Derivatives and isoxazol pharmaceutical composition based on them

 

(57) Abstract:

The invention relates to new isoxazol derivative of General formula I, where R1denotes optionally substituted C6-C14airgroup or 5-6-membered heterocyclic group containing one heteroatom selected from nitrogen, oxygen, sulfur; R2denotes a hydrogen atom, halogen atom, optionally substituted C1-C6alkyl group, a C2-C6alkenylphenol group2-C6alkylamino group3-C10cycloalkyl group3-C10cycloalkenyl group, cyano, carboxitherapy,1-C7alkanoglu,2-C7alkoxycarbonyl group or optionally substituted carbamoyl; R3denotes optionally substituted by an amino group or a saturated 5-6-membered heterocyclic group containing a nitrogen atom; X represents an oxygen atom or a sulfur atom; n denotes an integer from 2 to 6, and their pharmaceutically acceptable salts. Pharmaceutical composition having inhibitory activity against monoamine oxidase type a, containing the compound of formula I or its pharmaceutically acceptable salt and a pharmaceutically prepletenie refers to isoxazol derivative and its pharmaceutically acceptable salts, who have any abscopal excellent activity against monoamine oxidase type A;

the compositions containing compounds for the treatment or prophylaxis of nervous disorders (particularly depression), including depression, Parkinson's disease, dementia Alzheimer's disease (impaired cognitive ability, characteristic of Alzheimer's disease) or cerebrovascular dementia (impaired cognitive abilities inherent in cerebrovascular dementia);

use connections to obtain pharmaceutical preparations for the treatment or prevention of the above diseases and

the method of treatment or prevention of these diseases through the introduction of a pharmaceutically effective amount of the compounds to warm blooded animals.

Depression is a disease that shows a normal state of depressed mood among mood disorders, and one of her reasons are functional disorders of the Central serotonergic and noradrenergic nervous systems. Serotonin and norepinephrine decompose and undergo metabolism by monoamine oxidase (primarily by monoamine oxidase type A) prior to the loss of their biological activities. PR is their inhibitors were intensively investigated and developed. Recently in the clinic comes Moclobemide as a selective inhibitor of monoamine oxidase type A.

The authors of the present invention was carried out during several years of intensive research synthesis isoxazol derivative and their pharmacological activity with the goal of developing excellent therapeutic tool against depression and found that isoxazol derivative having a specific structure, find a strong inhibitory monoamine oxidase type A activity and have therapeutic or preventive actions (in particular, therapeutic effect) in relation to nervous disorders (particularly depression), including depression, Parkinson's disease, dementia Alzheimer's disease (impaired cognitive ability, characteristic of Alzheimer's disease) or cerebrovascular dementia (impaired cognitive abilities inherent in cerebrovascular dementia).

This invention relates to a

derivative isoxazol and their pharmaceutically acceptable salts, which have excellent inhibitory activity against monoamine oxidase type A;

the compositions containing compounds for the treatment or prevention nerve cognitive abilities, characteristic of Alzheimer's disease) or cerebrovascular dementia (impaired cognitive abilities inherent in cerebrovascular dementia);

use connections to obtain pharmaceutical preparations for the treatment or prevention of the above diseases and

the method of treatment or prevention of these diseases through the introduction of pharmaceutically effective amounts of compounds of warm-blooded animals.

Derivatives isoxazol of the present invention have the General formula (I):

< / BR>
where R1represents C6-C14airgroup, optionally having 1 to 3 substituents, which may be the same or different from each other and selected from the following group of substituents, or a 5 - or 6-membered aromatic heterocyclic group optionally have 1 to 3 substituents and having one heteroatom selected from the group consisting of nitrogen atoms, oxygen and sulfur [a group of substituents is halogen; C1-C6alkyl, C1-C6alkyl substituted by halogen; C1-C6alkoxy; phenyl; phenoxy; benzyloxy; benzylamino; nitro; hydroxyl; C1-C7alkanoyl; amino group;

R2denotes a hydrogen atom; at the2-C6quinil; C3-C10cycloalkyl; C3-C10cycloalkenyl; cyano; carboxyl; C1-C7alkanoyl; C2-C7alkoxycarbonyl; carbarnoyl; mono(C1-C6alkyl)carbarnoyl;

R3denotes amino, mono-C1-C6alkyl amino, di(C1-C6alkyl)amino, mono-C1-C7alkanolamine, mono C2-C7alkoxycarbonyl, mono C7-C15arylcarboxamide,

or 5 - or 6-membered saturated heterocyclic group connected through the nitrogen atom of the ring, which contains one nitrogen atom and optionally may contain another nitrogen atom or oxygen atom.

X denotes an oxygen atom or sulfur and

n denotes an integer from 2.

In addition, the active ingredient is an inhibitor of monoamine oxidase of the present invention is derived isoxazol formula (I).

In the formula (I) "halogen atom" in the definition of R2in the definition of the substituent included in R1may be, for example, fluorine atom, chlorine, bromine or iodine, preferably fluorine atom or chlorine, more preferably a chlorine atom.

In the formula (I), "C1-C6altergroup" in the definition of R2group, having from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl or 2-ethylbutyrate. Deputy included in R1is preferably C1-C4accelgroup, more preferably methyl or telgraph and, most preferably, methylgroup. In addition, R2preferably represents C1-C4accelgroup, more preferably ethyl, propyl, isopropyl, isobutyl or tertBUTYLPEROXY, most preferably isopropylate.

In the formula (I), "C2-C6alkenyl group" in the definition of R2may be, for example, linear or branched alkenyl group having from 2 to 6 carbon atoms with one or two double bonds, such as vinyl, 1-propenyl, allyl, 1 - methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-1-propenyl, Isopropenyl, alltel, 1-butenyl, 2-butenyl, 3-butenyl, 2 - pentenyl, isoprenyl, 5-hexenyl or 1,4-hexadienyl, preferably vinyl, 1-propenyl, allyl, 1-methyl-1-propagable preferably allgraph.

In the formula (I), "C2-C6alkylalcohol" in the definition of R2may be, for example, linear or branched quinil group having from 2 to 6 carbon atoms, such as ethinyl, 1-PROPYNYL, propargyl, 1-methyl-2-PROPYNYL, 2-methyl-2-PROPYNYL, 2-ethyl-2-PROPYNYL, 2-butynyl, 1-methyl-2-butenyl, 2 - methyl-2-butenyl, 3-butenyl, 2-pentenyl, 5-hexenyl or 2-methyl-4 - pentinga, preferably ethinyl, propargyl, 2-butenyl or 3-butenyl group, more preferably preparinga.

In the formula (I), "C3-C10cycloalkylcarbonyl" in the definition of R2may be, for example, 3 - to 10-membered saturated cyclic hydrocarbon group, which may form a condensed ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl or adamantina, preferably cyclopropyl, cyclopentyl or cyclohexylprop, more preferably cyclopropyl.

In the formula (I), "C3-C10cycloalkenyl" in the definition of R2may be, for example, 3 - to 10-membered unsaturated cyclic hydrocarbon group which may form a condensed ring having one double bond, such as 2-cyclopropyl, 2-cyclobutene heptenyl, 3 norbornanyl or 3-adamantinoma, preferably 2-cyclopentenyl, 3-cyclopentenyl, 2-cyclohexenyl or 3-cyclohexylprop, more preferably 2-cyclopentenyl.

In the formula (I), "C1-C6accelgroup, substituted with halogen in the definition of R2in the definition of the substituent included in R1indicates the group in which 1 to 5 halogen atoms", mentioned above, are associated with the above-mentioned "C1-C6altergroup".

The group in which the halogen is associated with C1-C6altergroup may be, for example, vermeil, deformity, trifluoromethyl, 2-foretel, 2-chloroethyl, 2,2,2-triptorelin, 3 - forproper, 3-chloropropyl, 3-bromopropyl, 4-terbutyl or 6 - itexpo.

Deputy included in R1is preferably C1-C6altergroup substituted by 1-3 halogen atoms or C1-C4alkoxy, more preferably vermeil, deformity, trifluoromethyl, 2-foretel, 2-chloroethyl, 2,2,2-triptorelin, methoxymethyl or methoxyethylmercury, even more preferably trifluoromethyl, 2,2,2-triptorelin or methoxymethyl, the most preferred is triptoreline. In addition, R2preferably indicates theatergruppe, more preferably trifluoromethyl, 2-foretel, 1-chloroethyl, or 2-chlorotalpa, most preferably 1-chlorotalpa.

In the formula (I), "C1-C6alkoxygroup" in the definition of substituent included in R1and in the definition of R2indicates the group in which the above-mentioned "C1-C6altergroup" is connected with an oxygen atom, and such a group can be, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentane, 2-methylbutoxy, neopentylene, 1 ethylpropoxy, hexyloxy, 4-methylpentylamino, 3 methylpentane, 2-methylpentane, 3 methylpentane, 1 methylpentylamine, 3,3-Dimethylbutane, 2,2-Dimethylbutane, 1,1-Dimethylbutane, 1,2-Dimethylbutane, 1,3-Dimethylbutane, 2,3-Dimethylbutane or 2-itivuttaka, preferably C1-C4alkoxygroup, more preferably methoxy or ethoxypropan, most preferably the methoxy group.

In the formula (I), "C6-C14allgraph, optionally having 1 to 3 substituents, which may be the same or different from each other and selected from the following group (a group of substituents is halogen, C1-C6alkyl or C1th group, having from 6 to 14 carbon atoms, optionally having 1 to 3 substituents, which may be the same or different from each other and selected from the group of substituents, and such group may be, for example, phenyl, forfinal, chlorophenyl, dichlorophenyl, were, trimetilfenil, methoxyphenyl, indenyl, methylindenyl, naphthyl, diplomatic, phenanthrene, hexylresorcinol, anthracene, dimethylanthracene or getselectionrange, preferably panelgroup, optionally having one or two substituent which may be the same or different from each other and selected from the group consisting of fluorine, chlorine, methyl and methoxy, more preferably phenyl, 4-forfinal, 4-chlorophenyl, 2,4-dichlorophenyl, 4-were-or 4-methoxyphenyl, most preferably panelgroup.

In the formula (I), "C1-C7alkanoglu" in the definition of substituent included in R1and in the definition of R2indicates the group in which the hydrogen atom or the above-mentioned "C1-C6alkyl associated with carbongraphite, and such group may be, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl or kaptanoglu, preferably formyl Il is kinogruppa" in the definition of R3indicates the group in which the above-mentioned "C1-C6altergroup" is associated with the amino group, and this group may be, for example, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamino, pentylamine or hexylamino, preferably C1-C4alkylamino, more preferably methylamino or etilenovomu, most preferably methylaminopropyl.

In the formula (I) di(C1-C6alkyl)amino" in the definition of R3may be, for example, N, N-dimethylamino, N-ethyl-N-methylamino, N-methyl-N-propylamino, N-isopropyl-N-methylamino, N-butyl-N-methylamino, N-isobutyl-N-methylamino, N-sec-butyl - N-methylamino, N-tert-butyl-N-methylamino, N,N-diethylamino, N-ethyl-N-propylamino, N-ethyl-N-isobutylamino, N,N-dipropylamino, N,N-dibutylamino, N, N-diphenhydamine or N,M is vexillaria, preferably di(C1-C4alkyl) amino group, more preferably N,N-dimethylamino or N,N-diethylaminopropyl, most preferably N,N-dimethylaminopropan.

In the formula (I), "C1-C7alkanolamine" in the definition of R3indicates the group in which the aforementioned "C1-C7alkanoglu" related is SUP> indicates the group in which the above-mentioned "C2-C7alkoxycarbonyl" is associated with the amino group, and this group may be, for example, methoxycarbonylamino, ethoxycarbonylethyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonylamino, solutionline, sec-butoxycarbonylamino, tert-butoxycarbonylamino, ventilatsioonile, isobutylacetophenone, 2-methyl-butoxycarbonylamino, neopentecostalism, 1-ethyl-propoxycarbonyl, hexyloxyphenyl, 4-methyl-ventilatsioonile, 3 methylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl, 1 methylbenzyloxycarbonyl, 3,3-dimethylbutylamino, 2,2-dimethylbutylamino, 1,1-dimethylbutylamino, 1,2-dimethylbutylamino, 1,3-dimethylbutylamino, 2,3-dimethylbutylamino or 2-eterbetalningsbelopp, preferably C2-C5alkoxycarbonylmethyl, more preferably, methoxycarbonylamino or ethoxycarbonylmethoxy, most preferably methoxycarbonylamino.

In the formula (I) mono C7-C15arylcarboxamide, optionally having 1 to 3 substituents, which she is halogen, C1-C6alkyl or C1-C6alkoxy)" in the definition of substituent included in R1and in the definition of R3indicates the group in which the above-mentioned "C6-C14allgraph, optionally having 1 to 3 substituents, which may be the same or different from each other and selected from the following group (a group of substituents is halogen, C1-C6alkyl or C1-C6alkoxy), is linked to carbylamines, and such group may be, for example, benzoylamine, tormentilla, chlorobenzylamino, dichloraniline, toluylene, trimethylindolenine, anisodamine, Ingenierie, methylindoline, naphthylamine, dichlorophenylamino, phenanthroline, existentially, entretenimento, dimethylethanolamine or geksiloksibenzoinaya, preferably benzoylamino, optionally having one or two substituent which may be the same or different from each other and selected from the group consisting of fluorine, chlorine, methyl and methoxy, more preferably benzoylamine, 4-perbenzoic, 4 - chlorobenzylamino, 2,4-dichloraniline, 4 tolylamino or 4 - antelminelli, most preferably Ben is a group attached through a nitrogen atom ring), containing one nitrogen atom and optionally containing one nitrogen atom or an oxygen atom" in the definition of R3may be, for example, pyrrolidinyl, imidazolidinyl, pyrazolidine, piperidyl, piperazinil or morpholinopropan, preferably piperidyl or morpholinyl.

In the formula (I) 5 - or 6-membered aromatic heterocyclic group having one or two heteroatoms, which may be the same or different from each other and selected from the group consisting of nitrogen atoms, oxygen and sulfur" in the definition of R1may be, for example, pyrrolyl, imidazolyl, pyrazolyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl,

In addition, with regard aromatic heterocyclic group, and ring isoxazol, the link is preferably formed on the carbon atom on the aromatic heterocycle.

In the formula (I), X preferably represents an oxygen atom.

In the formula (I), n preferably represents an integer from 2 to 4, more preferably 2.

The compound (I) according to this invention can be converted into additive salt with the acid in the usual way. For example, salt may is, esters or alcohols, especially ethers) at room temperature for 5-30 minutes, and collecting the precipitated crystals by filtration or removal of the solvent by evaporation. Such salt includes a salt of an inorganic acid, such as hydroptere, hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, sulfate and phosphate; salt of sulfonic acid, such as methanesulfonate, triftorbyenzola, aconsultant, bansilalpet and p-toluensulfonate; salt of carboxylic acid, such as fumarate, succinate, citrate, tartrate, oxalate and maleate, and the salt of the amino acids such as glutamate and aspartate, preferably the salt of an inorganic acid (preferably hydrochloride).

The compound (I) according to this invention sometimes have an asymmetric carbon atom in the molecule, and sometimes there are stereoisomers R-configuration and S-configuration. Each stereoisomer or mixture of isomers in an optional proportion, all included in the invention.

The compound (I) and its salt from time to time absorb moisture when they are left in the atmosphere, and they sometimes form hydrates when they are subjected to recrystallization. Such products containing water, also vkluchenija, in which R1represents C6-C14aryl group optionally having from 1 to 3 substituents, which may be the same or different from each other and selected from the following group of substituents, or a 5 - or 6-membered aromatic heterocyclic group containing one heteroatom selected from the group consisting of nitrogen atoms, oxygen and sulfur [a group of substituents is halogen; C1-C6alkyl, C1-C6alkyl substituted by halogen; C1-C6alkoxy; phenyl, phenoxy, benzyloxy; nitro; hydroxyl group; acetoxy; benzoylamine,

(2) compounds in which R1represents C6-C14aryl group optionally having from 1 to 3 substituents, which may be the same or different from each other and selected from the following group of substituents, or a 5 - or 6-membered aromatic heterocyclic group having one or two heteroatoms, which may be the same or different from each other and selected from the group consisting of nitrogen atoms, oxygen and sulfur [a group of substituents is halogen; C1-C6alkyl, C1-C6alkyl substituted by halogen; C1-C6alkoxy; phenyl]

(3) compounds in which R1 is the same or different from each other and selected from the following group of substituents, or 5 - or 6-membered aromatic heterocyclic group containing one heteroatom selected from the group consisting of nitrogen atoms, oxygen and sulfur [a group of substituents is halogen, C1-C4alkyl, vermeil, deformity, trifluoromethyl, 2-foretel, 2,2,2-triptorelin, C1-C4alkoxy, phenyl]

(4) compounds in which R1denotes panelgroup, optionally having 1 to 3 substituents, which may be the same or different from each other and selected from the following substituents, or furyl, thienyl or pyridium [a group of substituents is halogen, methyl, ethyl, trifluoromethyl, methoxy, phenyl, methoxycarbonyl],

(5) compounds in which R1denotes panelgroup, optionally having one or two substituent which may be the same or different from each other and selected from the following group of substituents, or furyl, thienyl or pyridium [a group of substituents is fluorine, chlorine, methyl, ethyl, trifluoromethyl and methoxy group],

(6) compounds in which R1denotes phenyl, forfinal, chlorophenyl, differenl, dichlorophenyl, were, 2-furyl, 3-furyl, 2-thienyl or 3-tailgroup,

(7) compounds in which R1denotes the where R2denotes hydrogen, halogen, C1-C6alkyl, vermeil, deformity, trifluoromethyl, 2-foretel, 1-chloroethyl, 2-chloroethyl, 2,2,2-triptorelin, methoxymethyl, methoxyethyl, C2-C6alkenyl, C2-C6quinil, cyclopropyl, cyclopentyl, cyclohexyl, 2-cyclopentenyl, 3-cyclopentenyl, 2-cyclohexenyl, 3-cyclohexenyl, methoxy, ethoxy, cyano, carboxyl, formyl, acetyl, methoxycarbonyl, etoxycarbonyl, carbarnoyl, methylcarbamoyl, ethylcarbitol or N,N-dimethylcarbamoyl.

(9) compounds in which R2denotes hydrogen, halogen, C1-C6alkyl, C2-C6alkenyl or C2-C6Altenilpe,

(10) compounds in which R2denotes hydrogen, halogen, C1-C4alkyl, allyl, Isopropenyl, 2-butenyl or properlyhow,

(11) compounds in which R2denotes hydrogen, chlorine, ethyl, propyl, isopropyl, isobutyl or tert-bodygraph,

(12) compounds in which R2denotes hydrogen or isopropylate,

(13) compounds in which R3denotes amino, mono-C1-C6alkylamino, di(C1-C6alkyl) amino or 5 - or 6-membered saturated heterocyclic group (provided that the group presideclared,

(14) compounds in which R3denotes amino, methylamino, ethylamino, N,N-dimethylamino, piperidyl or morpholinyl,

(15) compounds in which R3denotes an amino group,

(16) compounds in which X denotes an oxygen atom, and

(17) compounds in which n is 2.

The preference for R1increases in ascending order from (1) to (7), R2increases in ascending order from (8) to (12) and R3increases in ascending order from (13) to (15).

In addition, the compounds of formula (I) include combinations of from two to five, selected from the group consisting of(1)-(7), (8)-(12), (13)-(15), (16) and (17), and preferred examples of such combinations are shown below.

(18) compounds in which R1represents C6-C14airgroup, optionally having 1 to 3 substituents, which may be the same or different from each other and selected from the following group of substituents, or a 5 - or 6 - membered aromatic heterocyclic group optionally have 1 to 3 substituents and having one or two heteroatoms, which may be the same or different from each other and selected from the group consisting of nitrogen atoms, oxygen and sulfur [group replacing the C6alkoxy, C1-C6alkoxy, C6-C14aryl, optionally having 1 to 3 substituents, which may be the same or different from each other and selected from the following group (a group of substituents is halogen, C1-C6alkyl or C1-C6alkoxy; cyano; C2-C7alkoxycarbonyl; carbarnoyl; mono (C1-C6alkyl) carbarnoyl and di(C1-C6alkyl) karmamarga],

R2denotes hydrogen, halogen, C1-C6alkyl, C2-C6alkenyl or C2-C6Altenilpe, and

R3denotes amino, mono-C1-C6alkylamino, di(C1-C6alkyl) amino group or a 5 - or 6-membered saturated heterocyclic group (provided that the group attached through a nitrogen atom of the ring containing one nitrogen atom and one nitrogen atom or oxygen.

(19) compounds in which R1represents C6-C14airgroup, optionally having 1 to 3 substituents, which may be the same or different from each other and selected from the following group of substituents, or a 5 - or 6 - membered aromatic heterocyclic group optionally have 1 to 3 substituents and having about is the present from nitrogen atoms, oxygen and sulfur [a group of substituents is halogen, C1-C6alkyl, C1-C6alkyl substituted by halogen or C1-C6alkoxy, C1-C6alkoxy, C6-C14aryl, optionally having 1 to 3 substituents, which may be the same or different from each other and selected from the following group [a group of substituents is halogen, C1-C6alkyl or C1-C6alkoxy; cyano; C2-C7alkoxycarbonyl; carbarnoyl; mono(C1-C6alkyl)carbarnoyl and di(C1-C6alkyl)karmamarga],

R3denotes hydrogen, halogen, C1-C6alkyl, C2-C6alkenyl or C2-C6Altenilpe,

R3denotes an amino group,

X denotes an oxygen atom, and

n is 2,

(20) compounds in which R1represents C6-C14aryl group optionally having from 1 to 3 substituents, which may be the same or different from each other and selected from the following group of substituents, or a 5 - or 6-membered aromatic heterocyclic group optionally having one or two substituent and having one or two heteroatoms, which may be the same or who is halogen, C1-C4alkyl, vermeil, deformity, trifluoromethyl, 2-foretel, 2,2,2-triptorelin, methoxymethyl, methoxyethyl, C1-C4alkoxy, phenyl, 4-forfinal, 4-chlorophenyl, 2,4-dichlorophenyl, 4-were, 4-methoxyphenyl, cyano, methoxycarbonyl, etoxycarbonyl, carbarnoyl, methylcarbamoyl, ethylcarbitol, N,N-dimethylcarbamoyl and N,N-diethylcarbamoyl],

R2denotes hydrogen, halogen, C1-C4alkyl, allyl, Isopropenyl, 2-butenyl or properlyhow,

R3denotes an amino group,

X denotes an oxygen atom, and

n is 2,

(21) compounds in which R1denotes panelgroup, optionally having 1 to 3 substituents, which may be the same or different from each other and selected from the following group of substituents, or furyl, thienyl or pyridium, optionally having one or two Deputy [a group of substituents is halogen, methyl, ethyl, trifluoromethyl, methoxy, phenyl, cyano, methoxycarbonyl, carbarnoyl, methylcarbamoyl, ethylcarbitol and N,N - dimethylcarbamoyl],

R2denotes hydrogen, halogen, C1-C4alkyl, allyl, Isopropenyl, 2-butenyl or properlyhow,

R3denotes an amino group,

X osoznanno having one or two substituent, which may be the same or different from each other and selected from the following group of substituents, or furyl, thienyl or pyridium, optionally having one Deputy [a group of substituents is fluorine, chlorine, methyl, ethyl, trifluoromethyl and methoxy group] ,

R2denotes hydrogen, chlorine, ethyl, propyl, isopropyl, isobutyl or tert-bodygraph,

R3denotes an amino group,

X denotes an oxygen atom, and

n is 2,

(23) compounds in which R1denotes forfinal, chlorophenyl, differenl, dichlorophenyl, were, 2-furyl, 3-furyl, 2-thienyl or 3-tailgroup,

R2denotes hydrogen, chlorine, ethyl, propyl, isopropyl, isobutyl or tert-bodygraph,

R3denotes an amino group,

X denotes an oxygen atom, and

n is 2,

(24) compounds in which R1denotes phenyl, 2-chlorophenyl, 4-chlorophenyl, 2,4-differenl, 2,4-dichlorophenyl, 2-furyl or 2-tailgroup,

R2denotes a hydrogen atom or isopropylate,

R3denotes an amino group,

X denotes an oxygen atom, and

n is 2.

With regard to the compounds described above, the degree of preference of connections increases in ascending order, the invention is not limited to them.

In table. 1 used the following abbreviations:

Ac: Acetyl

All: Allyl

Bn: Benzyl

Bu: Butyl

Bui: Isobutyl

Bus: sec-Butyl

But: tert-Butyl

Bun (2): 2-Butenyl

Bz: Benzoyl

Et: Ethyl

Fur (2): 2-furyl

Hex: Hexyl

Imid (2): 2-Imidazolyl

Inde (1): 1-Indenyl

Isothiz (3): 3-Isothiazolin

Isox (3): 3-Isoxazolyl

Me: Methyl

Moc: Methoxycarbonyl

Mor (4): 4-Morpholinyl

Np (1): 1-Naphthyl

Np (2): 2-Naphthyl

Oxa (2): 2-Oxazolyl

Penc(2): 2-Cyclopentenyl

Ph: Phenyl

Pip (1): 1-Piperidyl

Piz (1): 1-Piperazinil

Pn: Pencil

Phc: Cyclopentyl

Pni: Isopentyl

Pr: Propyl

Rrc: Cyclopropyl

Pri: Isopropyl

Prei: Isopropenyl

Prg: Propargyl

Pym is not (2): 2-Pyrimidinyl

Pyr (2): 2-Pyridyl

Pyr (3): 3-Pyridyl

Pyr (4): 4-Pyridyl

Pyrd (1): 1-Pyrrolidinyl

Pyrr (3): 3-Pyrrolyl

Pyz (2): 2-Pyrazinyl

Pyza (1): 1-Pyrazolyl

Pyzn (3): 3-Pyridazinyl

Thi (2): 2-Thienyl

Thi (3): 3-Thienyl

Thiz (2): 2-Thiazolyl

< / BR>
From isoxazol derivative, are presented in table. 1 of the invention, preferred compounds are

1, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 25, 27, 28, 29, 30, 32, 368, 190, 194, 206, 208, 212, 224, 226, 230, 242, 244, 248, 260, 262, 263, 264, 266, 278, 296, 298, 314, 316, 332, 334, 350, 357, 363, 368, 379, 386, 397, 408, 469, 475, 481, 505, 510, 511, 517, 523, 535, 538, 539, 540, 541, 542, 543, 544, 545, 546, 562, 568, 574, 580, 586, 592, 598, 604, 610, 616, 622, 628, 724, 728, 729, 730, 731, 732, 733, 752, 764, 776, 788, 794, 800, 806, 812, 818, 824, 1056, 1061, 1347, 1348, 1349, 1350, 1351, 1357, 1359, 1386, 1388, 1390, 1392, 1394, 1396, 1398, 1400, 1402, 1404, 1406, 1408, 1410, 1412, 1414, 1416, 1459, 1495, 1499, 1500, 1526, 1545, 1549, 1550, 1576, 1590, 1604, 1618, 1632, 1646, 1660, 1674, 1688, 1702, 1716, 1809 or 1811,

more preferred compounds are

1, 4, 5, 6, 7, 8, 9, 11, 13, 14, 15, 30, 32, 36, 48, 50, 54, 66, 70, 74, 93, 95, 99, 111, 113, 117, 125, 127, 131, 143, 147, 149, 150, 151, 170, 172, 176, 188, 190, 194, 206, 208, 212, 224, 226, 230, 242, 244, 248, 260, 262, 263, 264, 266, 278, 296, 298, 314, 316, 332, 334, 350, 357, 363, 368, 379, 386, 397, 408, 469, 475, 481, 505, 510, 511, 517, 523, 535, 538, 539, 540, 541, 542, 543, 544, 545, 546, 562, 568, 574, 580, 586, 592, 598, 604, 610, 616, 622, 628, 724, 728, 729, 730, 731, 732, 733, 752, 764, 776, 788, 794, 800, 806, 812, 818, 824, 1056, 1061, 1392, 1394, 1398, 1809 or 1811,

even more preferred compounds are 1, 4, 5, 6, 7, 8, 9, 11, 13, 14, 15, 30, 48, 66, 74, 93, 111, 117, 125, 143, 149, 150, 151, 170, 176, 188, 206, 224, 242, 260, 296, 314, 332, 350, 368, 386, 408, 469, 475, 481, 505, 510, 511, 517, 523, 535, 538, 539, 543, 568, 586, 598, 604, 622, 724, 733, 1392, 1394 or 1398, and in particular, the preferred compounds are 1, 4, 5, 6, 7, 8, 9, 11, 13, 66, 93, 111, 117, 125, 143, 149, 150, 151, 170, 176, 224, 260, 332, 386, 510, 535, 539, 543, 604, 1392, 1394 or 1398.

The most preferred compounds are:

Compound No. 1: 3-(2-N 7: 3-(2-aminoethoxy)-4-ethyl-5-phenylisoxazol.

The compound N 8: 3-(2-aminoethoxy)-5-phenyl-4-propylenoxide.

The compound N 9: 3-(2-aminoethoxy)-4-isopropyl-5-phenylisoxazol.

Compound No. 11: 3-(2-aminoethoxy)-4-isobutyl-5-phenylisoxazol.

The compound N 117: 3-(2-aminoethoxy)-5-(2-chlorophenyl)-4 - isopropylthiazole.

The compound N 143: 3-(2-aminoethoxy)-5-(4-chlorophenyl)-isoxazol.

The compound N 151: 3-(2-aminoethoxy)-5-(4-chlorophenyl)-4-isopropylthiazole.

The compound N 176: 3-(2-aminoethoxy)-5-(2,4-dichlorophenyl)- 4-isopropylthiazole.

The compound N 510: 3-(2-aminoethoxy)-5-(2-furyl)-4-isopropylthiazole.

The compound N 535: 3-(2-aminoethoxy)-5-(2-thienyl)isoxazol.

The compound N 539: 3-(2-aminoethoxy)-4-chloro-5-(2-thienyl)isoxazol.

The compound N 543: 3-(2-aminoethoxy)-4-isopropyl-5-(2-thienyl)isoxazol or

The compound N 1392: 4-allyl-3-(2-aminoethoxy)-5-phenyl-isoxazol.

Methods of making compounds of this invention are illustrated below.

Method A (see the end of the description).

The protective group of an amino group or a mono C1-C6alkylamino Ra3can be used without particular limitations, as long as this group is used as a protective group for amine, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl or hexanoyl group; C1-C4alkanoyloxy substituted by halogen or C1-C4alkoxy, such as chloroacetyl, dichloroacetyl, trichloroacetyl, TRIFLUOROACETYL, 3-forproposal, 4,4-dichlorobutene, methoxyacetyl, butoxyethyl, ethoxypropanol or propoxymethyl group, unsaturated C1-C4alkanoyloxy, such as acryloyl, propiolic, methacryloyl, crotonoyl or isocrotonic group; C6-C10arylcarboxylic, optionally substituted with halogen, C1-C4the alkyl, C1-C4alkoxy, C1-C4alkoxycarbonyl, C6-C10the aryl or nitro, such as benzoyl, - -naphtol - naphtol, 2-perbenzoic, 2-bromobenzoyl, 2,4-dichlorobenzoyl, 6-chloro-naphtol, 4-toluoyl, 4-propylbenzyl, 4-tert-butylbenzoyl, 2,4,6-trimethylbenzoyl, 6-ethyl-naphtol, 4-anisoyl, 4-propoxyphenol, 4-tert-butoxybenzoyl, 6-ethoxy--naphtol, 2-ethoxycarbonylbutyl, 4-tert-butoxycarbonylmethyl, 6-methoxycarbonyl--naphtol, 4-phenylbenzyl, 4-phenyl-naphtol, 6--nativeson, 4-nitrobenzoyl, 2-nitrobenzoyl or 6-nitro-aftercrop; C1-C4alkoxycarbonyl, optionally substituted with halogen or three, C is the IMT, butoxycarbonyl, isobutoxide, second-butoxycarbonyl, tert-butoxycarbonyl, chlorocarbons, 2,2,2-trichlorocyanuric, 2-forprofessional, 2-bromo-tert-butoxycarbonyl, 2,2-dibromo-tert - butoxycarbonyl, triethylchlorosilane, 2-trimethylsilylethynyl, 4-dipropylenetriamine or tert-butyldimethylchlorosilane; C2-C5alkenylcyclopropenes, such as vinyloxycarbonyl, allyloxycarbonyl, 1,3-butadienestyrene or 2-interracialporno; aryldiazonium, such as talergroup; arlbergpass, such as benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl-naphthylmethyl-naphthylmethyl, diphenylmethyl, triphenylmethyl or aftermarketgroup or 9-intelligroup; or C7-C15uralelectromontrage, optionally substituted by methoxy or nitro, such as benzyloxycarbonyl, (1-phenyl)benzyloxycarbonyl-naphthylenediamine-naphthylenediamine, 9-antimetastasis, p-methoxybenzenesulfonyl or p-nitrobenzenediazonium, preferred C1-C4alkanoyl; TRIFLUOROACETYL; methoxyacetyl; benzoylurea; -naphtol; -naphtol; anisoyl; nitrobenzoyl; C1-C4alcox oxycarbonyl; 2-trimethylsilylethynyl; vinyloxycarbonyl; allyloxycarbonyl; phthaloyl; benzyl; benzyloxycarbonyl or nitrobenzenediazonium preferably formyl, acetyl, benzoyl, 4-anisoyl, 4-nitrobenzoyl, methoxycarbonyl, etoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, phthaloyl, benzyl, benzyloxycarbonyl or p-nitrobenzenediazonium preferred tert-butoxycarbonyl.

Leaving group Y does not particularly limited, while it is a common leaving group, as nucleophilic residual group, and may be, for example, a halogen atom, such as chlorine atoms, bromine and iodine; C1-C4alkanesulfonyl, such as methanesulfonate, econsultancy, propanesulfonate or butanesulfonate; halogen-(C1-C4alkanesulfonyl, such as tripterocalyx, 2,2,2-trichloroacetonitrile, 3,3,3-tribromophenoxy or 4,4,4-tripterocalyx; or C6-C10arylsulfonamides, optionally having from one to three C1-C4Akilov, such as benzosulfimide, naftiliaki, naftiliaki, p-toluensulfonate, 4-Trey chlorine atoms, bromine or iodine, methanesulfonate, econsultancy, tripterocalyx, 2,2,2-trichloroacetonitrile, benzosulfimide, toluensulfonate or mesitylenesulfonic preferably chlorine atoms, bromine or iodine, methanesulfonate, tripterocalyx, benzosulfimide, p-toluensulfonate or mesitylenesulfonic.

The halogen atom Z can be, for example, fluorine atoms, chlorine, bromine or iodine and preferably chlorine atom.

Method a is a method for the synthesis of compounds of General formula (I).

At stage A1, the compound of formula (III) are obtained by reaction of compound (II) with a halogenation agent in an inert solvent or without solvent (preferably in an inert solvent in the presence of a base or without (preferably in the presence of a base).

Solvent used is not specifically limited, if it does not interfere with the reaction and can dissolve a certain amount of source material. Examples of suitable solvents may be aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; anbesol or dichlorobenzene; or ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol, preferably halogenated hydrocarbons (particularly methylene chloride) or ethers (particularly tetrahydrofuran or dioxane).

Used can be based, for example, carbonates of alkali metals such as sodium carbonate, potassium carbonate or lithium carbonate; acid carbonates (bicarbonates) of alkali metals, such as sodium bicarbonate, potassium bicarbonate or lithium bicarbonate; and organic amines such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N, N-dimethylamino)pyridine, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo-[2.2.2]octane (DABCO) or 1,8-diazabicyclo[5.4.0] undec-7-ene (DBU), preferably the carbonates of alkali metals or organic amines, preferably organic amines (in particular, triethylamine or pyridine).

The halogenation agent for use herein may be, for example, phosphorus oxychloride, oxybromide phosphorus, oxided phosphorus or pentachloride phosphorus or their mixture, preferably phosphorus oxychloride, the waters of the starting material and the reagent, and is usually from 0oC to 150oC, preferably from 10 to 100oC.

The reaction time may vary depending on the nature of the source material, the reagent and the reaction temperature and is usually from 30 minutes to 10 hours, preferably from 1 to 5 o'clock

After completion of the reaction, the target compound of this phase is recovered from the reaction mixture by usual method. For example, the target compound is obtained by removal of the solvent by evaporation, adding water to the reaction mixture, adding a hydrophobic solvent (e.g. benzene, simple ether, ethyl acetate, etc.,) to the mixture for extraction of the target compounds, washing of extracted organic layer with water, drying it over anhydrous magnesium sulfate and removal of solvent by evaporation. Thus obtained target compound can be subjected to further purification, if necessary, a conventional method, for example by recrystallization, re-precipitation or chromatography.

At stage A2, the compound of formula (V) are obtained by reacting compound (III) with a compound of General formula (IV) in an inert solvent in the presence of a base.

Solvent used is not specifically limited, if rastvoritelei can be aliphatic hydrocarbons, such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol; amides, such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; or sulfoxidov, such as dimethylsulfoxide or sulfolane, preferably ethers (in particular, diethyl ether, tetrahydrofuran or dioxane) or amides (particularly dimethylformamide).

Used can be based, for example, carbonates of alkali metals such as sodium carbonate, potassium carbonate or lithium carbonate; acid carbonates (bicarbonates) of alkali metals, such as sodium bicarbonate, potassium bicarbonate or bicarbonate of lithium; hydrides of alkali metals such as lithium hydride, sodium hydride or potassium hydride; hydroxides of alkali metals such as sodium hydroxide, potassium hydroxide or lithium hydroxide; organic amines such as triethylamine, tributylamine, ,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo-[2.2.2] octane (DABCO) or 1,8-diazabicyclo[5.4.0] undec-7-ene (DBU); acility, such as motility, utility or utility; or alkylamide lithium, such as diisopropylamide lithium, or dicyclohexylamine lithium, preferably the carbonates of alkali metals, hydrides of alkali metals or organic amines, preferably the carbonates, alkali metal (particularly sodium carbonate or potassium carbonate) or hydrides of alkali metals (in particular, sodium hydride).

In this case, for the more effective carrying out of the reaction to the reaction mixture can also be added simple crown ethers such as dibenzo-18-crown-6.

The reaction temperature may vary depending on the nature of the starting material and the reagent, and is usually from -10oC to 150oC, preferably from 0oC to 80oC.

The reaction time may vary depending on the nature of the source material, the reagent and the reaction temperature and is usually from 30 minutes to 30 hours, preferably from 1 to 10 hours

After completion of the reaction, the target compound of this phase is recovered from the reaction mixture by usual method. For example, the target connection get pobjedio, in the case where there are insoluble substances, removing the solvent by evaporation, adding water to the reaction mixture, adding a hydrophobic solvent (e.g. benzene, simple ether, ethyl acetate, etc.,) to the mixture for extraction of the target compounds, washing of extracted organic layer with water, drying the organic layer containing the desired product over anhydrous magnesium sulfate and removal of solvent by evaporation. Thus obtained target compound can be subjected to further purification, if necessary, a conventional method, for example by recrystallization, re-precipitation or chromatography.

On stage A3 compound of General formula (I) is obtained by removal of the protective group of an amino group or alkylamino, if necessary.

The removal of the protective group of amino group varies depending on the type of its, and its exercise is usually as follows, the conventional method in organic chemistry.

When the protective group of the amino group is C1-C6alkanoglu (preferably formyl or hazelgrove); C6-C10kilcarbery (preferably benzoylurea); C12-C5alkenylcarbazoles (preferably vinyloxycarbonyl); or (C7-C15aracelikarsaalyna, optionally substituted by methoxy or nitro (preferably benzyloxycarbonyl, (1-phenyl)benzyloxycarbonyl, 9-antrel-methoxycarbonyl, p-methoxybenzenesulfonyl or p-nitrobenzenediazonium), it can be removed by treatment with acid in an inert solvent or aqueous solvent. In addition, in this case, the target compound can be also obtained as a salt. Acid for use herein may be, for example, acid such as chloromethane acid, sulfuric acid, phosphoric acid, Hydrobromic acid or triperoxonane acid, preferably chloromethane acid, sulfuric acid, Hydrobromic acid or triperoxonane acid.

Solvent used is not specifically limited, if it does not interfere with the reaction and can dissolve a certain amount of source material. Examples of suitable solvents may be aliphatic uglevodorov or xylene; halogenated hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol; esters such as methyl acetate or ethyl acetate; alcohols such as methanol, ethanol, propanol, isopropanol or butanol; amides, such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; sulfoxidov, such as dimethylsulfoxide or sulfolane; aliphatic acids such as formic acid or acetic acid; water; or a water mixture of the above solvents, preferably halogenated hydrocarbons, ethers, alcohols, aliphatic acid or an aqueous mixture of the above solvents, preferably halogenated hydrocarbons (particularly methylene chloride), ethers (particularly tetrahydrofuran or dioxane), aliphatic acids (particularly acetic acid) water or an aqueous mixture of the above solvent.

The reaction temperature may vary depending on the nature of the source material used solvent or the reaction Time may vary depending on the nature of the source material, used solvent or acid and is usually from 5 minutes to 20 hours, preferably from 10 min to 5 h

After completion of the reaction, the target compound of this phase is recovered from the reaction mixture by usual method. For example, the target compound is obtained by collecting the precipitated target compound in the reaction mixture by filtration or the corresponding neutralization of the reaction mixture, removal of the solvent by evaporation, adding water to the reaction mixture, adding a hydrophobic solvent (e.g. benzene, simple ether, ethyl acetate, etc.,) to the mixture for extraction of the target compounds, washing of extracted organic layer with water, drying the organic layer containing the target compound over anhydrous magnesium sulfate and removal of solvent by evaporation. Thus obtained target compound can be subjected to further purification, if necessary, by conventional methods, for example by recrystallization, re-precipitation or chromatography.

When the protective group of the amino group is alkanoyl, arylcarbamoyl, alkenylacyl, aprildecember, aralkyl or Uralelectromed, it can be removed put the m can be for example, a carbonate of an alkali metal such as sodium carbonate, potassium carbonate or lithium carbonate; an acid carbonate (bicarbonate) an alkali metal such as sodium bicarbonate, potassium bicarbonate or bicarbonate of lithium; alkali metal hydride such as lithium hydride, sodium hydride or potassium hydride; alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide; alkali metal alkoxide such as sodium methoxide, ethoxide sodium tert-piperonyl potassium or lithium methoxide; mercaptide alkali metal, such as methylmercaptan sodium or ethylmercaptan sodium, preferably the carbonates of alkali metals (in particular, sodium carbonate or potassium carbonate or a hydroxide of alkali metal (in particular sodium hydroxide or potassium hydroxide), alkoxides of alkali metals (in particular, sodium methoxide, ethoxide or sodium tert-piperonyl potassium) or organic amines (in particular, hydrazine or methylamine).

Solvent used is not specifically limited, if it does not interfere with the reaction and can dissolve a certain amount of source material. Examples of suitable solvents may be aliphatic hydrocarbons such as hexane, g ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol; alcohols, such as methanol, ethanol, propanol, isopropanol or butanol; amides, such as dimethylacetamide or hexamethylphosphoric triamide; sulfoxidov, such as dimethylsulfoxide or sulfolane, or an aqueous mixture of the above solvents, preferably halogenated hydrocarbons, ethers, alcohols or aqueous mixture of the above solvent, more preferably ethers (particularly tetrahydrofuran or dioxane), alcohols (particularly methanol or ethanol) or an aqueous mixture of the above solvent.

The reaction temperature may vary depending on the nature of the source material used solvent or base and is usually from -10oC to 150oC, preferably from 0oC to 50oC.

The reaction time may vary depending on the nature of the source material used solvent or base and is usually from 30 minutes to 20 hours, preferably from 1 to 5 o'clock

After completion of the reaction, the target compound of this phase is recovered from the reaction mixture by usual method. For example, the project or the removal of the solvent by evaporation, adding water to the reaction mixture, the precipitate from the mixture by filtration or by adding a hydrophobic solvent (e.g. benzene, simple ether, ethyl acetate, etc.,) to the mixture for extraction of the target compounds, washing of extracted organic layer containing the target compound with water, drying it over anhydrous magnesium sulfate and removal of solvent by evaporation. Thus obtained target compound can be subjected to further purification, if necessary, by conventional methods, for example by recrystallization, re-precipitation or chromatography.

Further, when the protective group of the amino group is tert-butoxycarbonyl, it can be removed by processing silyl connection or especially acid in an inert solvent.

Silyl connection for use here may be, for example, trimethylsilyloxy, trimethylsilylmethyl or trimethylsilyl-triftorbyenzola.

Used here, the acid may be, for example, aluminum chloride, chloromethane acid or triperoxonane acid.

Solvent used is not specifically limited, if it does not interfere with rogut be halogenated hydrocarbons, such as methylene chloride, chloroform or carbon tetrachloride; ethers, such as diethyl ether, tetrahydrofuran or dioxane, NITRILES, such as acetonitrile, preferably halogenated hydrocarbons (particularly methylene chloride or chloroform) or a nitrile (particularly acetonitrile).

The reaction temperature may vary depending on the nature of the source material, reagent or solvent and is usually from -20oC to 100oC, preferably from 0oC to 50oC.

The reaction time may vary depending on the nature of the source material, reagent, solvent, or the reaction temperature and is usually from 10 minutes to 10 hours, preferably from 30 minutes to 3 hours

After completion of the reaction, the target compound of this phase is recovered from the reaction mixture by usual method. For example, the target compound is obtained by separation of the precipitated desired compound from the reaction mixture by filtration or the addition of water to the reaction mixture, alkalizing water layer to separate the precipitated compounds from the mixture by filtration or by adding a hydrophobic solvent (e.g. benzene, simple ether, ethyl acetate, etc.,) it is received from the imposition, water, drying it over anhydrous magnesium sulfate and removal of solvent by evaporation. Thus obtained target compound can be subjected to further purification, if necessary, in the usual way, for example by recrystallization, re-precipitation or chromatography.

Further, when the protective group of the amino group is allyloxycarbonyl, it can be removed using palladium and triphenylphosphine or tetracarbonylnickel under the reaction conditions such as solvent, reaction temperature, reaction time and the like, similar to the reaction conditions removal Uralkaliy etc. catalytic reductive reagent.

When the protective group of the amino group is kalkilya or C7-C11aralkylamines, the protective group can be easily removed by contacting it with a reducing agent (preferably catalytic hydrogenation reaction in the presence of a catalyst) in an inert solvent or by reacting removal using an oxidizing agent.

In the case of the reaction of removing the protective group by catalytic hydrogenation reactions in the catalytic reduction, ISOE is rastvoritelei can be aliphatic hydrocarbons, such as hexane or cyclohexane; aromatic hydrocarbons such as toluene, benzene or xylene; ethers, such as diethyl ether, tetrahydrofuran or dioxane; esters, such as ethyl acetate or propyl; alcohols such as methanol, ethanol or isopropanol; aliphatic acids such as formic acid or acetic acid, or an aqueous mixture of the above solvents, preferably aliphatic hydrocarbons, ethers, esters, alcohols, aliphatic acid or an aqueous mixture of the above solvent, more preferably an alcohol (particularly methanol or ethanol), aliphatic acids (in particular formic acid or acetic acid) or an aqueous mixture of the above solvent.

The used catalyst is not specifically limited, if it does not interfere with the reaction of catalytic reduction. Examples of suitable catalysts may be palladium black, palladium - carbon, Raney Nickel, rhodium-aluminum oxide or palladium-barium sulfate, preferably palladium-carbon or Raney Nickel.

The hydrogen pressure is not specifically limited, and it is usually between 1 and 10 atmospheric pressure, preferably 1-atmospheric-used solvent and reductant and is typically 0oC to 100oC, preferably from 0oC to 50oC.

The reaction time may vary depending on the nature of the source material, solvent, reducing agent or the reaction temperature and is usually from 15 min to 10 h, preferably from 30 minutes to 3 hours

After completion of the reaction, the target compound of this phase is recovered from the reaction mixture by usual method. For example, the target compound is obtained by removal of the catalyst by filtration, removal of solvent by evaporation, adding water to the reaction mixture, alkalizing the aqueous layer to precipitate from the mixture by filtration or by adding a hydrophobic solvent (e.g. benzene, simple ether, ethyl acetate, etc.,) to the mixture for extraction of the desired compound, washing the organic layer containing the desired compound with water, drying it over anhydrous magnesium sulfate and removal of solvent by evaporation. Thus obtained target compound can be subjected to further purification, if necessary, in the usual way, for example by recrystallization, re-precipitation or chromatography.

The reaction of removing the protective group by oxidation ispolzuya can be ketones, such as acetone; halogenated hydrocarbons, such as methylene chloride, chloroform or carbon tetrachloride; NITRILES, such as acetonitrile; ethers, such as diethyl ether, tetrahydrofuran or dioxane; amides, such as dimethylformamide, dimethylacetamide or hexamethylphosphoric treated; sulfoxidov, such as dimethylsulfoxide, water or a mixture of the above solvent, preferably ketones, halogenated hydrocarbons, NITRILES, ethers, amides, sulfoxidov or an aqueous mixture of the above solvent, more preferably ketones (particularly acetone), halogenated hydrocarbons (particularly methylene chloride), nitrile (particularly acetonitrile), amides (in particular, hexamethylphosphoric triamide), sulfoxidov (in particular, dimethyl sulfoxide), or a water mixture of the above solvent.

Oxidant for use here may be, for example, potassium persulfate, sodium persulfate, cerium nitrate-ammonium (CAN) or 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), preferably cerium nitrate-ammonium (CAN) or 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ).

The reaction temperature may vary depending on the nature of the source material used S="ptx2">

The reaction time may vary depending on the nature of the source material, solvent and oxidant and is usually from 15 minutes to 24 hours, preferably from 30 minutes to 5 hours

After completion of the reaction, the target compound of this phase is recovered from the reaction mixture by usual method. For example, the target compound is obtained by removal of the oxidizing agent by filtration, removal of solvent by evaporation, adding water to the reaction mixture, alkalizing water layer to separate the precipitate by filtration or by adding a hydrophobic solvent (e.g. benzene, simple ether, ethyl acetate, etc.,) to the mixture for extraction of the desired compound, washing the organic layer containing the desired compound with water, drying it over anhydrous magnesium sulfate and removal of solvent by evaporation. Thus obtained target compound can be subjected to further purification, if necessary, in the usual way, for example by recrystallization, re-precipitation or chromatography.

In addition, when the protective group of the amino group is removed with acid, the desired compound usually obtained in the form of a salt, but the amino group of the desired compounds m the content of inorganic fillers chemistry.

Method B is an alternative method of synthesis of compound (Va), where X denotes the oxygen atom in the intermediate compound (V) Process A.

At stage B1, the compound of formula (Va) are obtained by reacting the compounds of formula (II) with the compound of the formula (IVa).

In the case where Y denotes a hydroxyl group, the reaction is carried out by dehydration-condensation between the compound (II) and the corresponding compound (IVA) in an inert solvent in the presence of a phosphine compound and azo compounds, as performed on the basis of the Mitsunobu reaction described in Bull. Chem. Soc. Jap., 40, 2380 (1967).

Solvent used is not specifically limited, if it does not interfere with the reaction and can dissolve a certain amount of source material. Examples of suitable solvents may be aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; or ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl EF the market, more preferably ethers (particularly diethyl ether or tetrahydrofuran).

The phosphine compound for use herein may be, for example, three-C1-C6alkylphosphine, such as trimethylphosphine, triethylphosphine, tripropyltin, tributylphosphine, triphenylphosphine or trihexalon; three-C6-C10arylphosphine, such as triphenylphosphine, TryEngineering or trination; or three-C6-C10arylphosphine, optional with C1-C4alkyl as a substituent, such as maildefinition, trailerforum, trimethyltin, tributylphosphine or three-6-ethyl-2-natterposted, preferably three-C1-C6alkylphosphine (in particular, trimethylphosphine, triethylphosphine, tripropyltin or tributylphosphine) or three-C6-C10arylphosphine (particularly triphenylphosphine, TryEngineering or trination, more preferably three-C6-C10arylphosphine (particularly triphenylphosphine).

Uzasadnienie to use here is not specifically limited, as long as it is well-known derivatives of azodicarboxylic acid, and may be, for example, di-C1-C4alkyl-azodicarboxylate, such as dimethyl-AZ is positive dimethyl-azodicarboxylate or diethyl-azodicarboxylate.

The reaction temperature may vary depending on the nature of the starting material and the reagent, and is usually from -10oC to 100oC, preferably from 0oC to 50oC.

The reaction time may vary depending on the nature of the source material, the reagent and the reaction temperature and is usually from 15 min to 48 h, preferably from 30 minutes to 24 hours

After completion of the reaction, the target compound of this phase is recovered from the reaction mixture by usual method. For example, the target compound is obtained by removal by filtration of insoluble substances when they are present, or adding water to the residue obtained by removing the solvent by evaporation, adding a hydrophobic solvent (e.g. benzene, simple ether, ethyl acetate, etc.,) to the mixture to perform the extraction, washing the extract with water, drying over anhydrous magnesium sulfate and removal of solvent by evaporation. Thus obtained target compound can be subjected to further purification, if necessary, in the usual way, for example by recrystallization, re-precipitation or chromatography.

In the case where Y denotes a leaving group, compounds and base in an inert solvent.

Solvent used is not specifically limited, if it does not interfere with the reaction and can dissolve a certain amount of source material. Examples of suitable solvents may be aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol; amides, such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; or sulfoxidov, such as dimethylsulfoxide or sulfolane, preferably amides and sulfoxidov, more preferably amides (particularly dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide).

Used may be, for example, a carbonate of an alkali metal such as sodium carbonate, potassium carbonate or lithium carbonate; an acid carbonate of an alkali metal such as sodium bicarbonate, potassium bicarbonate or bicarbonate of lithium; the hydride is how the sodium hydroxide, the potassium hydroxide or lithium hydroxide; alkali metal alkoxide such as sodium methoxide, ethoxide sodium tert-piperonyl potassium or lithium methoxide; mercaptide alkali metal, such as methylmercaptan sodium or ethylmercaptan sodium; organic amine, such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO) or 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU); acility, such as motility, utility or utility; or alkylamide lithium, such as diisopropylamide lithium or dicyclohexylamine lithium, preferably the carbonates of alkali metals, hydrides of alkali metals or hydroxides of alkali metals, more preferably hydrides of alkali metals (in particular, sodium hydride).

To improve the reaction may be added simple crown ether, such as dibenzo-18-crown-6.

The reaction temperature may vary depending on the nature of the source material, reagent, etc. and usually ranges from -10oC to 100oC, preferably from 0oC to 50oC.

The reaction time may vary depending on the nature of the.

After completion of the reaction, the target compound of this phase is recovered from the reaction mixture by usual method. For example, the target compound is obtained by a corresponding neutralization of the reaction mixture, removing insoluble substances by filtration in the case when they are present, removal of the solvent by evaporation, adding water to the reaction mixture, adding a hydrophobic solvent (e.g. benzene, simple ether, ethyl acetate, etc.,) to the mixture to perform the extraction, washing the organic layer containing the target compound with water, drying it over anhydrous magnesium sulfate and removal of solvent by evaporation. Thus obtained target compound can be subjected to further purification, if necessary, a conventional method, for example by recrystallization, re-precipitation or chromatography.

Method C is an alternative method of synthesis of compounds (1) method A.

Stage C1 is carried out, if necessary, and it includes

reaction (a): reaction in which accelgroup, alkoxygroup or carboxypropyl give isoxazol ring or an aromatic ring included in R1,

reaction (b): reaction in which hydroc the action, in which the hydroxyl group contained in hydroxyalkylated obtained by reacting (b), is converted into a halogen atom,

reaction (d): reaction in which a hydroxyl group contained in hydroxyalkylated obtained by reacting (b), is subjected to the reaction of 1,2-elimination (elimination),

reaction (e): reaction in which hydroxyalkyl obtained by the reaction of (b) into carbonero,

reaction (f): reaction in which a carboxyl group atrificial,

reaction (g): reaction in which alkoxycarbonyl group turned into carbamoyl,

reaction (h): reaction in which a carboxyl group is transformed into carbamoyl,

reaction (i): reaction in which carbamoyl turned into cyano,

reaction (j): reaction in which alkoxygroup on the aromatic ring is converted into a hydroxyl group,

reaction (k): reaction in which a hydroxyl group or the amino group is subjected to interaction acylation,

reaction (l): reaction in which a hydroxyl group or the amino group is subjected to interaction aralkylamines,

reaction (m): reaction in which the nitro-group is converted into the amino group, and
<>/P>These reactions are carried out appropriately in any order.

Reaction (a):

The reaction by which accelgroup, alkoxygroup or carboxypropyl give isoxazol ring or an aromatic ring in R1carry out conventional method in organic chemistry. For example, the reaction is carried out by reacting the halogen-C1-C6alkane, di-C1-C6alkalicarbonate or carbon dioxide (preferably halogen-C1-C6alkane or carbon dioxide) in the presence of a base in an inert solvent.

Halogen-C1-C6alkanol for use here may be, for example, methyl chloride, methyl bromide, methyliodide, ethylchloride, ethyliodide, propyl bromide, utilidad, pentolite or hexalite, preferably the bromide or methyliodide, more preferably methyliodide.

Di-C1-C6alkalicarbonate may be, for example, dimethylcarbonate, diethylcarbamyl, dipropylamine, Diisopropylamine, dibutylamine, di-sec-BUTYLCARBAMATE, di-tert-BUTYLCARBAMATE, dimenticarono or digoxigenin, preferably dimethylcarbonate or diethylcarbamyl.

Solvent used is not specifically limited, common solvents can be aliphatic hydrocarbons, such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol, diamines such as N,N,N',N'- tetramethylethylenediamine; amides, such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; or sulfoxidov, such as dimethylsulfoxide or sulfolane, preferably ethers, amides or sulfoxidov, more preferably ethers (particularly tetrahydrofuran).

Used may be, for example, alkali metal hydride such as lithium hydride, sodium hydride or potassium hydride; acility, such as motility, utility, utility or second - utility; or alkylamide lithium, such as diisopropylamide lithium, dicyclohexylamine lithium bis(trimethylsilyl)amide and lithium bis(trimethylsilyl)amide or potassium bis(trimethylsilyl)amide, sodium, preferably alkality (in particular, utility) or alkylamide lithium (castshadow material, reagent, etc. and is usually from -100oC to 30oC, preferably from -70oC and 0oC.

The reaction time may vary depending on the nature of the source material, the reagent and the reaction temperature and is usually from 5 minutes to 10 hours, preferably 10 minutes to 5 hours

After completion of the reaction, the target compound of this phase is recovered from the reaction mixture by usual method. For example, the target compound is obtained by removal of the solvent by evaporation or by adding water to the residue obtained by removing the solvent by evaporation, acidification of the aqueous layer, if desired, adding a hydrophobic solvent (e.g. benzene, simple ether, ethyl acetate, etc.,) to the mixture for extraction of the desired compound, washing of extracted organic layer with water, drying it over anhydrous magnesium sulfate and removal of solvent by evaporation. Thus obtained target compound can be subjected to further purification, if necessary, in the usual way, for example by recrystallization, re-precipitation or chromatography.

Reaction (b):

The reaction by which hydroxyalkyl injected into the ring isoxazol or tlaut by the interaction of compounds with aldehydes or ketones in the presence of a base in an inert solvent.

Aldehydes can be, for example, linear or branched, alkanal having from 2 to 6 carbon atoms, such as acetaldehyde, Propionaldehyde, butylaldehyde, Isobutyraldehyde, valeraldehyde, isovaleraldehyde or Hexaldehyde, preferably C2-C4alkanol, more preferably acetaldehyde.

Ketones can be, for example, linear or branched alkenone having from 3 to 6 carbon atoms, such as acetone, 2-butanone, 2-pentanone, 3-pentanone, 3-methyl-2-butanone, 2-hexanone, 3-hexanone, 3-methyl-2-pentanone, 4-methyl-2-pentanon or 3,3-dimethyl-2-butanone, preferably acetone, 2-butanone or 3-butanone, more preferably acetone.

Solvent used is not specifically limited, if it does not interfere with the reaction and can dissolve a certain amount of source material. Examples of suitable solvents may be aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; ethers, such as diethyl ether, diisopropyl is N,N,N',N'- tetramethylethylenediamine; amides, such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide or hexamethylphosphoric triamide; or sulfoxidov, such as dimethylsulfoxide or sulfolane, preferably ethers, amides or sulfoxidov, more preferably ethers (particularly tetrahydrofuran).

Used may be, for example, alkali metal hydride such as lithium hydride, sodium hydride or potassium hydride; acility, such as motility, utility, utility or second - utility; or alkylamide lithium, such as diisopropylamide lithium, dicyclohexylamine lithium bis(trimethylsilyl)amide and lithium bis (trimethylsilyl)amide or potassium bis(trimethylsilyl)amide, sodium, preferably alkality (in particular, utility) or alkylamide lithium (in particular, diisopropylamide lithium).

The reaction temperature may vary depending on the nature of the source material, reagent, etc. and is usually from -100oC to 30oC, preferably from -70oC and 0oC.

The reaction time may vary depending on the nature of the source material, the reagent and the reaction temperature and is usually from 5 minutes to 10 hours, preferably 10 minutes to 5 hours

Response (s):

The reaction in which a hydroxyl group in hydroxyalkylated obtained by reacting (b), is converted into a halogen atom, conduct conventional method in organic chemistry. For example, the reaction is carried out by reacting a hydroxyl group with a halogen acid in an inert solvent.

Halogen acid for use herein may be, for example, hydrofluoric acid, chloromethane acid, Hydrobromic acid or iodomethane acid, preferably chlorine is eacli and can dissolve a certain amount of source material. Examples of suitable solvents may be aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; ethers, such as diethyl ether,

diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol, esters such as methyl acetate or ethyl acetate; water or an aqueous mixture of the above solvent, preferably ethers, amides or sulfoxidov, more preferably ethers (in particular, dioxane) or a mixture of ethers and water.

The reaction temperature may vary depending on the nature of the starting material and the reagent, and is usually from -50oC to 80oC, preferably from 0oC to 50oC.

The reaction time may vary depending on the nature of the source material, the reagent and the reaction temperature and is usually from 5 minutes to 10 hours, preferably 10 minutes to 5 hours

After completion of the reaction, the target compound of this phase is recovered from reacts evaporation or adding water to the residue, obtained by removing the solvent by evaporation, adding a hydrophobic solvent (e.g. benzene, simple ether, ethyl acetate, etc.,) to the mixture for extraction of the desired compound, washing of extracted organic layer with water, drying it over anhydrous magnesium sulfate and removal of solvent by evaporation. Thus obtained target compound can be subjected to further purification, if necessary, in the usual way, for example by recrystallization, re-precipitation or chromatography.

Reaction (d):

The reaction in which a hydroxyl group in hydroxyalkyl group, obtained by reacting (b), is subjected to the reaction of 1,2-elimination (elimination), conduct conventional method in organic chemistry. For example, the reaction is carried out by reacting a hydroxyl group with an acid in an inert solvent.

Acid for use herein may be, for example, inorganic acid, such as hydrofluoric acid, chloromethane acid, Hydrobromic acid, iodomethane acid, nitric acid, Perlina acid, sulfuric acid or phosphoric acid; sulfonic acid such as means the p-toluensulfonate acid, or carboxylic acid, such as triperoxonane acid, fumaric acid, succinic acid, citric acid, tartaric acid, oxalic acid or maleic acid, preferably inorganic acids (in particular, chloromethane acid).

Solvent used is not specifically limited, if it does not interfere with the reaction and can dissolve a certain amount of source material. Examples of suitable solvents may be aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol, or complex esters such as methyl acetate or ethyl acetate; preferably ethers, amides or sulfoxidov, more preferably ethers or esters, more preferably ethers (in particular, dioxane).

The reaction temperature may vary depending on the nature recognize the LASS="ptx2">

The reaction time may vary depending on the nature of the source material, the reagent and the reaction temperature and is usually from 5 minutes to 10 hours, preferably 10 minutes to 5 hours

After completion of the reaction, the target compound of this phase is recovered from the reaction mixture by usual method. For example, after the reaction, the target compound is obtained by removal of the solvent by evaporation or by adding water to the residue obtained by removing the solvent by evaporation, adding a hydrophobic solvent (e.g. benzene, simple ether, ethyl acetate, etc.,) to the mixture for extraction of the desired compound, washing of extracted organic layer with water, drying it over anhydrous magnesium sulfate and removal of solvent by evaporation. Thus obtained target compound can be subjected to further purification, if necessary, in the usual way, for example by recrystallization, re-precipitation or chromatography.

Reaction (e):

The reaction by which hydroxyalkyl obtained by reacting (b), is transformed into carbonero, conduct conventional method in organic chemistry. For example, the reaction is performed by reacting hydroxyl the W if it is used for the oxidation reaction, and may be, for example, inorganic metal oxidant, such as manganese oxides, such as potassium permanganate or manganese dioxide; ruthenium oxide, such as ruthenium tetroxide; a compound of silver, such as silver oxide; a compound of chromium acid, such as potassium chromate, a complex of chromic acid and sulfuric acid or a complex of chromic acid and pyridine, or a combination of cerium, such as cerium nitrate-ammonium (CAN); a reagent used for oxidation of DMSO (complex of dimethyl sulfoxide and dicyclohexylcarbodiimide, oxalicacid, acetic anhydride or phosphorus pentoxide or a complex of pyridine and sulfur trioxide); succinimide, such as N-bromosuccinimide; or the connection of a quinone such as 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), preferably inorganic metal oxidizing agents or reagents used for oxidation of DMSO, more preferably inorganic metal oxidants (in particular, the complex of chromic acid and pyridine).

Solvent used is not specifically limited, if it does not interfere with the reaction and can dissolve a certain amount of source material. Examples of suitable solvent is e hydrocarbons, such as benzene, toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol; ketones, such as acetone; esters such as methyl acetate or ethyl acetate; NITRILES, such as acetonitrile; amides, such as dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; sulfoxidov, such as dimethyl sulfoxide; or a water mixture of the above solvents, preferably halogenated hydrocarbons, ethers, ketones, the NITRILES, amides or sulfoxidov, more preferably halogenated hydrocarbons (particularly methylene chloride).

The reaction temperature may vary depending on the nature of the starting material and the reagent, and is usually from 0oC to 100oC, preferably from 20 to 50oC.

The reaction time may vary depending on the nature of the source material, the reagent and the reaction temperature and is usually from 30 min to 48 h, preferably from 1 to 30 PM

After completion of the reaction target is by filtering off the oxidizer, removal of the solvent by evaporation or by adding water to the residue obtained by removing the solvent by evaporation, adding a hydrophobic solvent (e.g. benzene, simple ether, ethyl acetate, etc.,) to the mixture for extraction of the desired compound, washing of extracted organic layer with water, drying it over anhydrous magnesium sulfate and removal of solvent by evaporation. Thus obtained target compound can be subjected to further purification, if necessary, in the usual way, for example by recrystallization, re-precipitation or chromatography.

Reaction (f):

The reaction in which a carboxyl group atrificial, conduct conventional method in organic chemistry. For example, the reaction is carried out by

(1) reaction with etherification agent in an inert solvent,

(2) reaction with active etherification agent in an inert solvent, to obtain an active ester, and then through the active interaction of ester with an alcohol in an inert solvent or

(3) reaction with a halogenation agent in an inert solvent, to obtain gelegenheid acid, and then by reacting halogenosilanes, as usual in organic chemistry, and may be, for example, diazoalkane or dialkylimidazolium, preferably C1-C6diazoalkane, such as diazomethane, diazoethane, diazopropane, Diisobutyl, diazapentane or diatheke, more preferably C1-C4diazoalkane or trimethylsilyldiazomethane, in particular, preferably diazomethane.

Solvent used in the reaction with diazo C1-C6alkanol not specifically limited, if it does not interfere with the reaction and can dissolve a certain amount of source material. Examples of suitable solvents may be aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol, esters such as methyl acetate or ethyl acetate; or a mixture of the above solvents, preferably halogenated hydrocarbons, ethers, complexity is th ether), esters (in particular, ethyl acetate) or a mixture of the above solvents.

Solvent used in the reaction with trimethylsilyldiazomethane not specifically limited, if it does not interfere with the reaction and can dissolve a certain amount of source material. Examples of suitable solvents may be alcohols, such as methanol, ethanol, propanol, isopropanol, butanol, Isobutanol, tert-butanol, pentanol or hexanol; or a mixture of a solvent selected from the group consisting of aliphatic hydrocarbons, such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol, and complex esters such as methyl acetate or ethyl acetate, and the abovementioned alcohols, preferably alcohols (particularly methanol) and the mixture of aromatic hydrocarbons (particularly benzene) and alcohols (particularly methanol).

The reaction temperature may argirov preferably from 10 to 50oC.

The reaction time may vary depending on the nature of the starting material and the reactant and the reaction temperature and is usually from 10 minutes to 10 hours, preferably from 15 min to 2 h

After completion of the reaction, the target compound of this phase is recovered from the reaction mixture by usual method. For example, after the reaction, the target compound is obtained by removal of the solvent by evaporation. Thus obtained target compound can be subjected to further purification, if necessary, by conventional methods, for example by recrystallization, re-precipitation or chromatography.

Active tarifitsiruemih agent used in the reaction (f2) is not specifically limited if it is used, as usual, in methods of organic chemistry, and may be, for example, an active ester, such as ethylchloride; N-gidroksosoedinenii, such as N-hydroxysuccinimide, 1-hydroxybenzotriazole or N-hydroxy-5-norbornene-2,3-dicarboximide, or disulfide compound, such as dipyridamole.

The esterification reaction is preferably conducted in the presence of a condensing agent, such as dicyclohexylcarbodiimide, carbonyldiimidazole or triphenylphosphine.

The reaction temperature may vary depending on the nature of the starting materials and reagents, and is usually from -70oC to 15.0oC (preferably from -10oC to 100oC) in the reaction of the active esterification and -20oC to 100oC (preferably from 0oC to 50oC) in the reaction of the active compounds of ester with alcohols.

The reaction time may vary depending on the nature of the starting materials, reagents and reaction temperatures and is usually from 30 minutes to 80 hours, preferably from 1 to 48 h) in both reactions.

After completion of the reaction, the target compound of this stage from what I solvent by evaporation or by adding water to the residue, obtained by removing the solvent by evaporation, adding a hydrophobic solvent (e.g. benzene, simple ether, ethyl acetate, etc.,) to the resulting mixture to extract the desired compound, washing of extracted organic layer with water, drying it over anhydrous magnesium sulfate and removal of solvent by evaporation. Thus obtained target compound can be subjected to further purification, if necessary, in the usual way, for example by recrystallization, re-precipitation or chromatography.

Halogenation agent used in the reaction (f3), is not specifically limited if it is used, as usual, in methods of organic chemistry, and may be, for example, oxalicacid, thionyl chloride, phosphorus oxychloride or pentachloride phosphorus, preferably thionyl chloride.

Solvent used in both reactions, is not specifically limited, if it does not interfere with the reaction and can dissolve a certain amount of source material. Examples of suitable solvents may be aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, chetyrehhloristy ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol, preferably ethers (particularly tetrahydrofuran).

The reaction temperature may vary depending on starting materials and reagents, and is usually from -70oC to 150oC (preferably from -10oC to 100oC) in the reaction of halogenation and -20oC to 100oC (preferably from 0oC to 50oC) in response gelegenheid acid with alcohol.

The reaction time in both reactions may vary depending on the nature of the starting materials and reagents and reaction temperatures and is usually from 30 minutes to 80 hours, preferably from 1 to 48 h).

After completion of the reaction, the target compound of this reaction is recovered from the reaction mixture by usual method. For example, after the reaction, the target compound is obtained by removal of the solvent by evaporation or by adding water to the residue obtained by removing the solvent by evaporation, adding a hydrophobic solvent (e.g. benzene, simple ether, ethyl acetate, etc.,) to the resulting mixture to extract the desired compound, washing of extracted organic layer with water, drying it over the be the may be subjected to further purification, if necessary, in the usual way, for example by recrystallization, re-precipitation or chromatography.

Reaction (g):

The reaction by which alkoxycarbonyl turned into carbamoyl in the reaction (g), conduct conventional method in organic chemistry. For example, the reaction is performed by reacting alkoxycarbonyl with gaseous ammonia or conc. ammonia in water in an inert solvent.

Solvent used is not specifically limited, if it does not interfere with the reaction and can dissolve a certain amount of source material. Examples of suitable solvents may be aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol; alcohols, such as methanol, ethanol, propanol, isopropanol, butanol or Isobutanol; diamines such as N,N,N',N'-tetramethylethylenediamine; amides, takane or sulfoxidov, such as dimethylsulfoxide or sulfolane, preferably ethers or alcohols, more preferably ethers (particularly tetrahydrofuran).

The reaction temperature may vary depending on the nature of the starting material and the reagent, and is usually from -10oC to 100oC, preferably from 0oC to 50oC.

The reaction time may vary depending on the nature of the source material, the reagent and the reaction temperature and is usually from 10 minutes to 10 hours, preferably from 30 minutes to 3 hours

After completion of the reaction, the target compound of this reaction is recovered from the reaction mixture by usual method. For example, after the reaction, the target compound is obtained by removal of the solvent by evaporation or by adding water to the residue obtained by removing the solvent by evaporation, adding a hydrophobic solvent (e.g. benzene, simple ether, ethyl acetate, etc.,) to the resulting mixture to extract the desired compound, washing of extracted organic layer with water, drying it over anhydrous magnesium sulfate and removal of solvent by evaporation. Thus obtained target compound can be subjected dallashomesreo.

Reaction (h):

The reaction by which carboxypropyl turned into carbamoyl, conduct conventional method in organic chemistry. For example, the reaction is carried out by condensation of the carboxyl group with ammonia in an inert solvent conventional method of peptide synthesis, such as azide method, the active method of ester, method, mixed acid anhydride or by the condensation method (preferred method, mixed acid anhydride).

In the above method, the azide method is carried out by interaction of amino acid hydrazide obtained by the reaction of hydrazine in an inert solvent (for example, in amide, such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide, preferably in dimethylformamide) at -10oC to 100oC (preferably from 0oC to 50oC) with a nitrite compound to obtain azide connection, and then the processing of ammonia.

Used nitrite compound can be, for example, alkali metal nitrite such as sodium nitrite, or alkylated, such as isoamylase.

The reaction is preferably carried out in an inert solvent, and the solvent for use here is iamid; sulfoxide, such as dimethylsulfoxide or sulfolane, or pyrrolidone, such as N-an organic, preferably amides (particularly dimethylformamide).

In addition, two stages of this reaction (sideropenia and reaction with ammonia) is usually carried out in the same reaction solution.

The reaction temperature may vary depending on the nature of the starting materials and reagents, and is usually from -70oC to 50oC (preferably from -50oC and 0oC) at the stage of sideropenia and usually from -70oC to 50oC (preferably from -10oC to 10oC) in the reaction with ammonia.

The time required for the reaction may vary depending on the nature of the source material, reagent and reaction temperature. It usually takes from 5 minutes to 3 hours, preferably from 10 min to 1 h) under sideropenia. In the reaction with ammonia is from 5 h to 7 days, preferably from 10 hours to 5 days).

After completion of the reaction, the target compound of this reaction is recovered from the reaction mixture by usual method. For example, after the reaction, the target compound is obtained by removal of the solvent by evaporation or by adding water to the residue obtained by removal of the solvent IP the military mixtures in order to extract the desired compound, washing of extracted organic layer with water, drying it over anhydrous magnesium sulfate and removal of solvent by evaporation. Thus obtained target compound can be subjected to further purification, if necessary, in the usual way, for example by recrystallization, re-precipitation or chromatography.

Method with the active participation of ester is carried out by interaction with the reagent to produce active complex ester in an inert solvent and then by the interaction of ester with ammonia in an inert solvent.

Solvent used in both reactions, is not specifically limited, if it does not interfere with the reaction and can dissolve a certain amount of source material, and may be, for example, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; simple ether, such as cititoy ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol; amide such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric is whether amides (in particular, dimethylformamide).

Reagent for production of the active complex ester may be, for example, N-gidroksosoedinenii, such as N-hydroxysuccinimide, 1-hydroxybenzotriazole or N-hydroxy-5-norbornene-2,3-dicarboximide, or disulfide compound, such as dipyridamole. The active reaction of esterification is preferably carried out in the presence of a condensing agent, such as dicyclohexylcarbodiimide, carbonyldiimidazole or triphenylphosphine.

The reaction temperature may vary depending on the nature of the source material and the reagent, and typically range from -70oC to 150oC (preferably from -10oC to 100oC) in the reaction of the active esterification and -20oC to 100oC (preferably from 0oC to 50oC) in the reaction of the active compounds of ester with ammonia.

The periods of time required for both reactions can vary depending on the nature of the starting materials, reagents and reaction temperatures and this is usually from 30 minutes to 80 hours, preferably from 1 to 48 h).

After completion of the reaction, the target compound of this reaction is recovered from the reaction mixture by usual method. For example, after the reaction, the target compound is obtained by puttaparti, adding a hydrophobic solvent (e.g. benzene, simple ether, ethyl acetate, etc.,) to the resulting mixture to extract the desired compound, washing of extracted organic layer with water, drying it over anhydrous magnesium sulfate and removal of solvent by evaporation. Thus obtained target compound can be subjected to further purification, if necessary, in the usual way, for example by recrystallization, re-precipitation or chromatography.

The method involving the mixed acid anhydride is carried out by interaction with the reagent to obtain a mixed acid anhydride in the presence of a base in an inert solvent and then by reacting the mixed acid anhydride with ammonia in an inert solvent.

Solvent used in the reaction for obtaining a mixed anhydride of the acid is not specifically limited, if it does not interfere with the reaction and can dissolve a certain amount of source material, and may be, for example, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; simple ether, such as diethyl aramid, such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; preferably ethers (particularly tetrahydrofuran).

Examples of reagents for producing mixed anhydrides of acids may be, for example, C1-C4alkylhalogenide, such as ethylchloride or isobutylparaben; C1-C5alkanolamine, such as pivaloyloxy; or C1-C4alkyl or CI-C6-C14arizonattorney acid, such as diethylthiophosphoryl acid or diphenylcyanoarsine acid, preferably1-C4alkylhalogenide (in particular, isobutylparaben).

Used here may be, for example, a carbonate of an alkali metal such as sodium carbonate, potassium carbonate or lithium carbonate; or an organic amine, such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO) or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), preferably organic amines (in particular, triethylamine).

The reaction temperature in the reaction of obtaining mixed anger the t -50oC to 100oC (preferably from -10oC to 50oC).

The reaction time in the reaction to obtain a mixed acid anhydride may vary depending on the nature of the source material, reagent and reaction temperature, and it usually takes from 5 min to 20 h, preferably from 10 min to 10 h).

Solvent used in the reaction of the mixed anhydride of the acid with ammonia, is not specifically limited, if it does not interfere with the reaction and can dissolve a certain amount of source material, and may be, for example, a simple ether, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol; or an amide such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; preferably ethers (particularly tetrahydrofuran).

The reaction temperature in the reaction of the mixed anhydride of the acid with ammonia can vary depending on the nature of the starting material and the reagent, and is usually from -30oC to 100oC (preferably from 0oC to 80oC).

The reaction time in the reaction of the mixed anhydride of the acid with ammonia may vary depending occhialino from 10 min to 5 h).

After completion of the reaction, the target compound of this reaction is recovered from the reaction mixture by usual method. For example, after the reaction, the target compound is obtained by removal of the solvent by evaporation or by adding water to the residue obtained by removing the solvent by evaporation, adding a hydrophobic solvent (e.g. benzene, simple ether, ethyl acetate, etc.,) to the resulting mixture to extract the desired compound, washing of extracted organic layer with water, drying it over anhydrous magnesium sulfate and removal of solvent by evaporation. Thus obtained target compound can be subjected to further purification, if necessary, in the usual way, for example by recrystallization, re-precipitation or chromatography.

The method of condensation is carried out by direct reaction of the carboxyl group with ammonia in the presence of a condensing agent in an inert solvent.

Used here, the condensing agent may be, for example, dicyclohexylcarbodiimide, carbonyldiimidazole or 1-methyl-2-chloro-pyridinediamine, preferably dicyclohexylcarbodiimide.

This reaction may be of conducting the reaction, the target compound of this reaction is recovered from the reaction mixture by usual method. For example, after the reaction, the target compound is obtained by removal of the solvent by evaporation or by adding water to the residue obtained by removing the solvent by evaporation, adding a hydrophobic solvent (e.g. benzene, simple ether, ethyl acetate, etc.,) to the resulting mixture to extract the desired compound, washing of extracted organic layer with water, drying it over anhydrous magnesium sulfate and removal of solvent by evaporation. Thus obtained target compound can be subjected to further purification, if necessary, in the usual way, for example by recrystallization, re-precipitation or chromatography.

Reaction (i):

The reaction in which carbamoyl converted into cyano group, conduct a conventional method in organic chemistry. For example, the reaction is performed by reacting carbarnoyl-group with a dehydrating agent in an inert solvent.

Solvent used is not specifically limited, if it does not interfere with the reaction and can dissolve a certain amount of source material, and may be, for example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; simple ether, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol; esters such as methyl acetate or ethyl acetate; a ketone, such as acetone; amide such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide or hexamethylphosphoric triamide; or a sulfoxide such as dimethylsulfoxide or sulfolane, preferably ethers, amides or sulfoxidov, more preferably amides (particularly dimethylformamide).

Used here dehydrating agent may be, for example, phosphorus oxychloride, triperoxonane anhydride, methanesulfonyl-chloride, para-toluensulfonyl-chloride or phosphorus pentoxide, preferably phosphorus oxychloride.

The reaction temperature may vary depending on the nature of the starting material and the reagent, and is usually from -30oC to 100oC, preferably from 0oC to 50oC.

The reaction time may vary depending on the nature of the source material, the reagent and the reaction temperature and is usually from 5 minutes to 10 hours, preferably a mixture of a conventional method. For example, the target compound is obtained by removal of the solvent by evaporation or by adding water to the reaction mixture, adding a hydrophobic solvent (e.g. benzene, simple ether, ethyl acetate, etc.,) to the mixture for extraction of the desired compound, washing the organic layer with water, drying it over anhydrous magnesium sulfate and removal of solvent by evaporation. Thus obtained target compound can be subjected to further purification, if necessary, in the usual way, for example by recrystallization, re-precipitation or chromatography.

Reaction (j):

Reaction, during which alkoxygroup on the aromatic ring is converted into a hydroxyl group, conduct conventional method in organic chemistry. For example, the reaction is performed by reacting alkoxygroup with aluminum chloride in an inert solvent.

Solvent used is not specifically limited, if it does not interfere with the reaction and can dissolve a certain amount of source material, and may be, for example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or the Tang, chlorobenzene or dichlorobenzene; simple ether, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol; or an ester such as methyl acetate or ethyl acetate; preferably halogenated hydrocarbons (particularly methylene chloride).

The reaction temperature may vary depending on the nature of the starting material and the reagent, and is usually from -10oC to 100oC, preferably from 10 to 50oC.

The reaction time may vary depending on the nature of the source material, the reagent and the reaction temperature and is usually from 1 to 72 h, preferably from 2 to 30 hours

After completion of the reaction, the target compound of this reaction is recovered from the reaction mixture by usual method. For example, the target compound is obtained by removal of the solvent by evaporation or by adding water to the reaction mixture, adding a hydrophobic solvent (e.g. benzene, simple ether, ethyl acetate, etc.,) to the mixture for extraction of the desired compound, washing the organic layer with water, drying it over anhydrous magnesium sulfate and removal of solvent by evaporation. Obtained in this arr is an EP by recrystallization, re-precipitation or chromatography.

Reaction (k):

The reaction in which a hydroxyl group or amino group acelerou, conduct conventional method in organic chemistry. For example, the reaction is carried out by reacting a hydroxyl group or an amino group by acylation agent (preferably with alkanolammonium, mixed anhydride of formic and acetic acid anhydride alkenylboronic acid, arylcarboxamide or anhydride arylcarbamoyl acid) in the presence of a base or without (preferably in the presence of a base) in an inert solvent.

Used here alkanolamines may be, for example, linear or branched alkanolamine having from 2 to 6 carbon atoms, such as acetylchloride, propionitrile, butyrylcholine, butylbromide, isobutyrate, valerianic, pivaloyloxy or hexanoate, preferably C2-C4alcoholclone, more preferably acetylchloride.

Used here anhydride alkenylboronic acid can be, for example, linear or branched anhydride alkenylboronic acid having from 4 to 12 carbon atoms, such as acetic anhydride, prli hexanoic anhydride, preferably C4-C8anhydride alkenylboronic acid, more preferably acetic anhydride.

Used here arylcarboxamide may be, for example, C6-C10the halide arylcarbamoyl acid, such as benzoyl chloride, benzylbromide, tormentilla, chlorobenzylchloride, dichlorobenzophenone, trouillard, Antillid, indenolol, indoorpool, aftercare, afterbrain, fentrenarprin or anthracenedione, preferably benzoyl chloride.

Used here anhydride arylcarbamoyl acid can be, for example, C6-C10anhydride arylcarbamoyl acid, such as benzoic anhydride, fervently anhydride, chlorbenzoyl anhydride, methylbenzoic anhydride, methoxybenzoic anhydride, the anhydride interchromosomal acid or anhydride naftilaminom acid, preferably benzoic anhydride.

Used here may be, for example, a carbonate of an alkali metal such as sodium carbonate, potassium carbonate or lithium carbonate; or an organic amine, such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, N,N-dimethyln the 7-ene (DBU), preferably organic amines (in particular, triethylamine, diisopropylethylamine, pyridine or 4-(N,N-dimethylamino)pyridine.

Solvent used is not specifically limited, if it does not interfere with the reaction and can dissolve a certain amount of source material, and may be, for example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; simple ether, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol; a ketone, such as acetone and methyl ethyl ketone; or amide, such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; preferably ethers (particularly tetrahydrofuran).

The reaction temperature may vary depending on the nature of the starting material and the reagent, and is usually from -50oC to 100oC, preferably from 0oC to 50oC.

The reaction time may vary depending on the nature of the up to 10 hours).

After completion of the reaction, the target compound of this reaction is recovered from the reaction mixture by usual method. For example, after the reaction, the target compound is obtained by removal of the solvent by evaporation or by adding water to the residue obtained by removing the solvent by evaporation, adding a hydrophobic solvent (e.g. benzene, simple ether, ethyl acetate, etc.,) to the mixture for extraction of the desired compound, washing the organic layer with water, drying it over anhydrous magnesium sulfate and removal of solvent by evaporation. Thus obtained target compound can be subjected to further purification, if necessary, in the usual way, for example by recrystallization, re-precipitation or chromatography.

Reaction (l):

The reaction in which a hydroxyl group or amino group aralkylated, conduct conventional method in organic chemistry. For example, the reaction is carried out by reacting a hydroxyl group or amino group with aralkylamines in the presence of a base or without (preferably in the presence of a base) in an inert solvent.

Used here, C6-C48aralkylamines can bytovye or different from each other and selected from the group consisting of halogen, C1-C6the alkyl and C1-C6alkoxy, such as benzylchloride, benzylbromide, 4-chlorobenzylchloride, 4-chlorobenzylamino, 4-bromobenzylamine, 4-bromobenzylamine, 2,4-differentinherit, 2,4-DICHLOROSILANE, 2,4-dichlorobenzamide, 4-methoxybenzylidene, 4-methoxybenzylamine, Fritillaria, titivated, dimethoxytrityl or afterdowningstreet, preferably benzylchloride or benzylbromide, which may have 1 to 3 substituents, which may be the same or different from each other and selected from the group consisting of halogen, C1-C4the alkyl and C1-C4alkoxy, more preferably benzylchloride or benzylbromide.

Used may be, for example, a carbonate of an alkali metal such as sodium carbonate, potassium carbonate or lithium carbonate; an acid carbonate of an alkali metal such as sodium bicarbonate, potassium bicarbonate or bicarbonate of lithium; alkali metal hydride such as lithium hydride, sodium hydride or potassium hydride; alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide; an organic amine such as triethylamine, tributylamine, Diisopropylamine]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO) or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); acility, such as motility, utility or utility; or alkylamide lithium, such as diisopropylamide lithium or dicyclohexylamine lithium, preferably the carbonates of alkali metals, hydrides of alkali metals or organic amines, preferably the carbonates, alkali metal (particularly sodium carbonate or potassium carbonate) or hydrides of alkali metals (in particular, sodium hydride).

Solvent used is not specifically limited, if it does not interfere with the reaction and can dissolve a certain amount of source material, and may be, for example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; simple ether, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol; a ketone, such as acetone or methyl ethyl ketone; or amide, such as formamide, dimethylformamide, dimethylacetamide, hexamethylol ariyavamsa depending on the nature of the starting material and the reagent, and is usually from -50oC to 100oC, preferably from 0oC to 50oC.

The reaction time may vary depending on the nature of the source material, the reagent and the reaction temperature and is usually from 5 minutes to 24 hours (preferably from 10 min to 5 h).

After completion of the reaction, the target compound of this reaction is recovered from the reaction mixture by usual method. For example, after the reaction, the target compound is obtained by removal of the solvent by evaporation or by adding water to the residue obtained by removing the solvent by evaporation, neutralize it, if it is desired, adding a hydrophobic solvent (e.g. benzene, simple ether, ethyl acetate, etc.,) to the mixture for extraction of the desired compound, washing the organic layer with water, drying it over anhydrous magnesium sulfate and removal of solvent by evaporation. Thus obtained target compound can be subjected to further purification, if necessary, in the usual way, for example by recrystallization, re-precipitation or chromatography.

Reaction (m):

The reaction by which the nitro-group is converted into the amino group, conduct a conventional method in organic chemistry. For example, the reaction ASS="ptx2">

Solvent used is not specifically limited, if it does not interfere with the reaction and can dissolve a certain amount of source material, and may be, for example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; simple ether, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol; alcohol, such as methanol, ethanol, propanol, isopropanol, butanol or Isobutanol; a diamine such as N,N,N',N'-tetramethylethylenediamine; amide such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide or hexamethylphosphoric triamide; a sulfoxide such as dimethylsulfoxide or sulfolane; water or an aqueous mixture of the above solvent, preferably water.

The reaction temperature may vary depending on the nature of the starting material and the reagent, and is usually from -10oC to 100oC, preferably from 0oC to 50oC.

Time is
is usually from 10 minutes to 10 hours, preferably from 30 minutes to 3 hours

After completion of the reaction, the target compound of this reaction is recovered from the reaction mixture by usual method. For example, after the reaction, the target compound is obtained by removal of the solvent by evaporation or by adding water to the residue obtained by removing the solvent by evaporation, neutralization of him, adding a hydrophobic solvent (e.g. benzene, simple ether, ethyl acetate, etc.,) to the mixture for extraction of the desired compound, washing the organic layer with water, drying it over anhydrous magnesium sulfate and removal of solvent by evaporation. Thus obtained target compound can be subjected to further purification, if necessary, in the usual way, for example by recrystallization, re-precipitation or chromatography.

Reaction (n):

The reaction for removing the protective group of the amino group included in the Ra3and so on, carried out in conditions similar to the conditions described in Stage A3.

The compound of formula (II), which is a starting material of the present invention, is a known compound or can be obtained according to a known method is the main application of Japan (Kokai) N Sho 59-216881, Patent publication Japan (Kokoku) N Sho 43-14704, and so on ].

And also, the compound of formula (IV) or (IVa) is a known compound or can be obtained by a known method [for example, Syntesis, 366 (1990), J. Med. Chem., 14, 1258 (1991), and so on].

In addition, the compound of formula (II), which is a starting material of the present invention, is a known compound or can be obtained in a known manner. The compound of General formula (VI), (X) or (XIII) can be obtained by reacting according to methods D, E, F (see the end of the description).

Method D is a process of obtaining the compound (II), which is a starting material in Process A or Process B.

On stage D1 compound of formula (VIII) receive:

(a) by reacting compounds of General formula (VI) in an inert solvent with a reagent to produce active complex ester with subsequent complex interaction of active ester with the compound of the formula (VII) in an inert solvent,

(b) by reacting compounds of General formula (VI) with a halogenation agent in an inert solvent with subsequent interaction of halogenated compounds with compound (VII) or

(c) by reacting the compounds of formula (V in terms similar to those described in reaction (f2) and reaction (f3) at Stage C1, respectively.

The acid used in Stage D1(c) is not specifically limited, while it is commonly used in the methods of organic chemistry, and this may be an inorganic acid, such as hydrofluoric acid, chloromethane acid, Hydrobromic acid, iodomethane acid, nitric acid, Perlina acid, sulfuric acid or phosphoric acid; sulfonic acid such as methanesulfonate acid, triftormetilfullerenov acid, econsultancy acid, benzolsulfonat acid or p-toluensulfonate acid; or a carboxylic acid such as fumaric acid, succinic acid, citric acid, tartaric acid, oxalic acid or maleic acid, preferably inorganic acids (in particular, sulfuric acid).

Solvent used is not specifically limited, if it does not interfere with the reaction and can dissolve a certain amount of source material, and may be, for example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated pleva is; Rostow ether, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol; a ketone, such as acetone and methyl ethyl ketone; an alcohol such as methanol, ethanol, propanol, isopropanol, butanol or Isobutanol; or an amide such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; preferably alcohols (particularly methanol or ethanol).

The reaction temperature may vary depending on the nature of the starting material and the reagent, and is usually from -50oC to 150oC (preferably from 20 to 100oC).

The reaction time may vary depending on the nature of the source material, the reagent and the reaction temperature and is usually from 5 minutes to 24 hours (preferably from 10 min to 5 h).

After completion of the reaction, the target compound of this reaction is recovered from the reaction mixture by usual method. For example, after the reaction, the target compound is obtained by removal of the solvent by evaporation or by adding water to the residue obtained by removing the solvent by evaporation, adding a hydrophobic solvent (e.g. benzene, simple ether, ethyl acetate, etc.,) to the resulting mixture Atom magnesium and removal of the solvent by evaporation. Thus obtained target compound can be subjected to further purification, if necessary, in the usual way, for example by recrystallization, re-precipitation or chromatography.

Stage D2 compound of formula (IX) are obtained by reacting the compound (VIII) with a molecule of halogen in an inert solvent.

Used here, the halogen molecule can be, for example, chlorine molecule or a molecule of bromine, preferably a molecule of bromine.

Solvent used is not specifically limited, if it does not interfere with the reaction and can dissolve a certain amount of source material, and may be, for example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; simple ether, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol; a ketone, such as acetone and methyl ethyl ketone; alcohol, such as methanol, ethanol, propanol, isopropanol, butanol or preferably halogenated hydrocarbons (in particular, chloroform or carbon tetrachloride).

The reaction temperature may vary depending on the nature of the starting material and the reagent, and is usually from -50oC to 100oC (preferably from 0oC to 50oC).

The reaction time may vary depending on the nature of the source material, the reagent and the reaction temperature and is usually from 5 minutes to 12 hours (preferably from 10 min to 5 h).

After completion of the reaction, the target compound of this reaction is recovered from the reaction mixture by usual method. For example, after the reaction, the target compound is obtained by removal of the solvent by evaporation or by adding water to the residue obtained by removing the solvent by evaporation, adding a hydrophobic solvent (e.g. benzene, simple ether, ethyl acetate, etc.,) to the mixture for extraction of the desired compound, washing the organic layer with water, drying it over anhydrous magnesium sulfate and removal of solvent by evaporation. Thus obtained target compound can be subjected to further purification, if necessary, in the usual way, for example by recrystallization, re-precipitation or chromatography.

organicheskoi acid and hydroxylamine (preferably with a salt of an inorganic acid and hydroxylamine in the presence of a base or without (preferably in the presence of a base) in an inert solvent.

Salt of inorganic acid and hydroxylamine used here may be, for example, hydrofloric hydroxylamine, hydroxylamine hydrochloride, hydroxylamine hydrobromide, hydroiodide hydroxylamine, a salt of nitric acid, hydroxylamine, salt perchloro acid hydroxylamine, a salt of sulfuric acid, hydroxylamine or a salt of phosphoric acid, hydroxylamine, preferably hydroxylamine hydrochloride.

Method E is an alternative method of obtaining the compound (II), which is a starting material in Process A or Process B.

At stage E1 compound of formula (XII) are obtained by reacting the compounds of formula (X) with the compound of the formula (XI) in the presence of a base in an inert solvent.

Solvent used is not specifically limited, if it does not interfere with the reaction and can dissolve a certain amount of source material, and may be, for example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; p is milovy ether of diethylene glycol; or a sulfoxide such as dimethylsulfoxide or sulfolane; preferably aromatic hydrocarbons, halogenated hydrocarbons or ethers, more preferably aromatic hydrocarbons (particularly benzene) or ethers (particularly tetrahydrofuran and dioxane).

Used here may be, for example, a carbonate of an alkali metal such as sodium carbonate, potassium carbonate or lithium carbonate; an acid carbonate of an alkali metal such as sodium bicarbonate, potassium bicarbonate or bicarbonate of lithium; alkali metal hydride such as lithium hydride, sodium hydride or potassium hydride; alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide; alkali metal alkoxide such as sodium methoxide, ethoxide sodium tert-piperonyl potassium or lithium methoxide; mercaptide alkali metal, such as methylmercaptan sodium or ethylmercaptan sodium, organic amine, such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0] non-5-ene (DBN), 1,4-diazabicyclo[2.2.2] octane (DABCO) or 1,8-diazabicyclo[5.4.0] undec-7-ene (DBU); alkylate cyclohexylamin lithium preferred alkylamide lithium (in particular, diisopropylamide lithium) or organic amines (in particular, or 1,8-diazabicyclo[5.4.0]undec-7-ene) (DBU).

The reaction temperature may vary depending on the nature of the starting material and the reagent, and is usually from -100oC to 100oC, preferably from -70oC to 50oC.

The reaction time may vary depending on the nature of the source material, the reagent and the reaction temperature and is usually from 5 minutes to 48 hours, preferably 10 minutes to 24 hours

After completion of the reaction, the target compound of this phase is recovered from the reaction mixture by usual method. For example, the target compound is obtained by removal of the solvent by evaporation, adding water to the reaction mixture, bringing the reaction mixture to slightly acidic pH, adding a hydrophobic solvent (e.g. benzene, simple ether, ethyl acetate, etc.,) to the mixture for extraction of the desired compound, washing the organic layer with water, drying it over anhydrous magnesium sulfate and removal of solvent by evaporation. Thus obtained target compound can be subjected to further purification, if necessary, ordinary and E2 compound of formula (II) are obtained by reacting the compounds of formula (XII) with hydroxylamine or a salt of an inorganic acid and hydroxylamine (preferably with a salt of an inorganic acid and hydroxylamine in the presence of a base or without (preferably in the presence of a base) in an inert solvent and spend it in terms similar to those described for Stage D3.

Method F is a process for obtaining compounds (Xlla), R2means a halogen atom, a C1-C6alkyl, C1-C6alkyl substituted by halogen or C1-C6alkoxy, C2-C6alkenyl, C2-C6quinil, C3-C10cycloalkyl, C3-C10cycloalkenyl, C2-C6alkanoyl or C1-C6alkoxycarbonyl in the intermediate compound (XII) Method E.

On stage F1 compound of formula (XIIa) are obtained by reacting the compounds of formula (XIII) with the compound of the formula (XIV) in the presence of a base in an inert solvent and spend it in conditions similar to those described for Stage E1.

Derived isoxazol (I) of this invention has excellent properties of inhibition of monoamine oxidase types A and is slightly toxic. Therefore, it is useful as a tool for the treatment or prophylaxis (in particular, as a means for treatment of nervous disorders, including depression, Parkinson's disease, dementia Alzheimer's disease (impaired cognitive ability, characteristic of Alzheimer's disease) or cerebrovascular dementia (impaired cognitive ability, with the I of the invention]

Hereinafter the invention is described in more detail using Examples, the Comparative examples. Experimental examples and preparation Examples, but the invention is not limited.

Example 1

Hydrochloride 3-(2-aminoethoxy)-5-phenylisoxazole (Compound No. 1)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy-5-phenylisoxazol

Triphenylphosphine (0.87 g) was dissolved in tetrahydrofuran (10 ml) and to the solution is added dropwise diethylazodicarboxylate (0,57 g) under ice cooling with stirring and the mixture is stirred at the same temperature for 10 minutes 3-Hydroxy-5-phenylisoxazole (0,48 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0,48 g) add to the reaction mixture and the resulting mixture is stirred under ice cooling for 10 min and at room temperature for 24 hours the Solvent is evaporated under reduced pressure and the residue purified column chromatography on silica gel (eluent: cyclohexane/ethyl acetate = 4/1) and crystallized from simple isopropyl ether to obtain specified in the header connection (0,63 g, 69%) as colorless crystals.

So pl.: 125-126oC.

IR spectrum (KBr)maxcm-1: 3322, 1721, 1710, 1619;

The NMR spectrum (CDCl3) memorial plaques: a 1.46 (9H, s), of 3.56 (2H, q, J = is telesocial

A solution of 4 N. chloroethanol acid/1,4-dioxane (4.0 ml) is added to 3-(2-(N-tert-butoxycarbonylamino)ethoxy-5-phenylisoxazole (0.50 g) and the mixture is stirred at room temperature for 15 minutes the Precipitate was separated from the mixture by filtration and washed with ethyl acetate to obtain specified in the title compound (0.39 g, 99%) as colorless crystals.

So pl.: 215-218oC (decomposes)

IR spectrum (KBr)maxcm-1: 3132, 2963, 2810, 2756, 1620, 1597, 1579;

NMR spectrum (DMSO-d6) memorial plaques: 3,26 (2H, t, J = 5,1 Hz), of 4.45 (2H, t, J = 5,1 Hz), 6,85 (1H, s), 7,51-EUR 7.57 (3H, m), 7,84-7,87 (2H, m), of 8.25 (3H, user. C).

Example 2

Hydrochloride 3-(2-aminoethoxy)-4-chloro-5-phenylisoxazole (Compound No. 5)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy-4-chloro-5-phenylisoxazol

4-Chloro-3-hydroxy-5-phenylisoxazole (0,58 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0,48 g) is subjected to interaction and subsequent processing is similar to that described in Example 1(a), to obtain specified in the title compound (0.73 g, 72%) as colorless crystals.

So pl.: 115-116oC;

IR spectrum (KBR)maxcm-1: 3346, 1720, 1709, 1616;

The NMR spectrum (CDCl3) memorial plaques: a 1.46 (9H, s), 3,61 (2H, q, J = 5,1 Hz), 4,42 (2H, t, J = 5,1 Hz), equal to 4.97 (1H, user.C) 7,46-7,53 (3H, m), 7,94-of 8.00 (2H, m).

(isoxazol (0.54 g) is subjected to interaction and subsequent processing is similar as described in Example (1b) to receive the specified header connection (0,41 g, 93%) as colorless crystals.

So pl.: 204-207oC (decomposes).

IR spectrum (KBR)maxcm-1: 2971, 2905, 2848, 2775, 1606, 1575, 1534;

NMR spectrum (DMSO-d6) ppm: 3,31 (2H, t, J = 5,1 Hz), 4,56 (2H, t, J = 5,1 Hz), to 7.59-to 7.67 (3H, m), 7,92-of 7.97 (2H, m), 8,27 (3H, user.C).

Example 3

Hydrochloride 3-(2-aminoethoxy)-5-(4-chlorophenyl)isoxazol (Compound N 143)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(4-chlorophenyl)isoxazol

5-(4-Chlorophenyl)-3-hydroxyaminoimino (0,58 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0,48 g) is subjected to interaction and subsequent processing is similar to that described in Example (1a), to obtain specified in the header connection (0,69 g, 68%) as colorless crystals.

So pl.: 128-129oC;

IR spectrum (KBr)maxcm-1: 3378, 1683, 1622;

The NMR spectrum (CDCl3) M. D.: a 1.46 (9H, s), of 3.56 (2H, q, J = 5,1 Hz), 4,35 (2H, t, J = 5,1 Hz), is 4.93 (1H, user.C) 6,14 (1H, s), the 7.43 (2H, d, J = 8.7 Hz), 7,66 (2H, d, J = 8.7 Hz).

(b) Hydrochloride of 3-(2-aminoethoxy)-5-(4-chlorophenyl)isoxazol

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(4-chlorophenyl)isoxazol (0.54 g) is subjected to interaction and subsequent processing is similar to that described in Example-223 isoC (decomp.);

IR spectrum (KBr)maxcm-1: 3135, 2998, 2809, 1618, 1603, 1594, 1575, 1567;

NMR spectrum (DMSO-d6) memorial plaques: 3,26 (2H, t, J = 5,1 Hz), of 4.45 (2H, t, J = 5,1 Hz) 6,91 (1H, s), 7,63 (2H, d, J = 8.7 Hz), 7,89 (2H, d, J = 8.7 Hz), of 8.25 (3H, user.C).

Example 4

Hydrochloride 3-(2-aminoethoxy)-4-isopropyl-5-phenylisoxazole (Compound No. 9)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-isopropyl-5-phenylisoxazol

3-Hydroxy-4-isopropyl-5-phenylisoxazol (0.50 g) and 2-(H-tert-butoxycarbonylamino)ethanol (0.40 g) is subjected to interaction and subsequent processing is similar to that described in Example 1(a) to receive the specified header connection (0,60 g, 69%) as colorless crystals.

So pl.: 98-99oC;

IR spectrum (KBr)maxcm-1: 3386, 1686, 1642;

The NMR spectrum (CDCl3) m e: of 1.29 (6H, d, J = 6,8 Hz) of 1.46 (9H, s), 3,06 (1H, q, J = 6.8 Hz), of 3.60 (2H, q, J = 5,1 Hz), to 4.38 (2H, t, J = 5,1 Hz), is 4.85 (1H, user.C), 7,42-to 7.50 (3H, m), 7,55-of 7.60 (2H, m).

(b) Hydrochloride of 3-(2-aminoethoxy)-4-isopropyl-5-phenylisoxazole

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-isopropyl-5-phenylisoxazol (0.50 g) is subjected to interaction and subsequent processing is similar to that described in Example 1(b), to obtain specified in the title compound (0.39 g, 95%) as colorless crystals. So pl.: 2) memorial plaques: of 1.26 (6H, d, J = 6.8 Hz), 3.04 from (1H, q, J = 6.8 Hz), or 3.28 (2H, t, J = 5,1 Hz), to 4.46 (2H, t, J = 5,1 Hz), 7,50-to 7.64 (5H, m), compared to 8.26 (3H, user.C).

Example 5

Hydrochloride 3-(2-aminoethoxy)-5-(2-thienyl)isoxazol (Compound N 535)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(2-thienyl)isoxazol

3-Hydroxy-5-(2-thienyl)isoxazol (0,42 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.40 g) is subjected to interaction and subsequent processing is similar to that described in Example 1(a) to receive the specified header connection (0,63 g, 82%) as colorless crystals.

So pl.: 129-130oC (decomposes);

IR spectrum (KBr)maxcm-1: 3323, 1708, 1694, 1618;

The NMR spectrum (CDCl3) memorial plaques: a 1.46 (9H, s), of 3.56 (2H, q, J = 5,1 Hz), 4,34 (2H, t, J = 5,1 Hz), is 4.93 (1H, user.C) equal to 6.05 (1H, s), 7,11 (1H, DD, J = 5,1 Hz, J = 3,7 Hz), 7,43-of 7.48 (2H, m).

(b) Hydrochloride of 3-(2-aminoethoxy)-5-(2-thienyl)isoxazol

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(2-thienyl)isoxazol (0.05 g) is subjected to interaction and subsequent processing is similar to that described in Example 1(b), to obtain specified in the header connection (0,37 g, 95%) as colorless crystals.

So pl.: 278-283oC (decomposes);

IR spectrum (KBr)maxcm-1: 3108, 3086, 2993, 2978, 2913, 1613, 1596;

NMR spectrum (DMSO-d6) memorial plaques: 3,CLASS="ptx2">

Example 6

Hydrochloride 3-(2-aminoethoxy)-4-chloro-5-(2-thienyl)isoxazol (Compound No. 539)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-chloro-5-(2 - thienyl)isoxazol

4-Chloro-3-hydroxy-5-(2-thienyl)isoxazol (0.50 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.40 g) is subjected to interaction and subsequent processing is similar to that described in Example 1(a) to receive the specified header connection (0,57 g, 66%) as colorless crystals.

So pl.: 94-95oC;

IR spectrum (KBr)maxcm-1: 3342, 1718, 1708, 1622;

NMR spectrum (CDCl3) memorial plaques: a 1.46 (9H, s), of 3.60 (2H, q, J = 5,1 Hz), and 4.40 (2H, t, J = 5,1 Hz), 4,96 (1H, user.C) 7,19 (1H, DD, J = 5,2 Hz, J = 3.6 Hz), 7,56 (1H, d, J = 5,2 Hz), 7,74 (1H, d, J = 3.6 Hz).

(b) Hydrochloride of 3-(2-aminoethoxy)-4-chloro-5-(2-thienyl)isoxazol

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-chloro-5-(2-thienyl)isoxazol (0.40 g) is subjected to interaction and subsequent processing is similar to that described in Example 1(b), to obtain specified in the title compound (0.31 g, 95%) as colorless crystals.

So pl.: 278-283oC (decomposes);

IR spectrum (KBr)maxcm-1: 3109, 2960, 2897, 1626, 1596, 1579;

NMR spectrum (DMSO-d6) memorial plaques: 3,30 (2H, t, J = 5,1 Hz), of 4.54 (2H, t, J = 5,1 Hz), 7,34 (1H, DD, J = 5,1 Hz, J = 3.6 Hz), 7,83 (1H, d, J = 3.6 Hz), 8,01 (1H, is the group of N 1056)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(3-pyridyl)isoxazol

3-Hydroxy-5-(3-pyridyl)isoxazol (0,41 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.40 g) is subjected to interaction and subsequent processing is similar to that described in Example 1(a), to obtain specified in the title compound (0.50 g, 65%) as colorless crystals.

So pl.: 97-98oC;

IR spectrum (KBr)maxcm-1: 3249, 3145, 1712, 1626;

The NMR spectrum (CDCl3) memorial plaques: a 1.46 (9H, s), of 3.57 (2H, q, J = 5,1 Hz), 4,37 (2H, t, J = 5,1 Hz), 4,94 (1H, user.C), and 6.25 (1H, s), 7,42 (1H, DD, J = 8.0 Hz, J = 4.9 Hz), of 8.04 (1H, d, J = 8.0 Hz), 8,64 (1H, d, J = 4.9 Hz), 8,97 (1H, s).

(b) the Dihydrochloride of 3-(2-aminoethoxy)-5-(3-pyridyl)isoxazol

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(3-pyridyl)isoxazol (0,48 g) is subjected to interaction and subsequent processing is similar to that described in Example 1(b), to obtain specified in the header connection (0,41 g, 92%) as colorless crystals.

So pl.: 222-227oC;

IR spectrum (KBr)maxcm-1: 3096, 3068, 3043, 2967, 2886, 2813, 1641, 1597, 1539;

NMR spectrum (DMSO-d6) memorial plaques: 3,26 (2H, q, J = 5,1 Hz), 4,48 (2H, t, J = 5,1 Hz), 7,11 (1H, s), to 7.77 (1H, DD, J = 8.0 Hz, J = 5,1 Hz), scored 8.38 (3H, user.C) 8,46 (1H, d, J = 8.0 Hz), 8,79 (1H, d, J = 5,1 Hz), of 9.21 (1H, s).

Example 8

The dihydrochloride of 3-(2-aminoethoxy)-)isoxazol

4-Chloro-3-hydroxy-5-(3-pyridyl)isoxazol (0,49 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.40 g) is subjected to interaction and subsequent processing is similar to that described in Example 1(a), to obtain specified in the title compound (0.54 g, 63%) as colorless crystals.

So pl.: 76-77oC;

IR spectrum (KBr)maxcm-1: 3353, 3248, 1754, 1721, 1709, 1616;

The NMR spectrum (CDCl3) memorial plaques: to 1.47 (9H, s), 3,62 (2H, q, J = 5,1 Hz), 4,43 (2H, t, J = 5,1 Hz), equal to 4.97 (1H, user.C) was 7.45 (1H, DD, J = 8.0 Hz, J = 5,1 Hz), 8,24 (1H, DDD, J = 8.0 Hz, J = 2.0 Hz, J = l,5 Hz), 8,72 (1H, DD, J = 5,1 Hz, J = l,5 Hz), 9,24 (1H, d, J = 2.0 Hz).

(b) the Dihydrochloride of 3-(2-aminoethoxy)-4-chloro-5-(3-pyridyl)isoxazol

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-chloro-5-(3-pyridyl)isoxazol (0.40 g) is subjected to interaction and subsequent processing is similar to that described in Example 1(b), to obtain specified in the title compound (0.35 g, 96%) as colorless crystals.

So pl.: 205-210oC (decomposes);

IR spectrum (KBr)maxcm-1: 3103, 3053, 2937, 2899, 2875, 2823, 2800, 1634, 1607, 1590, 1541;

NMR spectrum (DMSO-d6) memorial plaques: 3,31 (2H, q, J = 5,1 Hz), 4,59 (2H, t, J = 5,1 Hz), 7,74 (1H, DD, J = 8.0 Hz, J = 5,1 Hz), 8,40 (1H, DDD, J = 8.0 Hz, J = 2.0 Hz, J = 1.5 Hz), 8,40 (3H, user.C) 8,82 (1H, DD, J = 5,1 Hz, J = l,5 Hz) to 9.15 (1H, d, J = 2.0 Hz).

Example 9

Guide the toxi)-5-(2 - methoxyphenyl)isoxazol

Triphenylphosphine (0.45 g) was dissolved in tetrahydrofuran (5 ml) and to the solution is added dropwise diethylazodicarboxylate (0,27 ml) under ice cooling with stirring and the resulting mixture was stirred at the same temperature for 30 minutes Then 2-(N-tert-butoxycarbonylamino)ethanol (0.20 g) and 3-hydroxy-5-(2-methoxyphenyl)isoxazol (0,22 g) add to the reaction mixture, followed by stirring the mixture under cooling with ice for 10 min and at room temperature for 24 hours the Solvent is evaporated under reduced pressure and the residue purified column chromatography on silica gel (eluent: hexane/ethyl acetate = 4/1) to obtain specified in the title compound (0.33 g, 86%) as colorless crystals.

So pl.: 131-133oC;

IR spectrum (KBr)maxcm-1: 3309, 1712, 1620;

The NMR spectrum (CDCl3) memorial plaques: a 1.46 (9H, s), of 3.57 (2H, q, J = 5,2 Hz), of 3.95 (3H, s), 4,36 (2H, t, J = 5,2 Hz), 4,96 (1H, user.C) to 6.43 (1H, s), 7,00 (1H, d, J = 7.8 Hz), 7,06 (1H, t, J = 7.8 Hz), 7,41 (1H, DDD, J = 7.8 Hz, J = 7.8 Hz, J = 1.7 Hz), to $ 7.91 (1H, DD, J = 7.8 Hz, J = 1.7 Hz).

(b) Hydrochloride of 3-(2-aminoethoxy)-5-(2-methoxyphenyl)isoxazol

3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-(2-methoxyphenyl)isoxazol (0.31 g) is dissolved in a solution of 4 N. chloromethane acid/1,4-dioxane (2.3 ml) and ri and the rest will recrystallized from a mixture of ethanol and isopropanol, to get listed in the title compound (0.21 g, 84%) as colorless crystals.

So pl.: 160-162oC (decomposes);

IR spectrum (KBr)maxcm-1: 3000, 2959, 2837, 1621, 1614;

NMR spectrum (DMSO-d6) memorial plaques: to 3.25 (2H, t, J = 5,1 Hz), of 3.94 (3H, s), of 4.45 (2H, t, J = 5,1 Hz), 6,56 (1H, s), 7,11 (1H, t, J = 7.8 Hz), 7.23 percent (1H, d, J = 7.8 Hz), 7,52 (1H, DDD, J = 7.8 Hz, J = 7.8 Hz, J = 1.7 Hz), 7,81 (1H, DD, J = 7.8 Hz, J = 1.7 Hz), of 8.25 (3H, user.C).

Example 10

Hydrochloride 3-(2-aminoethoxy)-5-(3-methoxyphenyl)isoxazol (Compound N 363)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(3 - methoxyphenyl)isoxazol

3-Hydroxy-5-(3-methoxyphenyl)isoxazol (0,22 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.20 g) is subjected to interaction and subsequent processing is similar to that described in Example 9(a), to obtain specified in the title compound (0.31 g, 82%) as a colorless powder.

So pl.: 89-90oC;

IR spectrum (KBr)maxcm-1: 3312, 1710;

The NMR spectrum (CDCl3) memorial plaques: a 1.46 (9H, s), of 3.56 (2H, q, J = 5,2 Hz), 3,86 (3H, s), 4,35 (2H, t, J = 5,2 Hz), is 4.93 (1H, user.C), 6,13 (1H, s), of 6.96-7,00 (1H, m), 7,26-7,42 (3H, m).

(b) Hydrochloride of 3-(2-aminoethoxy)-5-(3-methoxyphenyl)isoxazol

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(3-methoxyphenyl)isoxazol (0,29 g) is subjected to interact like a t is to receive the specified header connection (0,19 g, 83%) as colorless crystals.

So pl.: 180-182oC (decomposes);

IR spectrum (KBr)maxcm-1: 2995, 2976, 2914, 1591;

NMR spectrum (DMSO-d6) memorial plaques: 3,26 (2H, t, J = 5,1 Hz), of 3.84 (3H, s), of 4.45 (2H, t, J = 5,1 Hz), to 6.88 (1H, s), 7,09-7,11 (1H, m), 7,38-of 7.48 (3H, m), 8,28 (3H, user.C).

Example 11

Hydrochloride 3-(2-aminoethoxy)-5-(4-methoxyphenyl)isoxazol (Compound N 350)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(4 - methoxyphenyl)isoxazol

3-Hydroxy-5-(4-methoxyphenyl)isoxazol (0,22 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.20 g) is subjected to interaction and subsequent processing is similar to that described in Example 9(a), to obtain specified in the title compound (0.32 g, 84%) as a colorless powder.

So pl.: 117-118oC;

IR spectrum (KBr)maxcm-1: 3344, 1719, 1623;

The NMR spectrum (CDCl3) memorial plaques: a 1.46 (9H, s), of 3.56 (2H, q, J = 5,2 Hz), 3,86 (3H, s), 4,34 (2H, t, J = 5,2 Hz), of 4.95 (1H, user.C) of 6.02 (1H, s), of 6.96 (2H, d, J = 8,9 Hz), 7,66 (2H, d, J = 8,9 Hz).

(b) Hydrochloride of 3-(2-aminoethoxy)-5-(4-methoxyphenyl)isoxazol

3-(2- (N-tert-Butoxycarbonylamino)ethoxy)-5-(4-methoxyphenyl)isoxazol (0,30 g) is subjected to interaction similar to that described in Example 9(b), and the reaction product is re-crystallized from a mixture of ethanol and isopropanol to the C (decomposes);

IR spectrum (KBr)maxcm-1: 2990, 2969, 2950, 2900, 1617;

NMR spectrum (DMSO-d6) memorial plaques: to 3.25 (2H, t, J = 5,1 Hz), 3,83 (3H, s), 4,43 (2H, t, J = 5,1 Hz), 6,69 (1H, s), to 7.09 (2H, d, J = 8,9 Hz), 7,79 (2H, d, J = 8,9 Hz), of 8.25 (3H, user.C).

Example 12

Hydrochloride 3-(2-aminoethoxy)-5-(2-chlorophenyl)isoxazol (Compound No. 111)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(2-chlorophenyl)isoxazol

5-(2-Chlorophenyl)-3-hydroxy-isoxazol (0,23 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.20 g) is subjected to interaction and subsequent processing is similar to that described in Example 9(a), to obtain specified in the title compound (0.35 g, 88%) as colorless powder.

So pl.: 125-127oC;

IR spectrum (KBr)maxcm-1: 3333, 1710, 1697, 1618;

The NMR spectrum (CDCl3) memorial plaques: a 1.46 (9H, s), of 3.57 (2H, q, J = 5,2 Hz), 4,37 (2H, t, J = 5,2 Hz), 4,96 (1H, user.C) 6,59 (1H, s), 7,33-the 7.43 (2H, m), 7,46-rate of 7.54 (1H, m), 7,87-7,94 (1H, m).

(b) Hydrochloride of 3-(2-aminoethoxy)-5-(2-chlorophenyl)isoxazol

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(2-chlorophenyl)isoxazol (0.33 g) is subjected to interaction similar to that described in Example 9(b), and the interaction product is re-crystallized from isopropanol to obtain specified in the title compound (0.20 g, 74%) as colorless crystals.

So the ) memorial plaques: 3,278 (2H, t, J = 5,1 Hz), 4,48 (2H, t, J = 5,1 Hz), to 6.80 (1H, s), 7,52-of 7.60 (2H, m), 7,68 (1H, DD, J = 7.5 Hz, J = 1.9 Hz), 7,87 (1H, DD, J = 7.5 Hz, J = 1.9 Hz), 8,27 (3H, user.C).

Example 13

Hydrochloride 3-(2-aminoethoxy)-5-(3-chlorophenyl)isoxazol (Compound No. 125)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(3-chlorophenyl)isoxazol

5-(3-Chlorophenyl)-3-hydroxyethoxy (0,23 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.20 g) is subjected to interaction and subsequent processing is similar to that described in Example 9(a), to obtain specified in the title compound (0.34 g, 85%) as colorless powder.

So pl.: 117-119oC;

IR spectrum (KBr)maxcm-1: 3385, 1685;

The NMR spectrum (CDCl3) memorial plaques: a 1.46 (9H, s), of 3.57 (2H, q, J = 5,2 Hz), 4,36 (2H, t, J = 5,2 Hz), is 4.93 (1H, user.C), 6,16 (1H, s), of 7.36-7,44 (2H, m), EUR 7.57-to 7.67 (1H, m), of 7.70 (1H, s).

(b) Hydrochloride of 3-(2-aminoethoxy)-5-(3-chlorophenyl)isoxazol

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(3-chlorophenyl)isoxazol (0.33 g) is subjected to interaction similar to that described in Example 9(b), and the interaction product is re-crystallized from a mixture of ethanol and isopropanol to obtain specified in the title compound (0.21 g, 78%) as colorless crystals.

So pl.: 204-208oC (decomposes);

IR spectrum (KBr)maxcm-1: is), of 7.96 (1H, s), by 8.22 (3H, user.C).

Example 14

Hydrochloride 3-(2-aminoethoxy)-4-methyl-5-phenylisoxazole (Compound No. 6)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-methyl-5-phenylisoxazol

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-phenylisoxazole (0,30 g) dissolved in tetrahydrofuran (10 ml) and add dropwise a solution of n-utility/n-hexane (1,56 M, 1.4 ml) at -70oC under a nitrogen atmosphere, followed by stirring the resulting mixture for 10 minutes Then the reaction mixture is added dropwise methyliodide (0,09 ml) and the resulting mixture is stirred for 10 minutes and Then the temperature of the reaction mixture was raised to 0oC, the reaction mixture is poured into ice water and the aqueous solution of potassium dihydrophosphate add to the mixture to bring the pH to a value of 6. The mixture is then extracted with ethyl acetate and the organic layer was washed with saturated aqueous NaCl, followed by drying over anhydrous magnesium sulfate. After filtration the solvent is evaporated under reduced pressure. The residue is purified column chromatography on silica gel (eluent: hexane/ethyl acetate = 4/1) to obtain specified in the header connection (0,29 g, 94%) as colorless powder.

So pl.: 118-120oC;

IR spectrum (KBr) of 5.1 Hz), 4,94 (1H, user.C), 7,40-7,53 (3H, m), of 7.69 (2H, d, J = 7.9 Hz).

(b) Hydrochloride of 3-(2-aminoethoxy)-4-methyl-5-phenylisoxazole

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-methyl-5-phenylisoxazol (0,29 g) is subjected to interaction similar to that described in Example 9(b), and the reaction product is re-crystallized from a mixture of methanol and ethanol to obtain specified in the title compound (0.18 g, 78%) as colorless crystals.

So pl.: 245-250oC (decomposes);

IR spectrum (KBr)maxcm-1: 3003, 2892, 1516;

NMR spectrum (DMSO-d6) memorial plaques: a 2.13 (3H, s), or 3.28 (2H, t, J = 5,1 Hz), to 4.46 (2H, t, J = 5,1 Hz), 7,50-to 7.59 (3H, m), 7,73 (2H, d, J = 7,2 Hz), 8,21 (3H, user.C).

Example 15

Hydrochloride 3-(2-aminoethoxy)-4-ethyl-5-phenylisoxazole (Compound # 7)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-ethyl-5-phenylisoxazol

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-phenylisoxazole (0.3 g) and ethyliodide (0,12 ml) is subjected to interaction and subsequent processing is similar to that described in Example 14(a), to obtain specified in the title compound (0.24 g, 73%) as a colourless oil.

IR spectrum (CHCl3)maxcm-1: 3460, 2980, 1713;

The NMR spectrum (CDCl3) memorial plaques: to 1.21 (3H, t, J = 7.5 Hz), of 1.46 (9H, s), of 2.56 (2H, q, J = 7.5 Hz) and 3.59 (2H, q, J = 5,2 Hz), to 4.38 (2H, t,

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-ethyl-5-phenylisoxazol (0.21 g) is subjected to interaction and subsequent processing is similar to that described in Example 9(b), to obtain specified in the title compound (0.12 g, 71%) as colorless crystals.

So pl.: 210-215oC (decomposes);

IR spectrum (KBr)maxcm-1: 2968, 2886, 1518;

NMR spectrum (DMSO-d6) memorial plaques: to 1.15 (3H, t, J = 7.5 Hz), 2,58 (2H, q, J = 7.5 Hz), 3,29 (2H, t, J = 5,1 Hz), to 4.46 (2H, t, J = 5,1 Hz), 7,51-to 7.59 (3H, m), to 7.67-of 7.70 (2H, m), of 8.25 (3H, user.C).

Example 16

Hydrochloride 3-(2-aminoethoxy)-5-phenyl-4-propylenoxide (Compound No. 8)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-phenyl-4-propylenoxide

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-phenylisoxazole (0.3 g) and propylitic (0,29 ml) is subjected to interaction and subsequent processing is similar to that described in Example 14(a) to receive the specified header connection (0,22 g, 65%) as a colourless oil.

IR spectrum (CHCl3)maxcm-1: 3460, 2966, 1713;

The NMR spectrum (CDCl3) memorial plaques : to 0.97 (3H, t, J = 7.4 Hz), of 1.46 (9H, s), 1,56 was 1.69 (2H, m), of 2.51 (2H, t, J = 7,6 Hz) to 3.58 (2H, q, J = 5,2 Hz), 4,37 (2H, t, J = 5,2 Hz), the 4.90 (1H, user.C), 7,43-7,53 (3H, m), 7,65-to 7.68 (2H, m).

(b) Hydrochloride of 3-(2-aminoethoxy)-5-phenyl-4-propylenoxide

3-( processing just as described in Example 9(b), to obtain specified in the title compound (0.10 g, 71%) as colorless crystals.

So pl.: 119-121oC (decomp.);

IR spectrum (KBr)maxcm-1: 2960, 2933, 2872, 1518;

NMR spectrum (DMSO-d6) memorial plaques: of 0.91 (3H, t, J = 7,3 Hz), 1,51-to 1.61 (2H, m), of 2.54 (2H, t, J = 7,7 Hz), or 3.28 (2H, t, J = 5,1 Hz), of 4.45 (2H, t, J = 5,1 Hz), 7,50-to 7.59 (3H, m), 7.68 per-of 7.70 (2H, m), to 8.20 (3H, user.C).

Example 17

Hydrochloride 3-(2-aminoethoxy)-4-butyl-5-phenylisoxazole (Compound No. 10)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-butyl-5-phenylisoxazol

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-phenylisoxazole (0.3 g) and butylated (0.17 ml) is subjected to interaction and subsequent processing is similar to that described in Example 14(a) to receive the specified header connection (0,23 g, 66%) as a colourless oil.

IR spectrum (CHCl3)maxcm-1: 3460, 2962, 1713;

The NMR spectrum (CDCl3) memorial plaques: of 0.93 (3H, t, J = 7,3 Hz), 1,31-to 1.63 (4H, m) of 1.46 (9H, s), of 2.53 (2H, t, J = 7,6 Hz) to 3.58 (2H, q, J = 5.3 Hz), to 4.38 (2H, t, J = 5.3 Hz), the 4.90 (1H, user.C), 7,42-7,51 (3H, m), 7,65-to 7.68 (2H, m).

(b) Hydrochloride of 3-(2-aminoethoxy)-4-butyl-5-phenylisoxazole

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-butyl-5-phenylisoxazol (0.20 g) is subjected to interaction and subsequent processing is similar CACR CLASS="ptx2">

So pl.: 104-106oC;

IR spectrum (KBr)maxcm-1: 3006, 2963, 2951, 2931, 2869, 1516;

NMR spectrum (DMSO-d6) memorial plaques: to 0.87 (3H, t, J = 7,3 Hz), of 1.27 to 1.37 (2H, m), 1,47-of 1.55 (2H, m), to 2.57 (2H, t, J = 7,7 Hz), or 3.28 (2H, t, J = 5,1 Hz), to 4.46 (2H, t, J = 5,1 Hz), 7,51-to 7.59 (3H, m), 7.68 per-of 7.70 (2H, m), 8,23 (3H, user.C).

Example 18

Hydrochloride 3-(2-aminoethoxy)-4-hexyl-5-phenylisoxazole (Compound N 1388)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-hexyl-5-phenylisoxazol

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-phenylisoxazole (0.4 g) and hexalite (0,23 ml) is subjected to interaction and subsequent processing is similar to that described in Example 14(a), to obtain specified in the title compound (0.31 g, 61%) as a colorless powder.

IR spectrum (KBr)maxcm-1: 3387, 2936, 1715;

The NMR spectrum (CDCl3) memorial plaques: to 0.88 (3H, t, J = 6.6 Hz), 1,23-of 1.42 (6H, m) of 1.46 (9H, s), 1,53 is 1.70 (2H, m), 2,52 (2H, t, J = 7,7 Hz) to 3.58 (2H, q, J = 5,1 Hz), 4,37 (2H, t, J = 5,1 Hz), the 4.90 (1H, user.C), 7,40-7,51 (3H, m), 7,65-to 7.68 (2H, m).

(b) Hydrochloride of 3-(2-aminoethoxy)-4-hexyl-5-phenylisoxazole

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-hexyl-5-phenylisoxazol (0.2 g) is subjected to interaction and subsequent processing is similar to that described in Example 9(b), to obtain specified in the header of the connection (of 0.13 g, 81%) as a colorless cu is About-d6) memorial plaques: or 0.83 (3H, t, J = 6.9 Hz), 1.18 to 1.32 to (6H, m), 1,48-of 1.55 (2H, m), of 2.56 (2H, t, J = 7,7 Hz), or 3.28 (2H, t, J = 5,1 Hz), of 4.45 (2H, t, J = 5,1 Hz), 7,50-to 7.59 (3H, m), to 7.67-of 7.69 (2H, m), 8,16 (3H, user.C).

Example 19

Hydrochloride 3-(2-aminoethoxy)-4-carboxy-5-phenylisoxazole (Compound N 1408)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-carboxy-5 - phenylisoxazol

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-phenylisoxazole (2.00 g) was dissolved in tetrahydrofuran (20 ml) and added dropwise utility (1,56 M solution in hexane, to 9.3 ml) at -70oC under nitrogen atmosphere and the resulting mixture was stirred for 10 min. Then the reaction mixture is bubbled with carbon dioxide for 10 min and the temperature of the reaction mixture was raised to 0oC. the Reaction mixture was poured into ice-cold water and bring the pH of the mixture to 6 with an aqueous solution of potassium dihydrophosphate, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous NaCl and dried over anhydrous magnesium sulfate. After filtration the solvent is evaporated under reduced pressure. The residue was washed with simple ether to obtain specified in the header connection (2,18 g, 95%) as a colorless powder.

IR spectrum (KBr)maxcm-1: 2982, 1706;

NMR spectrum (DMSO-d6
3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-carboxy-5-phenylisoxazol (0.12 g) is subjected to interaction and subsequent processing is similar to that described in Example 9(b), to obtain specified in the title compound (0.06 g, 60%) as colorless crystals.

So pl.: 180-183oC (decomposes);

IR spectrum (KBr)maxcm-1: 3149, 2873, 2820, 1755, 1709;

NMR spectrum (DMSO-d6) memorial plaques: 3,30 (2H, t, J = 5.3 Hz), of 4.54 (2H, t, J = 5.3 Hz), 7,54-the 7.65 (3H, m), a 7.85-7,87 (2H, m), by 8.22 (3H, user.C).

Example 20

Hydrochloride 3-(2-aminoethoxy)-4-carbarnoyl-5-phenylisoxazole (Compound N 1414)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-carbarnoyl-5 - phenylisoxazol

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-carboxy-5-phenylisoxazol (0.6 g) dissolved in tetrahydrofuran (6 ml) and add carbonyldiimidazole (0.31 g) under ice cooling with stirring, followed by stirring the mixture at room temperature for 30 minutes Then the reaction mixture is added dropwise aqueous ammonia (1 ml) and the mixture is stirred at room temperature for one hour. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous NaCl and dried over anhydrous sulfate is lowke connection (0,60 g, quantitative) as a colorless powder.

IR spectrum (KBr)maxcm-1: 3439, 3371, 3149, 1694, 1680;

NMR spectrum (DMSO-d6) memorial plaques: of 1.39 (9H, s), 3,39 (2H, q, J = 5.0 Hz), 4,30 (2H, t, J = 5.0 Hz), 7,38 (1H, user.C) 7,51-EUR 7.57 (3H, m), 7,71 (1H, user.C), to $ 7.91-7,94 (2H, m).

(b) Hydrochloride of 3-(2-aminoethoxy)-4-carbarnoyl-5-phenylisoxazole

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-carbarnoyl-5-phenylisoxazol (0,22 g) is subjected to interaction and subsequent processing is similar to that described in Example 9(b), to obtain specified in the header connection (0,13 g, 72%) as colorless crystals.

So pl.: 225-230oC (decomposes),

IR spectrum (KBr)maxcm-1: 3407, 3213, 2963, 2878, 1662;

NMR spectrum (DMSO-d6) memorial plaques: of 3.32 (2H, t, J = 4.9 Hz), of 4.54 (2H, t, J = 4.9 Hz), 7,52-of 7.60 (4H, m), to 7.77 (1H, user.C), 7,92-7,94 (2H, m), 8,29 (3H, user.C).

Example 21

Hydrochloride 3-(2-aminoethoxy)-4-cyano-5-phenylisoxazole (Compound N 1406)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-cyano-5-phenylisoxazol

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-carbarnoyl-5-phenylisoxazol (0,38 g) dissolved in dimethylformamide (4 ml) and added dropwise phosphorus oxychloride (of 0.11 ml) in 5oC under a nitrogen atmosphere, followed by stirring the mixture at room temperature and is washed with saturated aqueous NaCl and dried over anhydrous magnesium sulfate. After filtration the solvent is evaporated under reduced pressure. The residue is purified column chromatography on silica gel (eluent: hexane/ethyl acetate = 3/1) to obtain specified in the title compound (0.28 g, 78%) as a colourless solid.

IR spectrum (KBr)maxcm-1: 3384, 2237, 1690, 1680;

NMR spectrum (CHCl3) memorial plaques: to 1.47 (9H, s), 3,61 (2H, q, J = 5,2 Hz), 4,43 (2H, t, J = 5,2 Hz), equal to 4.97 (1H, user.C), 7,52-to 7.64 (3H, m), 8,01-with 8.05 (2H, m).

(b) Hydrochloride of 3-(2-aminoethoxy)-4-cyano-5-phenylisoxazole

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-cyano-5-phenylisoxazol (0.25 g) is subjected to interaction and subsequent processing is similar to that described in Example 9(b), to obtain specified in the header of the connection (of 0.13 g, 65%) as colorless crystals.

So pl.: 200-205oC (decomposes);

IR spectrum (KBr)maxcm-1: 2967, 2236, 1611;

NMR spectrum (DMSO-d6) memorial plaques: of 3.32 (2H, t, J = 5,1 Hz), 4,60 (2H, t, J = 5,1 Hz), 7.68 per-7,76 (3H, m), 7,98 shed 8.01 (2H, m), 8,29 (3H, user.C).

Example 22

Hydrochloride 3-(2-aminoethoxy)-4-methoxycarbonyl-5-phenylisoxazole (Compound N 1412)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-methoxycarbonyl-5 - phenylisoxazol

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-carboxy-5-phenylisoxazol (0,2 the solution in hexane) under ice cooling, followed by stirring the mixture at room temperature for 30 minutes The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous NaCl and dried over anhydrous magnesium sulfate. After filtration the solvent is evaporated under reduced pressure. The residue is purified column chromatography on silica gel (eluent: hexane/ethyl acetate = 3/1) to obtain specified in the title compound (0.17 g, 81%) as a colourless solid.

IR spectrum (KBr)maxcm-1: 3355, 1725, 1691;

The NMR spectrum (CDCl3) memorial plaques: a 1.46 (9H, s), 3,62 (2H, q, J = 5,1 Hz), 3,85 (3H, s), 4,43 (3H, t, J = 5,1 Hz), to 5.03 (1H, user.C) 7,46-rate of 7.54 (3H, m), 7,87-to $ 7.91 (2H, m).

(b) Hydrochloride of 3-(2-aminoethoxy)-4-methoxycarbonyl-5-phenylisoxazole

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-methoxycarbonyl-5 - phenylisoxazol (0.16 g) is subjected to interaction and subsequent processing is similar to that described in Example 9(b), to obtain specified in the title compound (0.08 g, 62%) as colorless crystals.

So pl.: 195-198oC (decomposes);

IR spectrum (KBr)maxcm-1: 3148, 2870, 2848, 2821, 1708;

NMR spectrum (DMSO-d6) memorial plaques: 3,30 (2H, t, J = 5,2 Hz), of 3.77 (3H, s), of 4.54 (2H, t, J = 5,2 Hz), 7,56-7,66 (3H, m), a 7.85-7,87 (2H, m), 8,24 (3H, user.C).

Example 23

Hydrochloride 3-(2-aminoet ethylaminomethyl-5 - phenylisoxazol

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-carboxy-5-phenylisoxazol (0.2 g) and methylamine (30% solution in methanol, 0,12 ml) is subjected to interaction and subsequent processing is similar to that described in Example 20(a), to obtain specified in the title compound (0.18 g, 87%) as colorless powder.

IR spectrum (KBr)maxcm-1: 3405, 3369, 1677;

The NMR spectrum (CDCl3) memorial plaques: a 1.45 (9H, s), of 2.97 (3H, d, J = 5.0 Hz), to 3.64 (2H, q, J = 5,1 Hz), of 4.44 (2H, t, J = 5,1 Hz), the 4.90 (1H, user.C), 7,30 (1H, user.C) 7,46 is 7.50 (3H, m), 8,05-of 8.09 (2H, m).

(b) Hydrochloride of 3-(2-aminoethoxy)-4-methylaminomethyl-5 - phenylisoxazole

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-methylaminomethyl-5 - phenylisoxazol (0.17 g) is subjected to interaction and subsequent processing is similar to that described in Example 14(a), to obtain specified in the title compound (0.08 g, 57%) as colorless crystals.

So pl.: 223-226oC (decomposes);

IR spectrum (KBr)maxcm-1: 3102, 2935, 2879, 1646;

NMR spectrum (DMSO-d6) memorial plaques: 2,78 (3H, d, J = 4.4 Hz), 3,32 (2H, t, J = 4,8 Hz), a 4.53 (2H, t, J = 4,8 Hz), 7,51-of 7.60 (3H, m), 7,89-a 7.92 (2H, m), 8,18 (1H, d, J = 4.4 Hz), 8,31 (3H, user.C).

Example 24

Hydrochloride 3-(2-aminoethoxy)-5-(4-chlorophenyl)-4-methylisoxazole (Compound N 148)

(a) 3-(2-(N-tert-Butoxide isoxazol (0.25 g) and methyliodide (0.06 ml) is subjected to interaction and subsequent processing is similar as described in Example 14(a) to receive the specified header connection (0,23 g, 89%) as colorless powder.

IR spectrum (KBr)maxcm-1: 3344, 2980, 1682;

The NMR spectrum (CDCl3) memorial plaques: a 1.46 (9H, s) of 2.10 (3H, s) to 3.58 (2H, q, J = 5,2 Hz), 4,37 (2H, t, J = 5,2 Hz), the 4.90 (1H, user.C) was 7.45 (2H, d, J = 8.6 Hz), 7,63 (2H, d, J = 8.6 Hz).

(b) Hydrochloride of 3-(2-aminoethoxy)-5-(4-chlorophenyl)-4-methylisoxazole

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(4-chlorophenyl)-4 - methylisoxazol (0,22 g) is subjected to interaction and subsequent processing is similar to that described in Example 9(b), to obtain specified in the title compound (0.09 g, 50%) as colorless crystals.

So pl.: 248-253oC (decomposes);

IR spectrum (KBr)maxcm-1: 3020, 2991, 2884, 1513;

NMR spectrum (DMSO-d6) memorial plaques: a 2.12 (3H, s), with 3.27 (2H, t, J = 5,1 Hz), of 4.45 (2H, t, J = 5,1 Hz), 7,63 (2H, d, J = 8.6 Hz), of 7.75 (2H, d, J = 8.6 Hz), 8,23 (3H, user.C).

Example 25

Hydrochloride 3-(2-aminoethoxy)-5-(4-chlorophenyl)-4-utilization (Compound N 149)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(4-chlorophenyl)-4 - utilization

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(4-chlorophenyl)isoxazol (0.4 g) and ethyliodide (0,11 ml) is subjected to interaction and subsequent processing is similar to that described in Example(KBr)maxcm-1: 3460, 2980, 1713;

The NMR spectrum (CDCl3) memorial plaques: of 1.20 (3H, t, J = 7.4 Hz), of 1.46 (9H, s) to 2.54 (2H, q, J = 7,4 Hz) and 3.59 (2H, q, J = 5,2 Hz), 4,37 (2H, t, J = 5,2 Hz), the 4.90 (1H, user.C) was 7.45 (2H, d, J = 8.5 Hz), to 7.59 (2H, d, J = 8,5 Hz).

(b) Hydrochloride of 3-(2-aminoethoxy)-5-(4-chlorophenyl)-4-utilizationa

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(4-chlorophenyl)-4 - utilization (0,22 g) is subjected to reaction and post-processing similar to that described in Example 9(b), to obtain specified in the header connection (0,13 g, 72%) as colorless crystals.

So pl.: 217 through 220oC (decomposes);

IR spectrum (KBr)maxcm-1: 2972, 2892, 1515;

NMR spectrum (DMSO-d6) memorial plaques: to 1.14 (3H, t, J = 7.5 Hz), 2,58 (2H, q, J = 7.5 Hz), or 3.28 (2H, t, J = 5,2 Hz), to 4.46 (2H, t, J = 5,2 Hz), to 7.64 (2H, d, J = 8.6 Hz), 7,71 (2H, d, J = 8.6 Hz), to 8.20 (3H, user.C).

Example 26

Hydrochloride 3-(2-aminoethoxy)-5-(4-chlorophenyl)-4-propylenoxide (Compound N 150)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(4-chlorophenyl)-4 - propylenoxide

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(4-chlorophenyl)isoxazol (0.4 g) and propylitic (0,14 ml) is subjected to interaction and subsequent processing is similar to that described in Example 14(a), to obtain specified in the title compound (0.21 g, 47%) as a colorless powder.

(b) Hydrochloride of 3-(2-aminoethoxy)-5-(4-chlorophenyl)-4-propylenoxide

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(4-chlorophenyl)-4 - propylenoxide (0,19 g) is subjected to interaction and subsequent processing is similar to that described in Example 9(b), to obtain specified in the header of the connection (of 0.13 g, 81%) as colorless crystals.

So pl.: 146-149oC (decomposes);

IR spectrum (KBr)maxcm-1: 2958, 2871, 2829, 1516;

NMR spectrum (DMSO-d6) memorial plaques: from 0.90 (3H, t, J = 7,3 Hz), 1,50-to 1.59 (2H, m), of 2.54 (2H, t, J = 7,3 Hz), or 3.28 (2H, t, J = 5,2 Hz), of 4.45 (2H, t, J = 5,2 Hz), 7,63 (2H, d, J = 8.7 Hz), 7,72 (2H, d, J = 8.7 Hz), 8,21 (3H, user.C).

Example 27

Hydrochloride 3-(2-aminoethoxy)-5-(4-were)isoxazol (Compound No. 260)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(4-were)isoxazol

3-Hydroxy-5-(4-were)isoxazol (1.5 g) and 2-(N-tert-butoxycarbonylamino)ethanol (1.5 g) is subjected to interaction and subsequent processing is similar to that described in Example 9(a), to obtain specified in the title compound (2.2 g, 82%) as a colorless powder.

IR spectrum (KBr)maxcm-1: 3375, 3356, 3332, 1719, 1684;

The NMR spectrum (CDCl

(b) Hydrochloride of 3-(2-aminoethoxy)-5-(4-were)isoxazol

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(4-were)isoxazol (0.3 g) is subjected to interaction and subsequent processing is similar to that described in Example 9(b), to obtain specified in the title compound (0.16 g, 67%) as colorless crystals.

So pl.: 215-220oC (decomposes);

IR spectrum (KBr)maxcm-1: 2993, 2979, 1622;

NMR spectrum (DMSO-d6) memorial plaques: is 2.37 (3H, s) of 3.25 (2H, t, J = 5.0 Hz), of 4.44 (2H, t, J = 5.0 Hz), 6,76 (1H, s), 7,35 (2H, d, J = 8.1 Hz), 7,74 (2H, d, J = 8.1 Hz), compared to 8.26 (3H, user.C).

Example 28

Hydrochloride 3-(2-aminoethoxy)-5-(4-triptoreline)isoxazol (Compound 332 N)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy-5-(4 - triptoreline)isoxazol

3-Hydroxy-5-(4-triptoreline)isoxazol (0.2 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.15 g) is subjected to interaction and subsequent processing is similar to that described in Example 9(a), to obtain specified in the title compound (0.26 g, 81%) as a colorless powder.

IR spectrum (KBr)maxcm-1: 3376, 1679, 1608;

The NMR spectrum (CDCl3) memorial plaques: a 1.46 (9H, s) to 3.58 (2H, q, J = 5,1 Hz), 4,37 (2H, t, J = 5,1 Hz) to 4.92 (1H, user.C), and 6.25 (1H, s), 7,72 (2H, d, J = 8,2 Hz), to 7.84 (2H, d, J = 8,2 Hz).

(b) Hydrochloride lpanel)isoxazol (0.24 g) is subjected to interaction and subsequent processing is similar as described in Example 9(b), to obtain specified in the title compound (0.14 g, 70%) as colorless crystals.

So pl.: 226-232oC (decomposes);

IR spectrum (KBr)maxcm-1: 2993, 2965, 2914, 1608;

NMR spectrum (DMSO-d6) memorial plaques: is 3.27 (2H, t, J = 5,1 Hz), 4,47 (2H, t, J = 5,1 Hz), 7,07 (1H, s), to 7.93 (2H, d, J = 8,3 Hz), of 8.09 (2H, d, J = 8,3 Hz), compared to 8.26 (3H, user.C).

Example 29

Hydrochloride 3-(2-aminoethoxy)-5-(4-forfinal)isoxazol (Compound N 66)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(4-forfinal)isoxazol

5-(4-Forfinal)-3-hydroxyethoxy (0.06 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.06 g) is subjected to interaction and subsequent processing is similar to that described in Example 9(a), to obtain specified in the title compound (0.08 g, 74%) as a colorless powder.

IR spectrum (KBr)maxcm-1: 3375, 1682;

The NMR spectrum (CDCl3) memorial plaques: a 1.46 (9H, s), of 3.56 (2H, q, J = 5,1 Hz), 4,35 (2H, t, J = 5,1 Hz), is 4.93 (1H, user.C) 6,09 (1H, s), to 7.15 (2H, t, J = 8.6 Hz), 7,71 (2H, DD, J = 8.6 Hz, J = 5.3 Hz).

(b) Hydrochloride of 3-(2-aminoethoxy)-5-(4-forfinal)isoxazol

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(4-forfinal)isoxazol (0.05 g) is subjected to interaction and subsequent processing is similar to that described in Example 9(b), to obtain a decree);

IR spectrum (KBr)maxcm-1: 2993, 2978, 2911, 1621;

NMR spectrum (DMSO-d6) memorial plaques: 3,26 (2H, t, J = 5.0 Hz), of 4.44 (2H, t, J = 5.0 Hz), at 6.84 (1H, s), 7,40 (2H, t, J = 8,8 Hz), to 7.93 (2H, DD, J = 8,8 Hz, J = 5.3 Hz), of 8.25 (3H, user.C).

Example 30

Hydrochloride 3-(2-aminoethoxy)-5-(1-naphthyl)isoxazol (Compound N 475)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(1-naphthyl)isoxazol

3-Hydroxy-5-(1-naphthyl)isoxazol (0.20 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.17 g) is subjected to interaction and subsequent processing is similar to that described in Example 9(a) to receive the specified header connection (0,30 g, 89%) as colorless powder.

IR spectrum (KBr)maxcm-1: 3318, 1712;

The NMR spectrum (CDCl3) memorial plaques: to 1.47 (9H, s), 3,61 (2H, q, J = 5.3 Hz), 4,42 (2H, t, J = 5.3 Hz), equal to 4.97 (1H, user.C), and 6.25 (1H, s), 7,52-to 7.61 (3H, m), to 7.77-7,79 (1H, m), of 7.90-to 7.99 (2H, m), 8,27-8,31 (1H, m).

(b) Hydrochloride of 3-(2-aminoethoxy)-5-(1-naphthyl)isoxazol

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(1-naphthyl)isoxazol (0.28 g) is subjected to interaction and subsequent processing is similar to that described in Example 9(b), to obtain specified in the title compound (0.18 g, 78%) as colorless crystals.

So pl.: 201-205oC (decomposes);

IR spectrum (KBr)maxcm-1: 3002, 2968, 2913, 1602;,30 (3H.user.C).

Example 31

Hydrochloride 3-(2-aminoethoxy)-4-bromo-5-phenylisoxazole (Compound N 1357)

(a) 4-Bromo-3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-phenylisoxazol

4-Bromo-3-hydroxy-5-phenylisoxazole (0.2 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.15 g) is subjected to interaction and subsequent processing is similar to that described in Example 9(a), to obtain specified in the title compound (0.26 g, 81%) as a colorless powder.

IR spectrum (KBr)maxcm-1: 3352, 2976, 1719, 1709;

The NMR spectrum (CDCl3) memorial plaques: to 1.47 (9H, s), 3,61 (2H, q, J = 5,1 Hz) to 4.41 (2H, t, J = 5,1 Hz), equal to 4.97 (1H, user.C), 7,47-of 7.55 (3H, m), 7,98-of 8.04 (2H, m).

(b) Hydrochloride of 3-(2-aminoethoxy)-4-bromo-5-phenylisoxazole

4-Bromo-3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-phenylisoxazole (0.24 g) is subjected to interaction and subsequent processing is similar to that described in Example 9(b), to obtain specified in the header of the connection (of 0.13 g, 65%) as colorless crystals.

So pl.: 192-198oC (decomposes);

IR spectrum (KBr)maxcm-1: 2991, 2921, 2894, 1614, 1594, 1574;

NMR spectrum (DMSO-d6) memorial plaques: of 3.32 (2H, t, J = 5,1 Hz), of 4.54 (2H, t, J = 5,1 Hz), 7,60-7,66 (3H, m), 7,95-7,98 (2H, m), 8,19 (3H, user.C).

Example 32

Hydrochloride 3-(2-aminoethoxy)-4-iodine-5-phenylisoxazole (Link is angry (0.2 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.12 g) is subjected to interaction and subsequent processing is similar as described in Example 9(a) to receive the specified header connection (0,22 g, 73%) as a colorless powder.

IR spectrum (KBr)maxcm-1: 3328, 2977, 1696;

The NMR spectrum (CDCl3) memorial plaques: to 1.47 (9H, s), 3,61 (2H, q, J = 5,2 Hz) to 4.41 (2H, t, J = 5,2 Hz), equal to 4.97 (1H, user.C), 7,47-of 7.55 (3H, m), 7,99-of 8.06 (2H, m).

(b) Hydrochloride of 3-(2-aminoethoxy)-4-iodine-5-phenylisoxazole

3-(2-(N-tert-butoxycarbonylamino)ethoxy)-4-iodine-5-phenylisoxazol (0.20 g) is subjected to interaction and subsequent processing is similar to that described in Example 9(b), to obtain specified in the title compound (0.12 g, 71%) as colorless crystals.

So pl.: 201-206oC (decomposes);

IR spectrum (KBr)maxcm-1: 2961, 2912, 1591;

NMR spectrum (DMSO-d6) memorial plaques: 3,30 (2H, t, J = 5.3 Hz), 4,51 (2H, t, J = 5.3 Hz), 7,58-to 7.64 (3H, m), of 7.96 shed 8.01 (2H, m), by 8.22 (3H, user.C).

Example 33

Hydrochloride 3-(2-aminoethoxy)-5-(4-isopropylphenyl)isoxazol (Compound N 1618)

(a) 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-(4 - isopropylphenyl)isoxazol

3-Hydroxy-5-(4-isopropylphenyl)isoxazol (0.2 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.17 g) is subjected to interaction and subsequent processing is similar to that described in Example 9(a) to receive the specified header connection (0,2 is Tr (CDCl3) memorial plaques: of 1.27 (6H, d, J = 6,9 Hz) of 1.46 (9H, s), 2,95 (1H, sq sq, J = 6,9 Hz, J = 6.9 Hz), of 3.56 (2H, q, J = 5,1 Hz), 4,35 (2H, t, J = 5,1 Hz), 4,94 (1H, user.C) 6,09 (1H, s), 7,31 (2H, d, J = 8,3 Hz], the 7.65 (2H, d, J = 8,3 Hz).

(b) Hydrochloride of 3-(2-aminoethoxy)-5-(4-isopropylphenyl)isoxazol

3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-(4-isopropylphenyl)isoxazol (0.25 g) is subjected to interaction and subsequent processing is similar to that described in Example 9(b), to obtain specified in the title compound (0.11 g, 55%) as colorless crystals.

So pl.: 162-166oC (decomposes);

IR spectrum (KBr)maxcm-1: 3000, 2959, 2924, 1623, 1604;

NMR spectrum (DMSO-d6) memorial plaques: to 1.23 (6H, d, J = 6.9 Hz), 2,96 (1H, sq sq, J = 6,9 Hz, J = 6.9 Hz), 3,26 (2H, t, J = 5,1 Hz), of 4.44 (2H, t, J = 5,1 Hz), 6,77 (1H, s), 7,41 (2H, d, J = 8,2 Hz), to 7.77 (2H, d, J = 8,2 Hz), to 8.20 (3H, user.C).

Example 34

Hydrochloride 3-(2-aminoethoxy)-5-(2-were)isoxazol (Compound 224 N)

(a) 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-(2-were)isoxazol

3-Hydroxy-5-(2-were)isoxazol (0.2 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.2 g) is subjected to interaction and subsequent processing is similar to that described in Example 9(a), to obtain specified in the title compound (0.31 g, 86%) as a colorless powder.

IR spectrum (KBr)

(b) Hydrochloride of 3-(2-aminoethoxy)-5-(2-were)isoxazol

3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-(2-were)isoxazol (0,30 g) is subjected to interaction and subsequent processing is similar to that described in Example 9(b), to obtain specified in the title compound (0.18 g, 75%) as colorless crystals.

So pl.: 165-167oC;

IR spectrum (KBr)maxcm-1: 2996, 2976, 2911, 1613;

NMR spectrum (DMSO-d6) memorial plaques: the 2.46 (3H, s), 3,26 (2H, t, J = 5,2 Hz), to 4.46 (2H, t, J = 5,2 Hz), 6,59 (1H, s), 7,34-7,46 (3H, m), to 7.67-of 7.69 (1H, m), 8,21 (3H, user.C).

Example 35

Hydrochloride 3-(2-aminoethoxy)-5-(4-phenylphenyl)isoxazol (Compound N 368)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(4-phenylphenyl)isoxazol

3-Hydroxy-5-(4-phenylphenyl)isoxazol (0.2 g) and 2-(N-tert-Butoxycarbonylamino)ethanol (0.15 g) is subjected to interaction and subsequent processing is similar to that described in Example 9(a) to receive the specified header connection (0,22 g, 69%) as a colorless powder.

IR spectrum (KBr)maxcm-1: 3345, 1694;

The NMR spectrum (CDCl3) memorial plaques: a 1.46 (9H, s) to 3.58 (2H, q, J = 5,1 Hz), 4,37 (2H, t, J = 5,1 Hz), of 4.95 (1H, user.C) 6,18 (1H, s), 7,37-7,51 (3H, m), to 7.61-of 7.70 (4H, m), 7,79-of 7.82 (2H, m).

(b) Hydrooxide (0.2 g) is subjected to interaction and subsequent processing is similar as described in Example 9(b), to obtain specified in the title compound (0.1 g, 63%) as colorless crystals.

So pl.: 212-218oC (decomposes);

IR spectrum (KBr)maxcm-1: 2996, 2966, 2909, 1619, 1602;

NMR spectrum (DMSO-d6) memorial plaques: is 3.27 (2H, t, J = 5,1 Hz), to 4.46 (2H, t, J = 5,1 Hz), make 6.90 (1H, s), 7,41-of 7.55 (3H, m), 7,74-7,76 (2H, m), 7,84-7,87 (2H, m), 7,94-of 7.96 (2H, m), 8,18 (3H, user.C).

Example 36

Hydrochloride 3-(2-aminoethoxy)-5-(4-phenoxyphenyl)isoxazol (Compound N 1632)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(4 - phenoxyphenyl)isoxazol

3-Hydroxy-5-(4-phenoxyphenyl)isoxazol (0.2 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.14 g) is subjected to interaction and subsequent processing is similar to that described in Example 9(a) to receive the specified header connection (0,23 g, 74%) as a colorless powder.

IR spectrum (KBr)maxcm-1: 3331, 1720;

The NMR spectrum (CDCl3) memorial plaques: a 1.46 (9H, s), of 3.56 (2H, q, J = 5,2 Hz), 4,34 (2H, t, J = 5,2 Hz), of 4.95 (1H, user.C) the 6.06 (1H, s), 7,02-was 7.08 (4H, m), 7,15-7,20 (1H, m), 7,35-7,42 (2H, m), 7,65-of 7.70 (2H, m).

(b) Hydrochloride of 3-(2-aminoethoxy)-5-(4-phenoxyphenyl)isoxazol

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(4-phenoxyphenyl)isoxazol (0.18 g) is subjected to interaction and subsequent processing is similar as described>/P>So pl.: 207-213oC (decomposes);

IR spectrum (KBr)maxcm-1: 3000, 2959, 2909, 1625;

NMR spectrum (DMSO-d6) memorial plaques: 3,26 (2H, t, J = 5,1 Hz), 4,43 (2H, t, J = 5,1 Hz), 6,76 (1H, s), 7,10-7,14 (4H, m), 7,21-of 7.25 (1H, m), 7,44-of 7.48 (2H, m), a 7.85-7,88 (2H, m), 8,18 (3H, user.C).

Example 37

Hydrochloride 3-(2-aminoethoxy)-5-(2-triptoreline)isoxazol (Compound N 296)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(2 - triptoreline)isoxazol

3-Hydroxy-5-(2-triptoreline)isoxazol (0.3 g) and 2-(N-tert-Butoxycarbonylamino)ethanol (0,23 g) is subjected to interaction and subsequent processing is similar to that described in Example 9(a), to obtain specified in the title compound (0.36 g, 74%) as a colourless oil.

IR spectrum (CHCl3)maxcm-1: 3457, 2983, 1712;

The NMR spectrum (CDCl3) memorial plaques: a 1.46 (9H, s) to 3.58 (2H, q, J = 5,2 Hz), 4,37 (2H, t, J = 5,2 Hz), 4,96 (1H, user.C), 6,21 (1H, s), 7,56-of 7.69 (2H, m), 7,75-of 7.82 (2H, m).

(b) Hydrochloride of 3-(2-aminoethoxy)-5-(2-triptoreline)isoxazol

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(2 - triptoreline)isoxazol (0.35 g) is subjected to interaction and subsequent processing is similar to that described in Example 9(b), to obtain specified in the header connection (0,22 g, 76%) as colorless crystals.

6) memorial plaques: for 3.28 (2H, t, J = 5,1 Hz), to 4.46 (2H, t, J = 5,1 Hz), 6,63 (1H, s), 7,79-7,89 (3H, m), of 7.96-7,98 (1H, m), by 8.22 (3H, user. C).

Example 38

Hydrochloride 3-(2-aminoethoxy)-5-(4-hydroxyphenyl)isoxazol (Compound N 1674)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(4 - hydroxyphenyl)isoxazol

3-Hydroxy-5-(4-hydroxyphenyl)isoxazol (0.1 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.1 g) is subjected to interaction and subsequent processing is similar to that described in Example 9(a), to obtain specified in the title compound (0.12 g, 67%) as a colorless powder.

IR spectrum (KBr)maxcm-1: 3331, 3247, 1698, 1666, 1645, 1619;

NMR spectrum (DMSO-d6) memorial plaques: to 1.38 (9H, s), of 3.32 (2H, q, J = 5.6 Hz), 4,17 (2H, t, J = 5.6 Hz), 6,53 (1H, s), 6.87 in (2H, d, J = 8,8 Hz), 7,05 (1H, user.C), 7,63 (2H, d, J = 8,8 Hz), 8,98 (1H, user.C).

(b) Hydrochloride of 3-(2-aminoethoxy)-5-(4-hydroxyphenyl)isoxazol

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(4-hydroxyphenyl)isoxazol (0.12 g) is subjected to interaction and subsequent processing is similar to that described in Example 9(b), to obtain specified in the title compound (0.05 g, 56%) as colorless crystals.

So pl.: 240-245oC (decomposes);

IR spectrum (KBr)maxcm-1: 3145, 3056, 1620;

NMR spectrum (DMSO-d6) memorial plaques: 3,24 (2H, rochloride 3-(2-aminoethoxy)-5-(2,4-dichlorophenyl)isoxazol (Compound N 170)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(2,4 - dichlorophenyl)isoxazol

5-(2,4-Dichlorophenyl)-3-hydroxyethoxy (0.2 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.17 g) is subjected to interaction and subsequent processing is similar to that described in Example 9(a), to obtain specified in the title compound (0.26 g, 81%) as a colorless powder.

IR spectrum (KBr)maxcm-1: 3386, 1681, 1606;

The NMR spectrum (CDCl3) memorial plaques: a 1.46 (9H, s), of 3.57 (2H, q, J = 5,2 Hz), 4,37 (2H, t, J = 5,2 Hz), 4,94 (1H, user.C) to 6.58 (1H, s), 7,38 (1H, DD, J = 8.5 Hz, J = 2.1 Hz), 7,53 (1H, d, J = 2.1 Hz), the 7.85 (1H, d, J = 8,5 Hz).

(b) Hydrochloride of 3-(2-aminoethoxy)-5-(2,4-dichlorophenyl)isoxazol

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(2,4-dichlorophenyl)isoxazol (0.24 g) is subjected to interaction and subsequent processing is similar to that described in Example 9(b), to obtain specified in the title compound (0.12 g, 60%) as colorless crystals.

So pl.: 192-195 (in Russian)oC (decomposes);

IR spectrum (KBr)maxcm-1: 3069, 3005, 2967, 1611;

NMR spectrum (DMSO-d6) memorial plaques: is 3.27 (2H, t, J = 5,1 Hz), 4,47 (2H, t, J = 5,1 Hz), at 6.84 (1H, s), to 7.64 (1H, DD, J = 8.7 Hz, J = 2.1 Hz), 7,89 (1H, d, J = 2.1 Hz), of 7.90 (1H, d, J = 8.7 Hz), to 8.20 (3H, user.C).

Example 40

Hydrochloride 3-(2-aminoethoxy)-5-(3,4-dichlorophenyl)isoxazol (Sol)-3-hydroxyethoxy (0.3 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0,23 g) is subjected to interaction and subsequent processing is similar as described in Example 9(a) to receive the specified header connection (0,41 g, 85%) as colorless powder.

IR spectrum (KBr)maxcm-1: 3369, 1687;

The NMR spectrum (CDCl3) memorial plaques: a 1.46 (9H, s), of 3.56 (2H, q, J = 5,1 Hz), 4,35 (2H, t, J = 5,1 Hz), 4,91 (1H, user.C), 6,16 (1H, s), 7,54 (2H, s), 7,80 (1H, s).

(b) Hydrochloride of 3-(2-aminoethoxy)-5-(3,4-dichlorophenyl)isoxazol

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(3,4-dichlorophenyl)isoxazol (0.4 g) is subjected to interaction and subsequent processing is similar to that described in Example 9(b), to obtain specified in the header connection (0,22 g, 67%) as colorless crystals.

So pl.: 202-210oC (decomposes);

IR spectrum (KBr)maxcm-1: 2993, 2977, 2915, 1617;

NMR spectrum (DMSO-d6) memorial plaques: 3,26 (2H, t, J = 5,1 Hz), of 4.45 (2H, t, J = 5,1 Hz), 7,02 (1H, s), to 7.84 (1H, d, J = 8,9 Hz), the 7.85 (1H, d, J = 8,9 Hz), 8,17 (4H, user.C).

Example 41

Hydrochloride 3-(2-aminoethoxy)-5-(2,3-dichlorophenyl)isoxazol (Compound N 1526)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(2,3 - dichlorophenyl)isoxazol

5-(2,3-Dichlorophenyl)-3-hydroxyethoxy (0.3 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0,23 g) is subjected to interaction and subsequent processing is similar to that described in Example 9(a), to obtain specified in the 1607;

The NMR spectrum (CDCl3) memorial plaques: a 1.46 (9H, s) to 3.58 (2H, q, J = 5,1 Hz), 4,37 (2H, t, J = 5,1 Hz), of 4.95 (1H, user.C) 6,60 (1H, s), 7,34 (1H, t, J = 7.9 Hz), 7,58 (1H, DD, J = 7.9 Hz, J = 1.4 Hz), 7,81 (1H, DD, J = 7.9 Hz, J = 1.4 Hz).

(b) Hydrochloride of 3-(2-aminoethoxy)-5-(2,3-dichlorophenyl)isoxazol

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(2,3-dichlorophenyl)isoxazol (0.36 g) is subjected to interaction and subsequent processing is similar to that described in Example 9(b), to obtain specified in the title compound (0.20 g, 67%) as colorless crystals.

So pl.: 183-186oC (decomposes);

IR spectrum (KBr)maxcm-1: 3010, 2979, 2908, 1604;

NMR spectrum (DMSO-d6) memorial plaques: is 3.27 (2H, t, J = 5,1 Hz), 4,48 (2H, t, J = 5,1 Hz), 6.87 in (1H, s), EUR 7.57 (1H, t, J = 7.8 Hz), 7,82-7,87 (2H, m), 8,19 (3H, user.C).

Example 42

Hydrochloride 3-(2-aminoethoxy)-5-(2,6-dichlorophenyl)isoxazol (Compound N 188)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(2,6 - dichlorophenyl)isoxazol

5-(2,6-Dichlorophenyl)-3-hydroxyethoxy (0.3 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0,23 g) is subjected to interaction and subsequent processing is similar to that described in Example 9(a), to obtain specified in the title compound (0.31 g, 65%) as colorless powder.

IR spectrum (KBr)maxcm-1: 3358, 1703, 1626;

YAM (b) Hydrochloride of 3-(2-aminoethoxy)-5-(2,6-dichlorophenyl)isoxazol

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(2,6-dichlorophenyl)isoxazol (0.16 g) is subjected to interaction and subsequent processing is similar to that described in Example 9(b), to obtain specified in the title compound (0.07 g, 54%) as colorless crystals.

So pl.: 148-151oC (decomposes);

IR spectrum (KBr)maxcm-1: 3005, 2966, 2935, 1631;

NMR spectrum (DMSO-d6) memorial plaques: is 3.27 (2H, t, J = 5.0 Hz), 4,47 (2H, t, J = 5.0 Hz), 6,69 (1H, s), to 7.61-7,71 (3H, m), 8,15 (3H, user.C).

Example 43

Hydrochloride 3-(2-aminoethoxy)-5-(2,4-differenl)isoxazol (Compound No. 93)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(2,4 - differenl)isoxazol

5-(2,4-Differenl)-3-hydroxyethoxy (0.3 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.27 g) is subjected to interaction and subsequent processing is similar to that described in Example 9(a) to receive the specified header connection (0,44 g, 85%) as colorless powder.

IR spectrum (KBr)maxcm-1: 3382, 1694;

The NMR spectrum (CDCl3) memorial plaques: a 1.46 (9H, s), of 3.57 (2H, q, J = 5,1 Hz), 4,36 (2H, t, J = 5,1 Hz), is 4.93 (1H, user.C) 6,30 (1H, s), 6.90 to-7,05 (2H, m), a 7.85-7,94 (1H, m).

(b) Hydrochloride of 3-(2-aminoethoxy)-5-(2,4-differenl)isoxazol

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(2,4-differenl)isoxazole specified in the title compound (0.32 g, 94%) as colorless crystals.

So pl.: 226-232oC (decomposes);

IR spectrum (KBr)maxcm-1: 2997, 2980, 2922, 1626;

NMR spectrum (DMSO-d6) memorial plaques: 3,26 (2H, t, J = 5,1 Hz), 4,47 (2H, t, J = 5,1 Hz), 6,63 (1H, s), 7,29-7,34 (1H, m), 7,53-to 7.59 (1H, m), 7,94-8,00 (1H, m), 8,21 (3H, user.C).

Example 44

Hydrochloride 3-(2-aminoethoxy)-4-(1-chloroethyl)-5-phenylisoxazole (Compound N 1390)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-(1 - hydroxyethyl)-5-phenylisoxazol

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-phenylisoxazole (0.8 g) dissolved in tetrahydrofuran (16 ml) and added dropwise utility (1.6 M solution in hexane, to 3.7 ml) at -70oC under nitrogen atmosphere and the mixture is stirred for 10 min. Then the reaction mixture is added dropwise acetaldehyde (0,22 ml) and the resulting mixture stirred for 10 min and the temperature of the mixture was raised to 0oC. the mixture is Then poured into ice water and the pH of the mixture was adjusted to a value of 6 aqueous solution of potassium dihydrophosphate. Then the reaction mixture was extracted with ethyl acetate and the organic layer was washed with saturated aqueous NaCl, the solvent is evaporated under reduced pressure. The residue is purified column chromatography on silica gel (eluent: hexane/ethyl acetate = 2/1) to get the UB>cm-1: 3602, 3459, 2982, 2936, 1712;

The NMR spectrum (CDCl3) memorial plaques: a 1.45 (9H, s) to 1.60 (3H, d, J = 6,7 Hz) of 2.64 (1H, user.C) to 3.58 (2H, q, J = 5.0 Hz), 4,39 (2H, t, J = 5.0 Hz), 4,90-5,10 (2H, m), 7,45 is 7.50 (3H, m), of 7.64-of 7.69 (2H, m).

(b) Hydrochloride of 3-(2-aminoethoxy)-4-(1-chloroethyl)-5-phenylisoxazole

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-(1-hydroxyethyl)-5 - phenylisoxazole (0.2 g) is subjected to interaction and subsequent processing is similar to that described in Example 1(b), to obtain specified in the header of the connection (of 0.13 g, 75%) as colorless crystals.

So pl.: 200-204oC (decomposes);

IR spectrum (KBr)maxcm-1: 2975, 1640;

NMR spectrum (DMSO-d6) memorial plaques: to 1.86 (3H, d, J = 7,0 Hz), with 3.27 (2H, t, J = 5,2 Hz) to 4.52 (2H, t, J = 5,2 Hz), 5,46 (1H, q, J = 7.0 Hz), 7,60-to 7.68 (3H, m), 7,71-to 7.77 (2H, m), to 8.20 (3H, user.C).

Example 45

Hydrochloride 4-acetyl-3-(2-aminoethoxy)-5-phenylisoxazole (Compound N 1410)

(a) 4-Acetyl-3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-phenylisoxazol

3-(2-(N-tert-butoxycarbonylamino)ethoxy)-4-(1-hydroxyethyl)-5 - phenylisoxazole (0.3 g) dissolved in methylene chloride (3 ml) and add bichromate pyridinium (0,49 g) at room temperature, followed by stirring the resulting mixture at the same temperature for 24 hours After the reaction, the insoluble matter about what matography on silica gel (eluent: hexane/ethyl acetate = 2/1), to get listed in the title compound (0.26 g, 87%) as colorless powder.

IR spectrum (KBr)maxcm-1: 3359, 1685;

The NMR spectrum (CDCl3) memorial plaques: to 1.47 (9H, s), of 2.51 (3H, s), the 3.65 (2H, q, J = 5,2 Hz), 4,48 (2H, t, J = 5,2 Hz), to 4.87 (1H, user.C), 7,40-7,63 (3H, m), 7,93-of 7.96 (2H, m).

(b) Hydrochloride of 4-acetyl-3-(2-aminoethoxy)-5-phenylisoxazole

4-Acetyl-3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5-phenylisoxazole (0.2 g) is subjected to interaction and subsequent processing is similar to that described in Example 9(b), to obtain specified in the title compound (0.12 g, 75%) as colorless crystals.

So pl.: 150-152oC (decomposes);

IR spectrum (KBr)maxcm-1: 3006, 2909, 1682;

NMR spectrum (DMSO-d6) memorial plaques: 2,52 (3H, s) to 3.35 (2H, t, J = 5.0 Hz), 4,59 (2H, t, J = 5.0 Hz), 7,54-to 7.64 (3H, m), a 7.85-7,88 (2H, m), 8,30 (3H, user.C).

Example 46

Hydrochloride 3-(2-aminoethoxy)-4-Isopropenyl-5-phenylisoxazole (Compound N 1394)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-(1 - hydroxyisopropyl)-5-phenylisoxazol

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-phenylisoxazole (0.8 g) dissolved in tetrahydrofuran (16 ml) is added dropwise utility (1.6 M solution in hexane, to 3.7 ml) at -70oC under nitrogen atmosphere and the resulting mixture of paramashiva peremeshivayte for 10 min, the temperature of the mixture was raised to 0oC. the Reaction mixture was poured into ice water and the pH of the mixture was adjusted to a value of 6 aqueous solution of potassium dihydrophosphate. The mixture is extracted with ethyl acetate and the organic layer was washed with saturated aqueous NaCl, followed by evaporation of the solvent under reduced pressure. The residue is purified column chromatography on silica gel (eluent: hexane/ethyl acetate = 3/1) to obtain specified in the header connection (0,42 g, 44%) as a colourless oil.

IR spectrum (CHCl3)maxcm-1: 3460, 2982, 2936, 1713;

The NMR spectrum (CDCl3) memorial plaques: a 1.46 (9H, s) of 1.50 (6H, s), 2,52 (1H, user. C) of 3.60 (2H, q, J = 5.3 Hz), to 4.41 (2H, t, J = 5.3 Hz), to 4.87 (1H, user.C), 7,41-7,49 (3H, m), 7,52-7,56 (2H, m).

(b) Hydrochloride of 3-(2-aminoethoxy)-4-Isopropenyl-5-phenylisoxazole

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-(1-hydroxyisopropyl)-5 - phenylisoxazole (0,13 g) is dissolved in a solution of 4 N. chloromethane acid/1,4-dioxane and the solution stirred at 100oC for one hour. After the reaction, the reaction mixture is left to cool, followed by evaporation of the solvent under reduced pressure. The residue is washed with ethyl acetate to obtain specified in the title compound (0.10 g, 83%) as a colorless crystal is ECTR (DMSO-d6) memorial plaques: 1,95 (3H, s), or 3.28 (2H, t, J = 5,2 Hz), 4,48 (2H, t, J = 5,2 Hz), 5,23 (1H, s) 5,33 (1H, s), 7,53-7,58 (3H, m), 7,62-7,71 (2H, m), to 8.20 (3H, user. C).

Example 47

Hydrochloride 3-(2-aminoethoxy)-5-(4-nitrophenyl)isoxazol (Compound N 1660)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(4-nitrophenyl)isoxazol

3-Hydroxy-5-(4-nitrophenyl)isoxazol (0.64 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.55 g) is subjected to interaction and subsequent processing is similar to that described in Example 9(a) to receive the specified header connection (0,86 g, 80%) as a colorless powder.

IR spectrum (KBr)maxcm-1: 3385, 1681;

The NMR spectrum (CDCl3) memorial plaques: a 1.46 (9H, s), of 3.57 (2H, q, J = 5,2 Hz), to 4.38 (2H, t, J = 5,2 Hz), the 4.90 (1H, user.C) 6,33 (1H, s), of 7.90 (2H, d, J = 8.6 Hz), with 8.33 (2H, d, J = 8.6 Hz).

(b) Hydrochloride of 3-(2-aminoethoxy)-5-(4-nitrophenyl)isoxazol

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(4-nitrophenyl)isoxazol (0.28 g) is subjected to interaction and subsequent processing is similar to that described in Example 9(b) to ghoulcity specified in the title compound (0.12 g, 52%) as colorless crystals.

So pl.: 216-220oC (decomposes);

IR spectrum (KBr)maxcm-1: 2994, 2977, 2913, 1620, 1608;

NMR spectrum (DMSO-d6) memorial plaques: for 3.28 (2H, t, J = 5,1 Hz), 4,47 (2H, t, J = 5, the hydroxy)-5-(4-AMINOPHENYL)isoxazol (Compound N 1702)

(a) 5-(4-AMINOPHENYL-3-(2-(N-tert-butoxycarbonylamino)ethoxy)isoxazol

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(4-nitrophenyl)isoxazol (0.55 g) was dissolved in a mixture of acetic acid and water (9:1, 5.5 ml) and added zinc powder (0.55 g) at room temperature, followed by stirring the resulting mixture at the same temperature for 2 hours After the reaction, the powder of the zinc is filtered off and the filtrate is extracted with ethyl acetate. The organic layer was washed with saturated aqueous NaCl and dried over anhydrous magnesium sulfate. After filtration the solvent is evaporated under reduced pressure. The residue is purified column chromatography on silica gel (eluent: hexane/ethyl acetate = 2/1) to obtain specified in the title compound (0.45 g, 90%) as colorless powder.

IR spectrum (KBr)maxcm-1: 3391, 3378, 3300, 1712, 1615;

The NMR spectrum (CDCl3) memorial plaques: a 1.46 (9H, s), 3,55 (2H, q, J = 5,1 Hz), 4,00 (2H, user. C) to 4.33 (2H, t, J = 5,1 Hz), 4,96 (1H, user.C) 5,94 (1H, s) 6,70 (2H, d, J = 8.7 Hz), 7,52 (2H, d, J = 8.7 Hz).

(b) the Dihydrochloride of 3-(2-aminoethoxy)-5-(4-AMINOPHENYL)isoxazol

5-(4-AMINOPHENYL-3-(2-(N-tert-butoxycarbonylamino)ethoxy)isoxazol (0.25 g) is subjected to interaction and subsequent processing is similar to that described in Example 242-248oC (decomposes);

IR spectrum (KBr)maxcm-1: 3039, 2939, 2584, 1625, 1597;

NMR spectrum (DMSO-d6) memorial plaques: to 3.25 (2H, t, J = 5.0 Hz), is 4.21 (2H, user. C) was 4.42 (2H, t, J = 5.0 Hz), 6,56 (1H, s) 6,94 (2H, d, J = 8,3 Hz), the 7.65 (2H, d, J = 8,3 Hz), of 8.25 (3H, user.C).

Example 49

Hydrochloride 3-(2-aminoethoxy)-5-(4-benzoylamino)isoxazol (Compound N 1716)

(a) 5-(4-Benzoylamino)-3-(2-(N-tert - butoxycarbonylamino)ethoxy)isoxazol

5-(4-AMINOPHENYL)-3-(2-(N-tert-butoxycarbonylamino)ethoxy)isoxazol (0.1 g) dissolved in tetrahydrofuran (1 ml) and successively added dropwise at 5oC under the atmosphere of nitrogen triethylamine (0.05 ml) and benzoyl chloride (0.04 ml), followed by stirring the mixture at room temperature for 30 minutes, the Reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous NaCl and dried over anhydrous magnesium sulfate. After filtration the solvent is evaporated under reduced pressure. The residue is purified column chromatography on silica gel (eluent: hexane/ethyl acetate = 3/1) to obtain specified in the title compound (0.08 g, 62%) as colorless powder.

IR spectrum (KBr)maxcm-1: 3375, 1712;

The NMR spectrum (CDCl3

(b) Hydrochloride of 3-(2-aminoethoxy)-5-(4-benzoylamino)isoxazol

5-(4-Benzoylamino)-3-(2-(N-tert - butoxycarbonylamino)ethoxy)isoxazol (0.07 g) is subjected to interaction and subsequent processing is similar to that described in Example 9(b), to obtain specified in the title compound (0.04 g, 68%) as colorless crystals.

So pl.: 242-248oC (decomposes);

IR spectrum (KBr)maxcm-1: 3322, 2959, 2910, 1645, 1621;

NMR spectrum (DMSO-d6) memorial plaques: 3,26 (2H, t, J = 5,1 Hz), of 4.44 (2H, t, J = 5,1 Hz), to 6.75 (1H, s), 7,53-the 7.65 (3H, m), 7,83-8,00 (6H, m), to 8.20 (3H, user. C), 10,55 (1H, s).

Example 50

Hydrochloride 3-(2-aminoethoxy)-5-(2,4-dichloro-3-were)isoxazol (Compound N 1576)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(2,4-dichloro-3 - were)isoxazol

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(2,4-dichlorophenyl)isoxazol (0.3 g) and methyliodide (0,08 ml) is subjected to interaction and subsequent processing is similar to that described in Example 14(a), to obtain specified in the title compound (0.14 g, 45%) as a colorless powder.

IR spectrum (KBr)maxcm-1: 3342, 1710;

The NMR spectrum (CDCl3) memorial plaques: a 1.46 (9H, s), of 2.56 (3H, s) to 3.58 (2H, q, J = 5,1 Hz), to 4.38 (2H, t, J = 5,1 Hz), of 4.95 (1H, user.C) is 6.54 (1H, s), 7,39 (1H, d, J = 8.5 Hz), 7,76 (1H, d, J = 8,5 Hz).

So pl.: 197-200oC (decomposes);

IR spectrum (KBr)maxcm-1: 3130, 2969, 2897, 1607;

NMR spectrum (DMSO-d6) memorial plaques: 2,52 (3H, s), with 3.27 (2H, t, J = 5,1 Hz), 4,47 (2H, t, J = 5,1 Hz), PC 6.82 (1H, s), the 7.65 (1H, d, J = 8.5 Hz), 7,71 (1H, d, J = 8.5 Hz), 8,17 (3H, user.C).

Example 51

Hydrochloride 3-(2-aminoethoxy)-5-(2,4-dichloro-3-ethylphenyl)isoxazol (Compound N 1590)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(2,4-dichloro-3 - ethylphenyl)isoxazol

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(2,4-dichlorophenyl)isoxazol (0.3 g) and ethyliodide (0.1 ml) is subjected to interaction and subsequent processing is similar to that described in Example 14(a), to obtain specified in the title compound (0.25 g, 78%) as colorless powder.

IR spectrum (KBr)maxcm-1: 3342, 1702;

The NMR spectrum (CDCl3) memorial plaques: to 1.21 (3H, t, J = 7.5 Hz), of 1.46 (9H, s), 3,05 (2H, q, J = 7.5 Hz), of 3.57 (2H, q, J = 5,1 Hz), 4,36 (2H, t, J = 5,1 Hz), 4,94 (1H, user.C) is 6.54 (1H, s), 7,40 (1H, d, J = 8.5 Hz), the 7.65 (1H, d, J = 8,5 Hz).

(b) Hydrochloride of 3-(2-aminoethoxy)-5-(2,4-dichloro-3-ethylphenyl)isoxazol

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(2,4-dichloro-3 - ethylphenyl)isoxazol (0,23 g) is subjected to interaction and th is g, 74%) as colorless crystals.

So pl.: 173-176oC (decomposes);

IR spectrum (KBr)maxcm-1: 2970, 2935, 2876, 1608;

NMR spectrum (DMSO-d6) memorial plaques: to 1.16 (3H, t, J = 7,4 Hz) of 3.00 (2H, q, J = 7.4 Hz), with 3.27 (2H, t, J = 5,1 Hz), 4,47 (2H, t, J = 5,1 Hz), PC 6.82 (1H, s), the 7.65 (1H, d, J = 8,4 Hz), of 7.70 (1H, d, J = 8,4 Hz), 8,21 (3H, user.C).

Example 52

Hydrochloride 5-(4-acetoxyphenyl)-3-(2-aminoethoxy)isoxazol (Compound N 1688)

(a) 5-(4-Acetoxyphenyl)-3-(2-(N-tert-butoxycarbonylamino) ethoxy)isoxazol

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(4-hydroxyphenyl)isoxazol (0.15 g) dissolved in tetrahydrofuran (1.5 ml) and added drop wise addition of triethylamine (0,07 ml) and acetylchloride (0.04 ml) in 5oC under a nitrogen atmosphere, followed by stirring the mixture at room temperature for 30 minutes, the Reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous NaCl and dried over anhydrous magnesium sulfate. After filtration the solvent is evaporated under reduced pressure. The residue is purified column chromatography on silica gel (eluent: hexane/ethyl acetate = 2/1) to obtain specified in the title compound (0.12 g, 71%) as colorless powder.

IR spectrum (KBr)4,94 (1H, user.C), 6,12 (1H, s), 7,20 (2H, d, J = 8,8 Hz), 7,74 (2H, d, J = 8,8 Hz).

(b) Hydrochloride of 5-(4-acetoxyphenyl)-3-(2-aminoethoxy)isoxazol

5-(4-Acetoxyphenyl)-3-(2-(N-tert-butoxycarbonylamino)ethoxy)isoxazol (0.1 g) is subjected to interaction and subsequent processing is similar to that described in Example 9(b), to obtain specified in the title compound (0.05 g, 63%) as colorless crystals.

So pl.: 202-212oC (decomposes);

IR spectrum (KBr)maxcm-1: 2996, 2977, 2912, 1755, 1621;

NMR spectrum (DMSO-d6) memorial plaques: is 2.30 (3H, s), 3,26 (2H, t, J = 5,1 Hz), of 4.45 (2H, t, J = 5,1 Hz), at 6.84 (1H, s), 7,32 (2H, d, J = 8.6 Hz), to $ 7.91 (2H, d, J = 8.6 Hz), by 8.22 (3H, user.C).

EXAMPLE 53

Hydrochloride 3-(2-aminoethoxy)-5-(4-benzyloxyphenyl)isoxazol (Compound N 1646)

(a) 5-(4-Benzyloxyphenyl)-3-(2-(N-tert-butoxycarbonylamino) ethoxy)isoxazol

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(4-hydroxyphenyl)isoxazol (0.2 g) dissolved in dimethylformamide (2 ml) and added 55% sodium hydride (oil, 0.03 g) in 5oC under a nitrogen atmosphere, followed by stirring the resulting mixture at the same temperature for 10 minutes Then thereto is added dropwise benzylbromide (0,08 ml) and the mixture is stirred at room temperature for 30 minutes, the Reaction mixture Cl and dried over anhydrous magnesium sulfate. After filtration the solvent is evaporated under reduced pressure. The residue is purified column chromatography on silica gel (eluent: hexane/ethyl acetate = 3/1) to obtain specified in the title compound (0.14 g, 54%) as a colorless powder.

IR spectrum (KBr)maxcm-1: 3338, 1698;

The NMR spectrum (CDCl3) memorial plaques: a 1.46 (9H, s), of 3.56 (2H, q, J = 5.0 Hz), 4,34 (2H, t, J = 5.0 Hz), 4,94 (1H, user.C) 5,12 (2H, s), of 6.02 (1H, s),? 7.04 baby mortality (2H, d, J = 8.7 Hz), 7,28-7,47 (5H, m), 7,66 (2H, d, J = 8.7 Hz).

(b) Hydrochloride of 3-(2-aminoethoxy)-5-(4-benzyloxyphenyl)isoxazol

5-(4-Benzyloxyphenyl)-3-(2-(N-tert-butoxycarbonylamino) ethoxy)isoxazol (0,13 g) is subjected to interaction and subsequent processing is similar to that described in Example 9(b), to obtain specified in the title compound (0.07 g, 64%) as colorless crystals.

So pl.: 205-210oC (decomposes);

IR spectrum (KBr)maxcm-1: 2997, 2966, 2912, 1621, 1604;

NMR spectrum (DMSO-d6), M. D.: of 3.25 (2H, t, J = 5,1 Hz), 4,43 (2H, t, J = 5,1 Hz), 5,19 (2H, s), 6,69 (1H, s), 7,17 (2H, d, J = 9.0 Hz), 7,33-of 7.48 (5H, m), 7,79 (2H, d, J = 9.0 Hz), 8,21 (3H, user.C).

Example 54

Hydrochloride 3-(2-aminoethoxy)-5-(2-furyl)-4-isopropylthiazole (Compound N 510)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(2-furyl)-4 - isopropylthiazole

5-estiu and subsequent processing is similar as described in Example 9(a) to receive the specified header connection (to 0.29 g, 83%) as colorless powder.

IR spectrum (KBr)maxcm-1: 3317, 2985, 1690;

The NMR spectrum (CDCl3) memorial plaques: of 1.28 (6H, d, J = 7,2 Hz), of 1.46 (9H, s) to 3.33 (1H, square q, J = 7.2 Hz, J = 7,2 Hz), to 3.58 (2H, q, J = 5,1 Hz), 4,35 (2H, t, J = 5,1 Hz), 4,84 (1H, user.C) of 6.52 (1H, DD, J = 3,4 Hz, J = 1.8 Hz), to 6.80 (1H, d, J = 3,4 Hz), 7,55 (1H, d, J = 1,8 Hz).

(b) Hydrochloride of 3-(2-aminoethoxy)-5-(2-furyl)-4-isopropylthiazole

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(2-furyl)-4 - isopropylthiazole (0.27 g) is subjected to interaction and subsequent processing is similar to that described in Example 1(b), to obtain specified in the title compound (0.17 g, 77%) as colorless crystals.

So pl.: 137-139oC;

IR spectrum (KBr)maxcm-1: 2972, 2898, 1560, 1513;

NMR spectrum (DMSO-d6) memorial plaques: of 1.26 (6H, d, J = 7,0 Hz), 3,24 (1H, sq sq, J = 7,0 Hz, J = 7,0 Hz), or 3.28 (2H, t, J = 5,2 Hz), of 4.44 (2H, t, J = 5,2 Hz), was 6.73 (1H, DD, J = 3,4 Hz, J = 1.8 Hz), 7,01 (1H, d, J = 3,4 Hz), of 7.97 (1H, d, J = 1.8 Hz), 8,21 (3H, user.C).

Example 55

Hydrochloride 3-(2-aminoethoxy)-4-(tert-butyl)-5-phenylisoxazole (Compound No. 13)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-(tert-butyl)-5 - phenylisoxazol

4-(tert-Butyl)-3-hydroxy-5-phenylisoxazole (0.15 g) and 2-(N-tert-butoxide the e 9(a), to get listed in the title compound (0.16 g, 64%) as a colorless powder.

IR spectrum (KBr)maxcm-1: 3374, 2974, 1683;

The NMR spectrum (CDCl3) memorial plaques: 1,18 (9H, s) of 1.46 (9H, s), of 3.60 (2H, q, J = 5,2 Hz), to 4.38 (2H, t, J = 5,2 Hz), is 4.85 (1H, user.C) of 7.36-of 7.55 (5H, m).

(b) Hydrochloride of 3-(2-aminoethoxy)-4-(tert-butyl)-5-phenylisoxazole

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-(tert-butyl)-5 - phenylisoxazole (0.14 g) is subjected to interaction and subsequent processing is similar to that described in Example 1(b), to obtain specified in the title compound (0.09 g, 82%) as colorless crystals.

So pl.: 230-234oC (decomposes);

IR spectrum (KBr)maxcm-1: 2961, 2910, 2890, 1516;

NMR spectrum (DMSO-d6) memorial plaques: to 1.16 (9H, s), 3,30 (2H, t, J = 5.3 Hz), to 4.46 (2H, t, J = 5.3 Hz), 7,44-EUR 7.57 (5H, m), to 8.20 (3H, user.C).

Example 56

Hydrochloride 3-(2-aminoethoxy)-4-cyclopropyl-5-phenylisoxazole (Compound N 1400)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-cyclopropyl-5 - phenylisoxazol

4-Cyclopropyl-3-hydroxy-5-phenylisoxazole (0.2 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.18 g) is subjected to interaction and subsequent processing is similar to that described in Example 9(a), to obtain specified in the title compound (0.25 g, 74%) 3
) memorial plaques: 0,66-of 0.75 (2H, m), from 0.88 to 0.95 (2H, m) of 1.46 (9H, s), 1,67-of 1.73 (1H, m) to 3.58 (2H, q, J = 5,1 Hz), 4,35 (2H, t, J = 5,1 Hz), the 4.90 (1H, user.C), 7,40-7,51 (3H, m), 7,84-7,87 (2H, m).

(b) Hydrochloride of 3-(2-aminoethoxy)-4-cyclopropyl-5-phenylisoxazole

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-cyclopropyl-5 - phenylisoxazol (0.15 g) is subjected to interaction and subsequent processing is similar to that described in Example 1(b), to obtain specified in the title compound (0.06 g, 49%) as colorless crystals.

So pl.: 180-182oC;

IR spectrum (KBr)maxcm-1: 2919, 2851, 1713, 1519;

NMR spectrum (DMSO-d6) memorial plaques : 0,68-0,76 (2H, m), or 0.83 to 0.92 (2H, m), 1,71-of 1.78 (1H, m), with 3.27 (2H, t, J = 5,2 Hz), of 4.44 (2H, t, J = 5,2 Hz), 7,51-of 7.60 (3H, m), 7,83-7,86 (2H, m), to 8.20 (3H, user.C).

Example 57

Hydrochloride 3-(2-aminoethoxy)-5-(2,4-dichlorophenyl)-4-isopropylthiazole (Compound No. 176)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(2,4 - dichlorophenyl)-4-isopropylthiazole

5-(2,4-Dichlorophenyl)-3-hydroxy-4-isopropylthiazole (0.06 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.04 g) is subjected to interaction and subsequent processing is similar to that described in Example 9(a) to receive the specified header connection (0,078 g, 86%) as a colourless oil.

IR spectrum (CHCl3)maxcm-1: 3460, 297,38 (2H, t, J = 5,2 Hz), is 4.85 (1H, user.C), 7,30 (1H, d, J = 8,3 Hz), 7,35 (1H, DD, J = 8,3 Hz, J = 1.9 Hz), 7,52 (1H, d, J = 1.9 Hz).

(b) Hydrochloride of 3-(2-aminoethoxy)-5-(2,4-dichlorophenyl)-4 - isopropylthiazole

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(2,4-dichlorophenyl)-4 - isopropylthiazole (0.07 g) is subjected to interaction and subsequent processing is similar to that described in Example 1(b), to obtain specified in the title compound (0.04 g, 68%) as colorless crystals.

So pl.: 171-173oC;

IR spectrum (KBr)maxcm-1: 2968, 2875, 1514;

NMR spectrum (DMSO-d6) memorial plaques: of 1.13 (6H, d, J = 7,0 Hz), 2,69 (1H, sq sq, J = 7,0 Hz, J = 7,0 Hz), 3,29 (2H, t, J = 5.3 Hz), to 4.46 (2H, t, J = 5.3 Hz), 7,56 (1H, d, J = 8.5 Hz), a 7.62 (1H, DD, J = 8.5 Hz, J = 2.0 Hz), 7,89 (1H, d, J = 2.0 Hz), 8,18 (3H, user.C).

Example 58

Hydrochloride 3-(2-aminoethoxy)-5-(2-chlorophenyl)-4-isopropylthiazole (Compound N 117)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(2-chlorophenyl)-4 - isopropylthiazole

5-(2-Chlorophenyl)-3-hydroxy-4-isopropylthiazole (0,13 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.1 g) is subjected to interaction and subsequent processing is similar to that described in Example 9(a), to obtain specified in the title compound (0.15 g, 72%) as a colorless powder.

IR spectrum (KBr)maxcm-1: is C), 4,39 (2H, t, J = 5,2 Hz), to 4.87 (1H, user.C), 7,34-7,51 (4H, m).

(b) Hydrochloride of 3-(2-aminoethoxy)-5-(2-chlorophenyl)-4-isopropylthiazole

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(2-chlorophenyl)-4 - isopropylthiazole (0,13 g) is subjected to interaction and subsequent processing is similar to that described in Example 1(b), to obtain specified in the title compound (0.08 g, 73%) as colorless crystals.

So pl.: 143-145oC;

IR spectrum (KBr)maxcm-1: 2970, 2937, 2896, 2879, 1513;

NMR spectrum (DMSO-d6) memorial plaques: of 1.13 (6H, d, J = 7,0 Hz), 2,69 (1H, sq sq, J = 7,0 Hz, J = 7,0 Hz), 3,29 (2H, t, J = 5,2 Hz), 4,47 (2H, t, J = 5,2 Hz), 7,50-to 7.68 (4H, m), 8,24 (3H, user.C).

Example 59

Hydrochloride 3-(2-aminoethoxy)-5-(4-chlorophenyl)-4-isopropylthiazole (Compound N 151)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(4-chlorophenyl)-4 - isopropylthiazole

5-(4-Chlorophenyl)-3-hydroxy-4-isopropylthiazole (0.15 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.11 g) is subjected to interaction and subsequent processing is similar to that described in Example 9(a) to receive the specified header connection (0,19 g, 79%) as colorless powder.

IR spectrum (KBr)maxcm-1: 3382, 2966, 1685;

The NMR spectrum (CDCl3) memorial plaques: of 1.29 (6H, d, J = 7,0 Hz) of 1.46 (9H, s), 3,03 (1H, sq sq, J = 7,0 Hz,toxi)-5-(4-chlorophenyl)-4-isopropylthiazole

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(4-chlorophenyl)-4 - isopropylthiazole (0.18 g) is subjected to interaction and subsequent processing is similar to that described in Example 1(b), to obtain specified in the title compound (0.12 g, 80%) as colorless crystals.

So pl.: 224-227oC;

IR spectrum (KBr)maxcm-1: 2971, 2919, 2851, 1639;

NMR spectrum (DMSO-d6) memorial plaques: of 1.26 (6H, d, J = 7,0 Hz), to 3.02 (1H, sq sq, J = 7,0 Hz, J = 7,0 Hz), or 3.28 (2H, t, J = 5.3 Hz), of 4.45 (2H, t, J = 5.3 Hz), a 7.62 (2H, d, J = 9.0 Hz), 7,63 (2H, d, J = 9.0 Hz), 8,18 (3H, user.C).

Example 60

Hydrochloride 4-allyl-3-(2-aminoethoxy)-5-phenylisoxazole (Compound N 1392)

(a) 4-Allyl-3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-phenylisoxazol

4-Allyl-3-hydroxy-5-phenylisoxazole (1,00 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.96 g) is subjected to interaction and subsequent processing is similar to that described in Example 1(a) to receive the specified header connection (1,57 g, 91%) as colorless crystals.

So pl.: 78-79oC;

IR spectrum (KBr)maxcm-1: 3327, 1708, 1644, 1526, 1518;

The NMR spectrum (CDCl3) memorial plaques: a 1.46 (9H, s), 3.27 to be 3.29 (2H, m), of 3.57 (2H, q, J = 5,1 Hz), to 4.38 (2H, t, J = 5,1 Hz), the 4.90 (1H, user.C) of 5.05-of 5.15 (2H, m), 5,91-6,01 (1H, m), 7,41-7,49 (3H, m), 7,63-to 7.68 (2H, m).

(b) Hydrochloride of 4-allyl-3-(2-and will eraut interaction and subsequent processing is similar as described in Example 1(b), to obtain specified in the title compound (160 mg, 98%) as colorless crystals.

So pl.: 95-96oC;

IR spectrum (KBr)maxcm-1: 2967, 2912, 2885, 2817, 2694, 1643, 1601, 1577, 1514, 1495;

NMR spectrum (DMSO-d6) memorial plaques: 3,25-3,30 (2H, m) to 3.35 (2H, t, J = 5,1 Hz), to 4.46 (2H, t, J = 5,1 Hz), 5,03-5,09 (2H, m), 5,91-6,00 (1H, m), 7,52-7,58 (3H, m), to 7.67-of 7.70 (2H, m), to 8.20 (3H, user.C).

Example 61

Hydrochloride 3-(2-aminoethoxy)-5-phenyl-4-propargyloxy (Compound N 1398)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-phenyl-4 - propargyloxy

3-Hydroxy-5-phenyl-4-propargyloxy (1,00 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.96 g) is subjected to interaction and subsequent processing is similar to that described in Example 1(a), to obtain specified in the title compound (1.44 g, 84%) as a colourless oil.

IR spectrum (KBr)maxcm-1: 3352, 3302, 1711, 1643, 1600, 1577, 1520, 1499;

The NMR spectrum (CDCl3) memorial plaques: a 1.46 (9H, s), is 2.09 (1H, t, J = 2,8 Hz), 3,43 (2H, d, J = 2,8 Hz), of 3.60 (2H, q, J = 5,1 Hz) to 4.41 (2H, t, J = 5,1 Hz), 5,02 (1H, user.C), 7,45-of 7.55 (3H, m), 7,74-7,76 (2H, m).

(b) Hydrochloride of 3-(2-aminoethoxy)-5-phenyl-4-propargyloxy

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-phenyl-4-propargyloxy (200 mg) is subjected to interaction and subsequent the ideal colorless crystals.

So pl.: 210-212oC (decomposes);

IR spectrum (KBr)maxcm-1: 3258, 2959, 2899, 2830, 1632, 1601, 1577, 1523;

NMR spectrum (DMSO-d6) memorial plaques: 2,97 (1H, t, J = 2,8 Hz), 3,30 (1H, t, J = 5,1 Hz) and 3.59 (2H, d, J = 2,8 Hz), 4,47 (2H, t, J = 5,1 Hz), 7,56 to 7.62 (3H, m), 7,79-of 7.82 (2H, m), 8,13 (3H, user.C).

Example 62

Hydrochloride 3-(2-aminoethoxy)-4-isobutyl-5-phenylisoxazole (Compound No. 11)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-isobutyl-5 - phenylisoxazol

3-Hydroxy-4-isobutyl-5-phenylisoxazol (217 mg) and 2-(N-tert-butoxycarbonylamino)ethanol (193 mg) is subjected to interaction and subsequent processing is similar to that described in Example 1(a), to obtain specified in the title compound (303 mg, 84%) as colorless crystals.

So pl.: 80-81oC;

IR spectrum (KBr) maxcm-1: 3377, 1683, 1637, 1516, 1498;

The NMR spectrum (CDCl3) memorial plaques : of 0.93 (6H, d, J = 6,8 Hz) of 1.46 (9H, s), 1,89 is 1.96 (1H, m), 2,42 (2H, d, J = 7,3 Hz) to 3.58 (2H, q, J = 5,1 Hz), 4,37 (2H, t, J = 5,1 Hz), 4,88 (1H, user.C), 7,40-7,49 (3H, m), 7,66-of 7.70 (2H, m).

(b) Hydrochloride of 3-(2-aminoethoxy)-4-isobutyl-5-phenylisoxazole

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-isobutyl-5-phenylisoxazol (200 mg) is subjected to interaction and subsequent processing is similar to that described in Example 1(b), to obtain specified in the header with the rmaxcm-1: 3005, 2957, 2869, 1629, 1601, 1576, 1514, 1495;

NMR spectrum (DMSO-d6) memorial plaques: 0,86 (6H, d, J = 6.8 Hz), 2,47 (2H, d, J = 7,3 Hz), with 3.27 (2H, t, J = 5,1 Hz), of 4.45 (2H, t, J = 5,1 Hz), 7,49-7,58 (3H, m), 7,70-7,74 (2H, m), 8,19 (3H, user.C).

Example 63

Hydrochloride 3-(2-aminoethoxy)-4-cyclopentyl-5-phenylisoxazole (Compound N 1402)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-cyclopentyl-5 - phenylisoxazol

3-Hydroxy-4-cyclopentyl-5-phenylisoxazol (229 mg) and 2-(N-tert-butoxycarbonylamino)ethanol (193 mg) is subjected to interaction and subsequent processing is similar to that described in Example 1(a), to obtain specified in the title compound (308 mg, 83%) as colorless crystals.

So pl.: 112-113oC;

IR spectrum (KBr)maxcm-1: 3391, 1691, 1655, 1643, 1531, 1515;

The NMR spectrum (CDCl3) memorial plaques: a 1.46 (9H, s), 1.56 to to 1.67 (2H, m), 1,71-of 1.92 (6H, m), 3,03-of 3.12 (1H, m) to 3.58 (2H, q, J = 5,1 Hz), to 4.38 (2H, t, J = 5,1 Hz), 4,82 (1H, user.C), 7,41-7,49 (3H, m), 7,55-to 7.61 (2H, m).

(b) Hydrochloride of 3-(2-aminoethoxy)-4-cyclopentyl-5-phenylisoxazole

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-cyclopentyl-5 - phenylisoxazol (200 mg) is subjected to interaction and subsequent processing is similar to that described in Example 1(b), to obtain specified in the title compound (161 mg, 97%) as a colourless, kristallov (DMSO-d6) memorial plaques : 1,57-to 1.63 (2H, m), 1,72 is 1.91 (6H, m), 2,98-of 3.07 (1H, m), with 3.27 (2H, t, J = 5,1 Hz), of 4.45 (2H, t, J = 5,1 Hz), 7,51-to 7.61 (5H, m), 8,07 (3H, user.C).

Example 64

Hydrochloride 3-(2-aminoethoxy)-4-(2-cyclopentyl)-5-phenylisoxazole (Compound N 1404)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-(2 - cyclopentyl)-5-phenylisoxazol

3-Hydroxy-4-(2-cyclopentyl)-5-phenylisoxazole (227 mg) and 2-(N-tert-butoxycarbonylamino)ethanol (193 mg) is subjected to interaction and subsequent processing is similar to that described in Example 1(a), to obtain specified in the title compound (295 mg, 80%) as colorless crystals.

So pl.: 81-82oC;

IR spectrum (KBr)maxcm-1: 3394, 1690, 1636, 1515, 1495;

The NMR spectrum (CDCl3) memorial plaques: a 1.46 (9H, s), 1,88-to 1.98 (1H, m), 2,24-of 2.34 (1H, m), 2,39-2,49 (1H, m), 2,52-2,61 (1H, m), 3,47-3,59 (2H, m), 4,01-4,06 (1H, m), 4,30 is 4.36 (2H, m), a 4.86 (1H, user.C) 5,63-5,67 (1H, m), of 5.89-of 5.92 (1H, m), 7,42-7,49 (3H, m), 7,60-7,63 (2H, m).

(b) Hydrochloride of 3-(2-aminoethoxy)-4-(2-cyclopentyl)-5-phenylisoxazole

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-(2-cyclopentyl)-5 - phenylisoxazole (200 mg) is subjected to interaction and subsequent processing is similar to that described in Example 1(b), to obtain specified in the title compound (156 mg, 94%) as colorless crystals.

So pl.: 157-160oC (razloga is. : 1,79 of 1.99 (1H, m), 2.21 are to 2.41 (2H, m), 2,44 of $ 2.53 (1H, m) of 3.25 (2H, user.s), 3.95 to as 4.02 (1H, m), of 4.38-4,48 (2H, m), 5,56-5,71 (1H, m), 5,85-of 5.89 (1H, m), 7,51-EUR 7.57 (3H, m), to 7.59-7,63 (2H, m), 8,12 (3H, user.C).

Example 65

Hydrochloride 3-(2-aminoethoxy)-4-pentyl-5-phenylisoxazole (Compound N 1386)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-pentyl-5-phenylisoxazol

3-Hydroxy-4-pentyl-5-phenylisoxazol (231 mg) and 2-(N-tert-butoxycarbonylamino)ethanol (193 mg) is subjected to interaction and subsequent processing is similar to that described in Example 1(a), to obtain specified in the title compound (305 mg, 82%) as a colourless oil.

IR spectrum (KBr)maxcm-1: 3461, 1713, 1640, 1510, 1496;

The NMR spectrum (CDCl3) memorial plaques: to 0.89 (3H, t, J = 7.0 Hz), 1,26-to 1.38 (2H, m) of 1.46 (9H, s), 1,49-to 1.61 (2H, m), 2,52 (2H, t, J = 7,7 Hz) and 3.59 (2H, q, J = 5,1 Hz), 4,37 (2H, t, J = 5,1 Hz), 4,89 (1H, user.C), 7,40-7,49 (3H, m), of 7.64-of 7.69 (2H, m).

(b) Hydrochloride of 3-(2-aminoethoxy)-4-pentyl-5-phenylisoxazole

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-pentyl-5-phenylisoxazol (100 mg) is subjected to interaction and subsequent processing is similar to that described in Example 1(b), to obtain specified in the title compound (80 mg, 95%) as colorless crystals.

So pl.: 107-109oC;

IR spectrum (KBr)maxcm-1: 3008, 2955, 2930, 2869, 1641, 1601, 1576= 5,1 Hz), of 4.45 (2H, t, J = 5,1 Hz), 7,51-to 7.59 (3H, m), 7,66-of 7.69 (2H, m), 8,10 (3H, user.C).

Example 66

Hydrochloride 3-(2-aminoethoxy)-4-(2-butenyl)-5-phenylisoxazole (Compound N 1396)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-(2-butenyl)-5 - phenylisoxazol

3-Hydroxy-4-(2-butenyl)-5-phenylisoxazole (215 mg) and 2-(N-tert-butoxycarbonylamino)ethanol (193 mg) is subjected to interaction and subsequent processing is similar to that described in Example 1(a), to obtain specified in the title compound (292 mg, 82%) as colorless crystals.

So pl.: 62-63oC;

IR spectrum (KBr)maxcm-1: 3378, 1682, 1634, 1514, 1497;

The NMR spectrum (CDCl3) memorial plaques: a 1.46 (9H, s), 1,68-of 1.74 (3H, m), 3,19-is 3.21 (2H, m), of 3.57 (2H, q, J = 5,1 Hz), 4,37 (2H, t, J = 5,1 Hz), 4,89 (1H, user.C), 5,46-the ceiling of 5.60 (2H, m), 7,40-7,52 (3H, m), of 7.64-to 7.68 (2H, m).

(b) Hydrochloride of 3-(2-aminoethoxy)-4-(2-butenyl)-5-phenylisoxazole

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-(2-butenyl)-5 - phenylisoxazole (200 mg) is subjected to interaction and subsequent processing is similar to that described in Example 1(b), to obtain specified in the title compound (162 mg, 98%) as colorless crystals.

So pl.: 123-125oC;

IR spectrum (KBr)maxcm-1: 3028, 2961, 2934, 2916, 2855, 1641, 1601, 1577, 1570, 1515, 1494;

NMR spectrum (DMSO-d6) memorial plaques:/P> Example 67

Hydrochloride 3-(2-aminoethoxy)-4-isopropyl-5-(2-thienyl)isoxazol (Compound N 543)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-isopropyl-5-(2 - thienyl)isoxazol

3-Hydroxy-4-isopropyl-5-(2-thienyl)isoxazol (209 mg) and 2-(N-tert-butoxycarbonylamino)ethanol (193 mg) is subjected to interaction and subsequent processing is similar to that described in Example 1(a), to obtain specified in the title compound (301 mg, 86%) as colorless crystals.

So pl.: 94-95oC;

IR spectrum (KBr)maxcm-1: 3325, 1711, 1693, 1635, 1542, 1528, 1508;

The NMR spectrum (CDCl3) memorial plaques: of 1.29 (6H, d, J = 7,1 Hz) of 1.46 (9H, s), 3,19 (1H, m) to 3.58 (2H, q, J = 5,1 Hz), 4,36 (2H, t, J = 5,1 Hz), a 4.83 (1H, user. C) 7,14 (1H, DD, J = 5.3 Hz, J = 3,7 Hz), 7,42 (1H, DD, J = 3,4 Hz, J = 1.4 Hz), 7,46 (1H, d, J = 5.3 Hz).

(b) Hydrochloride of 3-(2-aminoethoxy)-4-isopropyl-5-(2-thienyl)isoxazol

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-isopropyl-5-(2 - thienyl)isoxazol (200 mg) is subjected to interaction and subsequent processing is similar to that described in Example 1(b), to obtain specified in the title compound (150 mg, 93%) as colorless crystals.

So pl.: 192-194oC (decomposes);

IR spectrum (KBr)maxcm-1: 3105, 3087, 2973, 1644, 1579, 1527, 1498;

NMR spectrum (DMSO-d6) memorial plaques: 1,27 (6 = 5,2 Hz), 8,13 (3H, user.C).

Example 68

Hydrochloride 3-(2-aminoethoxy)-4-fluoro-5-phenylisoxazole (Compound # 4)

(a) 4-Methoxyethoxy-5-phenylisoxazol

3-Hydroxy-5-phenylisoxazole (8,05 g) dissolved in dimethylformamide (80 ml) and add dropwise sodium methoxide (28% solution, 3,24 g), followed by stirring the mixture at room temperature for one hour. While the reaction mixture is cooled to 5oC, add to it a simple chloromethylation ester (4.83 g), followed by stirring the resulting mixture at the same temperature for one hour. The reaction mixture was poured into ice water (200 ml) and extracted with simple ether (200 ml x 2) and the organic layer is dried over anhydrous magnesium sulfate. After filtration the solvent is evaporated under reduced pressure. The residue is purified column chromatography on silica gel (eluent: hexane/ethyl acetate = 4/1) to obtain specified in the header connection (6,30 g, 61%) as a colourless oil.

IR spectrum (KBr)maxcm-1: 1621, 1596, 1577, 1512;

The NMR spectrum (CDCl3) memorial plaques: to 3.58 (3H, s), lower than the 5.37 (2H, s), 7,40-of 7.48 (3H, m), 7,71-of 7.95 (2H, m).

(b) 4-Fluoro-3-methoxyethoxy-5-phenylisoxazol

3 Methoxyethoxy-5-phenylisoxazol (2,05 g) dissolve the s (1.68 M solution in hexane, of 7.1 ml) and the resulting mixture was stirred at the same temperature for 15 minutes Then the reaction mixture is added N-forbindelseshastighed (3,15 g), followed by stirring the resulting mixture at the same temperature for 15 minutes the Cooling bath is removed and the temperature of the mixture was raised to room temperature. The reaction mixture was poured into ice water (200 ml) and extracted with simple ether (200 ml x 2). The organic layer is dried over anhydrous magnesium sulfate. After filtration the solvent is evaporated under reduced pressure. The residue is purified column chromatography on silica gel (eluent: hexane/ethyl acetate = 4/1) to obtain specified in the title compound (1.78 g, 80%) as a colourless oil.

IR spectrum (KBr)maxcm-1: 1672, 1545;

The NMR spectrum (CDCl3) memorial plaques: 3,62 (3H, s), the 5.45 (2H, s), 7,43-7,52 (3H, m), 7,70-7,80 (2H, m).

(c) 4-Fluoro-3-hydroxy-5-phenylisoxazol

4-Fluoro-3-methoxyethoxy-5-phenylisoxazol (0,44 g) is dissolved in a solution of 4 N. chloromethane acid/dioxane (5.0 ml) and the solution stirred at room temperature for one hour. After the reaction, the solvent is evaporated under reduced pressure and the thus obtained crystalline material was washed with dichlor the/P> IR spectrum (KBr)maxcm-1: 3059, 3014, 2995, 2919, 2851, 2822, 2747, 2645, 2565, 1674, 1582, 1527;

NMR spectrum (DMSO-d6) memorial plaques: 7,51-to 7.61 (3H, m), 7,73-7,74 (2H, m), USD 12.6 (1H, user.C).

(d) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-fluoro-5-phenylisoxazol

4-Fluoro-3-hydroxy-5-phenylisoxazole (100 mg) and 2-(N-tert-butoxycarbonylamino)ethanol (108 mg) is subjected to interaction and subsequent processing is similar to that described in Example 1(a), to obtain specified in the title compound (132 mg, 73%) as colorless crystals.

So pl.: 103-104oC;

IR spectrum (KBr)maxcm-1: 3325, 1718, 1667, 1549, 1532;

The NMR spectrum (CDCl3) memorial plaques: a 1.46 (9H, s), of 3.60 (2H, q, J = 5,1 Hz) to 4.41 (2H, t, J = 5,1 Hz), equal to 4.97 (1H, user.C), 7,41-7,52 (3H, m), 7,76-7,79 (2H, m).

(e) of the Hydrochloride of 3-(2-aminoethoxy)-4-fluoro-5-phenylisoxazole

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-fluoro-5-phenylisoxazol (110 mg) is subjected to interaction and subsequent processing is similar to that described in Example 1(b), to obtain specified in the title compound (82 mg, 93%) as colorless crystals.

So pl.: 207-211oC (decomposes);

IR spectrum (KBr)maxcm-1: 2999, 2965, 2909, 2845, 1665, 1602, 1581, 1555, 1532;

NMR spectrum (DMSO-d6) memorial plaques: of 3.32 (2H, t, J = 5,1 Hz), 4,55 (2H, t, J = 5,1 Hz), 7,55-to 7.64 (3H, m), 7,75-7,78 (2) - Rev. N 27)

(a) 3-(2-Bromoethoxy)-5-phenylisoxazol

Triphenylphosphine (15.7 g) was dissolved in toluene (200 ml) and the solution cooled to 5oC. To the solution was added diethyldithiocarbamic (10.4 g) and the resulting mixture was stirred at the same temperature for 10 minutes and Then 3-hydroxy-5-phenylisoxazole (8.0 g) and 2-bromoethanol (7.5 g) is added in that order to the reaction mixture, followed by stirring the resulting mixture at the same temperature for 10 min and then at room temperature for 2 hours, the Insoluble matter is filtered from the mixture and the solvent is evaporated under reduced pressure. The residue is purified column chromatography on silica gel (eluent: hexane/ethyl acetate = 4/1) to obtain specified in the title compound (12.1 g, 90%) as colorless crystals.

IR spectrum (KBr)maxcm-1: 3148, 1623, 1597, 1576, 1510;

The NMR spectrum (CDCl3) memorial plaques: 3,71 (2H, t, J = 5,9 Hz), to 4.62 (2H, t, J = 5,9 Hz), to 6.19 (1H, s), 7,42-7,49 (3H, m), 7,70-to 7.77 (2H, m).

(b) 3-(2-Dimethylaminoethoxy)-5-phenylisoxazol

After dissolving the hydrochloride, dimethylamine (815 mg) in methanol (50 ml) and add to it 3-(2-bromoethoxy)-5-phenylisoxazole (268 mg) and triethylamine (2.8 ml), followed by boiling under reflux the mixture for 8 the target is washed with saturated aqueous NaCl (20 ml) followed by drying the organic layer over anhydrous magnesium sulfate. After filtration the solvent is evaporated under reduced pressure. The residue is purified column chromatography on silica gel (eluent: ethyl acetate) to obtain specified in the title compound (146 mg, 63%) as colorless crystals.

So pl.: 28-29oC;

IR spectrum (KBr)maxcm-1: 2980, 2951, 1625, 1597, 1577, 1514;

The NMR spectrum (CDCl3) memorial plaques: of 2.34 (6H, s) of 2.75 (2H, t, J = 5.4 Hz), and 4.40 (2H, t, J = 5.4 Hz), 6,18 (1H, s), 7,40-of 7.48 (3H, m), 7,69-7,73 (2H, m).

(c) the Hydrochloride of 3-(2-dimethylaminoethoxy)-5-phenylisoxazole

3-(2-Dimethylaminoethoxy)-5-phenylisoxazole (130 mg) was dissolved in dioxane (1.0 ml) and add to it a solution of 4 N. chloromethane acid/dioxane (0.2 ml) and the resulting mixture left at room temperature for 15 minutes the Solvent is evaporated under reduced pressure and the residue is washed with ethyl acetate to obtain specified in the title compound (148 mg, 98%) as colorless crystals.

So pl.: 163-164oC (decomposes);

IR spectrum (KBr)maxcm-1: 3133, 1624, 1597, 1577, 1513;

NMR spectrum (DMSO-d6) memorial plaques: 2,84 (6H, s), 3,55 (2H, t, J = 5.0 Hz), br4.61 (2H, t, J = 5.0 Hz), 7,50-7,58 (3H, m), 7,81-7,87 (2H, m), 10,31 (1H, user.C).

Example 70

Hydrochloride 5-phenyl-3-(2-(1-piperidyl)ethoxy)isoxazol (Compound No. 28)

(a) 5-Phenyl-3-keys to him piperidine (426 mg), followed by boiling the mixture under reflux for 3 hours Then the reaction mixture was added to ice water (20 ml) and extracted with simple ether (20 ml x 2), the organic layer is dried over anhydrous magnesium sulfate. After filtration the solvent is evaporated under reduced pressure. The residue is purified column chromatography on silica gel (eluent: ethyl acetate) to obtain specified in the title compound (251 mg, 92%) as colorless crystals.

So pl.: 75-76oC;

IR spectrum (KBr) maxcm-1: 3149, 1625, 1598, 1577, 1513;

The NMR spectrum (CDCl3) memorial plaques: to 1.42 to 1.48 (2H, m), 1,54-to 1.67 (4H, m) of 2.50 (4H, user.C), and 2.79 (2H, t, J = 5.8 Hz), 4,42 (2H, t, J = 5.8 Hz), 6,16 (1H, s), 7,41-of 7.48 (3H, m), 7,69 to 7.75 (2H, m).

(b) Hydrochloride of 5-phenyl-3-(2-(1-piperidyl)ethoxy)isoxazol

5-phenyl-3-(2-(1-piperidyl)ethoxy)isoxazol (200 mg) is subjected to interaction and subsequent processing is similar to that described in Example 1(b), to obtain specified in the title compound (181 mg, 80%) as colorless crystals.

So pl.: 190-192oC (decomposes);

IR spectrum (KBr)maxcm-1: 2950, 2938, 1620, 1595, 1576, 1511;

NMR spectrum (DMSO-d6) memorial plaques : 1,32-of 1.44 (2H, m), 1,68 is 1.86 (4H, m), 2.95 and totaling 3.04 (2H, m), 3.45 points-to 3.58 (4H, m), with 4.64 (2H, t, J = 4,7 Hz), 6.87 in (1H, s), 7,50-7,58 (3H, m), 7,81-a 7.85 (2H, m), 9,94 of 10.05 (1H, user.C).

Example 71

Hydrochloride 5-phenyl-3-(2-(1-pyrrol the (710 mg) are added to 3-(2-bromoethoxy)-5-phenylisoxazole (268 mg) and the mixture was stirred at 100oC for one hour. Then ice water (20 ml) is added to the reaction mixture and the mixture is extracted with simple ether (20 ml x 2), the organic layer is dried over anhydrous magnesium sulfate. After filtration the solvent is evaporated under reduced pressure. The residue is purified column chromatography on silica gel (eluent: ethyl acetate) to obtain specified in the title compound (211 mg, 82%) as colorless crystals.

So pl.: 61-62oC;

IR spectrum (KBr)maxcm-1: 1623, 1596, 1575, 1509;

The NMR spectrum (CDCl3) memorial plaques: 1,77-to 1.87 (4H, m), 2.57 m-to 2.65 (4H, m), of 2.92 (2H, t, J = 5.5 Hz), 4,43 (2H, t, J = 5.5 Hz), 6,18 (1H, s), 7,40-of 7.48 (3H, m), 7,69 to 7.75 (2H, m).

(b) Hydrochloride of 5-phenyl-3-(2-(1-pyrrolidinyl)ethoxy)isoxazol

5-Phenyl-3-(2-(1-pyrrolidinyl)ethoxy)isoxazol (200 mg) is subjected to interaction and subsequent processing is similar to that described in Example 1(b), to obtain specified in the title compound (211 mg, 93%) as colorless crystals.

So pl.: 182-184oC (decomposes);

IR spectrum (KBr)maxcm-1: 2982, 2950, 2884, 2848, 2671, 2653, 2607, 2560, 2480, 1619, 1595, 1576, 1511;

NMR spectrum (DMSO-d6) memorial plaques : 1,83-of 2.08 (4H, m), 3,01-is 3.21 (2H, m), 3,50-3,68 (4H, m), 4,60 (2H, t, J = 5,1 Hz), 6.87 in (1H, s), 7,50-7,58 (3H, m), 7,81-7,87 (2H, m), as 10.63 (1H, user.C).

Example 72

Morpholine (871 mg) are added to 3-(2-bromoethoxy)-5-phenylisoxazole (268 mg) and the mixture was stirred at 100oC for one hour. Then ice water (20 ml) is added to the reaction mixture and the resulting mixture extracted with simple ether (20 ml x 2), the organic layer is dried over anhydrous magnesium sulfate. After filtration the solvent is evaporated under reduced pressure. The residue is purified column chromatography on silica gel (eluent: ethyl acetate) to obtain specified in the title compound (250 mg, 91%) as colorless crystals.

So pl.: 66-67oC;

IR spectrum (KBr)maxcm-1: 3152, 1623, 1596, 1575, 1512;

The NMR spectrum (CDCl3) memorial plaques: to 2.57 (2H, t, J = 5.4 Hz), 2,82 (2H, t, J = 5.4 Hz in), 3.75 (2H, t, J = 5.5 Hz), of 4.44 (2H, t, J = 5.5 Hz), 6,17 (1H, s), 7,41-to 7.50 (3H, m), 7,69-7,76 (2H, m).

(b) Hydrochloride of 3-(2-(4-morpholinyl)ethoxy)-5-phenylisoxazole

3-(2-(4-Morpholinyl)ethoxy-5-phenylisoxazol (200 mg) is subjected to interaction and subsequent processing is similar to that described in Example 1(b), to obtain specified in the title compound (202 mg, 89%) as colorless crystals.

So pl.: 180-182oC (decomposes);

IR spectrum (KBr)maxcm-1: 2981, 2925, 2897, 2878, 2683, 2646, 2584, 2512, 2469, 1620, 1595, 1576, 1512;

NMR spectrum (DMSO-d6) m Il.C).

Example 73

The dihydrochloride of 5-phenyl-3-(2-(1-piperazinil)ethoxy)isoxazol (Compound N 1351)

(a) 3-(2-(4-N-tert-Butoxycarbonyl-1-piperazinil)ethoxy)-5 - phenylisoxazol

3-(2-bromoethoxy)-5-Phenylisoxazole (268 mg) dissolved in methanol (1.0 ml) and add to it piperazine (861 mg), followed by boiling the mixture under reflux for 3 h Then the reaction mixture was added to dilute aqueous solution of NaCl (40 ml) and extracted with dichloromethane (40 ml x 2), the organic layer is dried over anhydrous magnesium sulfate. After filtration the solvent is evaporated under reduced pressure. The residue is dissolved in dichloromethane (5 ml) and to the mixture is added di-tert-BUTYLCARBAMATE (1,09 g), followed by stirring the mixture at room temperature for 30 minutes After the reaction the solvent is evaporated under reduced pressure and the residue purified column chromatography on silica gel (eluent: hexane/ethyl acetate = 2/1) to obtain specified in the title compound (310 mg, 83%) as colorless crystals.

So pl.: 110-111oC;

IR spectrum (KBr)maxcm-1: 3146, 1696, 1626, 1598, 1577, 1514;

The NMR spectrum (CDCl3) memorial plaques: a 1.46 (9H, s), of 2.51 (2H, t, J = 5.0 Hz), and 2.83 (2H, t, J = 5.5 Hz), 3,47 (2H, t, J = 5.0 Hz), 4,43 (2H, t, JBR>
3-(2-(4-tert-Butoxycarbonyl-1-piperazinil)ethoxy)-5-phenylisoxazole (250 mg) is subjected to interaction and subsequent processing is similar to that described in Example 1(b), to obtain specified in the title compound (222 mg, 95%) as colorless crystals.

So pl.: 216-222oC (decomposes);

IR spectrum (KBr)maxcm-1: 3443, 3189, 3123, 3001, 2972, 2950, 2915, 2771, 2715, 2623, 2527, 2422, 1704, 1648, 1621, 1596, 1578, 1565, 1514;

NMR spectrum (DMSO-d6) memorial plaques: 3,00-3,85 (10H, user.C), with 4.64 (2H, user.C) 6,86 (1H, s), 7,50-EUR 7.57 (3H, m), 7,82-a 7.85 (2H, m), 9,10-9,80 (1H, user.C).

Example 74

Hydrochloride 3-(2-N-methylenedioxy)-5-phenylisoxazole (Compound No. 25)

(a) 3-(2-(4-N-tert-Butoxycarbonyl-N-methylamino)ethoxy)-5 - phenylisoxazol

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-phenylisoxazole (304 mg) was dissolved in dimethylformamide (3 ml) and add sodium hydride [>55% (oily), 52 mg], followed by stirring the mixture at room temperature for one hour. The reaction mixture is cooled to 5oC and add to it methyliodide (220 mg), followed by stirring the resulting mixture at the same temperature for 15 min and then at room temperature for 1 h In the end of this period the reaction mixture we use is m magnesium. After filtration the solvent is evaporated under reduced pressure. The residue is purified column chromatography on silica gel (eluent: hexane/ethyl acetate = 4/1) to obtain specified in the title compound (296 mg, 93%) as colorless crystals.

So pl.: 72-73oC;

IR spectrum (KBr)maxcm-1: 3125, 1680, 1626, 1596, 1578, 1514;

The NMR spectrum (CDCl3) memorial plaques: for 1.49 (9H, s), of 2.97 (3H, s) to 3.64 (2H, user. C) to 4.41 (2H, user.C) 6,14 (1H, s), 7,41-7,52 (3H, m), 7,69 to 7.75 (2H, m).

(b) Hydrochloride of 3-(2-N-methylenedioxy)-5-phenylisoxazole

3-(2-(N-tert-Butoxycarbonyl-N-methylamino)ethoxy)-5-phenylisoxazole (250 mg) is subjected to interaction and subsequent processing is similar to that described in Example 1(b), to obtain specified in the title compound (197 mg, 99%) as colorless crystals.

So pl.: 219-221oC (decomposes);

IR spectrum (KBr)maxcm-1: 3134, 3022, 2981, 2954, 2883, 2869, 2843, 2803, 2785, 2734, 1621, 1597, 1578, 1516;

NMR spectrum (DMSO-d6) memorial plaques: 2,62 (3H, s), 3,37 (2H, t, J = 5,1 Hz), 4,50 (1H, t, J = 5,1 Hz), 6,85 (1H, s), 7,50-7,58 (3H, m), 7,82-7,88 (2H, m), 8,79 (2H, user.C).

Example 75

3-(2-Acetylbenzoate)-5-phenylisoxazole (Compound N 1347)

3-(2-Aminoethoxy)-5-phenylisoxazole hydrochloride (240 mg) is suspended in anhydrous tetrahydrofuran (5 ml) and su is mesilat at the same temperature for 30 minutes At the end of this period the reaction mixture was added to ice water (40 ml) and extracted with ethyl acetate (40 ml x 2). Then the organic layer is dried over anhydrous magnesium sulfate. After filtration the solvent is evaporated under reduced pressure. Thus obtained crystals recrystallized from ethyl acetate to obtain specified in the title compound (225 mg, 91%) as colorless crystals.

So pl.: 144-145oC;

IR spectrum (KBr)maxcm-1: 3316, 1641, 1624, 1597, 1578, 1547, 1509;

The NMR spectrum (CDCl3) memorial plaques: 2,03 (3H, s), 3,70 (2H, q, J = 5,1 Hz), 4,39 (2H, q, J = 5,1 Hz), 6,16 (1H, user.C) of 6.26 (1H, s), 7,41-7,49 (3H, m), 7,70 to 7.75 (2H, m).

Example 76

3-(2-Benzoylamino)-5-phenylisoxazole (Compound N 1349)

3-(2-Aminoethoxy)-5-phenylisoxazole hydrochloride (240 mg) is suspended in anhydrous tetrahydrofuran (5 ml) and the suspension cooled to 5oC. Add to it benzoylchloride (168 mg) and triethylamine (243 mg), followed by stirring the resulting mixture at the same temperature for 30 minutes At the end of this period the reaction mixture was added to ice water (40 ml) and extracted with ethyl acetate (40 ml x 2). Then the organic layer is dried over anhydrous magnesium sulfate. After filtration the solvent ispca compound (276 mg, 90%) as colorless crystals.

So pl.: 129-130oC;

IR spectrum (KBr) maxcm-1: 3359, 1641, 1626, 1597, 1578, 1534, 1518;

The NMR spectrum (CDCl3) memorial plaques: to 3.92 (2H, q, J = 5,1 Hz) to 4.52 (2H, q, J = 5,1 Hz), 6,17 (1H, s), 6,74 (1H, user.C), 7,42-7,53 (6H, m), 7,71-7,74 (2H, m), 7,79-7,88 (2H, m).

Example 77

3-(2-Ethoxycarbonylmethoxy)-5-phenylisoxazole (Compound N 1348)

3-(2-Aminoethoxy)-5-phenylisoxazole hydrochloride (240 mg) is suspended in anhydrous tetrahydrofuran (5 ml) and the suspension cooled to 5oC. Add to it methylchloroform (113 mg) and triethylamine (243 mg) and the mixture was stirred at the same temperature for 30 minutes At the end of this period the reaction mixture was added to ice water (40 ml) and extracted with ethyl acetate (40 ml x 2). Then the organic layer is dried over anhydrous magnesium sulfate. After filtration the solvent is evaporated under reduced pressure. Thus obtained crystals is recrystallized from a mixture of ethyl acetate and simple ether to obtain specified in the title compound (233 mg, 89%) as colorless crystals.

So pl.: 95-96oC;

IR spectrum (KBr)maxcm-1: 3293, 1729, 1624, 1596, 1577, 1552, 1516;

The NMR spectrum (CDCl3) memorial plaques: 3,63 (2H, q, J = 5,1 Hz), 3,70 (3H, s), 4,37 (2H, q, J = is isoxazole (Compound No. 15)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethylthio)-5-phenylisoxazol

2-(N-tert-Butoxycarbonylamino)ethanthiol (300 mg) is dissolved in dimethylformamide (3.0 ml) and the mixture is cooled tooC followed by the addition of sodium hydride [>55% (oil), 73 mg]. The resulting mixture was stirred at the same temperature for 30 minutes Then the reaction mixture is added 3-chloro-5-phenylisoxazol (300 mg), followed by stirring of the mixture at the same temperature for 30 min and then at room temperature for 3 days. At the end of this period the reaction mixture was added to ice water (40 ml) and extracted with ethyl acetate (40 ml x 2). Then the organic layer is dried over anhydrous magnesium sulfate. After filtration the solvent is evaporated under reduced pressure. The residue is purified column chromatography on silica gel (eluent: hexane/ethyl acetate = 4/1) to obtain specified in the title compound (130 mg, 24%) as colorless crystals.

So pl.: 87-88oC;

IR spectrum (KBr)maxcm-1: 3376, 1682, 1613, 1572, 1521, 1494;

The NMR spectrum (CDCl3) memorial plaques: the 1.44 (9H, s), with 3.27 (2H, t, J = 6.3 Hz), 3,53 (2H, q, J = 6.3 Hz), free 5.01 (1H, user.C) 6,44 (1H, s), 7,42-to 7.50 (3H, m), 7,71-7,76 (2H, m).

(b) Hydrochloride of 3-(2-aminoacetic)-5-phenylisoxazole

3-(2-(N just as described in Example 1(b), to obtain specified in the title compound (40 mg, 78%) as colorless crystals.

So pl.: 196-198oC (decomposes);

IR spectrum (KBr)maxcm-1: 3141, 2988, 2951, 2923, 1609, 1590, 1569, 1492;

NMR spectrum (DMSO-d6) memorial plaques: 3,18 (2H, t, J = 7.2 Hz), to 3.36 (2H, t, J = 7.2 Hz), 7.23 percent (1H, s), 7,53-to 7.59 (3H, m), 7,83-of 7.97 (2H, m), of 7.97 (3H, user. C).

Example 79

The dihydrochloride of 3-(2-aminoethoxy)-4-isopropyl-5-(3-pyridyl)isoxazol (Compound No. 1065)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-isopropyl-5-(3 - pyridyl)isoxazol

3-Hydroxy-4-isopropyl-5-(3-pyridyl)isoxazol (0.12 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.09 g) is subjected to interaction and subsequent processing is similar to that described in Example 9(a), to obtain specified in the title compound (0.14 g, 74%) as a colorless powder.

IR spectrum (KBr)maxcm-1: 3323, 3247, 2979, 1753, 1690;

The NMR spectrum (CDCl3) memorial plaques: is 1.31 (6H, d, J = 6,8 Hz) of 1.46 (9H, s), 3,06 (1H, sq sq, J = 6,8 Hz, J = 6,8 Hz), of 3.60 (2H, q, J = 5,2 Hz), 4,39 (2H, t, J = 5,2 Hz), 4,84 (1H, user.C) the 7.43 (1H, DD, J = 8.0 Hz, J = 4,7 Hz), of 7.90 (1H, DDD, J = 8.0 Hz, J = 2.0 Hz, J = 1.4 Hz), 8,69 (1H, DD, J = 4,7 Hz, J = 1.4 Hz), 8,83 (1H, d, J = 2.0 Hz).

(b) the Dihydrochloride of 3-(2-aminoethoxy)-4-isopropyl-5-(3-pyridyl)isoxazol

3-(2-(N-tert-Butoxycarbonylamino, as described in Example 9(b), to obtain specified in the title compound (0.07 g, 64%) as colorless crystals.

So pl.: 193-197oC (decomposes);

IR spectrum (KBr)maxcm-1: 3049, 2963, 2874, 1549;

NMR spectrum (DMSO-d6) memorial plaques: of 1.27 (6H, d, J = 7,0 Hz), 3,03 (1H, sq sq, J = 7,0 Hz, J = 7,0 Hz), 3,29 (2H, t, J = 5.4 Hz), 4,48 (2H, t, J = 5.4 Hz), to 7.68 (1H, DD, J = 8.0 Hz, J = 5.0 Hz), 8,12 (1H, DDD, J = 8.0 Hz, J = 2.0 Hz, J = 1.4 Hz), of 8.28 (3H, user.C) 8,78 (1H, DD, J = 5.0 Hz, J = 1.4 Hz), cent to 8.85 (1H, d, J = 2.0 Hz).

Example 80

Hydrochloride 3-(2-aminoethoxy)-4-(1-chloropropyl)-5-phenylisoxazole (Compound N 1802)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-(1 - hydroxypropyl)-5-phenylisoxazol

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-phenylisoxazole (0.2 g), utility (1.6 M solution in hexane, 0.9 ml) and Propionaldehyde (0.06 ml) is subjected to interaction and subsequent processing is similar to that described in Example 44(a), to obtain specified in the title compound (0.14 g, 58%) as a colourless oil.

IR spectrum (CHCl3)maxcm-1: 3602, 3459, 2980, 2937, 1712;

The NMR spectrum (CDCl3) memorial plaques : of 0.95 (3H, t, J = 7.4 Hz), a 1.45 (9H, s), 1,83-of 2.08 (2H, m), of 2.51 (1H, user.C) of 3.57 (2H, q, J = 5,2 Hz), 4,39 (2H, t, J = 5,2 Hz), and 4.68 (1H, t, J = 7.2 Hz), 4,94 (1H, user.C), 7,43-7,52 (3H, m), of 7.64 to 7.75 (2H, m).

(b) Hydrochloride of 3-(2-aminoet oxazol (0,13 g) is subjected to interaction and subsequent processing is similar as described in Example 1(b), to obtain specified in the title compound (0.10 g, 91%) as colorless crystals.

So pl.: 122-124oC;

IR spectrum (KBr)maxcm-1: 2974, 2936, 2878, 1631, 1600, 1577;

NMR spectrum (DMSO-d6) memorial plaques: to 0.94 (3H, t, J = 7,3 Hz), 2,11-of 2.28 (2H, m), and 3.31 (2H, t, J = 5,1 Hz), 4,50 (2H, t, J = 5,1 Hz), 5,14 (1H, t, J = 6.5 Hz), to 7.61-the 7.65 (3H, m), 7,72 to 7.75 (2H, m).

Example 81

Hydrochloride 3-(2-aminoethoxy)-4-(1-chloroisobutyl)-5-phenyltetrazole (Compound N 1804)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-(1 - hydroxyisobutyryl)-5-phenylisoxazol

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-phenylisoxazole (0.2 g), utility (1.6 M solution in hexane, 0.9 ml) and Isobutyraldehyde (0,07 ml) is subjected to interaction and subsequent processing is similar to that described in Example 44(a), to obtain specified in the title compound (0.21 g, 84%) as a colourless oil.

IR spectrum (CHCl3)maxcm-1: 3606, 3459, 2981, 2937, 1712, 1637;

The NMR spectrum (CDCl3) memorial plaques: of 0.79 (3H, d, J = 6.6 Hz), is 1.11 (3H, d, J = 6.6 Hz), a 1.45 (9H, s), 2,16-to 2.29 (1H, m), of 2.56 (1H, user.C) to 3.58 (2H, q, J = 5,1 Hz), 4,30-4,48 (3H, m), 4,94 (1H, user.C) 7,46-7,51 (3H, m), 7,70-7,74 (2H, m).

(b) Hydrochloride of 3-(2-aminoethoxy)-4-(1-chloroisobutyl)-5-phenylisoxazole

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-(1 - hydroxy in Example 1(b), to get listed in the title compound (0.11 g, 65%) as colorless crystals.

So pl.: 165-167oC;

IR spectrum (KBr)maxcm-1: 2967, 2902, 2870, 1636, 1600;

NMR spectrum (DMSO-d6) memorial plaques: to 0.78 (3H, d, J = 6.6 Hz) and 1.15 (3H, d, J = 6.6 Hz), 2,53-2,63 (1H, m), 3,30 (2H, t, J = 5,2 Hz), 4,50 (2H, t, J = 5,2 Hz), is 4.85 (1H, d, J = 10,7 Hz), 7,60-the 7.65 (3H, m), 7,71 to 7.75 (2H, m), of 8.25 (3H, user.C).

Example 82

Hydrochloride 3-(2-aminoethoxy)-4-(1-chloropentyl)-5-phenylisoxazole (Compound N 1806)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-(1 - hydroxydiphenyl)-5-phenylisoxazol

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-phenylisoxazole (0.2 g), utility (1.6 M solution in hexane, 0.9 ml) and isovaleraldehyde (0,09 ml) is subjected to interaction and subsequent processing is similar to that described in Example 44(a), to obtain specified in the title compound (0.2 g, 77%) as a colourless oil.

IR spectrum (CHCl3)maxcm-1: 3601, 3459, 2981, 2961, 2936, 1712, 1639;

The NMR spectrum (CDCl3) memorial plaques: to 0.87 (3H, d, J = 6.3 Hz), to 0.92 (3H, d, J = 6.3 Hz), a 1.45 (9H, s), 1,63-of 1.78 (2H, m), 1,83-to 1.98 (1H, m) to 3.58 (2H, q, J = 5,2 Hz), and 4.40 (2H, t, J = 5,2 Hz), 4.75 V-5,00 (2H, m), 7,44 is 7.50 (3H, m), 7,66-7,71 (2H, m).

(b) Hydrochloride of 3-(2-aminoethoxy)-4-(1-chloropentyl)-5-phenylisoxazole

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-(1-AK described in Example 1(b), to get listed in the title compound (0.11 g, 69%) as colorless crystals.

So pl.: 134-136oC;

IR spectrum (KBr)maxcm-1: 2961, 2905, 2873, 1630;

NMR spectrum (DMSO-d6) memorial plaques: of 0.79 (3H, d, J = 6.6 Hz), of 0.82 (3H, d, J = 6.6 Hz), of 1.57 (1H, sq sq, J = 6,6 Hz, J = 6.6 Hz), 2.00 in a 2.12 (2H, m), and 3.31 (2H, t, J = 5.4 Hz), 4,51 (2H, t, J = 5.4 Hz), to 5.21 (1H, t, J = 8.0 Hz), 7,62-the 7.65 (3H, m), 7,69-7,72 (2H, m), by 8.22 (3H, user.C).

Example 83

Hydrochloride 3-(2-aminoethoxy)-5-(2,4-differenl)-4-isopropylthiazole (Compound N 99)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(2,4 - differenl)-4-isopropylthiazole

5-(2,4-Differenl)-3-hydroxy-4-isopropylthiazole (0.2 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.16 g) is subjected to interaction and subsequent processing is similar to that described in Example 1(a), to obtain specified in the title compound (0.25 g, 78%) as colorless powder.

IR spectrum (KBr)maxcm-1: 3400, 2980, 2936, 1683;

The NMR spectrum (CDCl3) memorial plaques: 1,22 (6H, d, J = 6,9 Hz) of 1.46 (9H, s), 2,78 (1H, sq sq, J = 6,9 Hz, J = 6,9 Hz) and 3.59 (2H, q, J = 5,2 Hz), to 4.38 (2H, t, J = 5,2 Hz), a 4.86 (1H, user.s), 6.90 to-7,03 (2H, m), 7,42-7,50 (1H, m).

(b) hydrochloride of 3-(2-aminoethoxy)-5-(2,4-differenl)-4 - isopropylthiazole

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(2,4-differenl)-4 - isopropyl who would get mentioned in the title compound (0.17 g, 85%) as colorless crystals.

So pl.: 177-179oC;

IR spectrum (KBr)maxcm-1: 2973, 2936, 1642, 1614, 1590;

NMR spectrum (DMSO-d6) memorial plaques: of 1.18 (6H, d, J = 6.9 Hz), was 2.76 (1H, sq sq, J = 6,9 Hz, J = 6.9 Hz), 3,29 (2H, t, J = 5.3 Hz), to 4.46 (2H, t, J = 5.3 Hz), 7,28-7,33 (1H, m), 7,50-7,56 (1H, m), 7,60-7,66 (1H, m), 8,12 (3H, user.C).

Example 84

Hydrochloride 3-(2-aminoethoxy)-4-isopropyl-5-(4-were)isoxazol (Compound N 266)

(a) 3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-isopropyl-5-(4 - were)isoxazol

3-Hydroxy-4-isopropyl-5-(4-were)isoxazol (0.2 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.16 g) is subjected to interaction and subsequent processing is similar to that described in Example 1(a), to obtain specified in the title compound (0.27 g, 82%) as a colorless powder.

IR spectrum (KBr)maxcm-1: 3383, 2965, 1686;

The NMR spectrum (CDCl3) memorial plaques: of 1.28 (6H, d, J = 7,0 Hz) of 1.46 (9H, s) to 2.41 (3H, s), 3,06 (1H, sq sq, J = 7,0 Hz, J = 7,0 Hz) and 3.59 (2H, q, J = 5,2 Hz), 4,37 (2H, t, J = 5,2 Hz), 4,84 (1H, user.C), 7,27 (2H, d, J = 8.1 Hz), 7,46 (2H, d, J = 8,1 Hz).

(b) Hydrochloride of 3-(2-aminoethoxy)-4-isopropyl-5-(4 - were)isoxazol

3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-isopropyl-5-(4 - were)isoxazol (0.25 g) is subjected to interaction and subsequent processing like tallow.

So pl.: 208-210oC;

IR spectrum (KBr)maxcm-1: 2971, 2877, 1641, 1522;

NMR spectrum (DMSO-d6) memorial plaques: a 1.25 (6H, d, J = 7,0 Hz), of 2.38 (3H, s), to 3.02 (1H, sq sq, J = 7,0 Hz, J = 7,0 Hz), or 3.28 (2H, t, J = 5,2 Hz), of 4.44 (2H, t, J = 5,2 Hz), 7,37 (2H, d, J = 8.1 Hz), 7,47 (2H, d, J = 8.1 Hz), to 8.20 (3H, user.C).

Comparative example 1

4-Chloro-5-(4-chlorophenyl)-3-hydroxyethoxy

(a) Ethyl ester of 4-harkerite acid

4-Harkrisnowo acid (300 g) is suspended in benzene (1200 ml) and add ethanol (340 g) and conc. sulfuric acid (14 ml), followed by boiling under reflux the mixture for 15 hours After the reaction mixture is washed successively with diluted aqueous NaCl solution (500 ml), saturated aqueous sodium hydrogen carbonate (500 ml) and dilute aqueous NaCl solution (500 ml), the organic layer is dried over anhydrous magnesium sulfate. After filtration the solvent is evaporated under reduced pressure. The residue is evaporated under reduced pressure to obtain specified in the title compound (334 g, 97%) as a colourless liquid.

So pl.: 147-148oC (4 mm RT.CT.);

The NMR spectrum (CDCl3) memorial plaques are equivalent: 1.33 (3H, t, J = 7.0 Hz), 4,30 (2H, q, J = 7.0 Hz), 6,47 (1H, d, J = 16.0 Hz), 7,63 (1H, d, J = 16.0 Hz), 7,63 (4H, almost).

(b) Ethyl ester ,- dibromo-4-(1200 ml) and added dropwise bromine (251 g) under stirring at room temperature. The resulting mixture was stirred at room temperature for 4 h and left overnight. The solvent is evaporated under reduced pressure to obtain specified in the title compound (572 g, 99%) as colorless crystals.

So pl.: 67-68oC;

The NMR spectrum (CDCl3) memorial plaques: to 1.34 (3H, t, J = 7.0 Hz), 4,37 (2H, q, J = 7.0 Hz), 4,80 (1H, d, J = 12.0 Hz), 5,32 (1H, d, J = 12.0 Hz), 7,37 (4H, almost).

(c) 5-(4-Chlorophenyl-3-hydroxyethoxy

Sodium hydroxide (151 g) was dissolved in methanol (600 ml) is added dropwise an aqueous solution (50 ml), hydroxylamine hydrochloride (45 g) under stirring at 0oC and then to the mixture is added dropwise a solution of ethyl ester ,- dibromo-4-harkerite acid (200 g) in dioxane (200 ml). The resulting mixture was stirred at room temperature for 4 h and then refluxed for 5 hours, the Reaction mixture is cooled to 5oC and the pH of the mixture was adjusted to a value of 2 conc. chloroethanol acid. Then the reaction mixture was added to water (5 l). The precipitate was separated from the mixture by filtration and washed with water (2 l) and then with ethanol (1 l) to obtain 90 g specified in the title compound (85%) as pale yellow powder.

So pl.: 215-220oC (decomposes),

NMR spectrum (DMF-d7ru 5-(4-chlorophenyl)-3-hydroxycarbazole (50.0 g) in dry tetrahydrofuran (300 ml) is added dropwise a solution of sulfurylchloride (34,5 g) in dry benzene (50 ml) under stirring at 5oC. the resulting mixture was stirred at the same temperature for 30 minutes and then at room temperature for one hour and then refluxed for 3 hours the Solvent from the reaction mixture is evaporated under reduced pressure and the thus obtained solid substance is recrystallized from ethanol, to obtain specified in the header connection (44,2 g, with 76.8%) as colorless needle crystals.

So pl. 235-238oC (decomposes),

NMR spectrum (DMF-d7) memorial plaques: 7,60-to 8.20 (4H, m), 12,6 of 13.6 (1H, user.C).

Comparative example 2

3-Hydroxy-5-(2-thienyl)isoxazol

2-Tifunctional acid is subjected to interaction and subsequent processing is similar to that described in Comparative example 1(a), Comparative example 1(b) and Comparative example 1(c), to obtain specified in the header of the connection.

So pl.: 163-165oC;

NMR spectrum (DMSO-d6) memorial plaques: 6,38 (1H, s), 7,20-of 7.25 (1H, m), 7,60-7,80 (2H, m), and 11.2 and 11.6 (1H, user.C).

Comparative example 3

4-Chloro-3-hydroxy-5-(2-thienyl)isoxazol

3-Hydroxy-5-(2-thienyl)isoxazol subjected to interaction and subsequent processing is similar to that described in Comparative example 1(d), to obtain specified in the header connect

Comparative example 4

3-Hydroxy-5-(3-pyridyl)isoxazol

3-Peridiniaceae acid is subjected to interaction and subsequent processing is similar to that described in Comparative example 1(a), Comparative example 1(b) and Comparative example 1(c), to obtain specified in the header of the connection.

So pl.: 212-214oC (decomposes),

NMR spectrum (DMF-d7) memorial plaques: 6,76 (1H, s), 7,40-7,80 (1H, m), 8,10-of 8.50 (1H, m), 8,66-9,00 (1H, m), 9,05 was 9.33 (1H, m).

Comparative example 5

4-Chloro-3-hydroxy-5-(2-pyridyl)isoxazol

3-Hydroxy-5-(2-pyridyl)isoxazol subjected to interaction and subsequent processing is similar to that described in Comparative example 1(d), to obtain specified in the header of the connection.

Comparative example 6

3-Hydroxy-4-isopropyl-5-phenylisoxazol

Ethyl-benzoylacetate subjected to interaction and subsequent processing is similar as described in Agric. Biol. Chem., EN. 50, 1831 (1986), to obtain specified in the header of the connection.

So pl.: 203-205oC;

NMR spectrum (DMSO-d6) memorial plaques: 1,24 (6H, d, J = 7,1 Hz), 3,01 (1H, q, J = 7,1 Hz), 7,47-to 7.61 (5H, m), and 11.2 and 11.6 (1H, user.C).

Comparative example 7

2-(N-tert-Butoxycarbonylamino)ethanol

2-Aminoethanol (6,1 g) solution of the AI with ice with stirring, followed by stirring the resulting mixture at the same temperature for one hour and then at room temperature for 5 hours Then to the reaction mixture are added ethyl acetate (200 ml) and the mixture is washed with water, the organic layer is dried over anhydrous magnesium sulfate. After filtration the solvent is evaporated under reduced pressure to obtain specified in the title compound (15.3 g, 95%) as a colourless oil.

The Rf value: 0.35 In (developing solution: cyclohexane/ethyl acetate = 1/1).

The NMR spectrum (CDCl3) memorial plaques: a 1.45 (9H, s), 2,35-2,50 (1H, user.C) 3,29 (2H, q, J = 5.3 Hz), 3,71 (2H, q, J = 5.3 Hz), 4,85-of 5.05 (1H, user.C).

Comparative example 8

4-(tert-Butyl)-3-hydroxy-5-phenylisoxazol

(a) Ethyl ester of 2-benzoyl-3,3-dimethylmaleic acid

Diisopropylamine (5.6 ml) dissolved in tetrahydrofuran (56 ml) is added dropwise utility (1.6 M solution in hexane, 25 ml) and 5oC with stirring under nitrogen atmosphere and the resulting mixture is stirred for 15 minutes, the Reaction mixture is cooled to -70oC and add to it dropwise ethyl ester of 3,3-dimethylmaleic acid (6,7 ml) followed by stirring the resulting mixture for 10 minutes Then to the reaction mixture dropwise added benzoyl chloride (2.3 ml) and the resulting mixture was stirred at the same temperature for 10 minutes After the reaction to the reaction mixture to relax the t saturated aqueous NaCl and dried over anhydrous magnesium sulfate. After filtration the solvent is evaporated under reduced pressure. The residue is purified column chromatography on silica gel (eluent: hexane/ethyl acetate = 20/1) to obtain specified in the title compound (4.5 g, 91%) as a colourless oil.

(b) 4-(tert-Butyl)-3-hydroxy-5-phenylisoxazol

Ethyl ester of 2-benzoyl-3,3-dimethylmaleic acid (2.0 g) dissolved in methanol (20 ml) and added dropwise sodium methoxide (28% solution in methanol, 1.6 ml) in 5oC under a nitrogen atmosphere, followed by stirring the resulting mixture for 10 minutes, the Reaction mixture was cooled to -30oC and the reaction mixture is added dropwise a suspension of hydroxylamine hydrochloride (1.1 g) and sodium methoxide (28% solution in methanol, 6.2 ml) in methanol (10 mm). The resulting mixture was stirred at the same temperature for 30 min and added to the reaction mixture 6 N. chloroethanol acid (14 ml) followed by stirring the resulting mixture at 80oC for one hour. After the reaction, the solvent is evaporated under reduced pressure. Then the residue is poured into ice water and extracted with ethyl acetate, the organic layer was washed with saturated aqueous NaCl and dried over anhydrous magnesium sulfate. Poslova ether, to get listed in the title compound (0.35 g, 20%) as colorless crystals.

IR spectrum (KBr)maxcm-1: 3027, 2993, 2960, 2936, 2869, 2790, 2697, 2623, 2574, 1644, 1600;

The NMR spectrum (CDCl3) memorial plaques: 1,22 (9H, s), 7,39-to 7.50 (5H, m).

Comparative example 9

5-(4-Chlorophenyl)-3-hydroxy-4-isopropylthiazole

(a) Ethyl ester of 2-(4-chlorbenzoyl)isovalerianic acid

4-Chlorobenzylchloride (2.5 ml) and ethyl ether isovalerianic acid (1.5 ml) is subjected to interaction and subsequent processing is similar to that described in Comparative example 8(a), to obtain specified in the title compound (2.2 g, 82%) as a colourless oil.

(b) 5-(4-Chlorophenyl)-3-hydroxy-4-isopropylthiazole

Ethyl ester of 2-(4-chlorbenzoyl)isovalerianic acid (2.1 g), hydroxylamine hydrochloride (1.1 g) and sodium methoxide (28% solution in methanol, 7.5 ml) is subjected to interaction and subsequent processing is similar to that described in Comparative example 8(b), to obtain specified in the title compound (1.3 g, 71%) as colorless crystals.

IR-spectrum (KBr)maxcm-1: 3065, 3018, 2970, 2935, 2875, 2820, 2768, 2695, 2609, 1646;

The NMR spectrum (CDCl3) memorial plaques: is 1.35 (6H, d, J = 7,0 Hz), 3,06 (1H, sq sq, J = 7,0 Hz, J = 7,0 Hz), 7,46 (2H, d, J = tilby ether 2,4-deformational acid

2,4-Deformational acid (10.1 g) was dissolved in ethanol (100 ml) and add it to the end. sulfuric acid (1 ml) and the resulting mixture is refluxed for 3 hours the Solvent is evaporated under reduced pressure and the residue poured into ice water and extracted with ethyl acetate. The extract is washed successively with 5% aqueous sodium hydrogen carbonate solution and saturated aqueous NaCl and the organic layer is dried over anhydrous magnesium sulfate. After filtration the solvent is evaporated under reduced pressure to obtain specified in the title compound (11.2 g, 97%) as a colourless oil.

(b) Ethyl ester ,- dibromo-2,4-deformational acid

Ethyl ester of 2,4-deformational acid (11.2 g) was dissolved in carbon tetrachloride (110 ml) and added dropwise bromine (2.7 ml) at room temperature with stirring, followed by stirring the mixture at room temperature for 3 hours After the reaction the solvent is evaporated under reduced pressure to obtain specified in the title compound (19.6 g, quantitative) as a colorless powder.

(c) 5-(2,4-Differenl)-3-hydroxyethoxy

Sodium hydroxide (10,9 g) dissolved in methanol (110 ml) and dobavljajut dropwise a solution of ethyl ester ,- dibromo-2,4-deformational acid (19.6 g) in tetrahydrofuran (20 ml) and the resulting mixture was stirred at room temperature for 2 h, followed by boiling under reflux for 5 hours The solvent is evaporated under reduced pressure and the residue poured into ice water. The pH value of the mixture was adjusted to 2 conc. chloroethanol acid and the reaction mixture is extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl and the organic layer is dried over anhydrous magnesium sulfate. After filtration the solvent is evaporated under reduced pressure. The residue is purified column chromatography on silica gel (eluent: cyclohexane/ethyl acetate = 1/1) to obtain specified in the title compound (8.2 g, 79%) as colorless crystals.

IR spectrum (KBr)maxcm-1: 3170, 3090, 3028, 2848, 2806, 2689, 2655, 2603, 1630;

NMR spectrum (DMSO-d6) memorial plaques: 6,38 (1H, s), 7,25-to 7.32 (1H, m), 7,47-7,56 (1H, m), 7,89-to 7.99 (1H, m), are 11.62 (1H, user.C).

Comparative example 11

3-Hydroxy-5-(2-triptoreline)isoxazol

(a) Ethyl ester of 2-triptoreline acid

2-Triptorelin acid (10.1 g), conc. sulfuric acid (1 ml) and ethanol (100 ml) is subjected to interaction and subsequent processing is similar to that described in Comparative example 10(a), to obtain specified in the title compound (10.8 g, 95%) as a colourless oil.

(b) Ethyl ester ,- dibromo-2-triptoreline acid

the design just as described in Comparative example 10(b), to obtain specified in the title compound (17.9 g, quantitative) as a colorless powder.

(c) 3-Hydroxy-5-(2-triptoreline)isoxazol

Ethyl ester ,- dibromo-2-triptoreline acid (17.9 g), hydroxylamine hydrochloride (3.8 g) and sodium hydroxide (9,1 g) is subjected to interaction and subsequent processing is similar to that described in Comparative example 10(c), to obtain specified in the title compound (7.6 g, 76%) as colorless crystals.

IR spectrum (KBr)maxcm-1: 3176, 3096, 3022, 2950, 2836, 2796, 2669, 1620, 1600;

NMR spectrum (DMSO-d6) memorial plaques: 6,34 (1H, s), 7,73-7,87 (3H, m), 7,92-of 7.95 (1H, m), 11,58 (1H, user.C).

Comparative example 12

3-Hydroxy-5-(4-triptoreline)isoxazol

(a) Ethyl-4-triptoreline

4-Triptorelin acid (10.2 g), conc. sulfuric acid (1 ml) and ethanol (100 ml) is subjected to interaction and subsequent processing is similar to that described in Comparative example 10(a) to receive the specified header connection (10,9 g, 95%) as a colourless oil.

(b) Ethyl ester ,- dibromo-4-triptoreline acid

Ethyl ester of 4-triptoreline acid (10.8 g) and bromine (2.4 ml) p get mentioned in the title compound (17.9 g, quantitative) as a colorless powder.

(c) 3-Hydroxy-5-(4-triptoreline)isoxazol

Ethyl ester ,- dibromo-4-triptoreline acid (17.9 g), hydroxylamine hydrochloride (3.8 g) and sodium hydroxide (9,1 g) move the interaction and subsequent processing is similar to that described in Comparative example 10(c) to receive the specified header connection (8,3 g, 83%) as colorless crystals.

IR spectrum (KBr)maxcm-1: 3154, 3018, 2987, 2838, 2788, 2673, 2637, 2607, 2547, 1631, 1614;

NMR spectrum (DMSO-d6) memorial plaques: 6,77 (1H, s), 7,88 (2H, d, J = 8,4 Hz), 8,03 (2H, d, J = 8,4 Hz), 11,60 (1H, user.C).

Comparative example 13

3-Hydroxy-5-(4-isopropylphenyl)isoxazol

(a) Ethyl ester of 4-isopropylamino acid

4-Isopropylamino acid (5.0 g), conc. sulfuric acid (0.5 ml) and ethanol (50 ml) is subjected to interaction and subsequent processing is similar to that described in Comparative example 10(a), to obtain specified in the title compound (5.5 g 97%) as a colourless oil.

(b) Ethyl ester ,- dibromo-4-isopropylamino acid

Ethyl ester of 4-isopropylamino acid (5.5 g) and bromine (1.3 ml) is subjected to interaction and subsequent processing is similar as described in Zrnovo powder.

(c) 3-Hydroxy-5-(4-isopropylphenyl)isoxazol

Ethyl ester ,- dibromo-4-isopropylamino acid (9.5 g), hydroxylamine hydrochloride (2.2 g) and sodium hydroxide (5.2 g) is subjected to interaction and subsequent processing is similar to that described in Comparative example 10(c), to obtain specified in the title compound (3.6 g, 71%) as colorless crystals.

IR spectrum (KBr)maxcm-1: 3013, 2964, 2934, 2893, 2872, 2793, 2665, 2631, 2542, 1624;

NMR spectrum (DMSO-d6) memorial plaques: 1,22 (6H, d, J = 6.9 Hz), to 2.94 (1H, sq sq, J = 6,9 Hz, J = 6.9 Hz), 6.48 in (1H, s), 7,39 (2H, d, J = 8,3 Hz), 7,72 (2H, d, J = 8,3 Hz).

Comparative example 14

3-Hydroxy-5-(4-phenoxyphenyl)isoxazol

(a) 4-Venexiana acid

4-Phenoxybenzaldehyde (10.0 g) and potassium acetate (9.8 g) is suspended in acetic anhydride (9.5 ml), followed by boiling under reflux at 180oC for 5 hours After the reaction the pH of the mixture was adjusted to a value of 2 chloroethanol acid and the resulting mixture extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl and the organic layer is dried over anhydrous magnesium sulfate. After filtration the solvent is evaporated under reduced pressure. The residue is purified column chromatography on silica gel (eluent: what P CLASS="ptx2">

(b) Ethyl ester of 4-proximately acid

4-Phenoxycarbonyl acid (4.0 g), conc. sulfuric acid (0.4 ml) and ethanol (40 ml) is subjected to interaction and subsequent processing is similar to that described in Comparative example 10(b), to obtain specified in the title compound (4.4 g, 98%) as a colourless oil.

(c) Ethyl ester ,- dibromo-4-proximately acid

Ethyl ester of 4-proximately acid (4.4 g) and bromine (0,84 ml) is subjected to interaction and subsequent processing is similar to that described in Comparative example 10(b), to obtain specified in the title compound (7.0 g, quantitative) as a colorless powder.

(d) 3-Hydroxy-5-(4-phenoxyphenyl)isoxazol

Ethyl ester ,- dibromo-4-proximately acid (7.0 g), hydroxylamine hydrochloride (1.4 g) and sodium hydroxide (3.3 g) is subjected to interaction and subsequent processing is similar to that described in Comparative example 10(c), to obtain specified in the title compound (3.4 g, 83%) as colorless crystals.

IR spectrum (KBr)maxcm-1: 3147, 3013, 2951, 2852, 2785, 2614, 2557, 1627;

NMR spectrum (DMSO-d6) memorial plaques: 6,47 (1H, s), 7,07-of 7.25 (5H, m), 7,42-of 7.48 (2H, m), 7,79-7,83 (2H, m), 11,36 (1H, user.C).

Comparative examples is as potassium (38,3 g) and acetic anhydride (36,9 ml) is subjected to interaction and subsequent processing is similar as described in Comparative example 14(a) to receive the specified header connection (22,4 g, 58%) as a colorless powder.

(b) Ethyl ester of 1-naftiliaki acid

1-Nattractive acid (9.5 g), conc. sulfuric acid (1 ml) and ethanol (100 ml) is subjected to interaction and subsequent processing is similar to that described in Comparative example 10(a), to obtain specified in the title compound (10.2 g, 94%) as a colourless oil.

(c) Ethyl ester ,- dibromo-1-naftiliaki acid

Ethyl ester of 1-naftiliaki acid (10.1 g) and bromine (2.5 ml) is subjected to interaction and subsequent processing is similar to that described in Comparative example 10(b) to receive the specified header connection (17,2 g, quantitative) as a colorless powder.

(d) 3-Hydroxy-5-(1-naphthyl)isoxazol

Ethyl ester ,- dibromo-1-naftiliaki acid (6.0 g), hydroxylamine hydrochloride (1.3 g) and sodium hydroxide (7.2 g) is subjected to interaction and subsequent processing is similar to that described in Comparative example 10(c), to obtain specified in the title compound (2.6 g, 78%) as colorless crystals.

IR spectrum (KBr)maxcm-1: 3136, 3045, 3017, 2790, 2710, 2640, 25�comparative example 16

3-Hydroxy-5-(4-hydroxyphenyl)isoxazol

3-Hydroxy-5-(4-methoxyphenyl)isoxazol (5.0 g) is suspended in dichloromethane (50 ml) and added aluminium chloride (7.0 g), followed by boiling under reflux the mixture for 66 hours At the end of this period the reaction mixture was poured into ice-cold water and add 6 N. chloroethanol acid, followed by extraction with ethyl acetate. Then the extract was washed with saturated aqueous NaCl, the organic layer is dried over anhydrous magnesium sulfate. After filtration the solvent is evaporated under reduced pressure. The residue is purified column chromatography on silica gel (eluent: cyclohexane/ethyl acetate = 2/1) to obtain specified in the title compound (3.8 g, 83%) as colorless crystals.

IR spectrum (KBr)maxcm-1: 3140, 3074, 1624, 1588;

NMR spectrum (DMSO-d6) memorial plaques: 6,24 (1H, s) 6,86 (2H, d, J = 8,2 Hz), a 7.62 (2H, d, J = 8,2 Hz), there is a 10.03 (1H, s), 11,24 (1H, user.C).

Comparative example 17

5-(2,4-Differenl)-3-hydroxy-4-isopropylthiazole

(a) Ethyl ester of 2-(2,4-differentail)isovalerianic acid

2,4-Differentiald (4,9 ml) and ethyl ether isovalerianic acid (3.0 ml) is subjected to interaction and subsequent tion (3,65 g, 68%) as a colourless liquid.

(b) 5-(2,4-Differenl)-3-hydroxy-4-isopropylthiazole

Ethyl ester of 2-(2,4-differentail)isovalerianic acid (1.7 g), hydroxylamine hydrochloride (0.9 g) and sodium methoxide (28% solution in methanol, 7.5 ml) is subjected to interaction and subsequent processing is similar to that described in Comparative example 8(b), to obtain specified in the header connection (0,59 g, 39%) as colorless crystals.

IR spectrum (KBr)maxcm-1: 3082, 3033, 2980, 2968, 2935, 2913, 2877, 2836, 2795, 2699, 2636, 2604, 1660, 1610;

NMR spectrum (DMSO-d6) memorial plaques: of 1.28 (6H, d, J = 7,0 Hz), of 2.81 (1H, sq sq, J = 7,0 Hz, J = 7,0 Hz), 6,91-7,05 (2H, m), 7,43-7,52 (1H, m).

Comparative example 18

4-Cyclopropyl-3-hydroxy-5-phenylisoxazol

(a) Methyl ester of 2-benzoyl-2-cyclopropylacetic acid

The benzoyl chloride (1.0 ml) and methyl ester of 2-cyclopropylacetic acid is subjected to interaction and subsequent processing is similar to that described in Comparative example 8(a) to receive the specified header connection (1,05 g, 28%) as a colourless liquid.

(b) 4-Cyclopropyl-3-hydroxy-5-phenylisoxazol

Methyl ester of 2-benzoyl-2-cyclopropylacetic acid (0.9 g), hydroxylamine hydrochloride (0.6 g) and met, the AK is described in Comparative example 8(b), to obtain specified in the title compound (0.32 g, 39%) as colorless crystals.

IR spectrum (KBr)maxcm-1: 3085, 3066, 3012, 2972, 2909, 2851, 2778, 2716, 2652, 2601, 1646;

The NMR spectrum (CDCl3) memorial plaques: 0,79-0,85 (2H, m), 0,91-0,98 (2H, m), 1,67-to 1.77 (1H, m), 7,43-7,53 (3H, m), 7,86-of 7.90 (2H, m).

Comparative example 19

3-Hydroxy-4-isopropyl-5-(3-pyridyl)isoxazol

(a) Ethyl ester of 2-nicotinereplacement acid

The hydrochloride of the acid chloride of nicotinic acid (0.9 g), ethyl ester of isovalerianic acid (2.3 ml), Diisopropylamine (2.1 ml) and utility (1.6 M solution in hexane, to 9.4 ml) is subjected to interaction and subsequent processing is similar to that described in Comparative example 8(a) to receive the specified header connection (0,78 g, 44%) as a colourless liquid.

(b) 3-Hydroxy-4-isopropyl-5-(3-pyridyl)isoxazol

Ethyl ester of 2-nicotinereplacement acid (0,76 g), hydroxylamine hydrochloride (0,46 g) and sodium methoxide (28% solution in methanol, 3,1 ml) is subjected to interaction and subsequent processing is similar to that described in Comparative example 8(b), to obtain specified in the title compound (0.15 g, 23%) as colorless crystals.

) memorial plaques: to 1.38 (6H, d, J = 7,0 Hz), 3,10 (1H, sq sq, J = 7,0 Hz, J = 7,0 Hz), was 7.45 (1H, DD, J = 7.9 Hz, J = 4.4 Hz), 7,94 (1H, d, J = 7.9 Hz), 8,72 (1H, d, J = 4.4 Hz), 8,88 (1H, s).

Comparative example 20

4-Chloro-3-hydroxy-5-(3-pyridyl)isoxazol

3-hydroxy-5-(3-pyridyl)isoxazol subjected to interaction and subsequent processing is similar to that described in Comparative example 1(d), to obtain specified in the header of the connection.

So pl. 220-224oC (decomposes),

NMR spectrum (DMF-d7) memorial plaques: 7,60-to 8.20 (4H, m), 12,6 of 13.6 (1H, user. C).

Example test 1

The ability to inhibit monoamine oxidase type A

The ability to inhibit monoamine oxidase type A is determined according to the method described in Biochem. Pharmacol., 12, 1439 (1963) and J. Neurochem., 35, 109 (1980). To 30 μl of the sample of crude mitochondria of mouse brain (30 µg protein) add 210 ál of phosphate buffer (pH 7,4) and the test compound (dissolved in a mixture of 10% DMSO and water) and the resulting mixture was pre-incubated at 38oC for 20 minutes After that, a pre-incubated mixture14C-5-hydroxytryptamine (5-HT, final concentration: 100 μm) in order to carry out the reaction at the 38oC for 20 min. then the reaction quenched by adding 2 N. chloroethanol acid (200 metal : toluene = 1:1) and14C-radioactivity was determined by liquid scintillation counter to obtain a concentration of a compound that reduces14C-radioactivity control at 50%.

The test results show that the compounds 1, 2, 3, 4, 5, 6, 54, 57, 58, 59, 60, 62 and 67 are particularly excellent activity IC5028 nm.

Sample preparation 1

Preparation of hard capsules

Mix 50 mg of powdered compounds of Example 4, 128,7 mg lactose 70 mg of cellulose and 1.3 mg of magnesium stearate and pass through a sieve of 60 mesh and the resulting powder is filled gelatin capsules N-3 250 mg, to obtain a preparation in the form of capsules.

Example preparation of 2

Preparation of tablets

Mix 50 mg of powdered compounds of Example 4, 124 mg of lactose, 25 mg of cellulose and 1 mg of magnesium stearate and formed into tablets on a tablet press machine to obtain tablets 200 mg. These tablets can be sugar coated if necessary.

[Industrial use]

Derivatives isoxazol having General formula (I) of this invention have excellent ability to inhibit monoamine oxidase type A and relatively free from unwanted poboc the treatment) nervous diseases, including depression, Parkinson's disease, dementia Alzheimer's disease (impaired cognitive ability, characteristic of Alzheimer's disease) or cerebrovascular dementia (impaired cognitive abilities inherent in cerebrovascular dementia), (in particular, depression).

When the compound (I) or their pharmaceutically acceptable salts according to this invention are used as therapeutic or preventive agent for nervous diseases, the compound (I) or their salts, as such, or their mixture, obtained by the appropriate mixing of the compound (I) with pharmaceutically acceptable excipients, diluents, etc., may be given by oral administration of tablets, capsules, granules, powders or syrups, or by parenteral administration by injection, or by suppository, etc.

Such pharmaceutical preparations are prepared in the usual way, using additives such as fillers (for example, sugar derivatives such as lactose, sucrose, glucose, mannitol and sorbitol; starch derivatives such as corn starch, potato starch, a - starch, dextrin and carboxymethyl-starch; cellulose derivatives such as crystalline cellulose, hydrocellulose and sodium salt of intramolecular crosslinked carmellose (croscarmellose); gum; dextran; pullulan; silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate or alumosilicate magnesium; salts of phosphoric acid such as calcium phosphate; salts of carbonic acid, such as calcium carbonate and salts of sulfuric acid, such as calcium sulfate), binders (for example, the above-mentioned fillers; gelatin; polyvinylpyrrolidone; macrogol and the like), substances that contribute to the disintegration of the dosage form (for example, the above-mentioned fillers; sodium salt croscarmellose; sodium salt of carboxymethyl amylum, starch, chemically modified like crosspovidone, derivatives of cellulose, and the like), lubricants (for example, talc; stearic acid; metal stearates such as calcium stearate and magnesium stearate; colloidal silicon dioxide; bee gum; waxes, such as spermaceti; boric acid; glycol; carboxylic acids such as fumaric acid and adipic acid; sodium carboxylates such as sodium benzoate; sulfates such as sodium sulfate; leucine; lauryl-sulfates, such as lauryl sulfate and lauryl-magnesium sulfate; silicic acid, such as silicic acid anhydride and hydrate kremnievoj as methylparaben and propylparaben; alcohols, such as chlorobutanol, benzyl alcohol and phenethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; the anhydride of acetic acid and sorbic acid), substances that mask the taste or smell (for example, a commonly used podslushivala, podnikatel and flavorings, and the like), thinners and solvents for injection (for example, water, ethanol, glycerin and the like).

Used doses vary depending on the condition and age of the patient. For example, in the case of oral administration, preferably administered 1 mg (preferably 10 mg) as a lower limit and 2000 mg (preferably, 400 mg) as an upper limit, and in the case of intravenous administration, it is desirable to introduce 0.1 mg (preferably 1 mg) as a lower limit and 500 mg (preferably, 300 mg) as an upper limit for an adult from one to 6 times a day depending on symptoms.

The data IC50are shown in table 2.

The claimed compounds have low toxicity.

1. Derived isoxazol formula I

< / BR>
where R1represents C6-C14aryl group optionally having from 1 to 3 substituents, which mo is th aromatic heterocyclic group, having one heteroatom selected from the group comprising atoms of nitrogen, oxygen and sulfur (Deputy is halogen; C1-C6alkyl, C1-C6alkyl substituted by halogen; C1-C6alkoxy; phenyl; phenoxy; benzyloxy; benzoylamine; nitro; hydroxyl; C1-C7alkanoyloxy, and (amino group);

R2denotes hydrogen; halogen; C1-C6alkyl, C1-C6alkyl substituted by halogen; C2-C6alkenyl; C2-C6quinil; C3-C10cycloalkyl; C3-C10cycloalkenyl; cyano; carboxyl; C1-C7alkanoyl; C2-C7alkoxycarbonyl; carbarnoyl; or mono(C1-C6alkyl)carbarnoyl;

R3denotes amino, mono(C1-C6alkyl)amino, di(C1-C6alkyl)amino, mono-C1-C7alkanolamine, mono-C2-C7alkoxycarbonyl, mono-C7-C15arylcarboxamide, or 5 - or 6-membered saturated heterocyclic group connected through the nitrogen atom of the ring, which contains one nitrogen atom and optionally contains one nitrogen atom or an oxygen atom;

X denotes an oxygen atom or a sulfur atom;

n denotes an integer from 2 to 6,

and6-C14aryl group having from 1 to 3 substituents, which may be the same or different from each other and selected from the following group of substituents, or a 5 - or 6-membered aromatic heterocyclic group containing one heteroatom selected from the group comprising atoms of nitrogen, oxygen and sulfur (Deputy is halogen; C1-C6alkyl, C1-C6alkyl substituted by halogen; C1-C6alkoxy; phenyl; phenoxy; benzyloxy; benzoylamine; nitro; hydroxyl; acetoxygroup; or amino group), or their pharmaceutically acceptable salts.

3. Derived isoxazol under item 1, where R1represents C6-C14aryl group optionally having from 1 to 3 substituents, which may be the same or different from each other and selected from the following group of substituents, or a 5 - or 6-membered aromatic heterocyclic group having one heteroatom selected from the group comprising atoms of nitrogen, oxygen and sulfur (Deputy is halogen; C1-C6alkyl; and phenyl group), or its pharmaceutically acceptable salt.

4. Derived isoxazol under item 1, where R1represents C6-C14aryl group, optional the following group of substituents, or 5 - or 6-membered aromatic heterocyclic group containing one heteroatom selected from the group comprising atoms of nitrogen, oxygen and sulfur (Deputy is halogen, C1-C4alkyl, vermeil, deformity, trifluoromethyl, 2-foretel, 2,2,2-triptorelin, C1-C4alkoxy and phenyl group), or its pharmaceutically acceptable salt.

5. Derived isoxazol under item 1, where R1denotes a phenyl group optionally having 1 to 3 substituents, which may be the same or different from each other and selected from the following group of substituents, or furyl, thienyl or pyridyloxy group (Deputy is halogen, methyl, ethyl, trifluoromethyl, methoxy and phenyl group), or its pharmaceutically acceptable salt.

6. Derived isoxazol under item 1, where R1denotes a phenyl group, optionally having one or two substituent which may be the same or different from each other and selected from the following group of substituents, or furyl, thienyl or pyridyloxy group (Deputy is fluorine, chlorine, methyl, ethyl, trifluoromethyl and methoxy group), or its pharmaceutically acceptable salt.

7. Derived isoxazol under item 1, enyl or 3-thienyl group, or its pharmaceutically acceptable salt.

8. Derived isoxazol under item 1, where R1denotes phenyl, 2-chlorophenyl, 4-chlorophenyl, 2,4-differenl, 2,4-dichlorophenyl, 2-furyl or 2-thienyl group, or its pharmaceutically acceptable salt.

9. Derived isoxazol under item 1, where R2denotes hydrogen, halogen, C1-C6alkyl, vermeil, deformity, trifluoromethyl, 2-foretel, 1-chloroethyl, 2-chloroethyl, 2,2,2-triptorelin, C2-C6alkenyl, C2-C6quinil, cyclopropyl, cyclopentyl, cyclohexyl, 2-cyclopentenyl, 3-cyclopentenyl, 2-cyclohexenyl, 3-cyclohexenyl, cyano, carboxyl, formyl, acetyl, methoxycarbonyl, etoxycarbonyl, carbarnoyl, methylcarbamoyl or ethylcarbazole group, or its pharmaceutically acceptable salt.

10. Derived isoxazol under item 1, where R2denotes hydrogen, halogen, C1-C6alkyl, C2-C6alkenyl or C2-C6alkylamino group, or its pharmaceutically acceptable salt.

11. Derived isoxazol under item 1, where R2denotes hydrogen, halogen, C1-C4alkyl, allyl, Isopropenyl, 2-butenyl or propargyl group, or its pharmaceutically acceptable salt.

12. t-boutelou group, or its pharmaceutically acceptable salt.

13. Derived isoxazol under item 1, where R2denotes hydrogen or ISO-propyl group, or its pharmaceutically acceptable salt.

14. Derived isoxazol under item 1, where R3denotes amino, mono-C1-C6alkylamino, di(C1-C6alkyl)amino or 5 - or 6-membered saturated heterocyclic group (provided that the group attached through a nitrogen atom ring) having one nitrogen atom and another is not necessarily containing one nitrogen atom or oxygen atom, or its pharmaceutically acceptable salt.

15. Derived isoxazol under item 1, where R3denotes amino, methylamino, ethylamino, N, N-dimethylamino, piperidyl or morpholinyl group, or its pharmaceutically acceptable salt.

16. Derived isoxazol under item 1, where R3denotes an amino group, or its pharmaceutically acceptable salt.

17. Derived isoxazol under item 1, where X denotes an oxygen atom, or its pharmaceutically acceptable salt.

18. Derived isoxazol under item 1, where R1represents C6-C14aryl group optionally having from 1 to 3 substituents, which may be the same or excellent the action group, having one heteroatom selected from the group comprising atoms of nitrogen, oxygen and sulfur (Deputy is halogen; C1-C6alkyl, C1-C6alkyl substituted by halogen; C1-C6alkoxy; and phenyl group), R2denotes hydrogen; halogen; C1-C6alkyl, C2-C6alkenyl; C2-C6alkylamino group, R3denotes amino, mono-C1-C6alkylamino, di(C1-C6alkyl)amino group or a 5 - or 6-membered saturated heterocyclic group (provided that the group attached through a nitrogen atom of the ring containing one nitrogen atom and one nitrogen atom or oxygen atom, or its pharmaceutically acceptable salt.

19. Derived isoxazol under item 1, where R1represents C6-C14aryl group optionally having from 1 to 3 substituents, which may be the same or different from each other and selected from the following group of substituents, or a 5 - or 6-membered aromatic heterocyclic group optionally having one heteroatom selected from the group comprising atoms of nitrogen, oxygen and sulfur (Deputy is halogen; C1-C6alkyl, C1-C6alkyl, substituted halog the ode, and n = 2, or its pharmaceutically acceptable salt.

20. Derived isoxazol under item 1, where R1represents C6-C14aryl group optionally having from 1 to 3 substituents, which may be the same or different from each other and selected from the following group of substituents, or a 5 - or 6-membered aromatic heterocyclic group optionally having one heteroatom which may be identical or different from each other and selected from the group comprising atoms of nitrogen, oxygen and sulfur (Deputy is halogen; C1-C4alkyl, vermeil, deformity, trifluoromethyl, 2-foretel, 2,2,2-triptorelin, C1-C4alkoxy and phenyl group), R2denotes hydrogen, halogen, C1-C4alkyl, allyl, Isopropenyl, 2-butenyl or propargyl group, R3denotes an amino group, X denotes an oxygen atom and n = 2, or its pharmaceutically acceptable salt.

21. Derived isoxazol under item 1, where R1denotes a phenyl group optionally having 1 to 3 substituents, which may be the same or different from each other and selected from the following group of substituents, or furyl, thienyl or pyridyloxy group (the Deputy is Yong, C1-C4alkyl, allyl, Isopropenyl, 2-butenyl or propargyl group, R3denotes an amino group, X denotes an oxygen atom and n = 2, or its pharmaceutically acceptable salt.

22. Derived isoxazol under item 1, where R1denotes a phenyl group, optionally having one or two substituent which may be the same or different from each other and selected from the following group of substituents, or furyl, thienyl or pyridyloxy group (Deputy is fluorine, chlorine, methyl, ethyl, trifluoromethyl and methoxy group), R2denotes hydrogen, chlorine, ethyl, propyl, isopropyl, isobutyl or tert-boutelou group, R3denotes an amino group, X denotes an oxygen atom and n = 2, or its pharmaceutically acceptable salt.

23. Derived isoxazol under item 1, where R1denotes phenyl, forfinal, chlorophenyl, differenl, dichlorophenyl, were, 2-furyl, 3-furyl, 2-thienyl or 3-thienyl group, R2denotes hydrogen, chlorine, ethyl, propyl, isopropyl, isobutyl or tert-boutelou group, R3denotes an amino group, X denotes an oxygen atom and n = 2, or its pharmaceutically acceptable salt.

24. Derived isoxazol under item 1, where R1oboznachaet a hydrogen atom or isopropyl group, R3denotes an amino group, X denotes an oxygen atom and n = 2, or its pharmaceutically acceptable salt.

25. Derived isoxazol under item 1, selected from the group including

3-(2-aminoethoxy)-5-phenylisoxazol,

3-(2-aminoethoxy)-4-chloro-5-phenylisoxazol,

3-(2-aminoethoxy)-4-ethyl-5-phenylisoxazol,

3-(2-aminoethoxy)-5-phenyl-4-propylenoxide,

3-(2-aminoethoxy)-4-isopropyl-5-phenylisoxazol,

3-(2-aminoethoxy)-4-isobutyl-5-phenylisoxazol,

3-(2-aminoethoxy)-5-(2-chlorophenyl)-4-isopropylthiazole,

3-(2-aminoethoxy)-5-(4-chlorophenyl)isoxazol,

3-(2-aminoethoxy)-5-(4-chlorophenyl)-4-isopropylthiazole,

3-(2-aminoethoxy)-5-(2,4-dichlorophenyl)-4-isopropylthiazole,

3-(2-aminoethoxy)-5-(2-furyl)-4-isopropylthiazole,

3-(2-aminoethoxy)-5-(2-thienyl)isoxazol,

3-(2-aminoethoxy)-4-chloro-5-(2-thienyl)isoxazol,

3-(2-aminoethoxy)-4-isopropyl-5-(2-thienyl)isoxazol and

4-allyl-3-(2-aminoethoxy)-5-phenylisoxazol

and their pharmaceutically acceptable salts.

26. Derived isoxazol or its pharmaceutically acceptable salt as defined in any of paragraphs. 1 - 25 possessing inhibitory activity against monoamine oxidase type a, when receiving the pharmaceutical precautions acceptable salt, as defined in any of paragraphs.1 - 25 possessing inhibitory activity against monoamine oxidase type a, upon receipt of pharmaceutical preparations for the treatment or prevention of depression.

28. Pharmaceutical composition having inhibitory activity against monoamine oxidase type a, containing the derived isoxazol and a pharmaceutically acceptable carrier, characterized in that said derivative isoxazol an effective amount of a derivative isoxazol or its pharmaceutically acceptable salt as defined in any of paragraphs.1 - 25.

 

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

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The invention relates to new chemical compounds, in particular derivatives (1,2,3-triazolyl)-1,2,5-oxadiazole General formula I, where R = NH2or< / BR>
and, if R1= N, R2lowest hydroxyalkyl, or, if R1- lower alkyl, lower hydroxyalkyl, aryl, R2= N, the lower hydroxyalkyl or a radical of General formula-C(O)R3where R3= HE, NH2, lower alkyl or lower alkoxyl, potentiating NO-dependent activation of the soluble form of guanylate cyclase (RGC)

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< / BR>
where X denotes O, S, NH or NA;

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R1indicatesor< / BR>
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R3denotes H, A or Ar;

A denotes alkyl with 1-6 C-atoms;

B denotes H, a, cycloalkyl with 3-7 C atoms, Ar-CkH2kor aydinbey the rest;

Ar denotes unsubstituted or mono - or twice substituted with A, Cl, Br, I, NO2, CN, OA, OH, NH2, NHA and/or NA2phenyl or benzyl residue;

"k" denotes 1, 2, 3 or 4;

"m" and "r" each, independently of one another, denote 0, 1, 2, 3 or 4; and

"n" represents 2, 3 or 4,

and their physiologically acceptable salts

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

R3- nonbranched alkyl with 2 to 4 carbon atoms,

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