RU2079496C1 - Piperidylhydroxy- or quinuclidinylhydroxy-isoxazole derivatives or their pharmaceutically acceptable salts, composition decreasing cognitive function disorders - Google Patents

Abstract

FIELD: chemistry of heterocyclic compounds. SUBSTANCE: product: piperidylhydroxy - or quinuclidinylhydroxy-isoxazole derivatives of the formula (I)

Description

 The invention relates to a series of new piperidyl-hydroxyisoxazole and quinuclidinyloxyisoxazole derivatives, which can be used in the treatment and prevention of various disorders, especially senile dementia / including Alzheimer's disease /. In accordance with the invention also provides methods and compositions using these compounds, as well as methods for their preparation.

 In recent years, the number of elderly people in the population has increased significantly and therefore the number of diseases and disorders associated with old age is increasing, especially for senile dementia, including Alzheimer's disease. Senile dementia is a serious and growing problem in the modern world, which can cause discomfort and severe malaise not only for those who suffer, but also for relatives and those who are responsible for them, so considerable efforts have been directed towards alleviating or improving the situation these people. In particular, Alzheimer's disease, in which senile dementia affects a patient prematurely, is a cause of severe malaise. Due to the fact that the causes of senile dementia and Alzheimer's disease are currently unknown, their treatment is difficult and, in general, should only be a profile of symptoms.

 It is known that a characteristic characteristic of patients suffering from senile dementia is a decrease in cerebral microcirculation and a decrease in silver metabolism, which together lead to cognitive dysfunction. In addition, the early stages of senile dementia are generally accompanied by depression, and the weakening of this depression could lead to an improvement in the patient's quality of life.

Acetylcholine is a chemical transmitter with a wide range of activities in the body, and a violation in its production and / or activity has been shown to lead to various disorders. It has been found that in patients with senile dementia, including Alzheimer's disease, the biosynthesis of acetylcholine in the brain is impaired, but even in such patients, the receptors for acetylcholine in the brain can be much less suppressed and they can still function satisfactorily. The receptors for acetylcholine located at the presynaptic terminals in the brain are M ₂ receptors, while the receptors located on the post-synaptic membranes in the brain are M ₁ and M ₃ receptors. M ₂ receptors are abundant in pre- and post-synapses of the heart, while many M ₁ 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 M ₁ receptors could be stimulated during the early stages of dementia, then the symptoms of dementia could be improved, and further deterioration could be prevented. On the other hand, it was desirable that any agent designed to stimulate the M ₁ receptors could not stimulate the M ₂ receptors, since the M ₂ receptors inhibit the release of acetylcholine, and so that they can minimize the side effects caused by stimulation of cardiac activity.

Currently, the applicant has developed a series of new piperidyloxyisoxazole and quinuclidinyloxyisoxazole derivatives, which have been found to bind selectively to M ₁ receptors, while binding to a much lesser extent to M _2c receptors, and which, as mentioned above, are of value in the treatment and prevention of senile dementia, including Alzheimer's disease.

Surprisingly, it has been found by the applicant that the compounds of the present invention also bind to 5-HT ₃ receptors and, thus, affect 5-HT ₃ activity. Since 5-HT ₃ antagonists are known to have anxiety suppressing, anti-depressant and antipsychotic activities, it can be expected that the compounds of the present invention are of value for a wider treatment of patients with consciousness disorders, in particular those with feelings anxiety, depression and psychosis.

в которой символы R каждый представляет различные группы и атомы, а символы R' могут представлять различные органические группы или вместе с атомом азота, к которому они присоединены, могут представлять гетероциклическую группу, включая пиперидиловую группу. Эти известные соединения отличаются от соединений настоящего изобретения тем, что пиперидиловая группа, представляемая при помощи NR'R' обязательна присоединена к остатку молекулы через атом азота и, это наиболее важно, присутствием в известных соединениях группы формулы:

которые до настоящего времени рассматривались как обладающие по существу целевой активностью и которые полностью отсутствуют в соединениях настоящего изобретения.Several isoxazole derivatives were previously proposed by the present applicant and other colleagues for use in the treatment and prevention of a wide variety of diseases and disorders, including cerebrovascular diseases that act through the central nervous system as muscle relaxants and as antidepressants. They are described, for example, in simultaneously filed US patent application N 07/620 842, November 30, 1990, US patent application N 07/537 517, filed June 13, 1990 and US patent application N 07/585 828, filed September 20 1990. Of these, the compounds closest in structure are proposed in US Patent Application No. 07/620 843, in which they are proposed. Among others, compounds of the formula:

in which the R symbols each represent different groups and atoms, and the R 'symbols may represent different organic groups or together with the nitrogen atom to which they are attached may represent a heterocyclic group, including a piperidyl group. These known compounds differ from the compounds of the present invention in that the piperidyl group represented by NR'R 'is bound to the remainder of the molecule via a nitrogen atom and, most importantly, by the presence in the known compounds of a group of the formula:

which to date have been considered as having substantially targeted activity and which are completely absent in the compounds of the present invention.

 A brief description of the invention.

 The purpose of the invention is to offer a series of new compounds that can be valuable in the treatment and prevention of senile dementia, including Alzheimer's disease.

 Another objective of the present invention is to provide compounds, some of which are more widely used in the treatment and prevention of disorders of consciousness.

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

в которой R¹ представляет атом водорода, атом галогена или алкильную группу, содержащую от 1 до 4 атомов углерода;
R² представляет атом водорода, алкильную группу, содержащую от 1 до 4 атомов углерода, фенольную группу, которая является незамещенной или которая замещена, по крайней мере, одним из заместителей /а/, определенных ниже, или гетероциклическую группу, которая содержит 5 или 6 атомов в цикле, из которых один является атомом азота или серы, причем вышеупомянутая гетероциклическая группа незамещена или замещена, по крайней мере, одним из заместителей /а/, определенных ниже, или
R¹ и R² вместе образуют группу формулы
CR⁴=CR⁵-CR⁶=CR⁷ -,
в которой R⁴, R⁵, R⁶ и R⁷, независимо друг от друга выбирают из группы, состоящей из атомов водорода, атомов галогенов, алкильных групп, содержащих от 1 до 4 атомов углерода или алкоксигрупп, содержащих от 1 до 4 атомов углерода,
R³ представляет пиперидильную группу, замещенную пиперидильную группу, в которой атом азота замещен алкильной группой, содержащей от 1 до 6 атомов углерода, или хинуклидиниловую группу;
заместители /а/,
атомы галогенов: алкокси группы, содержащие от 1 до 4 атомов углерода, и гидрокси группы, и приемлемыми с фармацевтической точки зрения их солями.The compounds of the present invention are compounds of formula I:

in which R ¹ represents a hydrogen atom, a halogen atom or an alkyl group containing from 1 to 4 carbon atoms;
R ² represents a hydrogen atom, an alkyl group containing from 1 to 4 carbon atoms, a phenolic group which is unsubstituted or which is substituted by at least one of the substituents / a / as defined below, or a heterocyclic group which contains 5 or 6 atoms in the cycle, of which one is a nitrogen or sulfur atom, the aforementioned heterocyclic group being unsubstituted or substituted by at least one of the substituents / a / as defined below, or
R ¹ and R ² together form a group of the formula
CR ⁴ = CR ⁵ -CR ⁶ = CR ⁷ -,
in which R ⁴ , R ⁵ , R ⁶ and R ⁷ are independently selected from the group consisting of hydrogen atoms, halogen atoms, alkyl groups containing from 1 to 4 carbon atoms or alkoxy groups containing from 1 to 4 carbon atoms ,
R ³ represents a piperidyl group, a substituted piperidyl group in which the nitrogen atom is substituted by an alkyl group containing from 1 to 6 carbon atoms, or a quinuclidinyl group;
substituents / a /,
halogen atoms: alkoxy groups containing from 1 to 4 carbon atoms, and hydroxy groups, and pharmaceutically acceptable salts thereof.

 In addition, in accordance with the invention, there is provided a pharmaceutical composition having the properties of reducing cognitive impairment for the treatment and prevention of consciousness disorders, comprising an effective amount of at least one active compound in admixture with a pharmaceutically acceptable carrier or diluent, the active the compound is 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 R ¹ represents a halogen atom, it may be a fluorine, chlorine, bromine or iodine atom, preferably a fluorine, chlorine or bromine atom.

In those cases where R ¹ and / or R ² represents an alkyl group containing from 1 to 4 carbon atoms, it may be a linear or branched chain group containing from 1 to 4 atoms, and examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl and isohexyl groups. Of these, alkyl groups containing from 1 to 4 carbon atoms are preferred, preferably methyl, ethyl, propyl, isopropyl, butyl and isobutyl groups, and in the most preferred embodiment, a methyl group.

When R ² represents a phenyl group, such a group can be either substituted or unsubstituted groups. Substituted groups may be substituted with one or more substituents (a) as defined above and examples of which are given below. If this group is replaced, then there are no restrictions on the number of substituents except those that may be imposed by the number of substituted positions, and steric restrictions may need to be taken into account, for example, a maximum of 5 substituents for the phenyl group. However, in the General case, preferably from 1 to 3 substituents. Examples of such substituents include:
halogen atoms such as fluorine, chlorine, bromine and iodine atoms;
alkoxy groups containing from 1 to 4, and in a preferred embodiment 1 or 2, carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy groups, in a preferred embodiment, a methoxy group; and hydroxy groups.

If R ² represents a heterocyclic group, it has 5 or 6 ring atoms. Of these atoms, one is a hetero atom selected from the group consisting of hetero atoms of nitrogen or sulfur.

 Such groups may be unsubstituted or they may be substituted by at least one (preferably 1 to 3) substituent / a /, which are defined together with the examples above. Examples of such unsubstituted groups include furyl, thienyl, pyrrolyl, pyridyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl, piperidonyl, pyridonyl and 2H-pyrrolyl. Such groups may be unsubstituted or they may have at least one substituent selected from the group consisting of substituents (a) as defined above and examples of which have already been given.

Alternatively, R ¹ and R ² may form a group of the formula —CR ⁴ CR ⁵ —CR ⁶ CR ⁷ in which R ⁴ , R ⁵ , R ⁶ and R ⁷ have already been defined above, i.e. they form an optionally substituted benzene ring fused to the isoxazole system.

If R ⁴ , R ⁵ , R ⁶ or R ⁷ represent a halogen atom, an alkyl group containing from 1 to 4 carbon atoms, an alkoxy group containing from 1 to 4 carbon atoms. They can be groups, examples of which are given above in connection with similar groups that were included in the substituents / a /.

R ³ may represent a substituted or unsubstituted piperidyl group or an unsubstituted quinuclidinyl group, which is preferably attached to the isoxazolyloxy group through a carbon atom. In the case of a substituted piperidyl group, the substituents are selected from the group consisting of alkyl groups containing from 1 to 6, preferably from 1 to 4, carbon atoms, such as those described above in connection with R ¹ and R ² .

Preferred classes of compounds of the present invention include those compounds of formula / I / and their salts, in which:
A / R ¹ represents a hydrogen atom, a halogen atom or an alkyl group containing from 1 to 3 carbon atoms.

B / R ² represents a hydrogen atom, an alkyl group containing from 1 to 3 carbon atoms, a phenyl group which may be unsubstituted or substituted by at least one of the substituents / a '/ as defined below, or a heterocyclic group which contains 5 or 6 ring atoms, one of which is nitrogen or sulfur, wherein the aforementioned group is unsubstituted or substituted by at least one of the substituents / a '/ as defined below;
substituents / a '/:
halogen atoms, alkoxy groups containing from 1 to 4 carbon atoms, and hydroxy groups.

/ C / R ¹ and R ³ together form a group of the formula:
-CR ⁴ CR ⁵ CR ⁶ CR ⁷
in which R ⁴ , R ⁵ , R ⁶ and R ^{7 are} independently selected from the group consisting of hydrogen atoms, halogen atoms, alkyl groups containing from 1 to 3 carbon atoms and alkoxy groups containing from 1 to 3 carbon atoms;
/ D / R ³ represents a piperidyl group, a substituted piperidyl group in which the nitrogen atom is substituted by an alkyl group containing from 1 to 6 carbon atoms, or a quinuclidinyl group.

Of these, those compounds of formula (I) and their salts are preferred in which R ¹ and R ² have already been defined in / A / and / B /, or c / C /, and R ³ has already been defined in / D / above .

More preferred classes of the compounds of the invention include those compounds of formula (I) and their salts, in which:
/ E / R ¹ represents a hydrogen atom or a halogen atom.

/ F / R ² represents a hydrogen atom, a phenyl group which is unsubstituted or which is substituted by at least one of the substituents / a '' /, defined below, or a heterocyclic group which contains 5 or 6 ring atoms, one of which is nitrogen or sulfur, wherein the aforementioned heterocyclic group may be unsubstituted or substituted with at least one substituent from / a ″ /, as defined below;
substituents / a '' /:
halogen atoms, alkoxy groups containing from 1 to 4 carbon atoms, and hydroxy groups.

/ G / R ¹ and R ² together form a group of the formula
-CR ⁴ CR ⁵ -CR ⁶ CR ⁷ ,
in which R ⁴ , R ⁵ , R ⁶ and R ^{7 are} independently selected from the group consisting of hydrogen atoms and halogen atoms.

/ H / R ³ represents a substituted piperidyl group in which the nitrogen atom is substituted by an alkyl group containing from 1 to 6 carbon atoms, or a quinuclidinyl group.

Of these, those compounds of formula (I) and their salts are preferred in which R ¹ and R ² have already been defined in / E / and / F / or in / G /, and R ³ has already been defined in / H / above.

где Z представляет:

обозначенных соответственно, как "п", "м" и "о"/, Z¹ представляет:

/обозначенных, соответственно, как "п" "м" /, a "Quin" представляет хинуклидиниловую группу.Examples of some compounds of the invention are represented by the following formulas / I-1 / - / I-4 /, in which the symbols used in these formulas are defined in table. 1-4, i.e., table. 1 relates to the formula / I-1 /, table. 2 refers to the formula / I-2 /, etc. In the table. 1, where the benzyloxazolyloxy group can be attached to 2-3 or 4 positions of the piperidine ring, this is indicated by o-, m- or p, respectively, so that, for example, the 2-isomer. 3-isomer to 18m, etc. A similar agreement is used in table. 3. The following abbreviations are used in the tables:
Bu butyl
iBu has invented
sBu-second-butyl
tBu tert-butyl
Et ethyl
Fur furry
Hx hexyl
Me methyl
Ph phenyl
Ph peptide
Pr cut
iPr isopropyl
Pyr pyridyl
Thi-thienyl

where Z represents:

designated respectively as "n", "m" and "o" /, Z ¹ represents:

/ designated, respectively, as "n""m" /, and "Quin" represents a quinuclidinyl 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 compounds N 1-2, 2-1, 2-2, 2-10, 2-20, 2 are more preferred. -21, 2-97, 2-98, 2-99, 2-100 and 2-107. Most preferred are Compounds N:
2-1. 3- / 3-quinuclidinyloxy / isoxazole, including the R - / + / - 3- / 3-quinuclidinyloxy / isoxazole and S - / - / - 3 / -3-quinuclidyloxy / isoxazole isomers;
2-20. 4-chloro-3- / 3-quinuclidinyl-oxy / isoxazole;
2-107. 4-chloro-3- / 3-quinuclinyloxy / -5-phenyloxazole; and their pharmaceutically acceptable salts, in particular hydrochlorides.

Y-R³
/в приведенных формулах R¹, R² и R³ уже были определены выше, а X и Y представляют дополнительные замещаемые группы/ при условиях, обеспечивающих конденсацию.Compounds of the invention can be prepared using a wide variety of methods well known in the preparation of compounds of this type. For example, in the General case, they can be obtained by condensation of the compounds of formula / II /:

Yr ³
/ in the above formulas, R ¹ , R ² and R ³ have already been defined above, and X and Y represent additional substituted groups / under conditions providing condensation.

 For example, X may represent a halogen atom (for example, a chlorine, bromine or iodine atom), and Y may represent an oxy group 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 both may represent an oxy group, in which case the reaction is carried out in the presence of a dehydrating agent. Then the compound can be, if necessary, converted into a salt to obtain its salt.

в которой R¹ и R² уже были определены выше /с соединением формулы V:
R³ OH
в которой R³ уже был определен выше/ в присутствии дегидратирующего агента, чтобы получить соединение формулы /I/, а затем, если это необходимо, превращение в соль полученного в результате соединения формулы /I/.In more detail, one preferred method for preparing the compounds of the present invention comprises reacting a compound of formula / IV /:

in which R ¹ and R ² have already been defined above / with a compound of formula V:
R ³ OH
in which R ³ has already been defined above / in the presence of a dehydrating agent to obtain a compound of formula / I /, and then, if necessary, conversion to a salt of the resulting compound of formula / I /.

в которой R² представляет фенильную группу, а Et представляет этильную группу.There is no particular restriction on the nature of the dehydrating agent used in this reaction, and any compound capable of participating in the condensation reaction can be used to remove elements of water, as is well known in the art, provided that it does not - any adverse effects on reagents. A particularly preferred dehydrating agent that can be used in the present reaction is a compound which is obtained by reacting diethyl azodicarboxylate with triphenylphosphine, namely

in which R ² represents a phenyl group, and Et represents an ethyl group.

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

 In particular, the reaction is preferably carried out in the presence of an organic solvent. There is no particular restriction on the nature of the solvent to be used, provided that it does not adversely affect the reaction or reagents, and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: aromatic hydrocarbons such as benzene or toluene; ethers such as dioxane or tertrahydrofuran; nitrides such as acetonitrile; ketones such as acetone or methyl ethyl ketone; amides, in particular fatty acid amides such as dimethylformamide or dimethylacetamide; and sulfoxides such as dimethyl sulfoxide.

 There are no particular restrictions on the molar ratio of the two reagents, and approximately equal amounts or a slight excess of the compound of formula / V / are preferably used.

This reaction can take place over a wide temperature range and the precise reaction temperature is not critical to the present invention. In the General case, it was found that it is preferable to carry out the reaction at a temperature of from -20 ^o C to +50 ^o C and in practice preferred and most preferred room temperature. The time required for the reaction can also vary widely, depending on many factors, especially the reaction temperature and the nature of the reagents. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 5 to 48 hours will generally suffice; in general, a period of about 24 hours will be suitable.

 The product of this reaction can be separated from the reaction mixture by known means. For example, one such extraction procedure comprises extracting the mixture using a suitable organic solvent, such as ethyl acetate, removing the solvent from the extract, generally by evaporation, and then, if necessary, the product is subjected to a subsequent purification step, for example, using recrystallization or one of chromatographic techniques such as column chromatography or preparative thin layer chromatography.

а другой из R^a и R^b представляет группу R³, как она определена выше. Предпочтительная реакция содержит взаимодействие соединения формулы /1X/:

в которой R¹, R² и x /уже были определены выше/ с оксисоединением формулы /X/:
HO-R³
или с соответствующим соединением металла формулы /Xa/.An alternative preferred method for preparing the compounds of the present invention, and in particular those in which R ¹ has already been defined above and R ² represents a possibly substituted phenyl group or heterocyclic group, comprises reacting a halogen or sulfo derivative or isoxazole compound or piperidyl or quinuclidinyl compound formulas / VI /:
R ³ X '/ VI /
with an oxy compound of the formula / YII /:
R ^B- OH / VII /
or with the corresponding metal compound of the formula / YIIa /:
R ^B -OM
in which X 'represents a halogen atom or a sulfo group; M represents a metal atom, in a preferred embodiment, an alkali metal atom and in the most preferred embodiment, a sodium or potassium atom; and one of R ^a and R ^b represents a group of formula / VIII /:

and the other of R ^a and R ^b represents a group R ³ as defined above. A preferred reaction comprises reacting a compound of formula / 1X /:

in which R ¹ , R ² and x / have already been defined above / with an oxy compound of the formula / X /:
HO-R ³
or with the corresponding metal compound of the formula / Xa /.

Mo-R ^a
/ in which M and R ³ have already been defined above /. In this reaction, [X] is preferably a halogen atom, and most preferably a chlorine atom.

 There are no particular restrictions on the molar ratio of these two reagents, although, since the reaction requires equal amounts of each reagent, approximately molar equality is preferred. However, a molar excess of one of the components is possible, although since any such excess is discarded, the excess is preferably minimized.

 The reaction is generally and preferably carried out in the presence of a non-aqueous solvent. There is no particular restriction on the nature of the solvent used, provided that it does not adversely affect the reaction or the reagents and that it can dissolve the reagents, at least to some extent.

 Examples of suitable solvents include: halogenated aliphatic hydrocarbons such as methylene chloride, 1, 2-dichloroethane, chloroform and carbon tetrachloride, ethers such as diethyl ether, dibutyl ether, diisobutyl 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 hexamethylsulfonamide; and mixtures of any two or more of these solvents.

The reaction can take place over a wide temperature range and the precise reaction temperature is not critical to the invention. In the General case, it was found that it is preferable to carry out the reaction at a temperature in the range from 0 ^o C to 100 ^o C, and in the implementation of the range from 0 to 50 ^o C is more preferable. The time required for the reaction can also vary widely, depending on numerous factors, especially the reaction temperature and the nature of the reagents. However, provided that the reaction is effected under the preferred conditions outlined above, a time of from 1 to 48 hours is generally sufficient, and in the case of from 1 to 20 hours is preferred.

 After completion of the reaction, the target compound can be separated from the reaction mixture using any suitable recovery procedure. For example, one such procedure comprises: the reaction mixture is poured into a mixture of ice-water; the mixture is extracted with a 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 a subsequent purification step, for example, by recrystallization or using one of the chromatographic techniques such as a chromatographic column or preparative thin layer chromatography.

 A compound of formula (1X), which is used as one of the starting materials, can be obtained, for example, as described in Chem. Ber. T. 100, pp. 3326-3330 / 1967 / or using similar known methods.

 The compounds of the invention may exist in the form of various optical isomers and diastereomers due to the existence of asymmetric carbon atoms in the molecule. Optical isomers can be resolved using known optical resolution techniques to provide optically active compounds. The present invention includes both individual isomers and mixtures (for example, racemic mixtures), whether they are obtained as a result of a synthesis reaction, or by bias. If individual isomers are required, they can be obtained from mixtures using known means, or they can be obtained using stereospecific methods of synthesis, which are well known to any person skilled in the art.

Salts of the compounds of formula (I) can be obtained using known methods of salt formation. For example, a compound of formula (I) is dissolved in a suitable, preferably non-aqueous, solvent, and then the necessary acid is added, optionally also dissolved in the solvent. The salt is generally precipitated / and the solvent or solvents are preferably chosen so that it does / and it can be removed by filtration or using similar techniques. There is no particular restriction on the nature of the solvent used, provided that it does not adversely affect the reaction or the reagents, and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include alcohols such as methanol or ethanol; ethers such as diethyl ether or tetrahydrofuran; and aromatic hydrocarbons such as benzene or toluene. There are no restrictions on the molar ratios of the compound of formula (I) to acid, but approximately equal parts or a slight excess of acid are preferred, for example, from 1 to 1.2 equivalents of acid per equivalent of the compound of formula / I /. The reaction takes place over a wide temperature range, and the exact value of the reaction temperature is not critical to the present invention. In the General case, it was found that it is preferable to carry out the reaction at a temperature in the range from -5 ^o C to 30 ^o C.

 The nature of the acid will, of course, depend on the salt that is preferred, but examples of suitable acids include: salts with mineral acids, especially hydrohalic acids (such as hydrofluoric acid, hydrobromic acid, hydroiodic acid or hydrochloric acid), nitric acid, carbonic acid sulfuric acid or phosphoric acid; salts with lower alkyl / mono / sulfonic acids such as methane / mono / sulfonic acid, trifluoromethane / mono / sulfonic acid or ethane / mono / sulfonic acid; salts with aryl / mono / sulfonic acids such as benzene / mono / sulfonic acid or para-toluene / mono / sulfonic acid; salts with organic carboxylic acids such as acetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid or citric acid; and salts with amino acids such as glutamic acid or aspartic acid.

 After separation, the salt may, if necessary, be purified by recrystallization from an appropriate solvent, for example an alcohol such as ethanol.

 Biological activity.

As experimentally confirmed below, the compounds of the present invention bind very specifically to muscarinic receptors, which are distributed in the brain among receptors for acetylcholine, which is a non-transmitter; in particular, they prefer to bind to the muscarinic 1 / M ₁ / receptors that are located on the postsynaptic membrane. In addition, they have antireserpine activity without antihistamine activity, which is essential for use as an antidepressant. In addition, they have antagonistic activity against 5-HT ₃ receptors. Since 5-HT ₃ antagonists are well known to have antiphobic and antipsychotic activities, it can be expected that the compounds of the present invention may be useful in treating the corresponding symptoms of patients with impaired consciousness. As a result of this property, the compounds of the present invention can be expected to be useful in the treatment and prevention of dementia such as Alzheimer's, senile dementia and Huntington’s chorea, which are apparently caused by disruption of the acetylcholine biosynthesis pathways, with minor side effects on the heart and digestive tract.

In addition, since 5-HT ₃ antagonists are known to be useful as antiemetics, and M ₁ antagonists are known to have non-narcotic analgesic activity on the central nervous system, it can be expected that the compounds of the present invention also useful as antiemetic agents and acting on the central nervous system, non-narcotic painkillers.

 It was also found that the compounds of the present invention have a beneficial effect on ischemia-induced increased blood viscosity, and this activity can also be expected to increase cerebral microcirculation in patients with impaired consciousness, which also improves the aforementioned symptoms.

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

 The compounds of the present invention can be used in the treatment and prophylaxis of disorders such as those mentioned above, and for this purpose can be used to prepare known pharmaceutical forms that are well known to those skilled in the art. Thus, the compounds can be applied orally, for example, in the form of tablets, capsules, granules, powders, syrups or other well-known forms, or parenterally, for example by injection, suppository, etc.

 Such pharmaceutical compositions can be obtained using known means and they can contain known additives that are generally used in this field, for example, carriers, binding agents, disintegrants, lubricants, “correction” agents, etc. depending on the upcoming use in the form of a preparation. The dose will depend on the condition, age and body weight of the patient, as well as on the type and extent of the disorder to be treated, but in the case of oral administration to an adult human patient, in general, the total daily dose should be from 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.

 The preparation of the present invention using the above compounds is further illustrated by the following examples, and the compositions of these compounds in the form of pharmaceutically acceptable doses are illustrated by the following forms. The biological activities of the compounds are then illustrated by subsequent experiments.

 Example 1. 4-chloro-5-methyl-3- / 3-quinuclidinyl-oxy / isoxazole.

A solution of 7.86 g of triphenylphosphine in 100 ml of tetrahydrofuran was cooled to 5 ^° C., then 5.22 g of diethyl azodicarboxylate was added dropwise to a cooled solution, then 4.00 g of 4-chloro-3-hydroxy-5-methylisoxazole. 3.81 g of 3-hydroxyquinuclidine was then added to the resulting mixture, 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 purified using a silica gel chromatography column using ethyl acetate as eluent to obtain 4.72 g / yield 64.8%). The title compound is a colorless powder, melting point 37-38 ^° C.

Infrared Absorption Spectrum / KBr / ν _max cm ^-1 : 1632, 1520, 1455.

Nuclear Magnetic Resonance Spectrum / CDCl ₃ / δ ppm: 1.34-2.00 / 4H, multiplet /, 2.25-2.39 / 1H, multiplet /, 2.33 / 3H, singlet /, 2, 68-3.04 / 5H, multiplet /, 3.26-3.35 / 1H, multiplet /, 4.71-4.78 / 1H, multiplet /.

 Example 2. 3- (3-Quinuclidinyloxy) isoxazole.

A solution of 9.18 g of triphenylphosphine in 100 ml of tetrahydrofuran was cooled to 5 ^° C. 6.10 g of diethyl azodicarboxylate was added dropwise to the cooled solution, after which 2.98 g of 3-hydroxyisoxazole and 4.45 g of 3-hydroxyquinuclidine were added, and the resulting as a result, the mixture was stirred at room temperature for 24 hours. At the end of this period, the solvent was removed by distillation under reduced pressure, and the resulting residue was purified by chromatography through a silica column using ethyl acetate as eluent to obtain 5.18 g / yield 76.6% / of the title compound as a colorless powder with a melting point of 80-81 ^o C.

Infrared Absorption Spectrum / KBr / ν _max cm ^-1 : 1581, 1486, 1465, 1423.

Nuclear Magnetic Resonance Spectrum / CDCl ₃ / δ ppm: 1.27-1.97 / 4H, multiplet /, 2.24-2.30 / 1H, multiplet /, 2.68-3.01 / 5H, multiplet /, 3.27-3.37 / 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. 4-Chloro-5-methyl-3- / 3-quinuclidinyloxy / isoxazole hydrochloride.

A solution of 2.30 g of 4-chloro-5-methyl-3- / 3-quinuclidinyloxy / isoxazole obtained in Example 1 in 30 ml of ethanol was cooled to 5 ^° C. 2.50 ml of 4 hydrogen chloride solution was added dropwise to the solution. in dioxane. The resulting mixture was stirred at the same temperature for 10 minutes. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the solid residue thus obtained was recrystallized from isopropanol to obtain 2.42 g (91.6% yield) of the title compound as a colorless powder having a melting point of 195 -198 ^o C / decomposition /.

Infrared Absorption Spectrum / KBr / ν _max cm ^-1 : 1633, 1521, 1461, 1425.

Nuclear Magnetic Resonance Spectrum (D ₂ O / δ 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-quinucledinylyloxy / isoxazole.

A solution of 1.70 g of 3- / 3-quinuclidinyl-oxy / isoxazole obtained in Example 2 in 20 ml of ethanol was cooled to 5 ^° C. 2.30 ml of 4N was added dropwise to the solution. a solution of hydrogen chloride in dioxane, and 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 obtain 1.83 g (yield 91.0%). The compounds from the title of the example in the form of a colorless powder, the melting point of which was 221-223 ^o C / decomposition /.

Infrared Absorption Spectrum / KBr / ν _max cm ^-1 : 1579, 1475, 1456, 1430.

Nuclear Magnetic Resonance Spectrum (D ₂ O / δ ppm: 1.16-2.35 / 4H, multiplet /, 2.64-2.70 / 1H / multiplet /, 3.28-3.53 / 5H, multiplet /, 3.75-3.84 / 1H, multiplet /, 5.05-5.11 / 1H, multiplet /, 6.24 / 1H, doublet, J = 1.97 Hz /, 8.41 (1H doublet, J = 1.97 Hz /.

 Example 5. R - / + / - 3- / 3-quinuclinyloxy / isoxazole.

 A solution of 62.50 g of 2,3-di-paratoluoyl-L-tartaric acid monohydrate in 200 ml of methanol was added to a solution of 30.00 g of 3- / 3-quinuclidinyloxy / isoxazole obtained as described in Example 2 in 800 ml of methanol , and the resulting mixture was kept overnight at room temperature. The crystals that precipitated were collected by filtration and washed with 300 ml of ethanol to obtain 28.21 g (62.8% yield) of crude crystals of 3- (3-R-quinuclidinyloxy) 2,3-di-paratoluene-L-tartrate isoxazole. The combination of these crude crystals and ethanol wash liquids was used as the starting material for the synthesis described in Example 6.

Meanwhile, the crude crystals were recrystallized three times from methanol to obtain 16.32 g of relatively pure 2,3- di-paratoluene-L-tartrate 3- / 3-R-quinuclidinyl oxy / isoxazole as colorless columnar crystals, melting point 165-166 ^o C / decomposition / having a refractive index [α] $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ -48.7 ^o / c = 1.0, dimethylformamide /.

16.00 g of the tartrate thus obtained were suspended in 200 ml of ethyl acetate, and the resulting solution was cooled to 5 ^° C. 36 ml of 1N was added to the suspension. 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 time period, the aqueous layer was separated and cooled to 5 ^° C. Then, 63 g of sodium carbonate was added thereto, 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 crystallized from diisopropyl ether to obtain 5.10 g / yield 34.0% / of the title compound as colorless columnar crystals, melting point 69 ^° -70 ^° C.

[α] $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ +7.70 / s 1.0, ethanol /.

Infrared Absorption Spectrum / KBr / ν _max cm ^-1 : 1577, 1473, 1424.

Nuclear Magnetic Resonance Spectrum / CDCl ₃ / δ ppm: 1.35 1.98 / 4H. multiplet /, 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-quinuclidinyl-oxy / isoxazole.

A mixture of the filtrate and washings obtained as described in Example 5 was concentrated by evaporation under reduced pressure, and the residue was suspended in 400 ml of ethyl acetate. The suspension was cooled to 5 ^° C. and 353 ml of 1N was added thereto. aqueous hydrochloric acid; it was then stirred for another 10 minutes. At the end of this time period, the aqueous was separated and cooled to 5 ^° C; then 75.2 g of sodium carbonate was added thereto, and then the resulting mixture was extracted three times, each time using 400 ml of ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, and then the drying agent was removed by filtration. Next, the solvent was removed from the filtrate by distillation under reduced pressure to obtain 20.01 g of 3- / 3-quinuclidinyl-oxy / isoxazole, containing mainly the isomer. All this product was dissolved in 700 ml of methanol, and the resulting solution was mixed with a solution of 39.80 g of 2,3-di-paratoluene-D-tartaric acid in 200 ml of methanol. The resulting mixture was kept overnight at room temperature. Crystals that precipitated were collected by filtration and washed with 300 ml of ethanol. They were then recrystallized three times from methanol to obtain 23.56 g / yield 52.7% / 3- / 3-S-quinuclidinyloxy / isoxazole di-paratoluene-D-tartrate as colorless columnar crystals melting at 165 166 ^o C / decomposition / and having a specific rotation [α] $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ +48.5 ^o / s 1.0, dimethylformamide /. 22.00 g of the tartrate thus obtained were suspended in 200 ml of ethyl acetate and the suspension was cooled to 5 ^° C. 50 ml of 1N was added to the suspension. an aqueous solution of hydrochloric acid and the resulting mixture was stirred at the same temperature for 10 minutes. At the end of this period of time, the aqueous layer was separated and cooled to 5 ^° C., then 10.59 g of sodium carbonate was added thereto, and the mixture was extracted twice, each time using 200 ml of ethyl acetate. The organic layer was separated and dried over anhydrous magnesium sulfate, and then the drying agent was removed by filtration. The solvent was then removed from the filtrate by distillation under reduced pressure. The resulting crystalline residue was recrystallized from diisopropyl ether to obtain 6.95 g / yield 46.3% / of the title compound as colorless columnar crystals, melting point 69 70 ^° C.

[α] $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ -7.6 ^o / s 1.0, ethanol /.

Infrared Absorption Spectrum / KBr / ν _max cm ^-1 : 1577, 1473, 1423.

Nuclear Magnetic Resonance Spectrum / CDCl ₃ / δ ppm: 1.35 1.98 (4H, multiplet /, 2.25 2.31 / 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 - / - / - 3- / 3-Quinuclidinyl-oxy / isoxazole.

A solution of 4.30 g of R - / + / - 3- / 3-quinuclidinyloxy / isoxazole / prepared according to Example 5 / in 50 ml of isopropanol was cooled to 5 ^° C and 6.07 ml of 4N was added thereto. a solution of hydrogen chloride in dioxane. The mixture was stirred for 10 minutes, and then the crystals that precipitated were collected by filtration and recrystallized from methanol to obtain 4.85 g (9.0% yield). The compounds from the title of the example in the form of colorless needles melting at a temperature of 255 257 ^o C / decomposition /.

[α] $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ -29.70 / s 1.0, H ₂ O /.

Infrared Absorption Spectrum / KBr / ν _max cm ^-1 : 1579, 1485, 1477, 1456, 1430.

Nuclear Magnetic Resonance Spectrum / D ₂₀ / δ 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 /, 5.05 5.11 / 1H, multiplet /, 3.24 / 1H, doublet, J 1.96 Hz /, 8.41 / 1H, doublet, J 1.96 Hz /.

 Example 8. S - / + / - 3- / 3-Quinuclidinyloxy / isoxazole hydrochloride.

A solution of 5.95 g of S - / - / - 3- / 3-quinuclidinyloxy / isoxazole / prepared according to Example 6 / in 60 ml of isopropanol was cooled to 5 ^° C and 8.41 ml of 4N was added thereto. a solution of hydrogen chloride in dioxane. The mixture was stirred for 10 minutes, and then the crystals that precipitated were collected by filtration and recrystallized from ethanol to obtain 6.64 g (94.0% yield) of the title compound as colorless needles melting at 255 257 ^o C / decomposition /.

[α] $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ +29.8 ^o / s 1.0 H ₂ O /.

Infrared Absorption Spectrum / KBr / ν _max cm ^-1 : 1579, 1484, 1477, 1456, 1430.

Nuclear Magnetic Resonance Spectrum / D ₂₀ / δ ppm: 1.86 2.34 / 4H, multiplet /, 2.63 2.69 / 1H, multiplet /, 3.30 3.58 / 5H, multiplet /, 3 74 3.83 (1H, multiplet), 5.05 (5.11) / 1H, multiplet (6.241H), doublet, J 1.96 Hz (8.41 / 1H, doublet, I 1.96 Hz).

 Example 9. 4-Chloro-3- [3-quinuclidinyloxy] -5-phenyldisoxazole.

A solution of 1.96 g of 3-quinuclidinol in 30 ml of dimethylformamide was cooled to 5 ^° C. under a nitrogen atmosphere. 67 g of sodium hydride was added to the cooling solution (as a 55% w / w 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 5 ^° C. and 3.0 g of 3,4-dichloro-5-phenylisoxazole was added. The resulting mixture was then stirred at room temperature for 5 hours. At the end of this time, it was poured into 100 ml of ice-water and extracted twice, each time using 100 ml of ethyl acetate. The ethyl acetate extracts were combined and washed twice, each time using 100 ml of a 10% w / w aqueous solution of sodium chloride; they were then dried over anhydrous magnesium sulfate, after which the drying agent was removed by filtration. The solvent was then removed from the filtrate by distillation under reduced pressure. The residue thus obtained was purified by silica gel column chromatography using a 10: 1 mixture / volumes / ethyl acetate and methanol as eluent to obtain 4.21 g / yield 98.7% / of the title compound as a colorless and clear oil. n $\genfrac{}{}{0ex}{}{\text{28}}{\text{D}}$ 1.5701.

Infrared Absorption Spectrum / CHC1 ₃ / ν _max cm ^-1 : 1625, 1520, 1460, 1375.

Nuclear Magnetic Resonance Spectrum / CDCl ₃ / δ 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. 4-Chloro-3- [3-quinocididinyl oxy-5-phenylisoxazole hydrochloride.

A solution of 1.12 g of 4-chloro-3- (3-quinuclidinyloxy) -5-phenylazoxazole / prepared as described in Example 9 / in 20 ml of ethanol was cooled to 5 ^° C. 2.1 ml was then added dropwise to the solution. 4n a 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 solid residue thus obtained was subjected to recrystallization from ethanol to obtain 2.35 g (yield 96.1%) of the title compound as a colorless powder, melting at a temperature 235 237 ^o C / decomposition /.

Infrared Absorption Spectrum / KBr / ν _max cm ^-1 : 1627, 1522, 1450, 1421.

 Nuclear Magnetic Resonance Spectrum / hexadeuterated dimethyl sulfoxide / δ ppm: 1.81 2.56 / 5H, multiplet /, 3.16 3.79 / 6H, multiplet /, 5.08 5.14 / 1H, multiplet /, multiplet /, 7.59 7.65 / 3H, multiplet /, 7.90 7.95 / 2H, multiplet /.

 Example 11. 5-Chloro-3- / 1-methyl-4-piperidyloxy / -1,2-benzyloxazole.

A solution of 1.53 g / 13.3 mmol / 4-hydroxy-1-methylpiperidine in 25 ml of dimethylformamide was cooled to 5 ^° C. under a nitrogen atmosphere. 0.58 g (13.3 mmol) of sodium hydrate (in the form of a 55% w / w dispersion in mineral oil) was added to the solution, and then the solution was stirred at room temperature for 30 minutes. The reaction mixture was cooled to 5 ^° C, and then 2.50 g / 13.3 mmol / 3,5-dichloro-1,2-benzyloxazole was added thereto; the resulting mixture was stirred at 5 ^° C. for 30 minutes, and then at room temperature for 1 hour. At the end of this time, the mixture was poured into 50 ml of ice-water, and then extracted twice, each time using 50 ml ethyl acetate. The ethyl acetate layer was separated and washed with 100 ml of a 10% w / v aqueous solution of sodium chloride; it was then dried over anhydrous magnesium sulfate and the drying agent was removed by filtration. The solvent was removed from the filtrate by distillation under reduced pressure. The resulting residue was purified using a silica gel chromatography column using ethyl acetate as an eluent to give 2.38 g (yield 67.00%). The title compound is a colorless powder melting at 55 56 ^o C.

Infrared Absorption Spectrum / CHCl ₃ / cm ^-1 ; 1535, 1470, 1440, 1360, 1310.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ / d ppm: 1.73 3.00 / 8H, multiplet /, 2.32 / 3H, singlet /, 4.92 / 1H, doublet of doublets of doublets, J 13.5, 9 , 0 and 4.5 Hz /, 7.30 / 7.76 / 3H, multiplet /.

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

A solution of 2.20 g / 8.24 mmol / 5-chloro-3- / 1-methyl-4-piperidyloxy / -1,2-benzisoxazole / prepared as described in example 11 / in 20 ml of ethanol was cooled to 5 ^o C. 2.5 ml of 4N was added dropwise to the cooled solution. a 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 (yield 98.7%). The compounds from the title of the example in the form of colorless, cottage cheese-like crystals melting at a temperature of 212 214 ^o C / decomposition /.

Infrared Absorption Spectrum / KBr / ν _max cm ^-1 ; 1532, 1471, 1440, 1311.

 Nuclear Magnetic Resonance Spectrum / hexadeuterated dimethyl sulfoxide / δ ppm: 2.06 2.43 / 4H, multiplet /, 5.16 / 1H, multiplet /, 7.66 8.03 / 3H, multiplet /.

 Example 13-108 Following the procedures similar to those described in examples 1 to 12, the following compounds were obtained.

 Examples 13. / + / - 4-chloro-5-phenyl-3- / 3-quinuclidinyloxy / isoxazole.

n $\genfrac{}{}{0ex}{}{\text{24}}{\text{d}}$ 1.6290
[α] $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ +8.4 ^o / s = 1.0 CHCl ₃ /.

 Example 14. / - / - 4-chloro-5-phenyl-3- / 3-quinuclidinyloxy / isoxazole.

n $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ = 1.6290
[α] $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ -8.5 ^o / s = 1.0, CHCl ₃ /.

 Example 15. Hydrochloride / + / - 4-chloro-5-phenyl-3- / 3-quinocididinyl oxy / isoxazole.

The temperature of the melting point 250 255 ^o C / decomposition /. [α] $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ = +33.3 ^o / c = 1.0, H ₂ O /.

 Example 16. Chlorohydrate of / - / - 4-chloro-5-phenyl-3- [3-quinoclinylyloxy / isoxazole.

The temperature of the melting point 250 255 ^o C / decomposition /. [α] $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ = -33.5 ^o / c = 1.0, H ₂ O /.

 Example 17. 5-Chloro-3- [4-piperidyloxy] -1,2-benzisoxazole hydrochloride.

The melting point temperature of 253 256 ^o C / decomposition /.

 Example 18. 5-Methyl-3- / 3-quinuclidinyl-oxy / isoxazole.

The melting point is 52 53 ^o C.

 Example 19. 5-Methyl-3- / 3-quinuclidinyl-oxy / isoxazole hydrochloride.

The temperature of the melting point 207 209 ^o C / decomposition /.

 Example 20. 5-Methyl-3- / 4-piperidyloxy / isoxazole hydrochloride.

The melting point temperature of 209 211 ^o C / decomposition /.

 Example 21. 5- / 3-Pyridyl / -3- / 3-quinuclidinyl-oxy / isoxazole hydrochloride.

Melting point temperature 250 253 ^o C / decomposition.

 Example 22. 3- (1-Methyl-4-piperidyloxy) -5- (3-pyridyl) isoxazole hydrochloride.

The temperature of the melting point 217 220 ^o C / decomposition /.

 Example 23. 4-Chloro-3- [1-methyl-3-piperidyloxy / -5-phenylisoxazole.

n $\genfrac{}{}{0ex}{}{\text{28}}{\text{D}}$ = 1.5579.

 Example 24. 4-Chloro-3- / 1-methyl-4-piperidyloxy / -5-phenylisoxazole.

The temperature of the melting point 43 44 ^o C.

 Example 25. 5-Phenyl-3- / 3-quinuclidinyloxy / isoxazole.

n $\genfrac{}{}{0ex}{}{\text{28}}{\text{D}}$ = 1.5712.

 Example 26. 3- (1-Methyl-3-piperidyloxy) -5-phenylisoxazole.

n $\genfrac{}{}{0ex}{}{\text{28}}{\text{D}}$ = 1.5612.

 Example 27. 3- (1-Methyl-4-piperidyloxy) -5-phenylisoxazole.

The melting point is 70.5 71.5 ^o C.

 Example 28. 5- (Para-chlorophenyl) -3- / 3-quinuclidinyl-oxy / isoxazole.

The melting point is 81 83 ^o C.

 Example 29. 5- (para-chlorophenyl) -3- [1-methyl-3-piperidyloxy / isoxazole.

n $\genfrac{}{}{0ex}{}{\text{28}}{\text{D}}$ = 1.5645.

 Example 30. 5- (para-chlorophenyl) -3- [1-methyl-4-piperidyloxy / isoxazole.

Melting point 122 123 ^o C
Example 31. 4-Chloro-3- [1-methyl-3-piperidyloxy] -5-phenylisoxazole hydrochloride.

Melting point 101 102 ^o C
Example 32. 4-Chloro-3- [1-methyl-4-piperidyloxy] -5-phenylisoxazole hydrochloride.

The temperature of the melting point 192 193 ^o C / decomposition /.

 Example 33. 5-Phenyl-3- [3-quinuclidinylsulfonyl / isoxazole hydrochloride.

The temperature of the melting point 238 240 ^o C / decomposition /.

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

The melting point is 189 190 ^o C.

 Example 35. Hydrochloride / 1-methyl-4-piperidyloxy / -5-phenyldisoxazole.

The temperature of the melting point 210 212 ^o C / decomposition /.

 Example 36. Hydrochloride 5- / para-chlorophenyl / -3- / 3-quinuclidinyl-oxy / isoxazole.

The temperature of the melting point 227 229 ^o C / decomposition /.

 Example 37. 5- (Para-chlorophenyl) -3- (1-methyl-1-piperidyloxy) isoxazole hydrochloride.

The temperature of the melting point of 215 217 ^o C / decomposition /.

 Example 38. 5- (Para-chlorophenyl) -3- (1-methyl-4-piperidyloxy) isoxazole hydrochloride.

The temperature of the melting point 209-211 ^o C / decomposition /.

 Example 39. 4,5-Dimethyl-3- / 3-quinuclidinyloxy / isoxazole.

n $\genfrac{}{}{0ex}{}{\text{26}}{\text{D}}$ = 1.5332.

 Example 40. 4,5-Dimethyl-3- / 1-methyl-4-piperidyloxy / isoxazole.

n $\genfrac{}{}{0ex}{}{\text{26}}{\text{D}}$ = 1.5437.

 Example 41. 5-Ethyl-3- / 3-quinuclidinyloxy / isoxazole.

The temperature of the melting point 71-72 ^o C.

 Example 42. 5-Ethyl-3- / 1-methyl-4-piperidyloxy / isoxazole.

n $\genfrac{}{}{0ex}{}{\text{26}}{\text{D}}$ = 1.5612.

 Example 43. 5-Isopropyl-3- / 3-quinuclidinyloxy / isoxazole.

The melting point is 75-76 ^o C.

 Example 44. 5-Isopropyl-3- / 1-methyl-4-piperidyloxy / isoxazole.

n $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ = 1.5634.

 Example 45. 4-Chloro-5-ethyl-3- / 1-methyl-4-piperidyloxy / isoxazole.

The temperature of the melting point 78-80 ^o C.

 Example 46. 4-Chloro-5-ethyl-3- / 1-methyl-4-piperidyloxy / isoxazole.

n $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ = 1.5802.

 Example 47. 4-Chloro-5-isopropyl-3- / 3-quinuclidinyloxy / isoxazole.

The temperature of the melting point 82-83 ^o C.

 Example 48. 4-Chloro-5-isopropyl-3- / 1-methyl-4-piperidyloxy / isoxazole.

n $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ = 1.5724.

 Example 49. 5-Methyl-3- / 1-methyl-4-piperidyloxy / isoxazole.

The temperature of the melting point of 39-40 ^o C.

 Example 50. 4-Chloro-5-methyl-3- / 1-methyl-4-piperidyloxy / isoxazole.

The temperature of the melting point 30-31 ^o C.

 Example 51. 3- (1-Methyl-4-piperidyloxy / isoxazole.

The temperature of the melting point of 40-40.5 ^o C.

 Example 52. 4-Chloro-3- / 1-methyl-4-piperidoxy / isoxazole.

n $\genfrac{}{}{0ex}{}{\text{26}}{\text{D}}$ = 1.6340.

 Example 53. 4-Fluoro-5-methyl-3- / 3-quinuclidinyloxy / isoxazole.

The temperature of the melting point of 40-41 ^o C.

 Example 54. 4,5-Dimethyl-3- / 3-quinucididinyloxy / isoxazole hydrochloride.

The temperature of the melting point 212-214 ^o C / decomposition /.

 Example 55. 4,5-Dimethyl-3- [1-methyl-4-piperidyloxy / isoxazole hydrochloride.

The temperature of the melting point of 219-222 ^o C / decomposition /.

 Example 56. 5-Ethyl-3- / 3-quinuclidinyloxy / isoxazole hydrochloride.

The temperature of the melting point 211 213 ^o C / decomposition /.

 Example 57. 5-Ethyl-3- [1-methyl-4-piperidyloxy / isoxazole hydrochloride.

The temperature of the melting point of 184-186 ^o C / decomposition /.

 Example 58. 5-Isopropyl-3- / 3-quinucididinyloxy / isoxazole hydrochloride.

The temperature of the melting point 210-212 ^o C / decomposition /.

 Example 59. 5-Isoparopyl-3- / 1-methyl-4-piperidyloxy / isoxazole hydrochloride.

The temperature of the melting point 196-198 ^o C / decomposition /.

 Example 60. 4-Chloro-5-ethyl-3- / 3-quinuclidinyl-oxy / isoxazole hydrochloride.

The temperature of the melting point of 219-222 ^o C / decomposition /.

 Example 61. 4-Chloro-5-ethyl-3- [1-methyl-4-piperidyloxy / isoxazole hydrochloride.

The temperature of the melting point 211-214 ^o C / decomposition /.

 Example 62. 4-Chloro-5-isopro-3- / 3-quinuclidinyl-oxy / isoxazole hydrochloride.

The temperature of the melting point 213-216 ^o C / decomposition /.

 Example 63. 4-Chloro-5-isopropyl-3- [1-methyl-4-piperidyloxy / isoxazole hydrochloride.

The temperature of the melting point 209-212 ^o With / decomposition /.

 Example 64. 5-Methyl-3- [1-methyl-4-piperidyloxy / isoxazole hydrochloride.

The temperature of the melting point 198-200 ^o C / decomposition /.

 Example 65. 4-Chloro-5-methyl-3- [1-methyl-4-piperidyloxy / isoxazole hydrochloride.

The temperature of the melting point 211-214 ^o C / decomposition /.

 Example 66. Fumarate 3- / 1-methyl-4-piperidyloxy / isoxazole.

The temperature of the melting point of 148-150 ^o C / decomposition /.

 Example 67. 4-Chloro-3- [1-methyl-4-piperidyloxy / isoxazole hydrochloride.

The temperature of the melting point 201-204 ^o C / decomposition /.

 Example 68. 4-Fluoro-5-methyl-3- / 3-quinuclidinyl-oxy / isoxazole hydrochloride.

The temperature of the melting point 200-203 ^o C / decomposition /.

 Example 69. 3- (1-Methyl-4-piperidyloxy) -1,2-benzisoxazole.

The melting point is 67-68 ^o C.

 Example 70. 6-Chloro-3- / 3-quinuclinyloxy / -1,2-benzisoxazole.

The melting point is 73.5-74.5 ^o C.

 Example 71. 6-Chloro-3- / 1-methyl-3-piperidyloxy / -1,2-benzisoxazole.

The melting point is 64-65 ^o C.

 Example 72. 6-Chloro-3- (1-methyl-4-piperidyloxy) -1,2-benzisoxazole.

The melting point is 106.5-107.5 ^o C.

 Example 73. 7-Chloro-3- / 3-quinuclidinoloxy / -1,2-benzisoxazole.

The temperature of the melting point 63-64 ^o C.

 Example 74. 7-Chloro-3- (1-methyl-4-piperidyloxy) -1,2-benzisoxazole.

The temperature of the melting point 74-75 ^o C.

 Example 75. 5-Methoxy-3- / 3-cnuclidinyl-oxy / -1,2-benzisoxazole.

The melting point is 85-86 ^o C.

 Example 76. 5-Methoxy-3- / 1-methyl-4-piperidyloxy / -1,2-benzisoxazole.

n $\genfrac{}{}{0ex}{}{\text{26}}{\text{D}}$ = 1.5390
Example 77. 5-Fluoro-3- / 3-quinuclidinyl-oxy / -1,2-benzisoxazole.

The melting point is 90-91 ^o C.

 Example 78. 5-Fluoro-3- (1-methyl-4-piperidyloxy) -1,2-benzisoxazole.

The temperature of the melting point of 83-84 ^o C.

 Example 79. 5-Chloro-3- (1-ethyl-4-piperidyloxy) -1,2-benzisoxazole.

The temperature of the melting point 62-63 ^o C.

 Example 80. 5-Chloro-3- (1-propyl-4-4-piperidyloxy) -1,2-benzisoxazole.

The temperature of the melting point 71-72 ^o C.

 Example 81. 5-Chloro-3 - / - isobutyl-4-piperidyloxy / -1,2-benzisoxazole.

The temperature of the melting point 76-77 ^o C.

 Example 82. 5-Methyl-3- / 3-quinuclidinyl-oxy / -1,2-benzisoxazole.

The melting point is 94-95 ^o C.

 Example 83. 5-Methyl-3- / 1-methyl-4-piperidyloxy / -1,2-benzisoxazole.

The temperature of the melting point 87-99 ^o C.

 Example 84. 5-Chloro-3- / 1-methyl-3-piperidyloxy / -1,2-benzisoxazole.

The temperature of the melting point 61-62 ^o C.

 Example 85. 5-Chloro-3- [3-quinuclidinyl-oxy] -1,2-benzisoxazole.

The temperature of the melting point 69-70 ^o c.

 Example 86. 5-Chloro-3- [4-piperidyloxy] -1,2-benzisoxazole.

The temperature of the melting point 81-82 ^o C.

 Example 87. 3- [1-Methyl-4-piperidyloxy] -1,2-benzoxazole hydrochloride.

The temperature of the melting point 197-199 ^o C / decomposition /.

 Example 88. 6-Chloro-3- [3-quinuclidnilyloxy] -1,2-benzisoxazole hydrochloride.

The temperature of the melting point 237-239 ^o C / decomposition /.

 Example 89. 6-Chloro-3- [1-methyl-3-piperidyloxy] -1,2-benzisoxazole hydrochloride.

The temperature of the melting point of 213-215 ^o C / decomposition /.

 Example 90. 6-Chloro-3- [1-methyl-4-piperidyloxy] -1,2-benzisoxazole hydrochloride.

The temperature of the melting point 238 240 ^o C / decomposition /.

 Example 91. 7-Chloro-3- [3-quinuclidinyl-oxy] -1,2-benzisoxazole hydrochloride.

The temperature of the melting point 251 253 ^o C / decomposition /.

 Example 92. 7-Chloro-3- [1-methyl-4-piperidyloxy] -1,2-benzisoxazole hydrochloride.

The temperature of the melting point 238 240 ^o C / decomposition /.

 Example 93. 5-Methoxy-3- / 3-quinucididinyloxy / -1,2-benzisoxazole hydrochloride.

The temperature of the melting point of 245 247 ^o C / decomposition /.

 Example 94. 5-Methoxy-3- [1-methyl-4-piperidyloxy / -1,2-benzisoxazole hydrochloride.

The temperature of the melting point 225 227 ^o C / decomposition /.

 Example 95. 5-Fluoro-3- / 3-quinucididinyloxy / -1,2-benzisoxazole hydrochloride.

The temperature of the melting point 231 233 ^o C / decomposition /.

 Example 96. 5-Fluoro-3- [1-methyl-4-piperidyloxy] -1,2-benzisoxazole hydrochloride.

The temperature of the melting point 234 236 ^o C / decomposition /.

 Example 97. 5-Chloro-3- [1-ethyl-4-piperidyloxy] -1,2-benzisoxazole hydrochloride.

The temperature of the melting point of 186 188 ^o C / decomposition /.

 Example 98. 5-Chloro-3- [1-propyl-4-piperidyloxy] -1,2-benzisoxazole hydrochloride.

The temperature of the melting point 226 228 ^o C / decomposition /.

 Example 99. 5-Chloro-3- [1-isobutyl-4-piperidyloxy / -1,2-benzisoxazole hydrochloride.

The temperature of the melting point of 215 217 ^o C / decomposition /.

 Example 100. Chlorohydrate of 5-methyl-3- / 3-quinuclidinyloxy / -1,2-benzisoxazole.

The temperature of the melting point 262 264 ^o C / decomposition /.

 Example 101. 5-Methyl-3- [1-methyl-4-piperidyloxy] -1,2-benzisoxazole hydrochloride.

The temperature of the melting point 223 235 ^o C / decomposition /.

 Example 102. 5-Chloro-3- [1-methyl-3-piperidyloxy] -1,2-benzisoxazole hydrochloride.

The temperature of the melting point 204 206 ^o C / decomposition /.

 Example 103. 5-Chloro-3- [3-quinuclidinyl-oxy] -1,2-benzisoxazole hydrochloride.

The temperature of the melting point 269 271 ^o C / decomposition /.

 Example 104. 3- [1-Methyl-3- [1-piperidyloxy] -1,2-benzisoxazole hydrochloride.

The temperature of the melting point of 188 190 ^o C / decomposition /.

 Example 105. 3- (3-Quinuclidinyl-oxy) -1,2-benzisoxazole hydrochloride.

The temperature of the melting point 248 250 ^o C / decomposition /.

 Example 106. 4-Chloro-5-phenyl-3- / 3-piperidyloxy / isoxazole hydrochloride.

The melting point is 111 113 ^o C.

 Example 107. 3- (3-Quinuclidinyl-oxy) -5- (2-thienyl) isoxazole hydrochloride.

The temperature of the melting point 240 242 ^o C / decomposition /.

 Example 108. 3- (1-Methylpiperidyloxy) -5- (2-thienyl) isoxazole hydrochloride.

The temperature of the melting point 216 218 ^o C / decomposition /.

Example 109. 4-Chloro-3- / 3-quinuclidinyloxy / isoxazole /
6.99 g / 40.2 mmol / diethyl diazodicarboxylate was added dropwise to a solution of 10.54 g / 40.2 mmol / triphenyl phosphate in 150 ml of tetrahydrofuran, while cooling to 0 10 ^° C, and the resulting mixture was stirred at the same temperature for 30 minutes At the end of this period of time, 5.10 g / 40.2 mmol / 3-quinuclidinol was added and the mixture was stirred at 0 ^° C. for 30 minutes and then at room temperature for 24 hours. At the end of this period, the solvent was removed by distillation under reduced pressure. and the resulting residue was further purified using a silica gel chromatography column using ethyl acetate as eluent to obtain 3.90 g / 50.9% yield / combining from the title of the example as a colorless powder melting at 68 69 ^o C.

Elemental analysis:
Calculated for C ₁₀ H ₁₃ N ₂ O ₂ Cl 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 / ν _max cm ^-1 1582, 1514, 1418.

Nuclear Magnetic Resonance Spectrum / CDCl ₃ /, 270 MHz / ppm: 1.36 2.00 / 4H, multiplet /, 2.27 2.33 / 1H, multiplet /, 2.68 - 3.05 / 3H, multiplet /, 3.27 3.36 / 1H, multiplet /, 4.74 4.80 / 1H, multiplet /, 8.18 / 1H, singlet /.

 Example 110. 4-Chloro-3- / 3-quinuclidinyl-oxy / isoxazole hydrochloride.

3.00 ml / 12.00 mmol / 4n. a solution of hydrogen chloride in dioaxane was added dropwise to a solution of 2.29 g / 10.0 mmol / 4-chloro-3- / 3-quinuclidinyloxy / isoxazole / obtained in example 109 / in 20 ml of ethanol, while cooling to 5 ^o C , 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 recrystallized from isopropanol to obtain 2.40 g / 90.4% yield of the title compound as a colorless powder, melting at 235,238 ^° C / with decomposition.

Elemental analysis:
Calculated for C ₁₀ H ₁₄ N ₂ O ₂ Cl C 45.30; H 5.32; N, 10.57; Cl 26.74.

 Found C, 44.55; H 5.37; N, 10.44; Cl 26.45.

Infrared Absorption Spectrum / KBr / ν _max cm ^-1 : 1590, 1513, 1484, 1455, 1422.

Nuclear Magnetic Resonance Spectrum / CDCl ₃ , 270 MHz / δ ppm: 1.87-2.39 4H, multiplet /, 2.68-2.75 / 1H, multiplet, J 0.97 Hz /, 3.28 -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, the following compounds were obtained.

Example 111. 5- (o-methoxy) phenyl-3 (3-quinuclidinyloxy) isoxazole. (CDCl ₃ ) d ppm: 1.32 - 2.20 (5H, multiplet); 2.48-3.42 (6H, multiplet); 3.82 (3H, singlet); 4.63-4.67 (1H, multiplet); 6.86 (3H-singlet); 7.01-7.62 (4H, multiplet).

Example 112. 5- (m-methoxy) phenyl-3- (3-quinuclidinoloxy) isoxazole NMR CDCl ₃ d ppm: 1.33 - 2.18 (5H, multiplet); 2.50-3.34 (6H, multiplet); 3.82 (3H, singlet); 4.62-4.68 (1H, multiplet); 6.84 (1H, singlet); 7.03 7.11 (1H, multiplet); 7.33 7.44 (3H, multiplet).

 Example 113. 5- (o-methoxy) phenyl-3- (3-quinuclidinyloxy) isoxazole hydrochloride.

Mp 252 253 ^o C (decomp.)
NMR (D ₂ O) d ppm: 1.8 2.64 (5H, multiplet); 3.29 3.85 (6H, multiplet); 3.93 (3H, singlet); 4.98 5.01 (1H, multiplet); 6.47 (1H, singlet); 7.09 7.08 (4H, multiplet).

 Example 114. 5- (m-tags) phenyl-3- (3-htnuclidinyloxy) isoxazole hydrochloride.

Mp 211 214 ^o C (decomp.)
NMR (D ₂ O) d ppm: 1.92 2.68 (5H, multiplet); 3.33 3.85 (6H, multiplet); 3.89 (3H, singlet); 5.04 5.08 (1H, multiplet); 6.47 (1H, singlet); 7.11 7.15 (1H, multiplet); 7.31 7.50 (3H, multiplet).

 Example 115. 5- (p-Methoxy) phenyl-3- (3-quinuclidinyloxy) isoxazole.

NMR (CDCl ₃ ) d ppm: 1.35 2.17 (5H, multiplet); 2.50 3.43 (6H, multiplet); 3.82 (3H, singlet); 4.62 4.65 (1H, multiplet); 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-quinuclidinyloxy) isoxazole.

NMR (CDCl ₃ ) d ppm: 1.32 2.35 (5H multiplet); 2.46 3.45 (6H, multiplet); 3.84 (3H, singlet); 3.86 (3H singlet); 5.63 4.66 (1H, multiplet); 6.53 (1H, singlet); 7.02 7.47 (3H, multiplet).

 Example 117. 5- (p-methoxy) phenyl-3- (3-quinuclidinyloxy) isoxazole hydrochloride.

Mp 235,238 ^o C (decomp.)
NMR (D ₂ O) d ppm: 1.91 2.66 (5H, multiplet); 3.32 3.84 (6H, multiplet); 3.89 (3H, singlet); 5.02 5.05 (1H, multiplet); 6.34 (1H, singlet); 7.08 (2H, doublet, J = 9.82 Hz); 8.72 (2H, doublet, J = 9.25 Hz).

 Example 118. 5- (3,4-Dimethoxy) phenyl-3- (3-quinuclidinyloxy) isoxazole hydrochloride.

T. pl. 198 201 ^o C (decomp.)
NMR (D ₂ O) d ppm: 1.93 2.66 (5H, multiplet); 3.32 3.85 (6H, multiplet); 3.87 (3H, singlet); 4.89 (3H, singlet); 5.00 5.03 (1H, singlet); 6.28 (1H, singlet); 7.02 7.32 (8H, multiplet).

 Example 119. 4-Chloro-5- (m-methoxy) phenyl-3- (3-quinuclidiniloxis) isoxazole.

NMR (CDCl ₃ ) d ppm: 1.36 2.42 (5H, multiplet); 2.79 3.44 (6H, multiplet); 3.86 (ZN, singlet); 4.80 4.86 (1H, multiplet); 7.04 - 7.12 (1H, multiplet); 7.32 7.48 (ZN, multiplet).

 Example 120. 5- (m-hydroxy) phenyl-3- (3-quinuclidinyloxy) isoxazole.

NMR (CDCl ₃ ) d ppm: 1.39 2.21 (5H, multiplet); 2.53 3.52 - (6H, multiplet); 4.67 4.70 (1H, multiplet); 6.74 (1H, singlet); 6.90 - 6.93 (1H, multiplet); 7.19 7.37 (ZN, multiplet).

 Example 121. 4-Chloro-5- (m-methoxy) phenyl-3-quinuclidinyl-oxy) isoxazole hydrochloride.

Mp 222 225 ^o C (decomp.)
NMR (D ₂ O) d ppm: 1.94 2.66 (5H, multiplet); 3.34 3.83 (6H, multiplet); 3.86 (3H, singlet); 5.0, 5.06 (1H, multiplet); 7.09 7.48 (4H, multiplet).

 Example 122. 5- (m-hydroxy) phenyl-3- (3-quinuclidinyloxy) isoxazole hydrochloride.

Mp 260,263 ^o C (decomp.)
NMR (D ₂ O) d ppm: 1.91 2.67 (5H, multiplet); 3.32 3.84 (6H, multiplet); 5.01 5.05 (1H, multiplet); 6.44 (1H, singlet); 7.01 7.05 (1H, multiplet); 7.22 7.45 (3H, multiplet).

 Example 123. 4-Chloro-5- (m-hydroxy) phenyl-3- (3-quinuclidinyl-oxy) isoxazole.

NMR (CDCl ₃ ) d ppm: 1.51 2.40 (5H, multiplet), 2.83 3.44 (6H, multiplet); 4.87 4.90 (1H, multiplet); 6.91 6.94 (1H, multiplet); 7.30 7.48 (3H, multiplet).

 Example 124. 4-Chloro-5- (m-hydroxy) phenyl-3- (3-quinuclidinyl-oxy) isoxazole hydrochloride.

Mp ^. 246-250 ^o C (decomposition).

NMR (D ₂ O) d ppm: 1.93 - 2.69 (5H, multiplet); 3.32 3.85 (6H, multiplet); 5.07 5.10 (1H, multiplet); 7.03 7.08 (1H, multiplet); 7.37 7.52 (3H, multiplet).

 Form 1.

Capsules, mg:
5-Chloro-3- (1-methyl-4-piperidyloxy) -1,2-benzisoxazole hydrochloride 10.0
Lactose 153.6 mg
Corn Starch 100.0
Magnesium Stearate 2.4
Total 280.0 mg.

 The powders of the above compounds were mixed and passed through a 60 mesh sieve (0.34 mm, Tyler standard), and 280 mg of the resulting powder was packaged in No. 3 gelatin capsule.

 Form 2.

 Powders. The powder obtained in accordance with the description for Form 1 was pressed to obtain tablets, each of which contains 120 mg, using a known tablet preparation.

 Form 3.

Capsules, mg:
3- / 3-Quinuclinyloxy / isoxazole hydrochloride 10.0
Lactose 153.6
Corn Starch 100.0
Magnesium Stearate 1.4
Total 280.0 mg.

 The powders of the above compounds were mixed and passed through a 60 mesh sieve (0.34 mm, Tyler standard) and 280 mg of the resulting powder were packaged in No. 3 gelatin capsule.

 Form 4.

 Powders. The powder obtained in accordance with the description for form 3, was pressed to obtain tablets, each of which contains 120 mg, using a known means for the manufacture of tablets.

 Experiment 1.

 Muscarinic receptor binding test.

A membrane fraction obtained from rat cerebral cortex was added to the test compound together with ³ H-oxotremorin-M / to a final concentration of 3 nM / and the mixture was allowed to interact at 30 ^° C for 60 minutes. At the end of this time, the mixture was filtered through filter paper. The 3H radioactivity associated with the membrane, which remains on the filter paper, was determined using a liquid scintillation counter.

Since the compound that binds to the muscarinic receptors will do this together with H-oxotremorine-M, the more significant maskarin binding activity of the test compound will be characterized by less radioactivity in the membrane remaining on the filter paper. The concentration of the compound to be tested, which reduces ³ H-radioactivity by 50% / lC ₅₀ /, is taken as an indicator of the ability to bind to the maskarin receptor of the test compound; the obtained indicators are given in table. 5.

Test for selective binding to M ₁ receptors.

The membrane fraction obtained from rat cerebral cortex (where the M ₁ receptors are abundant) was added to the test compound together with H-pirenzepine / to a final concentration of 1 nM / and the mixture was allowed to interact at a temperature of 30 ^° C for 60 minutes. Meanwhile, the membrane fraction obtained from the heart of rats (where M ₂ receptors are predominant) was added to the test compound together with H-quinuclidinyl benzylate / which binds nonselectively to both M ₁ and M ₂ receptors to a final concentration of 0, 12 nM /, and the mixture was allowed to interact at a temperature of 30 ^o C 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 the same procedure as described above. These results are also collected in table. 5.

B2": RS-86, который имеет формулу:

B3: AF 102-B, который имеет формулу:

B4: Ареколин, который имеет формулу:

В таблице Охо-М обозначает ³H-оксотреморин, Pirenzp обозначает ³H-пирензепин, а QNB обозначает ³H-хинуклидинил бензилат.Test compounds are shown in table. 5 by the following notation:
A1: 5-Chloro-3- (1-methyl-4-piperidyloxy) -1,2-benzisoxazole hydrochloride / the compound of the invention obtained as described in Example 12 /;
B1: oxotremorine, a known M ₁ agonist that has the formula:

B2 ": RS-86, which has the formula:

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

B4: Arecolin, which has the formula:

In the table, Oxo-M stands for ³ H-oxotremorine, Pirenzp stands for ³ H-pirenzepine, and QNB stands for ³ H-quinuclidinyl benzylate.

 Experiment 2.

 Antireserpine action.

 It appears that the sedation caused by the use of reserpine or tetrabenzine in mice or rats is similar in terms of symptoms of clinical depression. Of the various pharmacological effects caused by these compounds, ptosis (lowering of the upper eyelid) and a decrease in body temperature were most widely used as indicators of their activity, and it was found that any compound that inhibits either ptosis or a decrease in body temperature will also be active against symptoms of clinical depression. Thus, antireserpine or antitetrabenzene effects have been widely used for a long time as a procedure, sieved for antidepressants. The test indicator used to evaluate the compounds of the invention is the antagonistic effect of the test compound against reserpine-induced ptosis in mice.

 The animals used in the test were adult male mice of the ddy family at the age of 4 weeks and each weighing 22 27 g. The animals were divided into groups, each of which included 3 mice. The test compound was dissolved or suspended in an appropriate solvent / or physiological saline, or 0.5% CMC / carboxymethyl cellulose / solution / and was applied orally to mice from the test groups at the dose indicated in the table. 6. Mice from the control group were given only a solvent without any active compound, which was introduced in the same way. Immediately after administration, 2 mg / kg of reserpine was administered to each mouse subcutaneously. After 90 min, it was determined how close the eyelid / degree of ptosis /, for this the mice were removed from their cells and observed the shape of the eye. To evaluate the results of “normal” mice, that is, without ptosis and, consequently, with a normal round eye, 0 were evaluated, while mice with ptosis in the 1/3 1/2 region were evaluated as 1, mice, which observed ptosis in 2/3 slightly open eyes, was rated 2, and mice with a completely closed eye were rated 3.

 The results are shown in table. 6 7.

При оценке результатов степени ингибирования не менее 71% от 41 до 70% и не более 40% рассматривали как /+/, /+/ и /-/ соответственно.The labels on the vials containing the solutions of the samples to be tested were all in the form of ciphers that were not known to those responsible for the application, and the application was carried out randomly so that the "evaluators" did not know which drug was used and which mouse. From the estimates obtained, the degree of inhibition for each dose level was calculated from the following equation:
The degree of inhibition /% /

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

The compounds used in the test were identified by the following codes:
A2: 4-Chloro-5-methyl-3- [3-quinuclidinyl-oxy] isoxazole hydrochloride prepared according to Example 3 /;
A3: 3- (3-Quinuclidinyl-oxy) isoxazole hydrochloride (prepared according to Example 4);
A4: 5-Methyl-3- [3-quinuclidinyl-oxy] isoxazole hydrochloride prepared according to Example 19 /.

 Experiment 3.

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

 The animals used were adult male males from the Whistar family. Either a solution of 3- / 3-quinuclidinyloxy / isoxazole hydrochloride / the compound obtained in Example 4 / in suspension in a 0.5% SMS carrier or the vehicle itself was injected into each mouse by dental means. Immediately after use for anesthesia, 40 mg / kg pentobarbital was administered intraperitoneally. The rat was fixed in a supine position and 0.6 ml blood samples were taken from the jugular vein on one side. The viscosity of each sample was measured using a viscometer / Biorgeolizer, trade name for the product from Tkio Keyki / at a Slice value of 37.5 / s, 75 / s, 150 / s and 375 / s. On the other hand, 0.5 ml blood samples were taken and the viscosity was measured using the same procedure.

 After the first two samples were taken, the carotid arteries were doped on both sides of each animal. One hour after ligation in the case of control animals / which only received the vehicle / blood viscosity values increased by 5-20% for each slice value / slower slice speed corresponds to a higher viscosity /. However, in the case of animals that were administered the compound of the invention, this increase was significantly inhibited for each cut speed.

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

 Experiment 4.

The study of binding to the 5-HT ₃ receptor.

The membrane fraction obtained from rat cerebral cortex was incubated with the test compound and with ³ H-GR 65630 / to a final concentration of 1 nM, as a ligand relative to 5-HT ₃ receptors / at a temperature of 37 ^° C for 45 minutes. At the end of this period of time, the samples were filtered. ³ H-radioactivity associated with filter paper was determined using a scintillation counter, as described in experiment 1. Non-specific binding was determined using ondansetron / 10 ^-5 M /. The results are shown in table. 8, from which it can be seen that the compounds of the invention bind to 5-HT ₃ receptors as strongly as ondansetron.

The compounds used in the test are indicated by the following numbers:
A5: 4-Chloro-3- [3-quinuclidinyl-oxy] -5-phenylisoxazole hydrochloride prepared according to Example 10 /.

 A6: 5-Chloro-3- (3-quinuclidinyl-oxy) -1,2-benzisoxazole / compound obtained according to example 85 /.

 A7: 5- (para-chlorophenyl) -3- (3-zinuclidinyl-oxy) isoxazole hydrochloride hydrochloride of the compound obtained in Example 28 /

 A8: 4-Chloro-5-phenyl-3- / 3-piperidyloxy / isoxazole hydrochloride prepared according to Example 106 /.

A9: 3- (3-Quinuclidinyl-oxy) -5- (2-thienyl) isoxazole hydrochloride prepared according to Example 107 /;
B5: Ondansetron.

 Experiment 5.

The ileum, extracted from a Guinean pig, was placed in a Magnus cup filled with Tyrod's solution. The contraction force exerted by the ileum in response to the use of the selective 5-HT ₃ antagonist, 2-methyl-5-HT, was determined using an isometric transducer. The test compound was then added to the bath and the contraction force was again measured 30 min after addition. The rate of inhibition of contraction force was calculated. The results are shown in table. 9, from which it can be seen that the compound of the invention, 4-chloro-3- [3-quinuclidinyl oxy] -5-phenylisoxazole hydrochloride (compound AS), is a potent antagonist like ondansetron.

 Experiment 6.

 Acute toxicity

 Each of the compounds of Examples 3 and 4 was suspended in a 0.5% SMS solution and the suspension was used in mice in an amount sufficient to provide a dose of the active compound of 75 mg / kg. Mice were observed for 5 days, during which no death of the animal was observed, and no mouse showed any painful symptoms.

Claims (4)

1. Piperidyloxy or quinuclidinyloxy isoxazole derivatives of the formula I

where R ^{1 is} hydrogen, halogen or an alkyl group having 1 to 4 carbon atoms;
R ^{2 is} hydrogen, an alkyl group having 1 to 4 carbon atoms, a phenyl group which is unsubstituted or substituted by at least one of the substituents (a) as defined below, or a heterocyclic group which has 5 or 6 atoms in the ring, of which one is nitrogen or sulfur, wherein said heterocyclic group is unsubstituted or substituted by at least one of the substituents (a) as defined below, or R ¹ and R ² together form a group of the formula —CR ⁴ = CR ⁵ —CR ⁶ = CR ⁷ -, where R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same or different and each hydrogen, halogen, an alkyl group having 1 4 carbon atoms or an alkoxy group having 1 4 carbon atoms; R ^{3 is a} piperidyl group, a substituted piperidyl group in which the nitrogen atom is a substituted alkyl group having 1 to 6 carbon atoms, or a quinuclidinyl group, where the substituents (a) are: halogen atoms, alkoxy groups having 1 to 4 carbon atoms or hydroxy groups, or pharmaceutically acceptable salts.  2. A composition having the properties of reducing cognitive impairment, characterized in that the active ingredient contains an effective amount of at least one compound of formula I or its salt according to claim 1 in a mixture with a pharmaceutically acceptable carrier or diluent. Priority by signs:
05/11/90 R ¹ and R ² together form a group of the formula —CR ⁴ = CR ⁵ —CR ⁶ = CR ⁷ - and a substituent R ³ —piperidyl group or a substituted piperidyl group in which the nitrogen atom is substituted by an alkyl group containing 1 6 carbon atoms . 08/17/90 R ¹ a hydrogen atom, a halogen atom or an alkyl group containing 1 to 6 carbon atoms, a substituent R ² a hydrogen atom, a C ₁ -C ₄ alkyl group or substituted or unsubstituted phenyl, and an R ³ substituent is a piperidyl group or a substituted piperidyl group in which the nitrogen atom is substituted by an alkyl group containing 1 to 6 carbon atoms or a quinuclidyl group. 05/08/91 R ^{2 is a} heterocyclic group containing 5 or 6 atoms, of which 1 is a nitrogen or sulfur atom.

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