3-/3-hinkleyville/isoxazol /obtained in example 19/.

Experiment 3.

Inhibition of the increase in blood viscosity caused by cerebral ischemia.

Used in the performance of the animals were adult male mouse family Wistar. Each mouse was injected tematicheskim way or solution of the hydrochloride of 3-/3-hinkleyville/isoxa is in order intraperitoneal anesthesia method was administered 40 mg/kg pentobarbital. The rat was fixed in a supine position and from the jugular vein on one side took blood samples at 0.6 ml Viscosity of each sample was measured using a viscometer /Borgersen, trade name of product manufactured by Dio birth the cakes/ when the value of the Slice of 37.5/75/150/375/C. on the other hand, took blood samples of 0.5 ml and the viscosity was measured using the same procedure.

After you have taken the first two samples, the carotid artery on both sides of each animal was Legerova. One hour after the ligation in the case of the control animals which were administered only the media/ the values of blood viscosity increases by 5 to 20% for each value of the cut /slower speed slice corresponds to a higher viscosity/. However, in the case of animals, which were injected compound which is the subject of the invention, this increase was significantly ingibirovalo for each speed slice.

Thus, the compounds have the ability to improve blood viscosity and can, therefore, improve microcirculation in the event of a collision.

Experiment 4.

Study of the binding of 5-HT3-receptor.

The membrane fraction obtained from cerebral cortex of rats, incubated with ISPreceptors/ at a temperature of 37oC for 45 minutes At the end of this time the samples were filtered.3H-radioactivity associated with the filter paper was determined using a scintillation counter, as described in experiment 1. Nonspecific binding was determined using ondansetron /10-5M/. The results are shown in table. 8, from which it can be seen that the compounds of the invention are associated with 5-HT3receptors as strongly as ondansetron.

Used in the connection test is indicated by the following figures:

A5: Hydrochloride 4-chloro-3-/3-hinkleyville/-5-phenylisoxazole /obtained in example 10/.

A6: 5-Chloro-3-/3-hinkleyville/-1,2-benzisoxazol /compound obtained in example 85/.

A7: Hydrochloride 5-/para-chlorophenyl/-3-/3-sinocleansky/isoxazol /hydrochloride of the compound obtained in example 28/.

A8: Hydrochloride 4-chloro-5-phenyl-3-/3-piperidinyloxy/isoxazol /obtained in example 106/.

A9: Hydrochloride 3-/3-hinkleyville/-5-/2-thienyl/isoxazol /obtained in example 107/;

B5: Ondansetron.

Experiment 5.

Ileum extracted from Guinea pig was placed in a Cup Reelecting 5-HT3antagonist, 2-methyl-5-HT was determined using an isometric transducer. Then the test compound was added to the bath and power cuts again measured 30 min after addition. To calculate the speed of the inhibiting force of contraction. The results are shown in table. 9, which shows that the compound of the invention, hydrochloride 4-chloro-3-/3-hinkleyville/-5-phenylisoxazole /connection AS/ such as strong antagonist, and ondansetron.

Experiment 6.

Acute toxicity.

Each of the compounds of examples 3 and 4 suspended in 0.5% CMC solution and the suspension was applied to mice in an amount sufficient to provide a dose of the active compound in 75 mg/kg Mice were observed for 5 days, during which there are no one-the death of the animal, and none of the mice showed no symptoms.

1. Piperidinyloxy or hinkleyville-isoxazoline derivatives of the formula I

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where R1hydrogen, halogen or an alkyl group having 1 to 4 carbon atoms;

R2hydrogen, an alkyl group having 1 to 4 carbon atoms, phenyl group which is unsubstituted or substituted by at least one of substituents (a), aprtt or sulphur, moreover, the specified heterocyclic group is unsubstituted or substituted by at least one of substituents (a) defined below, or R1and R2together form a group of the formula-CR4=CR5-CR6=CR7- where R4, R5, R6and R7are the same or different and each is hydrogen, halogen, an alkyl group having 1 to 4 carbon atoms or alkoxygroup having 1 to 4 carbon atoms; R3piperideine group, substituted piperideine group in which the nitrogen atom is substituted by an alkyl group having 1 to 6 carbon atoms, or hinkleyville group, where the substituents (a) are: halogen atoms, alkoxygroup having 1 to 4 carbon atoms or hydroxy-group, or their pharmaceutically acceptable salts.

2. The composition having the property to reduce violations cognitive abilities, characterized in that as the active ingredient contains an effective amount of at least one compound of formula I or its salts under item 1 in a mixture with a pharmaceutically acceptable carrier or diluent.

Priority signs:

11.05.90 R1and R2together form a group of the formula-CR4=CR5-CR6

17.08.90 R1a hydrogen atom, a halogen atom or an alkyl group containing 1 to 6 atoms operad, Deputy R2a hydrogen atom, a C1-C4is an alkyl group or a substituted or unsubstituted phenyl and the substituent R3piperideine group or substituted piperideine group in which the nitrogen atom is substituted by an alkyl group containing 1 to 6 carbon atoms or genocidally group.

08.05.91 R2heterocyclic group containing 5 or 6 atoms, of which 1 atom of nitrogen or sulfur.

 

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where a group

< / BR>
where m and n are independent of each other represent 1 or 2,

Q group of formulae

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Q' группаNR, where R denotes hydrogen or alkyl with 1 to 4 carbon atoms, unsubstituted or substituted with halogen or hydroxyl, or a group NRR', where R' is alkyl with 1 to 4 carbon atoms, or R and R' together form alkylene with 4 to 6 carbon atoms, and in the case of the fourth connection to the positive charge of the nitrogen atom is the equivalent of the anion (X),,

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Rahydrogen, fluorine, chlorine or methyl, provided that when a represents 3-tropanol, R1hydroxyl and R
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