Derivatives isoxazol, their use in the production inhibits monoamine oxidase agent, pharmaceutical composition and method of inhibiting monoamine oxidase type b

 

(57) Abstract:

Describes the new isoxazol derivative of the following General formula I, where R1represents a hydrogen atom; a halogen atom; alkyl group; alkoxygroup; a hydroxyl group; alkylthiols; the amino group; alkylamino; alkanoyloxy; alkoxycarbonyl group; carboxypropyl; karbamoilnuyu group; a nitro-group; or cyano; R2represents an amino group; m represents an integer from 1 to 3; n represents an integer from 1 to 6; the ring A represents A phenyl ring, naphtalene ring or an aromatic 5 - or 6-membered heterocycle; X represents an oxygen atom or a sulfur atom. The above compounds have excellent inhibiting the monoamine oxidase activity and are an excellent therapeutic or prophylactic agents against neuropathies (Parkinson's disease, etc). In addition, the invention discloses pharmaceutical compositions containing as an active ingredient derived isoxazol. 4 C. and 35 C.p. f-crystals, 17 PL.

The invention relates to the derivatives of isoxazol demonstrating excellent inhibiting activity against monoamine oxidase type A and type B (ooperati, including Parkinson's disease, depression and Alzheimer's disease (especially Parkinson's disease). It also refers to the monoamine oxidase inhibitors containing as the active component derived isoxazol.

Parkinson's disease is a progressive, chronic disease that causes akineziyu, muscle stiffness and tremor as a result of degeneration dopaminergic neurons in the substantia nigra. It was known that Parkinson's disease is caused by reducing cerebral concentrations of dopamine, a neurotransmitter, especially in the caudate nucleus and the putamen due to degenerative, vascular and inflammatory changes in the basal nuclei. The introduction of levodopa is the most effective therapy and is widely used to Supplement the reduced concentrations of dopamine in the brain, especially in the striatum. However, therapy due to one only levodopa causes problems because it is associated with serious harmful reactions. Recently actively conducting research for the treatment of Parkinson's disease through inhibition of monoamine oxidase type-B, which is an enzyme that destroys dopamine, thereby preventing destruction of dopamine, and deprenyl was released as the inhibitor is of isoxazole, such as compounds A and B, can be used as a local analgesic, antihistaminic agents, anti-inflammatory agents, tonic and antispasmodic agents with shared effects on the nervous system, as well as with cardiovascular effects.

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In addition, Farmaco, Ed. Sci. 23, 1081 (1968), ibid, 24,440 (1969) mentions that compound B has anti-inflammatory and local (infiltration) anesthetic effects. However, it is quite unknown that compounds A and B have activity of inhibiting the monoamine oxidase.

The authors stress investigated the synthesis and pharmacological action of isoxazoles with the goal of developing excellent therapeutic agent for the treatment of Parkinson's disease for a long time and found that isoxazol derivative with a specific structure have effective inhibitory effect on monoamine oxidase type-A and type-B (inhibition of monoamine oxidase type B is particularly effective); and therapeutic or preventive effect against neuropathies, including Parkinson's disease, depression and Alzheimer's disease (especially Parkinson's disease) has led to completion of the invention.

Derivatives isoxazol of the present invention have a General formula I

< / BR>
where R1represents a hydrogen atom; a halogen atom; alkyl group containing from 1 to 6 carbon atoms; an alkyl group containing from 1 to 4 carbon atoms and substituted by a halogen atom; alkoxygroup containing from 1 to 6 carbon atoms; haloalkoxy with 1-6 carbon atoms; a hydroxyl group; allylthiourea containing from 1 to 6 carbon atoms; the amino group; monoalkylamines, the alkyl part of which contains from 1 to 6 carbon atoms; dialkylamino in which each alkyl fragment independently contains from 1 to 6 carbon atoms; alkanoyloxy, containing from 1 to 6 carbon atoms; alkoxycarbonyl group containing from 1 to 6 carbon atoms; carboxypropyl; karbamoilnuyu group; a nitro group, or cyano;

R2represents an amino group;

m represents an integer from 1 to 3;

n represents an integer from 1 to 6;

ring A represents A phenyl ring fused with isoxazoline ring; naphtalene ring, to the in or two heteroatoms, selected from the group consisting of atoms of oxygen, nitrogen and sulfur, fused with isoxazoline ring; and

X represents an oxygen atom or a sulfur atom; provided that if m represents the integer 2 or 3, the substituents R1the same or different; or its pharmaceutically acceptable salt.

In addition, the active components of the inhibitor monoamine-oxidase of the present invention are isoxazoline derivatives of the General formula II

< / BR>
where R1represents a hydrogen atom; a halogen atom; alkyl group containing from 1 to 6 carbon atoms; an alkyl group containing from 1 to 4 carbon atoms and substituted by a halogen atom or alkoxygroup containing from 1 to 4 atoms angle of the genus; alkoxygroup containing from 1 to 6 carbon atoms; haloalkoxy containing from 1 to 6 carbon atoms; a hydroxyl group; allylthiourea containing from 1 to 6 carbon atoms; the amino group; monoalkylamines, the alkyl part of which contains from 1 to 6 carbon atoms; dialkylamino, in which each alkyl fragment independently contains from 1 to 6 carbon atoms; alkanoyloxy group containing from 1 to 6 carbon atoms; alkanolamines containing from 1 to 6 athu from 1 to 6 carbon atoms; carboxypropyl; karbamoilnuyu group; monoalkylammonium group, the alkyl part of which contains from 1 to 6 carbon atoms; dialkylamino group, each alkyl part of which independently contains from 1 to 6 carbon atoms; a nitro-group, or cyano;

R2is monoalkylamines, the alkyl part of which contains 1 to 4 carbon atoms; dialkylamino, each alkyl part of which independently contains from 1 to 4 carbon atoms;

m represents an integer from 1 to 3;

n represents an integer from 1 to 6;

ring A represents A phenyl ring fused with isoxazoline ring; naphtalene ring condensed with isoxazoline ring; or an aromatic heterocyclic 5 - or 6-membered ring which contains one or two heteroatoms selected from the group consisting of oxygen atoms, nitrogen atoms and sulfur atoms, condensed with isoxazoline ring; and

X represents an oxygen atom or a sulfur atom; provided that if m represents the integer 2 or 3, the substituents R1the same or different.

"Halogen atom" in the above definition of R1in the General formula (I) and (II) may be an atom is ora or chlorine.

"C1-C6alkyl radical" in the above definition of R1represents a branched or unbranched alkyl radical containing from 1 to 6 carbon atoms. It can be, for example, methyl, ethyl, sawn, ISO-propyl, botulinum, isobutylene, second-botilinum, tert-botilinum, pantiliner, isopentenyl, 2-methylbutyryl, neopentyl, 1-ethylpropyl, EXILIM, 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 - dimethyl-botulinum or 2-ethylbutyl radical, preferably C1-C4alkyl radical and more preferably a methyl or ethyl radical. The most preferred methyl radical.

Galijasevic alkyl radical can be, for example, permethrinum, deformational, triptorelin, 2-veretillum, 2-chloraniline, 2,2,2-triptorelin, 3-fluoro-through 3 - chloropropionyl, 3-bromopropyl, 4-fluoro-botulinum or 4 - chlorobutyryl radical, whereas alkoxy-substituted alkyl radical may be methoxymethyl, ethoxymethyl, propoxymethyl, butoxymethyl, the method is dekalim, preferably, permethrinum, deformational, triptorelin, 2-veretillum, 2-chloraniline, 2,2,2-triptorelin, methoxymethyl or methoxyaniline radical and more preferably, permethrinum, deformational, triptorelin, 2-veretillum, 2,2,2-triptorelin, methoxymethyl or methoxyaniline radical and even more preferably, triptorelin, 2,2,2-triptorelin or methoxymethyl radical. The most preferred triptoreline radical.

"C1-C6alkoxy radical" in the above definition of R1is radical, in which "C1-C6alkyl radical", mentioned earlier, is the radical associated with the oxygen atom, and may be methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec - butoxy, tert-butoxy, pentox, isopentane, 2-methylbutoxy, neopentane, 1 ethylpropoxy, hexyloxy, 4-methylphenoxy, 3 methylpentane, 2-methylpentane, 1 methylphenoxy, 3,3 - Dimethylbutane, 2,2-Dimethylbutane, 1,1-Dimethylbutane, 1,2 - Dimethylbutane, 1,3-Dimethylbutane, 2,3-Dimethylbutane or 2 - ethylbutane radical, preferably, C1-C4alkoxy radical, and more preferably methoxy or ethoxy radical. the second definition of R1represents a radical in which the halogen atom is linked to C1-C6alkoxy radicals mentioned previously, and can be formatosi, chloromethoxy, bromoethoxy, iodomethane, deformedarse, dichloromethoxy, dibromethane, triptoreline, trichlormethane, 1 floratone, 2-floratone, 2-chloroethoxy, 2,2,2-triptoreline, 2,2,2-trichloroethane, 3 forproperty, 3 bromopropane, 4-forbooks, 5-fermentate or 6 iodohexane radical, preferably, formatosi, chloromethoxy, deformedarse, dichloromethoxy, triptoreline, trichlormethane, 1 floratone, 2-floratone, 2 chloroethoxy or 2,2,2-triptoreline radical and more preferably, formatosi, deformedarse, triptoreline or 2,2,2-triptoreline radical. The most preferred deformedarse radical.

"C1-C6alkylthio radical" in the above definition of R1is radical, in which "C1-C6alkyl radical", as indicated previously, is associated with the sulfur atom and may be methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutyric, sec-butylthio, tert-butylthio, pentylthio, isopentyl, 2-methyl-butylthio, neopentyl, 1 ethylpropyl, hexylthio, 4-methyl-pentylthio, 3 methylphenylthio, 2-methylpentylamino, 2,3-dimethylbutyl or 2-ethylbutyl radical, preferably C1-C4alkylthio radical and more preferably methylthio or ethylthio radical. The most preferred methylthio radical.

Mono-C1-C6alkylamino radical" in the above definition of R1is radical, in which "C1-C6alkyl radical", as indicated previously, is associated with amino radical. It can be methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamino, pentylamine or hexylamino radical, preferably mono-C1-C4alkylamino radical and more preferably, methylamino or ethylamino radical. The most preferred methylamino radical.

"Di-C1-C6alkylamino radical" in the above definition of R1may be, for example, dimethylamino, ethylmethylamino, methylpropylamine, isopropylethylene, butylmethylamine, isobutyl-methylamino, sec-butylmethylamine, tert-butylmethylamine, diethylamino, ethylpropylamine, ethylisopropylamine, dipropylamino, dibutylamino, diphenhydamine or digoxigenin radical, preferably CI-C1- C4alkylamino radical and more PR is x2">

"C1-C6alcoholly radical" in the above definition of R1represents a branched or unbranched alcoholly radical containing from 1 to 6 carbon atoms, and it may be formyl, acetyl, propionyl, botilinum, ISO - botilinum, pentanoyl, pivaloyl, valeriynik or ISO - valeriynik radical, preferably C1-C4alkanoyl radical and more preferably formyl or acetyl radical.

"C1-C6alkanolamine radical" in the above definition of R1is branched or unbranched, alkanolamine radical containing from 1 to 6 carbon atoms, and may represent formylamino, acetylamino, propionamido, bucillamine, isobutylamino, pentanediamine, paulolino, Valeriano or isovaleramide radical and more preferably, formylamino or acetylamino radical.

"C1-C6alkanoyloxy radical" in the above definition of R1is branched or unbranched, alkanoyloxy radical containing from 1 to 6 carbon atoms, and it can be formyloxy, atomic charges, propionyloxy, butyryloxy, isobutyryloxy, pentanoate, beer is m, and more preferably, formyloxy or the atomic charges of the radical.

"C1-C6alkoxycarbonyl radical" in the above definition of R1can be methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxy-carbonyl, solutionline, second-butoxycarbonyl, tert-butoxycarbonyl, phenoxycarbonyl or hexyloxybenzoyl radical, preferably C1- C4alkoxycarbonyl radical and more preferably, methoxycarbonyl or ethoxycarbonyl radical. The most preferred methoxycarbonyl radical.

Mono-C1-C6alkylcarboxylic radical" in the above definition of R1can imagine methylcarbamoyl, ethylcarbitol, profilirovannyj, isopropylcarbamate, butylcarbamoyl, isobutylbarbituric, second-butylcarbamoyl, tert-butylcarbamoyl, intercalatory or hexylcinnamaldehyde radical, preferably mono-C1-C4alkylcarboxylic radical and more preferably, methyl-carbamoyl or ethylcarbazole radical.

"Di-C1-C6alkylcarboxylic radical" in the above definition of R11-C4alkylcarboxylic and more preferably, dimethylcarbamoyl or diethylcarbamoyl radicals. The most preferred dimethylcarbamoyl radical.

"Aromatic heterocyclic ring, 5 - or 6-membered ring containing 1 or 2 heteroatoms selected from the group consisting of atoms of oxygen, nitrogen and sulfur, fused with a isoxazol" in the aforementioned definition of ring A can be, for example, FullName, thienyl, pyrrolidinyl, imidazolidinyl, pyrazolidine, thiazolidine, isothiazolinones, oxazolidinyl, isoxazolyl, pyridinium, pyrazinediium, pyrimidinium or pyridazinyl ring, preferably, FullName, thienyl or pyridinium ring, and more preferably, pyridinium ring.

In addition, the above isoxazoline connection, condensed with FullName, thienyl or pyridinium ring is a compound with the structure represented by formula (III) to(XII) below. Preferably, the jet is more preferable, (IX) or (XII). The most preferable compounds, represented by formula (XII).

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Mono-C1-C4alkylamino radical" in the above definition of R2has previously indicated for R1values and the most preferred methylamino radical.

"Di-C1-C4alkylamino radical" in the above definition of R2has previously indicated for R1values and preferred dimethylamino radical.

Heterocyclic ring with 5 or 6 members containing 1 nitrogen atom and optionally another nitrogen atom or an oxygen atom (provided that the moiety in question, linked to the nitrogen atom)" in the above definition of R2may be, for example, pyrrolidinyl, imidazolidinyl, pyrazolidine, pyrrolidinyl, pyrrolidinyl, imidazolidinyl, imidazolylalkyl, pyrazolidinone, pyrazolidine, piperidinyl, piperazinilnom or morpholinyl radical, preferably piperidinyl or morpholinyl radical.

If R1is such a basic moiety, such as amino or alkylamino radical in the compounds (I) and (II) of the present invention, it can be converted into the corresponding farmaceuticas what they compound (I) or (II) with an appropriate acid for 5-30 minutes in a solvent (for example, in ethers, particularly in dioxane) at room temperature, and either filtering the precipitated precipitate crystals, or removing the solvent, viparita it under reduced pressure. This salt can be such a mineral acid salt, such as hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, sulfate or phosphate, such sulfonate, as methanesulfonate, triftorbyenzola, aconsultant, bansilalpet or para - toluensulfonate so carboxylate as fumarate, succinate, citrate, tartrate, oxalate or maleate, or a salt of the amino acids, such as glutamine or aspartate.

If R1in compounds (I) and (II) of the present invention is such acid radicals as hydroxyl or carboxyl group, it can be converted to the corresponding pharmaceutically acceptable salt due to the alkali treatment in the usual way. For example, the salt of the compound (I) or (II) can be obtained by processing the compound (I) or (II) the appropriate basis for 5-30 minutes in a solvent (e.g. ether, the preferred ether or tetrahydrofuran) at room temperature, or filtering the precipitated precipitate crystals, or removing the solvent by evaporation under ponizhennogo metal, as a salt of calcium or magnesium, or a salt of an organic amine, as guanidine, triethylamine or dicyclohexylamine.

The compound (I) or (II) of the present invention or their salts can absorb moisture to absorb water and turn into hydrates, if left in the air, or by recrystallization, and these salts containing water molecules, also included in the scope of the invention.

The compound (I) or (II) of the present invention or their salts may contain asymmetric carbon atom in their molecules, and, thus, the stereoisomers of R - and S-configurations can exist. Such such compounds, and mixtures thereof in an arbitrary ratio is also included in the scope of the present invention.

The preferred compounds of the present invention of formula (I) are (I) those compounds in which R1represents hydrogen, halogen, C1-C4alkyl, vermeil, deformity, trifluoromethyl, 2-foretel, 2-chloroethyl, 2,2,2-triptorelin, methoxymethyl, methoxyethyl, C1-C4alkoxy, formatosi, chloromethoxy, deformedarse, dichloromethoxy, triptoreline, trichlormethane, 1 floratone, 2-floratone, 2-chloroethoxy, 2,2,2 - triptoreline, hydroxy, C1-C4 is Ino, acetylamino, C1-C4alkanoyloxy, C1-C4alkoxycarbonyl, carboxy, carbarnoyl, nitro or cyano;

(2) those compounds in which R1represents hydrogen, halogen, C1-C4alkyl, vermeil, deformity, trifluoromethyl, 2-foretel, 2,2,2-triptorelin, methoxymethyl, methoxyethyl, C1-C4alkoxy, deformedarse, hydroxy, C1-C4alkylthio, amino, methylamine, ethylamino, dimethylamino, diethylamino, formyl, acetyl, formylamino, acetylamino, C1-C4alkoxycarbonyl, carboxy, carbarnoyl, nitro or cyano;

(3) those compounds in which R1represents hydrogen, fluorine, chlorine, bromine, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, deformedarse, hydroxy, methylthio, ethylthio, amino, methylamino, ethylamino, dimethylamino, formyloxy, atomic charges, methoxycarbonyl, etoxycarbonyl, carboxy, carbarnoyl, nitro or cyano.

(4) those compounds in which R1represents hydrogen, fluorine, chlorine, bromine, methyl, methoxy, methylthio, deformedarse, methoxycarbonyl, nitro or cyano.

(5) those compounds in which m is 2.

(6) those compounds in which m is 1.

(7) those compounds in which n takes values from 2 to 4.

(8) the connection is Anil, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolin, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl.

(10) those compounds in which ring a represents phenyl, naphthyl or pyridyl.

(11) those compounds in which a represents phenyl or pyridyl.

(12) those compounds in which ring a is phenyl.

(13) those compounds in which X represents oxygen.

(14) 3-(2-aminoethoxy)benzisoxazol,

3-(2-aminoacetic)benzisoxazol,

3-(2-aminoethoxy)-ferberization,

3-(2-aminoacetic)-ferberization,

3-(2-aminoethoxy)-fluoro-methylbenzothiazol,

3-(2-aminoacetic)-fluoro-methylbenzothiazol,

3-(2-aminoethoxy)-fluoro-methylthiosemicarbazone,

3-(2-aminoethoxy)-fluoro-methoxycarbonylbenzyl,

3-(2-aminoethoxy)-fluoro-carbamoylaspartate,

3-(2-aminoethoxy)-fluoro-cyanobenzoate,

3-(2-aminoacetic)-fluoro-cyanobenzoate,

3-(2-aminoethoxy)-chlorobenzotriazol,

3-(2-aminoacetic)chlorobenzotriazol,

3-(2-aminoethoxy)-dichlorobenzothiazole,

3-(2-aminoacetic)-dichlorobenzothiazole,

3-(2-aminoethoxy)-chloro-methylbenzothiazol,

3-(2-aminoacetic)-chloro-methylbenzo is R>
3-(2-aminoacetic)-chloro-cyanobenzoate,

3-(2-aminoethoxy)-dichloro-methylbenzothiazol,

3-(2-aminoethoxy)-BROKBUSINESS,

3-(2-aminoethoxy)-bromo-methylbenzothiazol,

3-(2-aminoethoxy)-methylbenzothiazol,

3-(2-aminoacetic)-methylbenzothiazol,

3-(2-aminoethoxy)-dimethylbenzoxazole,

3-(2-aminoethoxy)-methyl-methoxybenzothiazole,

3-(2-aminoethoxy)-methyl-methylthiosemicarbazone,

3-(2-aminoethoxy)-methyl-methoxycarbonylbenzyl,

3-(2-aminoethoxy)-methyl-carbamoylaspartate,

3-(2-aminoethoxy)-methyl-cyanobenzoate,

3-(2-aminoethoxy)-triftoratsetata,

3-(2-aminoethoxy)-methoxybenzothiazole,

3-(2-aminoacetic)-methoxybenzothiazole,

3-(2-aminoethoxy)-differentoccasions,

3-(2-aminoethoxy)-hydroxybenzotriazol,

3-(2-aminoethoxy)-aminobenzotriazole,

3-(2-aminoacetic)-aminobenzotriazole,

3-(2-aminoethoxy)-methylaminoethanol,

3-(2-aminoethoxy)-dimethylaminobenzoate,

3-(2-aminoethoxy)-acetyloxybenzoic,

3-(2-aminoethoxy)-carboxybenzoyl,

3-(2-aminoethoxy)-methoxycarbonylbenzyl,

3-(2-aminoethoxy)-carbamoylaspartate,

3-(2-aminoethoxy)-natisocial,

3-(2-aminoethoxy)-pyridoxal,

3-(2-aminoethoxy)-chloronicotinoyl,

3-(2-aminoacetic)-chloronicotinoyl,

3-(2-aminoethoxy)-methylpyridoxine, or

3-(2-aminoethoxy)-triftormetilfullerenov.

Preferred are also the compounds that are any combination of from 1 to 5, selected from the group(1)-(4), (5)-(6), (7)-(8), (9)-(12) and (13), and the following combinations are given as examples:

(15) (1) and (7),

(16) (2), (7) and (9),

(17) (2), (8) and (10),

(18) (3), (8) and (10),

(19) (3), (5), (8) and (11),

(20) (4), (8) and (10),

(21) (4), (5), (8) and (11),

(22) (4), (5), (8) and (12).

The following compounds are preferable as the compound (II), the active component of the inhibitor of monoamine oxidase of the present invention;

(1) those compounds, in which R1represents hydrogen, halogen, C1-C4alkyl, vermeil, deformity, trifluoromethyl, 2-foretel, 2-chloroethyl, 2,2,2-triptorelin, methoxymethyl, methoxyethyl, C1-C4alkoxy, formatosi, chloromethoxy, deformedarse, dichloromethoxy, triptoreline, trichlormethane, 1 floratone, 2-floratone, 2-chloroethoxy, 2,2,2-triptoreline, hydroxy, C1- C4alkylthio, amino, what>
-C4alkanoyloxy, C1-C4alkoxycarbonyl, carboxy, (methylthio)thiocarbonyl (ethylthio)thiocarbonyl, carbamoyl, methylcarbamoyl, ethylcarbitol, dimethylcarbamoyl, diethylcarbamoyl, nitro or cyano.

(2) those compounds in which R1represent hydrogen, halogen, C1-C4alkyl, vermeil, deformity, trifluoromethyl, 2-foretel, 2,2,2-triptorelin, methoxymethyl, methoxyethyl, C1-C4alkoxy, deformedarse, hydroxy, C1-C4alkylthio, amino, methylamino, ethylamino, dimethylamino, diethylamino, formyl, acetyl, formylamino, acetylamino, C1-C4alkoxycarbonyl, carboxy, carbarnoyl, methylcarbamoyl, ethylcarbitol, dimethylcarbamoyl, diethylcarbamoyl, nitro or cyano.

(3) those compounds in which R1represents hydrogen, fluorine, chlorine, bromine, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, deformedarse, hydroxy, methylthio, ethylthio, amino, methylamino, ethylamino, dimethylamino, formyloxy, atomic charges, methoxycarbonyl, etoxycarbonyl, carboxy, carbarnoyl, nitro or cyano.

(4) those compounds in which R1represents hydrogen, fluorine, chlorine, bromine, methyl, methoxy, methylthio, deformedarse, methoxycarbonyl, nitro or iiano.

(6) those compounds in which Ra2represents amino, piperidinyl or morpholinyl.

(7) those compounds in which Ra2represents amino.

(8) those compounds in which m is 2.

(9) those compounds in which m is 1.

(10) those compounds in which n takes values from 2 to 4.

(11) those compounds in which n is 2.

(12) those compounds in which ring A represents phenyl, naphthyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolin, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl.

(13) those compounds in which ring A represents phenyl, naphthyl, or pyridyl.

(14) those compounds in which ring A is phenyl or pyridyl.

(15) those compounds in which ring A is phenyl.

(16) those compounds in which X represents oxygen.

(17) 3-(2-aminoethoxy)benzisoxazol,

3-(2-aminoacetic)benzisoxazol,

3-(2-aminoethoxy)-ferberization,

3-(2-aminoacetic)-ferberization,

3-(2-aminoethoxy)-formativeness,

3-(2-aminoacetic)-fluoro-methylbenzothiazol,

3-(2-aminoethoxy)-fluoro-methylthiosemicarbazone,

3-(2-aminoethoxy)-fluoro-cyanobenzoate,

3-(2-aminoacetic)-fluoro-cyanobenzoate,

3-(2-aminoethoxy)-chlorobenzotriazol,

3-(2-aminoacetic)-chlorobenzotriazol,

3-(2-aminoethoxy)-dichlorobenzothiazole,

3-(2-aminoacetic)-dichlorobenzothiazole,

3-(2-aminoethoxy)-chloro-methylbenzothiazol,

3-(2-aminoacetic)-chloro-methylbenzothiazol,

3-(2-aminoethoxy)-chloro-carbamoylaspartate,

3-(2-aminoethoxy)-chloro-cyanobenzoate,

3-(2-aminoacetic)-chloro-cyanobenzoate,

3-(2-aminoethoxy)-dichloro-methylbenzothiazol,

3-(2-aminoethoxy)-BROKBUSINESS,

3-(2-aminoethoxy)-bromo-methylbenzothiazol,

3-(2-aminoethoxy)-methylbenzothiazol,

3-(2-aminoacetic)-methylbenzothiazol,

3-(2-aminoethoxy)-dimethylbenzoxazole,

3-(2-aminoethoxy)-methyl-methoxybenzothiazole,

3-(2-aminoethoxy)-methyl-methylthiosemicarbazone,

3-(2-aminoethoxy)-methyl-methoxycarbonylbenzyl,

3-(2-aminoethoxy)-methyl-carbamoylaspartate,

3-(2-aminoethoxy)-methyl-cyanobenzoate,

3-(2-aminoethoxy)-triftoratsetata,

3-(2-aminoethoxy)-methoxybenzothiazole,

3-(2-aminoacetic)-methoxybenzothiazole,

3-(2-aminoethanethiol,

3-(2-aminoacetic)-aminobenzotriazole,

3-(2-aminoethoxy)-methylaminoethanol,

3-(2-aminoethoxy)-dimethylaminobenzoate,

3-(2-aminoethoxy)-acetyloxybenzoic,

3-(2-aminoethoxy)-carboxybenzoyl,

3-(2-aminoethoxy)-methoxycarbonylbenzyl,

3-(2-aminoethoxy)-carbamoylaspartate,

3-(2-aminoethoxy)-nitrobenzisoxazole,

3-(2-aminoacetic)-nitrobenzisoxazole,

3-(2-aminoethoxy)-cyanobenzoate,

3-(2-aminoethoxy)-natisocial,

3-(2-aminoethoxy)-pyridoxal,

3-(2-aminoethoxy)-chloro-peridotite,

3-(2-aminoacetic)-chloronicotinoyl,

3-(2-aminoethoxy)-methylpyridoxine or

3-(2-aminoethoxy)-triftormetilfullerenov.

Preferred combinations 1-6 selected from the group(1)-(4), (5)-(7), (8)-(9), (10)-(11), (12)-(15) and (16), and the following combinations are given as examples:

(17) - (1), (5) and (10),

(18) - (2), (7), (10) and (12)

(19) - (2), (7), (11) and (13),

(20) - (3), (7), (11) and (13),

(21) - (3), (7), (11), (8) and (14),

(22) - (4), (7), (11) and (13),

(23) - (4), (7), (8), (11) and (14),

(24) - (4), (7), (8), (11) and (15).

Presented in the tables below connections are typical compounds of the present invention, but the volume of the sludge

Et is ethyl,

Me is methyl,

Ph is phenyl,

Pip - piperidino,

Priisopropyl,

Mor - morpholino,

provided that R1)mrepresents 1, 2 or 3 substituted radical on the ring A in all.

In the above formulas, R1, R2, m, n, ring A and X have the previously indicated meanings, a Ra1- C1-C6alkyl, C1-C6Alki and C1-C6alkoxycarbonyl, carboxy, dithiocarbonic or (C1-C6alkylthio)thiocarbonyl, Rb1represents C1-C6alkyl radical, R3represents an ester residue, Ra3represents C1-C4alkyl radical, R4is protected aminoacyl, Y represents hydroxy or tsepliaeva group, Z represents a halogen atom and m' represents an integer from 1 to 2.

C1-C6alkyl part is C1-C6alkyl radical or a C1-C6alkylthio the radical Ra1have the previously indicated meanings; Ra1may represent, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, 4-methylpentyl, 3-methylpentyl, 2,3-dimethylbutyl, 2-ethylbutyl, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutyric, Deut.-butylthio, tert.-butylthio, pentylthio, isopentyl, 2-methylbutyl, neopentyl, 1 ethylpropyl, hexylthio, 4-methylphenylthio, 3 methylphenylthio, 2-methyl-pentylthio, 1 methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxide, Deut.- butoxycarbonyl, tert.-butoxycarbonyl, pentyloxybenzoyl, hexyloxymethyl, carboxy, dithiocarbonic, or (methylthio)thiocarbonyl, preferably, C1-C4alkyl, C1- C4alkylthio, C1-C4alkoxycarbonyl, carboxy or dithiocarbonic, and, more preferably, methyl, ethyl, methylthio, ethylthio or carboxy.

C1-C6the alkyl radicals Rb1have these values, and may be, for example, 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-dimethylbutylamino, C1-C4alkyl, and more preferably, methyl or ethyl.

Ester residue in R3may be, for example, a C1-C6alkyl radicals as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert. -butyl, pentyl or hexyl; or such substituted C1-C4alkyl radical (Deputy may be a halogen atom, a C1-C4alkoxy, halogen or C1-C4alkoxy-substituted C1- C4alkoxy, C1-C4aryl or

C6-C14aryl substituted by 1-3 radicals selected from the group consisting of C1-C4alkyl, C1-C4-alkoxy radicals, nitro - and cyano groups and halogen), such as 2-foretel, 2-chloroethyl, 2-bromacil, 2,2-dibromoethyl, 2,2,2-trichloroethyl, 3-forprofit, 4-chlorobutyl, methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, n-propoxymethyl, isopropoxide, n-butoxymethyl, tert.-butoxymethyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, 1-(isopropoxy) ethyl, 3-methoxypropyl-4-methoxybutyl, pharmacokinetic, 2,2,2-trichloroacetyl, bis(2-chloroethoxy) methyl,

3-forprofessional, 4-chlorotoxin, dibromomethyl, 2-chlorethoxyfos, pharmacokinetic, 2-methoxyethoxymethyl, ethoxymethylene, diphenylmethyl, triphenylmethyl - naphthylmethyl, 9-antimetal, 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenylalanine, 2-nitrobenzyl, 4-nitrobenzyl, 4-Chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl, 4-cyanobenzaldehyde, bis(2-nitrophenyl) methyl or piperonyl, preferably, C1-C4alkyl, 2-foretel, 2-chloroethyl, 2-bromacil, 2,2,2-trichlorethyl, methoxymethyl, ethoxymethyl, pharmacokinetic, 2,2,2-trichloroacetyl, bis(2-chloroethoxy) methyl, benzyl, phenethyl, 4-methylbenzyl, 2,4,6-trimethylbenzyl, 4-methoxybenzyl, 4-nitrobenzyl, 4-Chlorobenzyl, or 4-cyanobenzyl, and, more preferably, methyl, ethyl, 2,2,2-trichlorethyl, methoxymethyl, ethoxymethyl, pharmacokinetic, 2,2,2-trichloroacetyl, benzyl, phenethyl, 4-methylbenzyl, 4-methoxybenzyl, 4-nitrobenzyl, 4-Chlorobenzyl or 4-cyanobenzyl. The most preferred methyl or ethyl.

C1-C4the alkyl radical in R3may represent, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl or tert.-butyl, preferably methyl or ethyl, more preferably methyl.

The protective group in the protected aminoacylase in R4not specifically limited and can be any organic radical, cor, Fermilab, acetyl, propionyl, Boutillon, isobutyryl, pentanoyl, pivaloyl, Valerian, isovaleryl, or hexanol; halogen - or C1-C4alkoxy-substituted C1-C4alkanoyl radical, such as chloroacetyl, dichloroacetyl, trichloroacetyl, TRIFLUOROACETYL, 3-forproposal, 4,4-dichlorobutene, methoxyacetyl, butoxyethyl, ethoxypropanol or propoxylation; unsubstituted C1-C4alkanoyl radical, such as acryloyl, propiolic, methacryloyl, crotonoyl or isocrotonic;

C6-C10arylcarbamoyl radical which can be substituted by halogen, C1-C4-alkyl, C1-C6-alkoxy, C1-C4alkoxycarbonyl, C6-C10the aryl or nitrocatechol, such as, for example, 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 - propoxy-benzoyl, 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 - naphtol; alkoxycarbonylmethyl, etoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxide, Deut.-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.-butyldimethylsilyloxy; C2-C5alkanolammonium radical, such as for example, vinyloxycarbonyl, allyloxycarbonyl, 1,3 - butadienestyrene or 2-interracialanal; therefore aryldiazonium radical, as for example, Ptolemy radical; such Uralkali radical, such as benzyl, phenetyl, 3-phenylpropyl, 4-phenylbutyl - naphthylmethyl - naphthylmethyl, diphenylmethyl, triphenylmethyl - naphthylmethyl or 9-antimetal; or C7-C15aracelikarsaalyna radical which can be substituted by methoxy or nitrocatechol, such as benzyloxycarbonyl, (1-phenyl)benzyloxycarbonyl - naphthylethylenediamine - naphthylenediamine, 9-antimetastasis, para - methoxybenzeneboronic, or para-nitrobenzenesulfonyl, preferably, C1-C/SUB>alkoxycarbonyl, methoxycarbonyl, etoxycarbonyl, tert.-butoxycarbonyl, 2,2,2-trichlorocyanuric, triethylchlorosilane, 2-trimethylsilylethynyl, vinyloxycarbonyl, allyloxycarbonyl, phthaloyl, benzyl, benzyloxycarbonyl or nitrobenzisoxazole, and more preferably formyl, acetyl, benzoyl, 4-anisoyl, 4-nitrobenzoyl, methoxycarbonyl, etoxycarbonyl, butoxycarbonyl, tert.-butoxycarbonyl, phthaloyl, benzyl, benzyloxycarbonyl or para-nitrobenzenesulfonyl. The most preferred tert.- butoxycarbonyl radical.

Tsepliaeva group in Y is not specifically limited provided that it is usually removed as a nucleophilic residue, and it can be, for example, such a halogen atom as fluorine, chlorine, bromine or iodine; therefore C1-C4alkanesulfonyl-radical, as methanesulfonate, econsultancy, propanesulfonate or butanesulfonate; halogen-(C1-C4alkanesulfonyl-radical, as tripterocalyx, 2,2,2-trichloroacetonitrile, 3,3,3 - tribromophenoxy or 4,4,4-tripterocalyx; or C6-C10arylsulfonamides, which may contain from 1 to 3 C1- C4alkyl, Raksi, 4-tert.-butylbenzenesulfonamide, mesitylenesulfonic or 6-ethyl- - naftiliaki. The preferred chlorine atoms, bromine, iodine; methansulfonate, econsultancy, tripterocalyx, 2,2,2-trichloroacetonitrile; benzosulfimide, toluensulfonate or mesitylenesulfonic, and more preferred chlorine atoms, bromine, iodine; methansulfonate, tripterocalyx, benzosulfimide, pair-toluensulfonate or mesitylenesulfonic.

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

Compound (XIII) or (XIX), which are the starting materials in the method of the present invention, are either known compounds, or such that can be easily synthesize well-known methods [e.g., Chem. Abstr. , 49, 11594 (1955), Tetpahedron, 38, 1457 (1982). , Japanese patent application N Kokai Hei 3-294267, Synth. Commun., 9,731 (1979), J. Org. Chem. 44, 3292/1979/ or Chem. Ber., 100, 954 (1967)].

The compound of General formula (XVII) can be a well-known compound, or can be synthesized by well-known method [for example. Synthesis, 366 (1990), or J. Med. Chem., 34, 1258 (1991)].

The compound of General formula (XV), in tsirovanna well-known method [for example, J. Med. Chem., 32,2116 (1989) or J. Chem, Soc. (C), 172 (1968)].

Method A is the method of synthesis of compound (I)

In method A1, the compound of General formula (XIII) is treated with hydroxylamine in an inert solvent in the presence of a base to obtain the compounds of General formula (XIV).

Solvent used is not specifically limited, provided that it does not interfere with the reaction and can dissolve a certain amount of source material, and it may be, for example, such aliphatic hydrocarbons as hexane, heptane, ligroin or petroleum ether;

such aromatic hydrocarbons as benzene, toluene or xylene; halogenated hydrocarbons like methylene chloride, chloroform, carbon tetrachloride, dichloroethane,

chlorobenzene or dichlorobenzene; an ether like diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol; therefore alcohol like methanol, ethanol, propanol, isopropanol, butanol or Isobutanol; therefore Amida as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoramide; therefore sulfoxide, as dimethylsulfoxide or sulfolane; water or a water mixture of the above organic solvents. His prepa, and more preferably, it was alcohol (particularly methanol or ethanol) or water-alcohol (especially aqueous methanol or aqueous ethanol).

As a basis you can use, for example, the carbonate of an alkali metal as sodium carbonate, potassium carbonate or lithium carbonate; bicarbonate of an alkali metal as sodium bicarbonate, potassium bicarbonate, or bicarbonate of lithium, an alkali metal hydride, as lithium hydride, sodium hydride or potassium hydride; and alkali metal hydroxide as potassium hydroxide, sodium hydroxide or lithium hydroxide, an alkoxide of an alkali metal as sodium methoxide, ethoxide sodium tert.-piperonyl potassium or lithium methoxide; alkali metal mercaptan, as nutrientlimited, or nutrientlimited; such organic amine like 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); this alkylate, as motility, utility or utility; this socialmiami as sitedisability or litigationrelated. The preferred carbonate u who led the alkali metal (especially sodium hydroxide or potassium hydroxide).

The reaction temperature can be changed depending on starting materials or reagents, but usually it happens in the interval -10oC to 100oC, and preferably from 0 to 50oC.

The reaction time may vary depending on the starting material, reagents and reaction temperature, but it usually takes a period of time from 10 minutes to 10 hours, and preferably from 30 minutes to 5 hours.

After completion of the reaction, the target compound in this way separated from the reaction mixture by conventional means. For example, the solvent is evaporated. After completion of the reaction to the residue water is added to obtain the acidic aqueous layer, and loose precipitated compound is filtered off. Or water added to the reaction mixture, and extraction of the target compounds add hydrophobic solvent (for example, benzene, ether, ethyl acetate). The organic layer is washed with water, dried over anhydrous magnesium sulfate and the solvent is evaporated to obtain the target compound. The obtained target compound can optionally be cleaned by conventional means, for example, by recrystallization, the resultant deposition rates, chromatographic, or turning it into a salt by adding an acid.shown in Chem. Ber, 100,954 (1967) due to:

(1) interaction with thionyl chloride, phosgene or their equivalents (for example, diphosgene) (preferably with thionyl chloride) in an inert solvent, and then

(2) communicating with a base in an inert solvent.

Solvents that can be used in the processes (1) and (2) not specifically limited, provided that they do not interfere with the reaction and dissolve some amount of source materials. They can be, for example, aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; such halogenated hydrocarbons like methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; such esters as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol; or such sulfoxidov as dimethylsulfoxide or sulfolane. Preferred halogenated hydrocarbons (particularly methylene chloride, chloroform, carbon tetrachloride or dichloroethane), or ethers (particularly diethyl ether, diisopropyl ether, tetrahydrofuran Elijah dioxane).

As the base used in the method (2) can be used, for example, the carbonate of an alkali metal as sodium carbonate, potassium carbonate or lithium carbonate; bicarbonate of an alkali metal as sodium bicarbonate, potassium bicarbonate or bicarbonate of lithium, an alkali metal hydride, as lithium hydride, sodium hydride or potassium hydride, an alkali metal hydroxide like sodium hydroxide, potassium hydroxide or lithium hydroxide, an alkoxide of an alkali metal as sodium methoxide, ethoxide sodium tert. -piperonyl potassium or lithium methoxide; alkali metal mercaptan, as methylmercaptan sodium or ethyl mercaptan sodium; such organic amine like triethylamine, tributylamine, Diisopropylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N,N-diethyl-aniline, 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); this alkylate as motility or utility; or such alkylamide lithium as diisopropylamide lithium or dicyclohexylamine lithium. Preferred organic amine, and, more preferred triethylamine, tributylamine, diisopropylethylamine, pyridine, 1,5 - diazabicyclo[4,3,0] non-5-ene, 1,4-diazabicyclo[2,2,2] the reactions at stages (1) and (2) change depending on the starting materials and reagents, but usually they are in the interval from -10 to 100oC, and preferably from 0 to 50oC.

Reaction times in stages (1) and (2) vary depending on starting materials, reagents or reaction temperatures, but they are usually from 10 minutes to 10 hours, preferably from 15 minutes to 5 hours.

After completion of the reaction, the target compound in this way separated from the reaction mixture by conventional means. For example, the target compound can be selected, viparita solvent, adding water to the reaction mixture, podkisst water layer in order to filter out the precipitated precipitate the product, or by adding a hydrophobic solvent (for example, benzene, ether, ethyl acetate), washing the extract with water, drying it over anhydrous magnesium sulfate and removing the solvent by evaporation. The obtained target compound can, if necessary, clean due to recrystallization, the resultant deposition rates or chromatography.

In method A3 compound (XVI) are synthesized by the reaction between the compound (XV) and palodiruyut agent in an inert solvent or without solvent in the presence of a base or without (preferably in the presence of a base).

Halogenous the Fort, and, preferably, laroxyl phosphorus, Piatigorsky phosphorus, or mixtures thereof.

Used rastvoritel not specifically limited, provided that it does not interfere with the reaction and dissolves a certain amount of source material, and it may be, for example, such aliphatic hydrocarbons as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons as benzene, toluene or xylene; halogenated hydrocarbons like methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; an ether like diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol; or a sulfoxide, as dimethylsulfoxide or sulfolane, preferably, halogenated hydrocarbons (particularly methylene chloride) or an ether (particularly tetrahydrofuran or dioxane).

As the base, for example, to use such a carbonate of an alkali metal as sodium carbonate, potassium carbonate or lithium carbonate; bicarbonate of an alkali metal as sodium bicarbonate, potassium bicarbonate or bicarbonate of lithium, an alkali metal hydride, as lithium hydride, sodium hydride or potassium hydride; the practical Amin, as triethylamine, tributylamine, Diisopropylamine, 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, the carbonate of an alkali metal or organic amine, and more preferably, the organic amine (in particular, triethylamine or pyridine).

The reaction temperature is changed depending on the starting material or reagents, but usually it is in the range from 0 to 150oC, and preferably from 10 to 100oC.

The reaction time varies depending on the starting material, reagent or the reaction temperature, but is usually from 30 minutes to 10 hours, and preferably from 1 to 5 hours.

After completion of the reaction, the target compound of this method is recovered from the reaction mixture in the usual way. For example, the target compound can be distinguished by removing the solvent by evaporation, adding to the reaction mixture with water followed by the addition of hydrophobic solvent (for example, benzene, ether, ethyl acetate for extraction connection, washing the organic layer with water, drying it over anhydrous magnesium sulfate and removing restartarii, the resultant deposition rates or chromatography.

In method A4 compound (XVIII) are synthesized by the reaction between the compound (XVI) and the compound of General formula (XVII) in an inert solvent in the presence of a base.

Solvent used is not specifically limited, provided that it does not interfere with the reaction and dissolves a certain amount of source material, and it can be such aliphatic hydrocarbons as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons as benzene, toluene or xylene; halogenated hydrocarbons like methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, or dichlorobenzene; an ether like diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol; or in such Amida as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoramide; or a sulfoxide, as dimethylsulfoxide or sulfolane. Preferred ether, amide or sulfoxide, and the preferred ether (particularly diethyl ether, tetrahydrofuran or dioxane) or an amide (particularly dimethylformamide).

As a basis you can use, for example, tako the second metal, as sodium bicarbonate, potassium bicarbonate or bicarbonate of lithium, an alkali metal hydride like sodium hydride or potassium hydride, an alkali metal hydroxide like sodium hydroxide, potassium hydroxide or lithium hydroxide; or an organic amine like triethylamine, tributylamine, Diisopropylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethyl-amino) pyridine, N, N-limecellen, 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); this alkylate as motility, utility or utility; this alkylamide lithium as diisopropylamide lithium, or dicyclohexylamine lithium; preferably, the carbonate of an alkali metal, a hydride of an alkali metal or organic amine, and more preferably, the carbonate of the alkali metal (especially sodium carbonate or potassium carbonate, or hydride of an alkali metal (especially sodium hydride).

For faster response you can add a crown ether, such as dibenzo-18-crown-6.

The reaction temperature is changed depending on the starting material or reagents, and usually it is in the range of from 10 to 150oC, preferably from 0 to 80oC.

The reaction time varies depending on ishodnogo 10 hours.

After completion of the reaction, the target compound of this method is recovered from the reaction mixture by conventional means. For example, the target compound can be selected by appropriately neutralizing the reaction mixture, filtering (in the presence) of insoluble material, viparita solvent, adding to the reaction mixture water, and then adding a hydrophobic solvent (for example, benzene, ether, ethyl acetate for extraction connection, washing the organic layer with water, drying it over anhydrous magnesium sulfate and removing the solvent by evaporation. The obtained target compound can, if necessary, clean due to recrystallization, the resultant deposition rates or chromatography.

In the method A5 amino-protective group is removed to obtain compound (1).

The method of removing the amino-protective group varies depending on the type of protective group, but it is carried out as follows, using a well-known method in the chemistry of organic synthesis.

If the amino-protective group is any of C1-C4alkanoyl radicals (preferably formyl or acetyl); C6-C10arylcarboxylic radicals (PR is m, or three-C1-C4- alkylsilanes (preferably methoxycarbonyl, etoxycarbonyl, tert.-butoxycarbonyl, 2-trimethylsilylethynyl, 2-bromo - tert. -butoxycarbonyl or 2,2-dibromo-tert. -butoxycarbonyl); C2-C5altneratively radicals which can be substituted by methoxy or nitro, preferably, vinyloxycarbonyl); or (C7-C15alkoxycarbonyl radicals which can be substituted by methoxy or nitro, preferably, benzyloxycarbonyl, (1-phenyl) benzyloxycarbonyl, 9-antimetastasis, para-methoxybenzeneboronic or para-nitrobenzenesulfonyl), it can be removed by treatment with acid in an inert solvent or in an aqueous solvent. The target product can be obtained in this case in the form of salt.

The acid can, for example, to use hydrochloric acid, sulfuric acid, phosphoric acid, Hydrobromic acid or triperoxonane acid, and is preferably, may be any one of hydrochloric, sulfuric, Hydrobromic or triperoxonane acids.

Solvent used is not specifically limited, provided that it does not interfere with the reaction and dissolves a certain amount of source material is fir; such aromatic hydrocarbons as benzene, toluene or xylene; halogenated hydrocarbons like methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, or dichloro - benzene; ether like diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol; or the complex ester as methyl acetate or ethyl acetate; an alcohol, like methanol, ethanol, propanol, isopropanol or butanol; therefore Amida as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoramide; therefore sulfoxide, as dimethylsulfoxide or sulfolane; such aliphatic acid, as formic acid or acetic acid; or water or a water mixture of the above solvents, preferably halogenated hydrocarbon, ether, alcohol, aliphatic acid, water or a water mixture of the above solvents, and, more preferably, halogenated hydrocarbons (particularly methylene chloride), an ether (particularly tetrahydrofuran or dioxane), aliphatic acid (particularly acetic acid), water or a water mixture of the above solvents.

The reaction temperature will change depending on Exod who, predpochtitelno, from 0 to 60oC.

The reaction time varies depending on the starting material, solvent or acid used, but is usually from 5 minutes to 20 hours, and preferably from 10 minutes to 5 hours.

After completion of the reaction, the target compound of this method is recovered from the reaction mixture by conventional means. For example, the target connection exhale, filtering the target product, precipitated precipitated from the reaction mixture, or neutralizing accordingly the reaction mixture, removing the solvent by evaporation, adding to the reaction mixture with water followed by the addition of hydrophobic solvent (for example, benzene, ether, ethyl acetate for extraction connection, washing the organic layer with water, drying it over anhydrous magnesium sulfate and viparita solvent. The obtained target compound can, if necessary, clean due to recrystallization, the resultant deposition rates or chromatography.

If the amino-protective group is any of alkanoyl, arylcarbamoyl, alkoxycarbonyl, alkenylcarbazoles, aryldiazonium or orelkinoservisa, it can be removed by treatment with base in an inert solution is t an alkali metal, as sodium carbonate, potassium carbonate or lithium carbonate; bicarbonate of an alkali metal as sodium bicarbonate, potassium bicarbonate or bicarbonate of lithium, an alkali metal hydride, as lithium hydride, sodium hydride or potassium hydride, an alkali metal hydroxide like sodium hydroxide, potassium hydroxide or lithium hydroxide, an alkoxide of an alkali metal as sodium methoxide, ethoxide sodium tert.-piperonyl potassium or lithium methoxide; alkali metal mercaptan, as methylmercaptan sodium or ethyl mercaptan sodium, preferably, the carbonate of the alkali metal (especially sodium carbonate or potassium carbonate), alkali metal hydroxide, especially sodium hydroxide or potassium hydroxide), alkali metal alkoxide (particularly sodium methoxide, ethoxide or sodium tert.-piperonyl potassium) or an organic amine (particularly hydrazine or methylamine).

Solvent used is not specifically limited, provided that it does not interfere with the reaction and dissolves a certain amount of source material, and it may be, for example, such aliphatic hydrocarbons as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons as benzene, toluene or xylene; halogen is dichlorobenzene; this ether as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol; therefore alcohol like methanol, ethanol, propanol, isopropanol or butanol; therefore Amida as dimethylacetamide or hexamethylphosphoramide; therefore sulfoxide, as dimethylsulfoxide or sulfolane; or a water mixture of the above solvents, preferably halogenated hydrocarbon, ether, alcohol or a water mixture of the above solvents, and more preferably an ether (particularly tetrahydrofuran or dioxane), an alcohol (particularly methanol or ethanol) or a water mixture of the above solvents.

The reaction temperature is changed depending on the starting material, solvent, or used, but usually it is in the range of from -10 to 150oC, and preferably from 0 to 50oC. the reaction Time varies depending on the starting material, solvent, or used, but usually it is the interval from 30 minutes to 20 hours, preferably from 1 to 5 hours.

After completion of the reaction, the target compound of this method is recovered from the reaction mixture by conventional means. For example, a target with which Rivonia solvent, add water to produce alkaline water layer for filtering off precipitated in the sediment of the product, or by adding a hydrophobic solvent (for example, benzene, ether, ethyl acetate for extraction connection, washing the organic layer containing the target product, water, drying it over anhydrous magnesium sulfate and evaporation of the solvent. The obtained target compound if necessary, you can clear due to recrystallization, the resultant deposition rates or chromatography.

If the amino-protective group is tert.-butoxycarbonyl radical, it can be removed by processing silyl compound or a Lewis acid in an inert solvent.

Used silyl compound may be, for example, trimethylsilylpropyne, trimethylsilylimidazole or trimethylsilyltrifluoromethane, and the Lewis acid can be used luminiare.

Solvent used is not specifically limited, provided that it does not interfere with the reaction, dissolve a certain amount of source material, and it may be, for example, a halogenated hydrocarbon like methylene chloride, chloroform or carbon tetrachloride; ether, sidirovanii hydrocarbons (particularly methylene chloride or chloroform) or a nitrile (particularly acetonitrile).

The reaction temperature is changed depending on the starting material, reagent or solvent, but usually it is between 20 and 100oC, and preferably from 0 to 50oC.

The reaction time varies depending on the starting material, reagent, solvent, or the reaction temperature, but it is usually a period of from 10 minutes to 10 hours, preferably from 30 minutes to 3 hours.

After completion of the reaction, the target compound of this method is recovered from the reaction mixture by conventional means. For example, the target connection exhale, removing the solvent by evaporation, adding to the reaction mixture water to produce alkaline water layer and allocation fallen precipitated product by filtration, or by adding a hydrophobic solvent (for example, benzene, ether, ethyl acetate for extraction connection, washing the organic layer containing the target product, water, drying it over anhydrous magnesium sulfate and removal of solvent by evaporation. The obtained target compound can, if necessary, clean due to recrystallization, the resultant deposition rates or chromatography.

In that case, if the amino-protecting group is allyloxycarbonyl the I) similar to those indicated for removal Arakelova radical due to catalytic hydrogenation using palladium and triphenylphosphine or tetracarbonyl Nickel.

In that case, if the amino-protective group is Aracely or C7-C11aracelikarsaalyna radical, it can be easily removed as a result of implementation of contact with the regenerating agent in an inert solvent (preferably by catalytic hydrogenation in the presence of a catalyst) or by using the developer.

As the solvent that can be used in catalytic hydrogenation to remove the protective group, it is possible to use any solvent, provided that it will not participate in the reaction and can be, for example, such aliphatic hydrocarbons as hexane or cyclohexane; an aromatic hydrocarbon like toluene, benzene or xylene; an ether like diethyl ether, tetrahydrofuran or dioxane; ether complex as propyl or ethyl acetate; an alcohol, like methanol, ethanol or isopropanol; aliphatic acid as formic acid or acetic acid;< / BR>
water or mixtures of these organic solvents. The preferred acid or aqueous mixtures of these solvents, and the preferred alcohol (particularly methanol or ethanol), aliphatic acid (especially formic acid or acetic acid or aqueous mixtures of these solvents.

The used catalyst is not specifically limited, provided that they are used usually during catalytic hydrogenation, and they can be, for example, palladium-on-charcoal, Nickel of Renee, rhodium-aluminiumoxide, or palladium-maricultura. Preferred palladium on coal and Nickel of Renee.

The hydrogen pressure is not specifically limited, but usually it ranges from 1 to 10 atmospheres, and preferably is 1 atmosphere.

The reaction temperature varies depending on the starting material, solvent or catalyst, but is usually from 0 to 0oC, and preferably from 10 to 50oC.

The reaction time varies depending on the starting material, solvent, catalyst, or the reaction temperature, but is usually a period of from 15 minutes to 10 hours, preferably from 30 minutes to 3 hours.

After completion of the reaction, the target compound of this method is recovered from the reaction mixture by conventional means. For example, the target connection exhale, viparita Ravina phase precipitate the product, or adding a hydrophobic solvent (for example, benzene, ether, ethyl acetate for extraction connection, washing with water the organic layer containing the target product, drying it over anhydrous magnesium sulfate and viparita solvent. The obtained target compound can, if necessary, clean due to recrystallization, the resultant deposition rates or chromatography.

The solvent used in the oxidation for the removal of the protective group is not specifically limited, provided that it does not participate in the reaction, and it may be for example, a ketone, such as acetone; halogenated hydrocarbons like methylene chloride, chloroform or carbon tetrachloride; NITRILES like acetonitrile; an ether like diethyl ether, tetrahydrofuran or dioxane; therefore Amida as dimethylformamide, dimethylacetamide or hexamethylphosphoramide; therefore sulfoxide as dimethyl sulfoxide; and water or a mixture of these organic solvents. Preferred any ketones, halogenated hydrocarbons, NITRILES, esters, amides, sulfoxidov water or a mixture of such solvents, and more preferred, ketones, especially acetone) halogenated hydrocarbons (particularly methylene chloride), NITRILES (axle mixtures of these solvents.

Used the oxidant can be, for example, potassium persulfate, sodium persulfate, ammoniumnitrate cerium (CAN) or 2,3 - dichloro-5,6-dicyano-p-benzoquinone (DDQ), and preferably, ammoniumnitrate cerium (CAN) or 2,3-dichloro-5,6-dicyano-p - benzoquinone (DDQ).

The reaction temperature varies depending on the material used, the solvent or oxidant, and is usually between 0 and 150oC, and preferably between 10 and 50oC.

The reaction time varies depending on the compound, solvent or the developer, but usually ranges from 15 minutes to 24 hours, preferably from 30 minutes to 5 hours.

After completion of the reaction, the target compound in this way separated from the reaction mixture by conventional means. For example, the target connection exhale, removing the solvent by evaporation, after filtered oxidizing agent, adding water and making the water alkaline layer, and filtering the precipitated precipitate the product, or by adding a hydrophobic solvent (for example, benzene, ether, ethyl acetate for extraction connection, washing the organic layer containing the target product, water, drying it over anhydrous magnesium sulfate and removing the solvent issue is Sardinia or chromatography.

Method B is a method of obtaining compound (XVIIIa), where X represents the oxygen in the intermediate compound (XVIII) of method A.

In method B1 compound (XVIIIa) are obtained by the reaction of compound (XV) with a compound of General formula (XVIIa).

If V represents a hydroxyl radical, the reaction of lead due to dehydration-condensation of the compound (XV) and the compound (XVIIa) in an inert solvent in the presence of phosphine compounds and azo-compounds according to the Mitsunobu reaction, published in Bull. Chem. Soc. Jap. 40,2380 (1967).

Solvent used is not specifically limited, provided that it does not interfere with the reaction and dissolves a certain amount of source material. It can be, for example, such aliphatic hydrocarbons as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons as benzene, toluene or xylene; halogenated hydrocarbons like methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; or an ether like diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol. Preferred aliphatic hydrocarbon, the Academy of Sciences).

Used the phosphine compound may be, for example, three-C1-C6alkylphosphines, such as trimethylphosphine, triethylphosphine, tripropyltin, tributylphosphine, triphenylphosphine or trihexalon; therefore C6-C10arylphosphine as triphenylphosphine, TryEngineering or trination; or in three-C6-C10-arylphosphine, which may have as a substituent C1-C4is an alkyl radical, such as maildefinition, trailerforum, trimethylphosphine, tributyltin-phosphinyl and three-6-ethyl-2-natterposted. The preferred three-C1-C6-alkylphosphine (especially trimethylphosphine, triethylphosphine, tripropyltin or tributylphosphine) or C6-C10-arylphosphine (particularly triphenylphosphine, TryEngineering or trination), and more preferred three-C6-C10arylphosphine (especially triphenylphosphine).

Azo-compound can be, for example, di-C1-C4-alkyl-azodicarboxylate, such as diethylazodicarboxylate, diethylazodicarboxylate, dipropylthiocarbamate or dibutyldithiocarbamate; preferred diethylazodicarboxylate or diethylazodicarboxylate.

The reaction temperature is changed according to at 50oC.

The reaction time varies depending on the starting material, reagent or the reaction temperature, but is usually the period of time from 15 minutes to 48 hours, preferably from 30 minutes to 24 hours.

After completion of the reaction, the target compound of this method is recovered from the reaction mixture by conventional means. For example, the target compound can be obtained by filtering out the insoluble part (if it is present) and removing the solvent by evaporation, or by adding water to the residue after removal of solvent, adding a hydrophobic solvent (for example, benzene, ether, ethyl acetate for extraction connection, washing with water, drying over anhydrous magnesium sulfate and viparita solvent. The obtained target compound can, if necessary, clean due to recrystallization, the resultant deposition rates or chromatography.

If Y is tsepliaeva group, the compound (XVIIIa) get in the interaction of the compound (XV) with an appropriate compound (XVIIa) in an inert solvent in the presence of a base.

Solvent used is not specifically limited, provided that it does not interfere with the reaction and dissolves a certain Koli is grain or petroleum ether; such aromatic hydrocarbons as benzene, toluene or xylene; halogenated hydrocarbons like methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; or an ether like diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol; therefore Amida as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoramide; or a sulfoxide, as dimethylsulfoxide or sulfolane. Preferred amide or sulfoxide, and the most preferred amide (particularly dimethylformamide, dimethylacetamide or hexamethylphosphoramide).

As a basis you can use, for example, the carbonate of an alkali metal as sodium carbonate, potassium carbonate or lithium carbonate; bicarbonate of an alkali metal as sodium bicarbonate, potassium bicarbonate or bicarbonate of lithium, an alkali metal hydride, as lithium hydride, sodium hydride or potassium hydride, an alkali metal hydroxide like sodium hydroxide, potassium hydroxide or lithium hydroxide, an alkoxide of an alkali metal as sodium methoxide, ethoxide sodium tert.-piperonyl potassium or lithium methoxide; such mercaptan alkaline melamin, 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); this alkylate as motility, utility or utility; this trialkylated lithium as diisopropylamide lithium or dicyclohexylamine lithium. The preferred carbonate of alkali metal, alkali metal hydride, or hydroxide of an alkali metal, and preferably a hydride of an alkali metal (especially sodium hydride).

For faster response you can add a crown ether, such as dibenzo-18-crown-6.

The reaction temperature is changed depending on the starting material or reagents, but typically a value between -10 and 100oC, and preferably between 0 and 50oC.

The reaction time varies depending on the starting material, reagent or the reaction temperature, but is usually between 30 minutes and 20 hours, and preferably between 1 and 5 hours.

After completion of the reaction, the target compound of this method is recovered from the reaction mixture by conventional means. For example, the target compound is recovered from the reaction mixture, the appropriate treatment is ritel due to evaporation, adding water to the reaction mixture, adding a hydrophobic solvent (for example, benzene, ether, ethyl acetate for extraction connection, washing the organic phase (containing the target compound) water, drying over anhydrous magnesium sulfate and viparita solvent. The obtained target compound can, if necessary, clean due to recrystallization, the resultant deposition rates or chromatography.

Method C is an alternative method of obtaining the compound (XV), which is an intermediate compound in the method A or the reference compound in method B.

In method C1 compound of General formula (XX) are obtained in the reaction of compounds of General formula (XIX) with diazo-C1- C4alkanol.

Diazo-C1-C4alkane may be any of diazomethane, diazoethane, diazopropane or diazomethane, and preferred diazomethane.

Solvent used is not specifically limited provided that it does not interfere with the reaction and dissolves a certain amount of source material. It can be, for example, such aliphatic hydrocarbons as hexane, heptane, ligroin or petroleum ether; aliphatic hydrocarbons as benzene, toluene or xylene; therefore g is l or dichlorobenzene; or so ether as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol; the complex ester as methyl acetate or ethyl acetate; or a mixture of the above solvents. Preferred halogenated hydrocarbon, ether, ester or mixtures of the abovementioned solvents, preferably an ether (particularly diethyl ether), esters (particularly ethyl acetate) or a mixture of the above solvents.

The reaction temperature is changed depending on the starting material or reagents, but usually it is from -10 to 100oC, and preferably from 10 to 50oC.

The reaction time varies depending on the starting material, reagent or the reaction temperature, but it usually takes from 10 minutes to 10 hours, preferably from 15 minutes to 3 hours.

After completion of the reaction, the target compound of this method is recovered from the reaction mixture by conventional means. For example, the target connection exhale, viparita solvent. The obtained target compound can, if necessary, clean due to recrystallization, the resultant deposition rates or chromatography.

In method C2 connection total of four who P CLASS="ptx2">

The solvent and base are the same as specified in method A1.

The reaction temperature will change depending on the starting material or reagents, but usually it is from -10 to 100oC, and preferably from 10 to 50oC.

The reaction time varies depending on the starting material, reagent or the reaction temperature, but is usually from 10 minutes to 10 hours, preferably from 30 minutes to 5 hours.

After completion of the reaction, the target compound of this method is recovered from the reaction mixture in the usual way. For example, the target compound can be selected, viparita solvent, adding water to the residue, podkisst water layer and filtering the precipitated precipitate the product, or adding water to the reaction mixture, podkisst water layer, adding a hydrophobic solvent (for example, benzene, ether or ethyl acetate for extraction of the target compounds, washing the extracted organic layer with water, drying over anhydrous magnesium sulfate and viparita solvent. The obtained target compound if necessary, you can clear due to recrystallization, the resultant deposition rates or chromatography.

In method C3 compound (XV) are obtained in the reaction of soybean is Yong, provided that it does not interfere with the reaction and dissolves a certain amount of source material. It can be, for example, such aliphatic hydrocarbons as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons as benzene, toluene or xylene; halogenated hydrocarbons like methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; or an ether like diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol; therefore Amida as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoramide; therefore sulfoxide, as dimethylsulfoxide or sulfolane; or water. Preferred amide, sulfoxide or water, and most preferred is water.

As a basis you can use, for example, the carbonate of an alkali metal as sodium carbonate, potassium carbonate or lithium carbonate; alkali metal hydride as lithium hydride, potassium hydride or sodium hydride; carbonates of alkali metal as sodium bicarbonate, potassium bicarbonate or bicarbonate of lithium, an alkali metal hydroxide like sodium hydroxide, potassium hydroxide or hydrox is in, 4-(N, N-dimethylamino)pyridine, N,N - dimethylalanine, 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); this alkylate as motility, utility or utility; this alkylamide lithium as diisopropylamide lithium or dicyclohexylamine lithium. The preferred carbonate, alkali metal bicarbonate, alkali metal or alkali metal hydroxide, the preferred hydroxide of alkaline metal (especially sodium hydroxide or potassium hydroxide).

The reaction temperature is changed depending on the starting material or reagents, but usually it is in the range from 0 to 150oC, more preferably from 10 to 100oC.

The reaction time varies depending on the starting material, reagents and reaction temperature, but it usually takes from 10 minutes to 10 hours, and preferably from 15 minutes to 5 hours.

After completion of the reaction, the target compound of this method is recovered from the reaction mixture by conventional means. For example, the target compound can be selected, podkisst the reaction mixture and filtering the precipitated precipitate the product, or podkisst the reaction mixture, adding a hydrophobic solvent (napalovanie) water, drying over anhydrous magnesium sulfate and removing the solvent by evaporation. The obtained target compound can, if necessary, clean due to recrystallization, the resultant deposition rates or chromatography.

Method D is a method of obtaining the compounds of formula (XXIII), in which the substituting radical on the ring A of the intermediate (XVIII) in the way that R contains Ra1< / BR>
In the method of D1 compound (XXIII) are obtained in the reaction of compound (XXII) with a halogen-C1-C6alkanol, carbon dioxide, carbon disulphide, di-C1-C6alkylsulfides, di-C1-C6alkalicarbonate, S-(trifluoromethyl)- dibenzothiophene triftoratsetata or S-(trifluoromethyl)-3,7 - dinitrobenzotrifluoride (preferred halogen-C1-C6alkyl, or carbon dioxide) in an inert solvent in the presence of a base.

Halogen-C1-C6alkane may represent, for example, methyl chloride, methyl bromide, methyliodide, ethyliodide, propyl bromide, utilidad, pentolite or exisited. The preferred methyl or methyliodide, and more preferred methyliodide.

Di-C1-C6alkyldimethyl may represent, for example, timeid, and preferably, dimethyl disulfide or diatinguished.

Di-C1-C6alkalicarbonate may be, for example, dimethylcarbonate, diethylcarbamoyl, dipropylamine, Diisopropylamine, dibutylamine, di-W. -BUTYLCARBAMATE, di-tert. -BUTYLCARBAMATE, dimetilkarbamida or digoxigenin, and preferred dimethylcarbonate or diethylcarbamyl.

Solvent used is not specifically limited, provided that it does not interfere with the reaction and dissolves a certain amount of source material. It can represent, for example, such aliphatic hydrocarbons as hexane, heptane, ligroin, or petroleum ether; an aromatic hydrocarbon like benzene, toluene or xylene; halogenated hydrocarbons like methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; an ether like diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether diethylenglycol; therefore diamine, N,N,N',N'-tetramethylethylenediamine; therefore amidon, such as dimethylformamide, dimethylacetamide, or hexamethylphosphoramide; or so sulfoxide, as formamide, dimethylsulfoxide or sulfolane. ptx2">

Used may be, for example, an alkali metal hydride, as lithium hydride, sodium hydride or potassium hydride; such alkylate as motility, utility or utility or Deut.-utility; this alkylamide lithium as diisopropylamide lithium, dicyclohexylamine lithium bis (trimethylsilyl) amide and lithium bis(trimethylsilyl) amide or potassium bis (trimethylsilyl) amide and sodium. Preferred alkality (especially utility) or alkylamide lithium (especially diisopropylamide lithium).

The reaction temperature is changed depending on the starting material or reagents, but usually it is in the range from -100 to 30oC, and preferably from -70 to 0oC.

The reaction time varies depending on the starting material, reagent or the reaction temperature, but it usually takes from 5 minutes to 10 hours, and preferably from 10 minutes to 5 hours.

After completion of the reaction, the target compound of this method is recovered from the reaction mixture in the usual way. For example, the target compound can be selected, viparita solvent, or viparita solvent, adding to the residue water, adding a hydrophobic solvent (for example, benzene, ether, ethyl acetate) to ekstragirovanie pariva solvent. The obtained target compound can, if necessary, clean due to recrystallization, the resultant deposition rates or chromatography.

Sometimes the target connection this method is used in further steps without isolation or purification after completion of the reaction.

Method E is a method of obtaining compound (XXVII) in which the substituents on the ring A is an intermediate compound (XVIII) in A way that contains carbamoyl radical, the compound (XXVIII), which is the starting compound for the method f

In the method E1 connection (XXVI) are obtained in the reaction of the compound (XXIV) with a compound of General formula (XXV) in an inert solvent in the presence of a base. If X in the compound (XXVI) represents a sulfur atom, it is the source material (XXVIII) to method F.

Solvent used is not specifically limited, provided that it does not interfere with the reaction and dissolves a certain amount of source material. It can be, for example, such aliphatic hydrocarbons as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons as benzene, toluene or xylene; halogenated hydrocarbons like methylene chloride, chloroform, celerey ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol; therefore diamine, N,N,N',N'-tetramethyl - Ethylenediamine; therefore Amida as formamide, dimethylformamide, diethylacetamide or hexamethylphosphoramide; or a sulfoxide, as dimethylsulfoxide or sulfolane. Preferred amide or sulfoxide, and the preferred amide (particularly dimethylformamide).

As a basis you can use, for example, the carbonate of an alkali metal as sodium carbonate, potassium carbonate or lithium carbonate; bicarbonate of an alkali metal as sodium bicarbonate, potassium bicarbonate or bicarbonate of lithium, an alkali metal hydride, as lithium hydride, sodium hydride or potassium hydride, an alkali metal hydroxide like sodium hydroxide, potassium hydroxide or lithium hydroxide; an organic amine like 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); this alkylate as motility, utility or utility; or such alkylamide lithium as diisopropylamide lithium, or dicyclohexylamine lit the and, and more preferred carbonate of an alkali metal (especially sodium carbonate, potassium carbonate or lithium carbonate).

The reaction temperature is changed depending on the starting material or reagents, but typically a value between -10 and 100oC, and preferably between 0 and 50oC.

The reaction time varies depending on the starting material, reagent or the reaction temperature, but is usually from 30 minutes to 30 hours, and preferably from 1 to 20 hours.

After completion of the reaction, the target compound of this method is recovered from the reaction mixture in the usual way. For example, the target connection exhale, viparita solvent, or viparita solvent, adding to the residue water, adding a hydrophobic solvent (for example, benzene, ether, ethyl acetate for extraction connections, rinsing, extracting the organic layer, drying over anhydrous magnesium sulfate and removing the solvent by evaporation. The obtained target compound can, if necessary, clean due to recrystallization, the resultant deposition rates or chromatography.

In the method E2 compound (XXVII) are obtained in the reaction of compound (XXVI) with gaseous ammonia or concentrated is on the ring A in compound (XVIII) contains carbamoyl radical.

Solvent used is not specifically limited, provided that it does not interfere with the reaction and dissolves a certain amount of source material. He can be such aliphatic hydrocarbons as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons as benzene, toluene or xylene; therefore gridironed hydrocarbon like methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; or an ether like diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol; therefore alcohol like methanol, ethanol, propanol, isopropanol, butanol or Isobutanol; therefore diamine, N,N,N',N'-tetramethylethylenediamine; therefore Amida as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoramide; or a sulfoxide, as dimethylsulfoxide or sulfolane. Preferred ether or alcohol, and preferably an alcohol (particularly methanol or ethanol).

The reaction temperature is changed depending on the starting material or reagents, but usually it is from -10 to 100oC, and preferably from 0 to 50oC.

The reaction time varies depending on Exod 20 hours.

After completion of the reaction, the target compound of this method is recovered from the reaction mixture by conventional means. For example, the target compound can be selected, viparita solvent, and removing the solvent by evaporation, adding to the residue water, adding a hydrophobic solvent (e.g. benzene, toluene or xylene), for the extraction of compounds, rinsing, extracting the organic layer with water, drying over anhydrous magnesium sulfate and viparita solvent. The obtained target compound can, if necessary, clean due to recrystallization, the resultant deposition rates or chromatography.

In the way E3 compound (XXVII) receive alternative due to the condensation of a compound (XXIV) with ammonia in an inert solvent, and it is carried out in accordance with the conventional method of peptide synthesis, for example, azide, active complex ester, mixed anhydride of the acid, or by condensation (preferably a method using a mixed acid anhydride).

In the method using the azide compound (XXIV) is treated with hydrazine in an inert solvent (for example, such amide as formamide, dimethylformamide, dimethylacetamide or hexaneoC). Hydrazide aminosilane thus obtained is converted into azide due to the implementation of the reaction with the compound nitrile, and then react with ammonia.

As nitrite can be used, for example, the nitrite of an alkali metal as sodium nitrite or alkylated as soliditet.

The reaction preferably are inert solvent, which can be so amidon as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoramide; therefore sulfoxide, as dimethylsulfoxide or sulfolane; or so pyrrolidone, N-organic; and the preferred amide (particularly dimethylformamide).

In addition, two methods (reaction formation azide and the reaction with ammonia) in this way can be carried out in one reactor.

The reaction temperature is changed depending on the starting material or reagents, but the reaction of formation of azide typically occurs at a temperature of from -70 to 50oC (preferably from -50 to 0oC), and the reaction with ammonia occurs in the temperature range from -70 to 50oC (preferably from -10 to 10oC).

The reaction time varies depending on the starting material, reagent or the temperature of reaction is the reaction with ammonia takes 5 hours to... (preferably, from 10 hours to 5 days).

After completion of the reaction, the target compound of this method is recovered from the reaction mixture by conventional means. For example, the target connection exhale, viparita solvent, or viparita solvent, adding to the residue water, adding a hydrophobic solvent (for example, benzene, ether, ethyl acetate for extraction connections, rinsing, extracting the organic layer with water, drying over anhydrous magnesium sulfate and removing the solvent by evaporation. The obtained target compound can, if necessary, clean due to recrystallization, the resultant deposition rates or chromatography.

The method using active complex ester is carried out, treating the compound (XXIV) with a reagent forming ester in an inert solvent, and treating the thus obtained ester with ammonia in an inert solvent.

Used in both reactions, the solvent is not particularly limited, provided that it does not interfere with the reaction and dissolves a certain amount of source material. The solvent can be used, for example, a halogenated hydrocarbon like methylene chloride, chloroform, even the new ether, tetrahydrofuran, dioxane, dimethoxyethane, or dimethyl ether of diethylene glycol; amide such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoramide; or a nitrile as acetonitrile. Preferred ether (particularly tetrahydrofuran) or an amide (particularly dimethylformamide).

As an active agent, forming an ester, can be used, for example, N - hydroxy containing compound as the N-hydroxysuccinimide, 1 hydroxybenzoate evil or N-hydroxy-5-Nord bornan-2,3 - dicarboximide, or a disulfide, as dipyridamole. Active etherification takes place preferably in the presence of such a condensing agent, as dicyclohexylcarbodiimide, carbonyldiimidazole or triphenylphosphine.

The reaction temperature is changed depending on the starting material or reagents, but is usually active esterification takes place at a temperature in the range from -70 to 150oC (preferably between -10 and 100oC), and the reaction with ammonia typically occurs at a temperature in the range of from -20 to 100oC (preferably from 0 to 50oC).

The reaction time varies depending on the starting material, reagent or the reaction temperature, but usually both the reactions the shares of the target connection this way separated from the reaction mixture in the usual way. For example, the target connection exhale, viparita solvent, or viparita solvent, adding to the residue water, adding a hydrophobic solvent (for example, benzene, ether, ethyl acetate for extraction connections, rinsing, extracting the organic layer with water, drying over anhydrous magnesium sulfate and viparita solvent. The obtained target compound can, if necessary, clean due to recrystallization, the resultant deposition rates or chromatography.

The method using a mixed acid anhydride is carried out, treating the compound (XXIV) with a reagent forming a mixed acid anhydride, in an inert solvent in the presence of a base, and treating the obtained mixed anhydride with ammonia in an inert solvent.

The solvent used in the reaction of obtaining the mixed anhydride of the acid is not specifically limited, provided that it does not interfere with the reaction and dissolves a certain amount of source material. You can use, for example, a halogenated hydrocarbon like methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; an ether such as diethyl ether, diisopropyl ether, t is methylformamide, dimethylacetamide or hexamethylphosphoramide, and preferably an ether (particularly tetrahydrofuran).

The reagent, forming a mixed anhydride of the acid may be, for example, a C1-C4alkylaminocarbonyl as ethylchloride or isobutylparaben; C1-C5alkanolamide as pivaloyloxy; or C1-C4alkylsulfonate or C6- C14arellanobover as diethylthiophosphate or definitionoutput. Preferred C1-C4alkylaminocarbonyl (especially isobutylparaben).

As the base, for example, to use such a carbonate of an alkali metal as sodium carbonate, potassium carbonate or lithium carbonate; or an organic amine like triethylamine, tributylamine, diisopropylethylamine, N-methyl-morpholine, 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), and the preferred organic amine, especially triethylamine).

The reaction temperature to obtain a mixed acid anhydride change depending on the starting material or reagents, but usually it is between -50 and 100oC (PTSA depending on the source material, reagents or reaction temperature, but is usually between 5 minutes and 20 hours, preferably, from 10 minutes to 10 hours).

As solvent in the reaction of the mixed anhydride of the acid with ammonia, it is possible to use any solvent, provided that it does not interfere with the reaction and dissolves a certain amount of source material. It can be, for example ether as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol; or in such Amida as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoramide; and the preferred ether (particularly tetrahydrofuran).

The reaction temperature of the mixed acid anhydride with ammonia vary depending on starting material or reagents, but usually it is between -30 and 100oC (preferably between 0 and 80oC).

The time of reaction of the mixed anhydride of the acid with ammonia varies depending on the starting material, reagents and reaction temperature, but it usually takes from 5 minutes to 24 hours (preferably from 10 minutes to 5 hours).

After completion of the reaction, the target compound of this method is recovered from the reaction mixture abyssimal, adding to the residue water, adding a hydrophobic solvent (for example, benzene, ether, ethyl acetate for extraction connections, rinsing, extracting the organic layer with water, drying over anhydrous magnesium sulfate and viparita solvent. The obtained target compound can, if necessary, clean due to recrystallization, the resultant deposition rates or chromatography.

The condensation is carried out by processing the compound (XXIV) directly with ammonia in an inert solvent in the presence of a condensing agent.

As the condensing agent, for example, to use dicyclohexylcarbodiimide, carbonyldiimidazole or 1-methyl-2-chloropyridine-trimethylamine, and the preferred dicyclohexylcarbodiimide.

This reaction can be conducted under conditions similar to the conditions described previously for the reaction of active complex ether.

After completion of the reaction, the target compound of this method is recovered from the reaction mixture in the usual way. For example, the target connection exhale, viparita solvent or viparita solvent, adding to the residue water, adding a hydrophobic solvent (for example, benzene, ether, ethyl acetate) to extras is Agnes and viparita solvent. If necessary, the target compound can be cleaned due to recrystallization, the resultant deposition rates or chromatography.

Method F is the alternative method of obtaining the compound (XXIX), which contains triptorelin radical as a substituent on the ring And the intermediate (XVIII) in method A.

The way F1 compound (XXIX) receive, through the interaction of the compound (XXVIII) with tetrabutylammonium (TBA+H2F3-) and 1,3-dibromo-5,5-dimethylhydantoin) (DBH) in an inert solvent according to the method described in Chemistry Letters, 927(1992).

Solvent used is not specifically limited, provided that it does not interfere with the reaction and dissolves a certain amount of raw materials. It can be, for example, a halogenated hydrocarbon like methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; or an ether like diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol, and the preferred halogenated hydrocarbons (particularly methylene chloride).

The reaction temperature vary depending on the source mater>The reaction time varies depending on the starting material, reagent or the reaction temperature, but it usually takes from 10 minutes to 5 hours, preferably from 30 minutes to 3 hours.

After completion of the reaction, the target compound of this method is recovered from the reaction mixture by conventional means; for example, the target connection exhale, viparita solvent, adding to the reaction mixture water, adding a hydrophobic solvent (for example, benzene, ether, ethyl acetate) to the extracted connection, washing the extract with water, drying over anhydrous magnesium sulfate and viparita solvent. The compound obtained can, if necessary, to purify by recrystallization, Peresada or chromatography.

Method G is an alternative method of obtaining the compound (XXXI), which contains ceanorhaditis as Deputy to the ring And the intermediate (XVIII) in method A.

In the way that GI compound (XXXI) receive, through the interaction of the compound (XXX) with a dehydrating agent in an inert solvent.

Solvent used is not specifically limited, provided that it does not interfere with the reaction and dissolves a certain amount of ishoy ether; such aromatic hydrocarbons as benzene, toluene or xylene; halogenated hydrocarbons like methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; an ether like diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol; the complex ester as methyl acetate or ethyl acetate; a ketone, such as acetone; therefore Amida as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoramide; or a sulfoxide, as dimethylsulfoxide or sulfolane. Preferred ether, amide or sulfoxide, and the preferred amide (particularly dimethylformamide).

As the dehydrating agent can use, for example, phosphorus oxychloride, triperoxonane anhydride, methanesulfonate, p-toluensulfonate or patikis phosphorus, preferably phosphorus oxychloride.

The reaction temperature vary depending on starting materials or reagents, but usually it is between -30 and 100oC, and preferably between -10 and 30oC.

The reaction time varies depending on the starting material, reagent or the reaction temperature, but usually accounted for the second connection this way separated from the reaction mixture by conventional means. For example, the target compound can be selected, viparita solvent, adding to the reaction mixture water, adding a hydrophobic solvent (for example, benzene, ether, ethyl acetate for extraction connection, washing the extract with water, drying it over anhydrous magnesium sulfate and viparita solvent. The obtained target compound if necessary, you can clear due to recrystallization, the resultant deposition rates or chromatography.

The compound (II), which is the active ingredient of the inhibitor of monoamine oxidase, well known, or it can be obtained by the interaction of the compound (XVI) and compounds of General formula;

HX - (CH2)n-Ra4, (XVIIb)

where X has the above value, a Ra4same as Ra2except that aminouracil and mono-C1-C4acylaminoacyl protected according to the method of A4, optionally removing the protective group V amino - and alkylamino by way A5.

Further, the compound containing an oxygen atom at X in the compound (II) obtained when the interaction of the compound (XVI) with a compound of General formula;

Y- (CH2)n- Ra4, (XVIIc)

where Ra4and Y have ukazannomu A5.

Derivatives isoxazol (I) and (II) of the present invention can be used as therapeutic agents or for the prevention of diseases such as Parkinson's and Alzheimer's disease (especially Parkinson's disease and depression, as they have excellent inhibiting the monoamine oxidase type B and type a action (especially effectively inhibited monoamine oxidase type B) and, in addition, they are low toxicity.

The preferred embodiment of the invention

Further, the present invention is described in detail, with examples, how to obtain and test methods, but this invention is in no way should be limited to the following examples.

Example 1.

3-(2-aminoethoxy)-5-chloro-1,2-benzisoxazole hydrochloride

(a) Ethyl-5-chlorosalicylic

To a suspension of 5-chlorosalicylic acid (500 g) in 2 l of ethanol is added concentrated sulfuric acid (40 ml) under stirring at room temperature. After the reaction mixture was refluxed for 12 hours, the solvent is evaporated under reduced pressure and the residue is dissolved in ethyl acetate. The organic layer is washed with 10% NaCl and 4% rastvorobetonny the solvent is evaporated under reduced pressure to obtain the title compound (514 g, 88%) as a pale yellow oil.

IR (KBr)maxcm-1: 1680, 1475

NMR spectrum (DMSO-d6) MD: 1,42 /3H, t, J=7,3 Hz/, 4,43 /2H, q, J= 7,3 Hz/, 6,93 /1H, d, J= 7,3 Hz/, 7,35 /1H, DD, J= 7,3 Hz, J= 2,5 Hz/, 7,82 /1H, d, J=2,5 Hz/, 11,80 /1H, s/.

(b) 5-chlorosalicylaldehyde acid

Hydroxylamine hydrochloride (197 g) dissolved in 400 ml of water and cooled to 5oC. Add a methanol solution (1.5 l) of potassium hydroxide (545 g), and further stirring at the same temperature was added dropwise a methanolic solution (400 ml) ethyl-5-chlorosalicylaldehyde of ester (500 g). After stirring for 30 minutes at a temperature in the range from 5 to 10oC, the stirring is continued for 3 hours at room temperature. The solvent is evaporated under reduced pressure, and the residue is dissolved in ice water (6 l). the pH of the resulting solution set 2 at the expense of concentrated hydrochloric acid, and is listed in the title compound (438 g, 93%) was obtained as colorless crystals, filtering the precipitated precipitate crystals, and washing them with water.

Melting point 216-220oC.

IR spectrum (KBr)maxcm-1: 3127, 1618, 1577, 1523, 1492, 1413;

NMR spectrum (DMSO-d6) MD: of 6.96 /1H, d, J=7,3 Hz/, 7,43 /1H, DD, J= 7,3 Hz, 2.5 Hz/is ru 5 - chlorosalicylaldehyde acid (216 g) in 600 ml of tetrahydrofuran, add thionyl chloride (100 ml) dropwise with stirring at 10-20oC. After stirring for 2 hours at the same temperature, the reaction mixture is evaporated under reduced pressure, and the residue is dissolved in dioxane (600 ml) and cooled to 0-5oC. To the reaction mixture 383 ml of triethylamine and stirred at room temperature for 1 hour. The solvent is evaporated under reduced pressure and to the residue add 3 l of ice water. the pH of the resulting mixture adjusted to 2 with concentrated hydrochloric acid, and precipitated precipitated crystals are filtered and washed with water. Specified in the title compound (172 g, 88%) was obtained as colorless needle-like crystals by recrystallization from ethyl acetate.

So melting 219-222oC.

IR spectrum (KBr)maxcm-1: 3400-2000, 1613, 1560, 1516;

NMR spectrum (DMSO-d6) MD: 7,43-7,72 /2H, m, of 7.82 /1H, d, J= 2,5 Hz/, 10,78-11,02 /1H, Shir.s/.

(d) 2-(N-tert.-butoxycarbonylamino)ethanol

To a solution of 2-aminoethanol (6,1 g) in a mixture of tetrahydrofuran and water (1:1, 100 ml) is added di-tert.- BUTYLCARBAMATE (21.8 g) with stirring under ice cooling. The reaction mixture was stirred at the same temperature for 1 hour and then at room temperature for 5 hours. To the reaction mixture is added 200 ml atorial is evaporated under reduced pressure to obtain the title compound (15.3 g) as a colourless oil.

Rf (cyclohexane:ethyl acetate = 1:1): 0,35;

The NMR spectrum (CDCl3) MD: of 1.45 (9H,s), 2,35-2,50 (1H,Shir.C) 3,29 (2H, sq J=5.3 Hz), 3,71 (2H, q, J= 5.3 Hz), 4,85-of 5.05 (1H, Shir.C).

(e) 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-5-chloro-1,2 - benzisoxazol.

To a solution of triphenylphosphine (0.87 g) in 10 ml of tetrahydrofuran was added dropwise diethylazodicarboxylate (0,57 g) with stirring under ice cooling. The reaction mixture was stirred at the same temperature for 10 minutes, then, to the reaction mixture are added successively 2-(N-tert.- butoxycarbonylamino) ethanol (0,48 g) and 5-chloro-3-hydroxy-1,2 - benzisoxazol (0.51 g), and stirred under cooling for 10 minutes at room temperature within 24 hours. The solvent is evaporated under reduced pressure and the residue is purified on a chromatographic column with silica gel, using as eluent cyclohexane/ethyl acetate (4/1). Specified in the title compound (0.70 g) obtained as colorless crystals by recrystallization from isopropyl ether.

So melting point: 106-107oC.

IR spectrum (KBr)maxcm-1: 3376, 1706, 1611, 1541, 1525;

The NMR spectrum (CDCl3) MD: of 1.46 (9H,s) to 3.64 (2H, q, J=5,1 Hz), 4,50 (2H, t, J= 5,1 Hz), of 4.95 (1H, Shir.C) 7,37 (1H, d, J= 8,8 Hz), 7,49 (1H, DD, J= 8,8 Hz, J= 2.0 Hz), 7,63 (1H, which amino)-ethoxy)-5-chloro-1,2 - benzisoxazole (0.50 g) is added a solution of 4n-hydrochloric acid/1,4-dioxane (4.0 ml) and stirred at room temperature for 15 minutes. After filtration of precipitated precipitated crystals and wash them with 1,4 - dioxane get mentioned in the title compound (0,38 g) as colorless crystals.

So melting point: 217-221oC (decomposition).

IR spectrum (KBr)maxcm-1: 3300-2400, 1612, 1534, 1519;

NMR spectrum (DMSO-d6) MD: to 3.33 (2H, t, J=5,1 Hz), br4.61 (2H, t, J= 5,1 Hz), 7,73 (2H, d, J=1.4 Hz), 7,88 (1H, d, J=1.4 Hz), 8,28 (3H, Shir.C).

Example 2.

3-(2-aminoethoxy)-1,2-benzisoxazole hydrochloride

(a) 3-(2-(N-tert.-butoxycarbonylamino(ethoxy)-1,2-benzisoxazol.

Specified in the title compound are obtained from 68% yield from 3 - hydroxy-1,2-benzisoxazole and 2-(N-tert.-butoxycarbonylamino)- ethanol due to reactions and treatments as described in example 1 (e).

Melting point: 106-107oC;

IR spectrum (KBr)maxcm-1: 3326, 1716, 1707, 1615, 1536;

The NMR spectrum (CDCl3) MD: of 1.46 (9H,c), the 3.65 (2H, q, J=5,1 Hz), 4,51 (2H, t, J=5,1 Hz), 4,90-of 5.05 (1H, Shir.C), 7,26-7,66 (4H, m).

(b) 3-(2-aminoethoxy)-1,2-benzisoxazole hydrochloride.

Specified in the title compound are obtained from 98% yield from 3-(2-(N-tert. -butoxycarbonylamino) ethoxy-1,2 - benzisoxazole in reactions and due to the treatments described in example 1(f).

Melting point: 194-197o< of 3.60 (2H, t, J=5,1 Hz), 4,94 (2H, t, J=5,1 Hz), 7,41-7,80 (4H, m).

Example 3.

3-(3-aminopropoxy)-1,2-benzisoxazole hydrochloride.

(a) 3-(N-tert.-butoxycarbonylamino) propanol.

Specified in the title compound get (1,65 g) of 3-aminopropanol (0.75 g) and di-tert.-BUTYLCARBAMATE (2,18 g) in the reactions and treatments mentioned in example 1(d).

Rf /cyclohexane: ethyl acetate = 1:1/: 0,35;

The NMR spectrum (CDCl3), MD: for 1.49 (9H, s) to 1.70 (2H, q, J=5,9 Hz), 2,85-2,95 (1H, Shir.C) to 3.33 (2H, q, J=5,9 Hz), 3,70 (2H, q, J= 5,9 Hz), 4,65-of 4.90 (1H, Shir.C).

(b) 3-(3-(N-tert.-butoxycarbonylamino)propoxy)-1,2-benzisoxazol.

Specified in the title compound are obtained from 75% yield from 3 - hydroxy-1,2-benzisoxazole and 3-(N-tert.-butoxycarbonylamino) - propanol in the reaction and treatment in accordance with example 1 (e).

Melting point: 59-60oC;

IR spectrum (KBr) maxcm-1: 3383, 1680, 1613, 1539, 1521;

The NMR spectrum (CDCl3) MD: the 1.44 (9H,s), is 2.05 and 2.13 (2H,m) to 3.36 (2H, q, J= 6.3 Hz), to 4.52 (2H, t, J=5,9 Hz), 4,70-is 4.85 (1H, Shir.C), 7,25-the 7.65 (4H, m).

(C) 3-(3-aminopropoxy)-1,2-benzisoxazole hydrochloride.

Specified in the title compound are obtained from 96% yield from 3-(3-(N-tert. -butoxycarbonylamino) propoxy)-1,2-benzisoxazole in rez is receiving);

IR spectrum (KBr)maxcm-1: 3300-2400, 1615, 1541, 1536;

NMR spectrum (D2O) MD: 2,29-of 2.36 (2H,m), and 3.31 (2H, t, J= 7,3 Hz), 4,59 (2H, t, J=5,9 Hz), 7,40 for 7.78 (4H,m).

Example 4.

3-(4-aminobutoxy)-1,2-benzisoxazole hydrochloride.

(a) 4-(N-tert.-butoxycarbonylamino)butanol

Specified in the title compound (1.80 g) obtained from 4-aminobutanol (0,89 g) and di-tert.-BUTYLCARBAMATE (2,18 g) in the reactions and treatments according to the method of example 1(d).

Rf /cyclohexane:ethyl acetate = 1:1/:0,35;

The NMR spectrum (CDCl3) MD: the 1.44 (9H,s), 1,55-1,65 (4H,m), and 3.16 (2H, q, J= 5,9 Hz), to 3.67 (2H, q, J=5,9 Hz), 4,55 - of 4.75 (1H, Shir. C).

(b) 3-(4-(N-tert.-butoxycarbonylamino)butoxy)-1,2-benzisoxazol

Specified in the title compound are obtained from 71% yield from 3-hydroxy-1,2-benzisoxazole and 4-(N - tert.-butoxycarbonylamino)-butanol in the reaction and treatment according to the method of example 1(e).

IR spectrum (KBr)maxcm-1: 3321, 1701, 1615, 1539, 1509.

The NMR spectrum (CDCl3) MD: 1,14 (9H,c), 1,62-of 1.74 (2H,m), 1,91-of 1.97 (2H, m), 3,15-of 3.27 (2H, Shir.C) to 4.46 (2H, t, J= 6.5 Hz), 4,55-4,70 (1H, Shir.C), 7,24-7,66 (4H, m).

(C) 3-(4-aminobutoxy)-1,2-benzisoxazole hydrochloride

Specified in the title compound are obtained from 97% yield from 3-(4-(N-tert.- butoxycarbonylamino)butoxy)-1,2-benr>o
C (decomposition);

IR spectrum (KBr)maxcm-1: 3300-2400, 1613, 1541;

NMR spectrum (D2O) MD: 1,88-of 1.97 (2H,m), 1,99 e 2.06 (2H,m), 3,14 (2H, t, J= 7,6 Hz), 4,50 (2H, t, J=6,1 Hz), 7,39 for 7.78 (4H, m).

Example 5.

3-(2-aminoethoxy)-5-fluoro-1,2-benzisoxazole hydrochloride.

(a) 3-(2-(N-tert.-butoxycarbonylamino)ethoxy)-5-fluoro-1,2 - benzisoxazol

Specified in the title compound are obtained from 60% yield from 5-fluoro-3-hydroxy-1,2-benzisoxazole and 2-(N-tert. -butoxycarbonyl, amino)ethanol as a result of reactions and treatments according to the method of example 1(e).

IR spectrum (KBr)maxcm-1: 3338, 1707, 1623, 1543, 1534, 1504;

The NMR spectrum (CDCl3) MD: of 1.46 (9H, s) to 3.64 (2H, q, J=5,1 Hz), 4,50 (2H, t, J=5,1 Hz), 4,88-to 5.03 (1H, Shir.C), 7,22-7,42 (3H, m).

(b) 3-(2-aminoethoxy)-5-fluoro-1,2-benzisoxazole hydrochloride.

Specified in the title compound are obtained from 98% yield from 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-5-fluoro - 1,2-benzisoxazol due to reactions and treatments according to the method of example 1(f).

Melting point: 209-211oC (decomposition);

IR spectrum (KBr)maxcm-1: 3300-2400, 1621, 1606, 1538, 1505;

NMR spectrum (D2O) MD: 3,59 (2H, t, J=5,1 Hz), to 4.73 (2H, t, J= 5,1 Hz), 7,42-7,58 (3H, m).

Example 6.

3-(2-aminoethoxy)-5-methoxy-1,2-be the

Specified in the title compound are obtained from 74% yield from 3-hydroxy-5-methoxy-1,2-benzisoxazole and 2-(N-tert. -butoxycarbonylamino)ethanol due to reactions and treatments according to the method of example 1(e).

IR spectrum (KBr)maxcm-1: 3255, 1698, 1615, 1540, 1508;

The NMR spectrum (CDCl) MD: of 1.46 (9H, s), the 3.65 (2H, q, J=5,1 Hz), 3,86 (3H, s), 4,50 (2H, t, J=5,1 Hz), 4,90-of 5.05 (1H, Shir.C) 6,98 (1H, d, J=2.6 Hz), to 7.15 (1H, DD, J=9,2 Hz, J= 2.6 Hz), 7,33 (1H, d, J=9,2 Hz).

(b) 3-(2-aminoethoxy)-5-methoxy-1,2-benzisoxazole hydrochloride

Specified in the title compound are obtained from 96% yield from 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-5-methoxy-1,2 - benzisoxazole in the reactions and treatments according to the method of example 1(f).

Melting point: 210-212oC (decomposition);

IR spectrum (KBr)maxcm-1: 3300-2400, 1606, 1538, 1521, 1505;

NMR spectrum (D2O) MD: 3,59 (2H, t, J=5,1 Hz), 3,90 (3H,s), 4,71 (2H, t, J= 5,1 Hz), 7,22 (1H, d, J=2.6 Hz), 7,32 (1H, DD, J=9,2 Hz, J=2.6 Hz), of 7.48 (1H, d, J=9,2 Hz).

Example 7.

3-(2-aminoethoxy)-5-methyl-1,2-benzisoxazole hydrochloride

(a) Ethyl-5-methyl salicylate

Specified in the title compound are obtained from 84% yield from 5-methylsalicylic acid in the reactions and treatments according to the method of example 1(a).

(b) 5-medicalillustrationcareer in the reactions and treatments according to the method of example 1(b).

Melting point: 172-175oC (decomposition);

NMR spectrum (DMSO-d6) MD: 2,22 (3H,s), is 6.78 (1H, d, J= 8.6 Hz), 7,17 (1H, d, J= 8.6 Hz), to 7.50 (1H,s), a 9.25 (1H,c), 11,33 (1H,c), 11,95 (1H,c).

(C) 3-hydroxy-5-methyl-1,2-benzisoxazol

Specified in the title compound are obtained from 94% yield from 5-melisalachikamascool acid in the reactions and treatments according to the method of example 1 (C).

Melting point: 95-97oC;

The NMR spectrum (CDCl3) MD: of 2.45 (3H,s), 7,13-the 7.43 (3H,m), 9.02-9.15 (1H, Shir.C).

(d) 3-(2-(N-tert.-butoxycarbonylamino)ethoxy)-5-methyl-1,2 - benzisoxazol

Specified in the title compound are obtained from 69% yield from 3-hydroxy-5-methyl-1,2-benzisoxazole and 2-(N-tert.-butoxycarbonylamino) of ethanol in the reaction and treatment according to the method of example 1(e).

IR spectrum (KBr)maxcm-1: 3367, 1717, 1614, 1538-1522;

The NMR spectrum (CDCl3) MD: of 1.46 (9H,s), a 2.45 (3H, s) to 3.64 (2H, q, J=5,1 Hz), 4,50 (2H, t, J=5,1 Hz), 4,90-of 5.05 (1H, Shir.C), 7,31-7,52 (3H, m).

(e) 3-(2-aminoethoxy)-5-methyl-1,2-benzisoxazole hydrochloride

Specified in the title compound are obtained from 97% yield from 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-5-methyl-1,2-benzisoxazole due to reactions and treatments according to the method of example 1(f).

The temperature has been melted down (DMSO-d6) MD: 2,43 (3H,s), 3,26-to 3.41 (2H,m), 4,60 (2H, t, J=5,1 Hz), of 7.48-of 5.55 (3H, m), 8,32 (3H, Shir.C).

Example 8.

3-(2-aminoethoxy)-5-nitro-1,2-benzisoxazole hydrochloride

(a) 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-5-nitro-1,2 - benzisoxazol

Specified in the title compound are obtained from 74% yield from 3-hydroxy-5-nitro-1,2-benzisoxazole and 2-(N-tert.- butoxycarbonylamino) of ethanol in the reaction (continuing the reaction for an additional three hours) and treated according to the method of example 1 (e).

Melting point: 136-137oC;

IR spectrum (KBr) maxcm-1: 3346, 1688, 1624, 1555, 1531;

The NMR spectrum (CDCl3) MD: of 1.46 (9H,s) to 3.67 (2H, q, J=5,1 Hz), 4,55 (2H, t, J= 5,1 Hz), 4,87-of 5.05 (1H, Shir.C), 7,56 (1H, d, J=9,2 Hz), 8,46 (1H, DD, J=9,2 Hz, J=2.2 Hz), to 8.62 (1H, d, J=2.2 Hz).

(b) 3-(2-aminoethoxy)-5-nitro-1,2-benzisoxazole hydrochloride

Specified in the title compound are obtained from 99% yield from 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-5-nitro-1, 2-benzisoxazole in the reactions and treatments according to the method of example 1(f).

Melting point: 228-231oC (decomposition);

IR spectrum (KBr)maxcm-1: 3300-2400, 1620, 1543, 1519;

NMR spectrum (DMSO-d6) MD: to 3.36 (2H, t, J=5,1 Hz), of 4.66 (2H, t, J= 5,1 Hz), to 7.93 (2H, d, J=9,2 Hz), 8.34 per (3H, Shir.C) 8,54 (1H, DD, J=9,2 Hz, JR> (a) 3-(2-(N-butoxycarbonylamino)ethoxy)-7-chloro-1, 2-gasoline-isoxazol.

Specified in the title compound are obtained from 62% yield from 3-hydroxy-7-chloro-1,2-benzisoxazole and 2-(N-tert.- butoxycarbonylamino) of ethanol in the reaction and treatment according to the method of example 1(e).

Melting point: 64-65oC;

IR spectrum (KBr)maxcm-1: 3355, 1714, 1690, 1536, 1580,

The NMR spectrum (CDCl3) MD of 1.46 (9H,s), the 3.65 (2H, q, J=5,1 Hz), a 4.53 (2H, t, J= 5,1 Hz), 4,87-to 5.03 (1H, Shir.C) of 7.23 (1H, DD, J=8.0 Hz, J=8.0 Hz), 7,52-7,58 (2H,m).

(b) 3-(2-aminoethoxy)-7-chloro-1,2 - benzisoxazole hydrochloride

Specified in the title compound are obtained from 98% yield from 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-7-chloro-1,2-benzisoxazole in the reactions and treatments according to the method of example 1(f). IR (KBr)maxcm-1: 3300-2400, 1616, 1599, 1541, 1516;

Melting point: 198-200oC (decomposition);

NMR spectrum (DMSO-d6) MD: the 3.35 (2H, t, J=5,1 Hz) and 4.65 (2H, t, J=5,1 Hz), 7,44 (1H, DD, J=8.0 Hz, J= 8.0 Hz), 7,79 (1H, d, J=8.0 Hz), 7,83 (1H, d, J=8.0 Hz), 8.34 per (3H, Shir.C).

Example 10.

3-(2-aminoethoxy)pyrido[3,2-d] -isoxazol hydrochloride and 3- (2-aminoethoxy)pyrido[3,2-d]isoxazolidinone

(a) Methyl-2-chloronicotinate

To a suspension of 2-chloronicotinic acid (of 15.75 g) in 200 ml of ethyl acetate is mesh stirred at the same temperature for 30 minutes. The solvent is evaporated under reduced pressure, and the residue is dissolved in ethyl acetate, adding coal. Specified in the title compound (15.5 g) receive, filtering the mixture and viparita her under reduced pressure.

(b) 2-chloropyridin-3-carbohidrazona acid

To a solution of gidroxinimesoulida (6.75 g) in 25 ml of water is added a solution of sodium hydroxide (of 7.65 g of sodium hydroxide in 50 ml water) with stirring under ice cooling. To the stirred solution was added methyl-2 - chloronicotinate (15.5 g) in methanol. After stirring at room temperature for 2.5 hours, pH set to 3.5 due to 6N. hydrochloric acid under ice cooling. After 1 hour, I get mentioned in the title compound (11,0 g), filtering the precipitated precipitate crystals and washing with water, and then with a mixture of methanol-ether (1:1).

Melting point: 179oC;

IR spectrum (Nujol)maxcm-1: 3154, 1645, 1580;

NMR spectrum (DMSO-d6) MD: 7,34 (1H, DD, J=7.5 Hz, J=5.0 Hz), 7,80 (1H, DD, J=7.5 Hz, 2.0 Hz), 8,42 (1H, DD, J=5.0 Hz, J=2.0 Hz), of 9.30 (1H,s), 11,00 Hz (1H,s).

(C) 3 hydroxypyrene[3,2-d]isoxazol

10% aqueous solution of sodium hydroxide (26 ml) is added 2-chloropyridin-3-karbogidratnogo acid (2,60 g) and boiled with reverse cold the reaction mixture is left to stand for 30 minutes at the same temperature. Specified in the title compound (1.68 g) receive, filtering the precipitated precipitate crystals and washing them with water, and then with a mixture of methanol-ether (1:1).

Melting point: 258oC;

IR spectrum (Nujol)maxcm-1: 2750-2050, 1620, 1600;

NMR spectrum (DMSO-d6) MD: 7,40 (1H, DD, J=8.0 Hz, J=5.0 Hz), 8,40-to 8.70 (2H, m).

(d) 3-(2-(N-tert.-butoxycarbonylamino)ethoxy)pyrido[3,2-d]isoxazol.

Specified in the title compound are obtained from the output 61% from 3-hydroxypyridine[3,2-d] isoxazol and 2-(N-tert.- butoxycarbonylamino)ethanol due to reactions and treatments according to the method of example 1(e).

Melting point: 127-128oC;

IR spectrum (KBr)maxcm-1: 3335, 1716, 1707, 1615, 1605, 1537;

The NMR spectrum (CDCl3) MD: of 1.46 (9H,c), the 3.65 (2H, q; J=5,1 Hz), of 4.54 (2H, t, J= 5,1 Hz), 4,85-of 5.05 (1H, Shir.C), 7,31 (1H, DD, J= 7.9 Hz, J=4.6 Hz), of 8.06 (1H, DD, J =7.9 Hz, J= 1.5 Hz), 8,61 (1H, DD, J=4,6 Hz, J=1.5 Hz).

(e) 3-(2-aminoethoxy)pyrido[3,2-d]isoxazolidinone

Specified in the title compound is obtained in yield of 99% of 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)pyrido- [3,2-d]isoxazol in the reactions and treatments according to the method of example 1(f).

Melting point: 204-210oC (decomposition);

IR spectrum (KBr)maxcm-1:6 Hz), a 8.34 (1H, DD, J= 7.9 Hz, J=1.5 Hz), 8.34 per (3H, Shir.C) to 8.70 (1H, DD, J=4,6 Hz, J =1.5 Hz)

(f) 3-(2-aminoethoxy)pyrido[3,2-d]isoxazol hydrochloride

To a solution of 3-(2-aminoethoxy)pyrido[3,2-d]isoxazolidinone in water (10 ml) is added aqueous 1N solution of sodium hydroxide (16 ml) with stirring under ice cooling, and then the resulting mixture was stirred at the same temperature for 5 minutes. The reaction mixture is evaporated under reduced pressure, and indicated in the title compound (3.2 g, 94%) was obtained as colorless crystals by recrystallization from a mixture of methanol-water (1:1).

Melting point: 210-213oC (decomposition);.

IR spectrum (KBr)maxcm-1: 3012, 3003, 2968, 2899, 2845, 2803, 2752, 1636, 1615, 1606, 1538, 1509;

NMR spectrum (DMSO-d6) MD: the 3.35 (2H, t, J=5,1 Hz) and 4.65 (2H, t, J=5,1 Hz), 7,54 (1H, DD, J= 7.9 Hz, J=4.6 Hz), a 8.34 (1H, DD, J=7.9 Hz, J=1.5 Hz), at 8.36 (3H, Shir.C) to 8.70 (1H, DD, J=4,6 Hz, J=1.5 Hz).

Example 11.

3-(2-aminoethoxy)-6-chloro-1,2-benzisoxazole hydrochloride

(a) 3-(2-(N-tert.-butoxycarbonylamino)ethoxy)-6-chloro-1,2 - benzisoxazol

Specified in the title compound are obtained from 66% yield from 3-hydroxy-6-chloro-1,2-benzisoxazole and 2-(N-tert.- butoxycarbonylamino) of ethanol in the reaction and treatment according to the method of example 1(e
The NMR spectrum (CDCl3) MD: of 1.46 (9H,s) to 3.64 (2H, q, J=5,1 Hz), 4,50 (2H, t, J= 5,1 Hz), 4,88-5,02, (1H, Shir.C), 7,27 (1H, DD, J=8,4 Hz, J=1.5 Hz), 7,47 (1H, d, J=1.5 Hz), 7,55 (1H, d, J=8,4 Hz).

(b) 3-(2-aminoethoxy)-6-chloro-1,2-benzisoxazole hydrochloride

Specified in the title compound are obtained from 97% yield from 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-6-chloro-1,2 - benzoxazole in the reactions and treatments according to the method of example 1(f).

Melting point: 198-202oC (decomposition);

IR spectrum (KBr)maxcm-1: 3300-2400, 1612, 1537;

NMR spectrum (DMSO-d6) MD: to 3.34 (2H, t, J=5,1 Hz), to 4.62 (2H, t, J=5,1 Hz), of 7.48 (1H, DD, J=8,4 Hz, J=1.5 Hz), 7,81 (1H, d, J=8,4 Hz), 7,92 (1H, d, J=1.5 Hz), at 8.36 (3H, Shir.C)

Example 12.

3-(2-aminoethoxy)-5,7-dichloro-1,2-benzisoxazole hydrochloride.

(a) 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-5,7-dichloro-1,2 - benzisoxazol.

Specified in the title compound are obtained from 68% yield from 3-hydroxy-5,7-dichloro-1,2-benzisoxazole and 2-(N-tert.-butoxycarbonylamino) of ethanol in the reaction and treatment according to the method of example 1(e).

Melting point: 94-95oC;

IR spectrum (KBr)maxcm-1: 3359, 1678, 1542, 1524;

The NMR spectrum (CDCl3) MD: of 1.46 (9H,s) to 3.64 (2H, q, J =5,1 Hz), 4,51 (2H, t, J=5,1 Hz), 4,85-5,00 (1H, Shir.C), 7,54 (2H, d, J=1.0 Hz).

Melting point: 198-203oC (decomposition);

IR spectrum (KBr)maxcm-1: 3300-2400, 1600, 1541, 1514;

NMR spectrum (DMSO-d6) MD: to 3.34 (2H, t, J=5,1 Hz), 4,63 (2H, t, J=5,1 Hz), to $ 7.91 (1H, d, J= 2.0 Hz), 8,03 (1H, d, J=2.0 Hz), 8,31 (3H, Shir.C).

Example 13.

3-(2-aminoethoxy)-7-methyl-1,2-benzisoxazole hydrochloride

(a) 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-7 - methyl-1,2-benzisoxazol

Specified in the title compound is obtained in yield of 66% from 3-hydroxy-7-methyl-1,2-benzisoxazole and 2-(N-tert.- butoxycarbonylamino) of ethanol in the reaction and treatment according to the method of example 1(e).

Melting point: 54-55oC;

IR spectrum (KBr)maxcm-1: 3332, 1713, 1699, 1615, 1539, 1506;

The NMR spectrum (CDCl3) MD: of 1.46 (9H,c). of 2.51 (3H,c), the 3.65 (2H, q, J=5,1 Hz), 4,51 (2H, t, J=5,1 Hz), 4,90-of 5.06 (1H, Shir.C), 7,15-7,47 (3H,m).

(b) 3-(2-aminoethoxy)-7-methyl-1,2-benzimidazole hydrochloride

Specified in the title compound are obtained from 99% yield from 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-7-methyl-1,2-benzisoxazole due to reactions and treatments according to the method of example 1(f).

Melting point: 195-197oC.

Example 14.

3-(2-aminoethoxy)-6-methyl-1,2-benzisoxazole hydrochloride

(a) 3-(2-(N-tert. -butoxycarbonylamino)ethoxy-6-methyl-1,2 - benzisoxazol.

Specified in the title compound are obtained from 64% yield from 3-hydroxy-6-methyl-1,2-benzisoxazole and 2-(N-tert.- butoxycarbonylamino) of ethanol in the reaction and treatment according to the method of example 1(e).

Melting point: 128-129oC;

IR spectrum (KBr)maxcm-1: 3331, 1718, 1708, 1629, 1613, 1534;

The NMR spectrum (CDCl3) MD: of 1.46 (9H,c) of 2.50 (3H,c), the 3.65 (2H, q, J= 5,1 Hz), of 4.49 (2H, t, J=5,1 Hz), 4,90-of 5.05 (1H, Shir.C), 7,10 (1H, d, J=8.0 Hz), 7.23 percent (1H,s) to 7.50 (1H, d, J=8.0 Hz).

(b) 3-(2-aminoethoxy)-6-methyl-1,2-benzisoxazole hydrochloride

Specified in the title compound are obtained from 92% yield from 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-6-methyl-1,2-benzoxazole in the reactions and processing according to the method of example 1(f).

Melting point: 207-212oC (decomposition);

IR spectrum (KBr)maxcm-1: 3300-2400, 1618, 1600, 1533;

NMR spectrum (DMSO-d6) MD: 2,48 (3H,c) to 3.33 (2H, t, J=5,1 Hz), 4,59 (2H, t, J=5,1 Hz), 7.23 percent (1H, d, J=8.0 Hz), 7,46 (1H,s), the 7.65 (1H, d, J=8.0 Hz), with 8.33 (3H, Shir.C).

Example 15.

3-(2-aminoethoxy)-5-bromo-1,2-benzisoxazol Ki-connection receive from 67% yield from 3-hydroxy-5-bromo-1,2-benzisoxazole and 2-(N-tert.- butoxycarbonylamino) of ethanol in the reaction and treatment according to the method of example 1(e).

Melting point: 123-124oC;

IR spectrum (KBr)maxcm-1: 3313, 1699, 1683, 1611, 1545;

The NMR spectrum (CDCl3) MD: of 1.46 (9H,c) to 3.64 (2H, q, J=5,1 Hz), 4,50 (2H, t, J=5,1 Hz), 4,85-5,00 (1H, Shir.C), 7,33 (1H, d, J= 8,9 Hz), a 7.62 (1H, DD, J=8,9 Hz, J=1.9 Hz), 7,80 (1H, d, J=1.9 Hz).

(b) 3-(2-aminoethoxy)-5-bromo-1,2-benzisoxazole hydrochloride

Specified in the title compound are obtained from 95% yield from 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-5 - bromo-1,2-benzisoxazole in the reactions and processing according to the method of example 1(f).

Melting point: 220-224oC (decomposition);

IR spectrum (KBr)maxcm-1: 3300-2400, 1611, 1535, 1516;

NMR spectrum (DMSO-d6) MD: to 3.38 (2H, t, J=5,1 Hz), br4.61 (2H, t, J=5,1 Hz), to 7.67 (1H, d, J=8,9 Hz), 7,83 (1H, DD, J=8,9 Hz,3=1.9 Hz), 8,02 (1H, d, J=1.9 Hz), of 8.25 (3H, Shir.C).

Example 16.

3,5-dichloro-1,2-benzisoxazol

To a suspension of 5-chloro-3-hydroxy-1,2-benzisoxazole (100 g) in phosphorus oxychloride (80 ml) is added pyridine (48 ml) dropwise over 1 hour under stirring at room temperature, and the mixture was refluxed for 5 hours. The reaction mixture was added to ice water (500 ml) and extracted with ethyl acetate; the combined organic extracts dried over anhydrous magnesium sulfate. Restructurization of the residue from petroleum ether in the form of colorless needles.

Melting point: 43-44oC;

IR spectrum (KBr)maxcm-1: 1468, 1419, 1285;

The NMR spectrum (CDCl3) MD: to 7.59 (2H, d, J=1.5 Hz), of 7.70 (1H, Shir. C).

Example 17.

3-(2-aminoethoxy)-5-fluoro-4-methyl-1,2-benzisoxazole hydrochloride

(a) 3-(2-(N-tert.-butoxycarbonylamino)ethoxy)-5-fluoro-1,2-benzisoxazol

To a solution of triphenylphosphine (0.87 g) in 20 ml of tetrahydrofuran is added by diethylazodicarboxylate (0,57 g) in the 5oC, and the resulting mixture was stirred at the same temperature for 15 minutes. Then add 5-fluoro-3-hydroxy-1,2-benzisoxazol (0,46 g), and the mixture was stirred at the same temperature for 15 minutes followed by the addition of N-tert.-butoxycarbonylmethylene (0,48 g), and stirred at room temperature for 24 hours. The solvent is evaporated and the residue is purified on a chromatographic column with silica gel, elwira a mixture cyclohexane/ ethyl acetate (9:1) to obtain the title compound (0,53 g, 60%) as a colorless powder.

Melting point: 104-105oC;

IR spectrum (KBr)maxcm-1: 3338, 1707, 1623, 1543, 1534, 1504;

The NMR spectrum (CDCl3) MD: of 1.46 (9H,s) to 3.64 (2H, q, J=5,1 Hz), 4,50 (2H, t, J=5,1 Hz), of 4.95 (1H, Shir.C), 7,22-7,42 (3H, m).

(b) 3-(2-(N-terminators)-5-fluoro-1,2 - benzisoxazole (0.27 g) in 10 ml of tetrahydrofuran, add diisopropylamide lithium (1.1 ml, 1.5 M solution in cyclohexane) dropwise, and stirred at - 70oC in nitrogen atmosphere, then the mixture is stirred at the same temperature for 15 minutes before adding methyliodide (0,13 g). After stirring at 70oC for 15 minutes, the temperature is allowed to rise to 0oC. the Reaction mixture was poured into ice-cold water (40 ml), extracted twice with ethyl acetate (40 ml each time), and the combined extracts dried over anhydrous magnesium sulfate and filtered. The solvent is evaporated under reduced pressure and the residue is purified on a chromatographic column with silica gel, using as eluent a mixture of cyclohexane/ethyl acetate (9:1) to obtain the title compound (0,22 g, 94% yield) as a colorless powder.

Melting point: 124-127oC;

IR spectrum (KBr)maxcm-1: 3353, 1688, 1539, 1505;

The NMR spectrum (CDCl3) MD: of 1.45 (9H,s) of 2.50 (3H, d, J= 2.0 Hz), the 3.65 (2H, q, J= 5,1 Hz), of 4.49 (2H, t, J=5,1 Hz), 4,88 (1H, Shir.C), 7,15 - 7,30 (2H,m).

(C) 3-(2-aminoethoxy))-5-fluoro-4-methyl-1,2-benzisoxazole hydrochloride

3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-5-fluoro - 4-methyl-1,2-benzisoxazol (0.15 g) was dissolved in a solution of 4n hydrochloric acid/dioxane (1.4 ml) and stirred for 15 minutee the title compound (0,13 g 98% yield) are obtained as a colourless powder, washing the crystals with ethyl acetate (3 ml).

Melting point: 213-215oC (decomposition);

IR spectrum (KBr)maxcm-1: 3300-2400, 1630, 1583, 1537, 1505;

NMR spectrum(DMSO-d6) MD: of 2.51 (3H, d, J=2.0 Hz), to 3.34 (2H, q, J=5,1 Hz), to 4.62 (2H, t, J=5,1 Hz), 7,4-of 7.55 (2H, m), with 8.33 (3H, Shir.C).

Example 18.

3-(2-aminoethoxy)-4-carbarnoyl-5-fluoro-1,2-benzisoxazole hydrochloride

(a) 3-(2-(N-tert.-butoxycarbonylamino)ethoxy)-4 - carboxy-5-fluoro-1,2-benzisoxazol.

To a solution of 3-(2-(N-tert.- butoxycarbonylamino)ethoxy)-5-fluoro-1,2-benzisoxazole (0,30 g) in 20 ml of tetrahydrofuran, add diisopropylamide lithium (1.4 ml, 1.5 M solution in cyclohexane) dropwise at -70oC in nitrogen atmosphere, and the reaction mixture was stirred at the same temperature for 15 minutes. Within 10 minutes serves gaseous carbon dioxide, and temperature allow to rise to 0oC. the Reaction mixture was poured into ice-cold water (40 ml) and washed twice with diethyl ether portions 40 ml. Secrete the aqueous layer, set pH 4 due to the potassium dihydrophosphate, then it is extracted with ethyl acetate twice portions 40 ml combined extracts dried over anhydrous magnesium sulfate, filtered, and the solvent is evaporated at below the

IR spectrum (KBr)maxcm-1: 3474, 3358, 3326, 3194, 1683, 1673, 1611, 1538,

The NMR spectrum (CDCl3) MD: to 1.38 (9H,c), 3,62 (2H, q, J=5,1 Hz) to 4.52 (2H, t, J= 5,1 Hz), 5,27 (1H, Shir.C), 6,04 (1H, Shir.C) 6,40 (1H, Shir.C), 7,34 (1H, t, J=9.1 Hz), of 7.48 (1H, DD, J=9.1 Hz, J=3.6 Hz).

(b) 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-4 - carbarnoyl-5-fluoro-1,2-benzisoxazol

To a solution of 3-(2-(N-tert.-butoxycarbonylamino)ethoxy)-4-carboxy - 5-fluoro-1,2-benzisoxazole (0.31 g) in 20 ml of tetrahydrofuran, add isobutylparaben (0.14 g) and triethylamine (0.11 g) under stirring at 5oC, and the resulting mixture is stirred for 15 minutes. Saturated ammonia solution of tetrahydrofuran (saturated at room temperature, 5 ml) is added to the reaction mixture and stirred for 15 minutes. The reaction mixture was poured into ice water (40 ml), extracted with diethyl ether (twice 40 ml) and the combined extracts dried over anhydrous magnesium sulfate and filtered. The solvent is evaporated under reduced pressure, and the residue is treated chromatography on a column of silica gel, elwira with a mixture of cyclohexane/ethyl acetate (4:1) to obtain the title compound (0.24 g, 78% yield) as a colorless powder. Melting point: 63-65oC;

IR spectrum (KBr)max), at 5.27 (1H, Shir.C), 6,04 (1H, Shir.C) 6,40 (1H, Shir.C), 7,34 (1H, t, J=9.5 Hz), of 7.48 (1H, DD, J=9.5 Hz, J=3.6 Hz).

(C) 3-(2-aminoethoxy)-4-carbarnoyl-5-fluoro-1,2-benzisoxazole hydrochloride

Specified in the title compound (20 mg, 99%) was obtained as colorless powder from 3-(2-(N-tert.- butoxycarbonylamino)ethoxy)-4-carbarnoyl-5-fluoro-1,2-benzisoxazole (25 mg) and a solution of 4n hydrochloric acid/dioxane (0.2 ml) due to reactions and treatments by way of example 17 (C).

Melting point: 201-205oC (decomposition);

IR spectrum (KBr)maxcm-1: 3382, 3400-2400, 1656, 1605, 1590, 1543;

NMR spectrum (DMSO-d6) MD: 3,30 (2H, t, J=5,1 Hz), to 4.62 (2H, t, J=5,1 Hz), 7,63 (1H, t, J=9.5 Hz), to 7.77 (1H, DD, J= 9.5 Hz, J=3.6 Hz), 7,86 (1H, Shir.C), 8,19 (4H, Shir.C).

Example 19.

3-(2-aminoethoxy)-4-cyano-5-fluoro-1,2-benzisoxazole hydrochloride

(a) 3-(2-(N-tert.-butoxycarbonylamino)ethoxy)-4-cyano-5-fluoro - 1,2-benzisoxazol

To a solution of 3-(2-(N-tert.-butoxycarbonylamino)ethoxy)-4-carbarnoyl - 5-fluoro-1,2-benzisoxazole (0.25 g) in 2.0 ml of dimethylformamide added phosphorus oxychloride (0.12 g) under stirring at 5oC, and then the resulting mixture was stirred at the same temperature for 15 minutes. Then the reaction mixture was poured into ice-cold water (20 ml), extracted with ethyl acetate (twice pariwat under reduced pressure, and the residue is purified on a chromatographic column with silica gel, elwira with a mixture of cyclohexane/ethyl acetate (4: 1) to obtain the title compound (0.20 g, 87% yield) as a colorless powder.

Melting point: 116-117oC;

IR spectrum (KBr)maxcm-1: 3368, 2240, 1702, 1532, 1507;

The NMR spectrum (CDCl3) MD: of 1.45 (9H,s) to 3.67 (2H, q, J=5,1 Hz), of 4.54 (2H, t, J=5,1 Hz), of 5.05 (1H, Shir. C) the 7.43 (1H, t, J 9.5 Hz), to 7.68 (1H, DD, J=9.5 Hz, J=3.6 Hz).

(b) 3-(2-aminoethoxy)-4-cyano-5-fluoro-1,2-benzisoxazole hydrochloride

Specified in the title compound (0.12 g, 96% yield) obtained as colorless powder from 3-(2-(N-tert-butoxy-carbylamine) ethoxy)-4-cyano-5-fluoro-1,2-benzisoxazole (0.17 g) and a solution of 4n hydrochloric acid/dioxane (1.3 ml) in the reactions and treatments by way of example 17 (C).

Melting point: 190-193oC (decomposition);

IR spectrum (KBr)maxcm-1: 3300-2400, 2240, 1607, 1541, 1505;

NMR spectrum (DMSO-d6) MD: to 3.34 (2H, t, J=5,2 Hz), 4.72 in (2H, t, J=5,2 Hz), to $ 7.91 (1H, t, J=9.5 Hz), 8,19 (1H, DD, J=9.5 Hz, J=3,7 Hz), 8,30 (3H, Shir.C).

Example 20.

3-(2-aminoethoxy)-5-fluoro-4-methoxycarbonyl-1,2-benzisoxazole hydrochloride

(a) 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-5 - fluoro-4-methoxycarbonyl-1,2-benzisoxazol

the ether add a solution of diazomethane/diethyl ether in 5oC to until the reaction mixture becomes yellow, and then the mixture is stirred for 15 minutes. The reaction mixture is evaporated under reduced pressure to obtain the title compound (0.32 g, 100% yield) as oil.

IR spectrum (KBr)maxcm-1: 3457, 1733, 1713, 1541, 1504;

The NMR spectrum (CDCl3) MD: of 1.46 (9H, s), 3,62 (2H, q, J=5,1 Hz) to 4.01 (3H, c), of 4.49 (2H, t, J=5,1 Hz), to 5.08 (1H, Shir.C) to 7.35 (1H, t, J=9.5 Hz), 7,52 (1H, DD, J=9.5 Hz, J=3.6 Hz).

(b) 3-(2-aminoethoxy)-5-fluoro-4-methoxycarbonyl-1,2-benzisoxazole hydrochloride

Specified in the title compound (0.15 g, 97% yield) obtained as colorless powder from 3-(2-(M-tert.- butoxycarbonylamino)ethoxy)-5-fluoro-4-methoxycarbonyl-1,2-benzisoxazole (0.18 g) and a solution of 4n hydrochloric acid/dioxane (1.3 ml) in the reactions and treatments by way of example 17 (C).

Melting point: 168-170oC (decomposition);

IR spectrum (KBr)maxcm-1: 3300-2400, 1729, 1584, 1539, 1501;

NMR spectrum (DMSO-d6) MD: and 3.31 (2H, t, J=5,1 Hz), of 3.96 (3H,s), to 4.62 (2H, t, J= 5,1 Hz), 7,73 (2H, t, J=9.5 Hz), of 7.96 (2H, DD, J=9.5 Hz, J=3.6 Hz), 8,23 (3H, Shir.C).

Example 21.

3-(2-aminoethoxy)-5-fluoro-4-methylthio-1,2-benzisoxazole hydrochloride

(a) 3-(2-(N-tert.-butoxycarbonylamino)ethoxy) -5-fluoro-4-METI the 20 ml of tetrahydrofuran, add diisopropylamide lithium (1.50 ml, 1.5 M solution in hexane) dropwise with stirring at -70oC in nitrogen atmosphere, and then stirred at the same temperature for 15 minutes, and added dimethyl sulfide (0.21 g). The reaction mixture is stirred for 15 minutes at -70oC and then the temperature was raised to 0oC. the Reaction mixture was poured into ice-cold water (40 ml), extracted with ethyl acetate (twice 40 ml) and the combined extracts dried over anhydrous magnesium sulfate. After filtration the solvent is evaporated under reduced pressure and the residue is purified on a chromatographic column with silica gel, elwira with a mixture of cyclohexane/ethyl acetate (9:1) to obtain the title compound (0.32 g, yield 94%) as colorless powder.

Melting point: 91-92oC;

IR spectrum (KBr)maxcm-1: 3355, 1694, 1618, 1540;

The NMR spectrum (CDCl3) MD: of 1.45 (9H,s), 2,60 (3H, d, J=2.1 Hz), to 3.67 (2H, q, J=5,1 Hz), 4,50 (2H, t, J=5,1 Hz), 5,04 (1H, Shir.C), 7,20-7,30 (2H, m).

(b) 3-(2-aminoethoxy)-5-fluoro-4-methylthio-1,2-benzisoxazole hydrochloride

Specified in the title compound (0.15 g, 99% yield) obtained as colorless powder from 3-(2-(N-tert.-butoxycarbonylamino)ethoxy) -5-fluoro-4-methylthio-1,2-benzisoxazole (0.18 g) and a solution of 4n hydrochloric acid/diox is
C (decomposition);

IR spectrum (KBr)maxcm-1: 3400-2400, 1617, 1592, 1535;

NMR spectrum (DMSO-d6) MD: to 2.57 (3H, d, J=1.4 Hz), the 3.35 (3H, t, J=5,1 Hz), with 4.64 (2H, t, J=5,1 Hz), to 7.59 (1H, t, J=9.5 Hz), 7,63 (1H, DD, J=9.5 Hz, J= 3.6 Hz), 8,24 (3H, Shir.C).

Example 22.

3-(2-aminoethoxy)-4-methoxycarbonyl-1,2-benzisoxazole hydrochloride and 3-(2-aminoethoxy)-7-methoxycarbonyl-1,2-benzisoxazole hydrochloride.

(a) 3-(2-(N-tert.-butoxycarbonylamino)ethoxy-1,2-benzisoxazol

To a solution of triphenylphosphine (0.95 g) in 20 ml of tetrahydrofuran is added by diethylazodicarboxylate (0,63 g) under stirring at 5oC, then stirred at the same temperature for 15 minutes. To the reaction mixture is added 3-hydroxy-1,2-benzisoxazol (0.45 g) and stirred for 15 minutes, then add N-tert. - butoxycarbonylmethylene (0,53 g), and the resulting mixture was stirred at room temperature for 24 hours. The solvent is evaporated under reduced pressure and the residue is purified on a chromatographic column with silica gel, elwira with a mixture of cyclohexane/ethyl acetate (9:1) to obtain the title compound (0,63 g, 68%).

Melting point: 106-107oC;

IR spectrum (KBr)maxcm-1: 3326, 1716, 1707, 1615, 1536;

NMR SPECT is starsonline)ethoxy)-4-methoxycarbonyl - 1,2-benzisoxazole and 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-7 - methoxycarbonyl-1,2-benzisoxazol.

To a solution of 3-(2-(N-tert.-butoxycarbonylamino) ethoxy)-1,2-benzisoxazole (0.28 g) in 30 ml of tetrahydrofuran, add utility (1,40 ml, 1.6 M solution in hexane) dropwise with stirring at -70oC in nitrogen atmosphere and the resulting mixture is then stirred at the same temperature for 15 minutes. In the reaction mixture is injected gaseous carbon dioxide for 10 minutes and then the temperature was raised to 0oC. the Reaction mixture was poured into ice-cold water (40 ml) and washed with diethyl ether (twice 40 ml). Secrete the aqueous layer was pH set 4 due to the potassium dihydrophosphate, and extracted with ethyl acetate (twice 40 ml). The combined extracts dried over anhydrous magnesium sulfate and filtered. The solvent is evaporated under reduced pressure and 3-(2- (N-tert.-butoxycarbonylamino)ethoxy)-7-carboxy-1,2-benzisoxazole and 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-7-carboxy-1,2 - benzisoxazol receive in the form of a colorless oil mixture (0.31 g, 92%). Then the resulting mixture was dissolved in 15 ml diethyl ether, and, after cooling to 5oC was added dropwise a solution of diazomethane/diethyl ether to until the reaction mixture is not Stanovaya under reduced pressure, and the residue is purified on a chromatographic column with silica gel, using as eluent cyclohexane/ethyl acetate (4: 1), to obtain specified in the title compounds, 3-(2-(N-tert.-butoxycarbonylamino) ethoxy)-4-methoxycarbonyl-1,2-benzisoxazole (0.15 g, 45%) and 3-(2-(N-tert. -butoxycarbonylamino) ethoxy)-7-methoxycarbonyl-1,2-benzisoxazole (0.08 g, 24%), respectively, as colorless powders. Results for 3-(2-(N - tert. -butoxycarbonylamino)ethoxy)-4-methoxycarbonyl-1,2 - benzisoxazole:

Melting point: 95-96oC;

IR spectrum (KBr) maxcm-1: 3397, 1705, 1601, 1533, 1524, 1503;

The NMR spectrum (CDCl3) MD: of 1.46 (9H,s), 3,66 (2H, q, J=5,1 Hz) to 3.99 (3H, c), 4,51 (2H, t, J=5,1 Hz), from 5.29 (1H, Shir.C), 7,55-the 7.65 (2H,m), a 7.85 (1H, d, J=7.5 Hz).

Results for 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-7 - methoxycarbonyl-1,2-benzisoxazole:

Melting point: 90-91oC;

IR spectrum (KBr)maxcm-1: 3387, 1718, 1693, 1620, 1610, 1552, 1525;

The NMR spectrum (CDCl3) MD: of 1.46 (9H,c), 3,66 (2H, q, J=5,1 Hz), a 4.03 (3H, s), of 4.54 (2H, t, J=5,1 Hz), 4,96 (1H, Shir.C) 7,37 (1H, t, J=8.1 Hz), the 7.85 (1H, d, J=8.1 Hz), 8,23 (3H, d, J=8.0 Hz).

(C) 3-(2-aminoethoxy)-4-methoxycarbonyl-1,2-benzisoxazole hydrochloride

Specified in the title compound (0.08 g, 100%) was obtained as colorless powder which slots/dioxane (1.0 ml) in the reactions and treatments by way of example 17 (C).

Melting point: 169-172oC (decomposition);

IR spectrum (KBr)maxcm-1: 3300-2400, 1718, 1601, 1525, 1499;

NMR spectrum (DMSO-d6) MD: to 3.34 (2H, t, J=5,1 Hz), 3,93 (3H,s), to 4.62 (2H, t, J=5,1 Hz), 7,75-a 7.85 (2H,m), 7,95 (1H, d, J=8.1 Hz), 8,23 (3H, Shir. C).

(d) 3-(2-aminoethoxy)-7-methoxycarbonyl-1,2-benzisoxazole hydrochloride

Specified in the title compound (0.06 g, 100%) was obtained as colorless powder from 3-(2-(N-tert.-butoxycarbonylamino) ethoxy)-7 - methoxycarbonyl-1,2-benzisoxazole (0.08 g) and a solution of 4n. hydrochloric acid/dioxane (1.0 ml) in the reactions and treatments by way of example 17 (C).

Melting point: 211-213oC (decomposition);

IR spectrum (KBr)maxcm-1: 3300-2400, 1730, 1719, 1618, 1608, 1550, 1502.

NMR spectrum (DMSO-d6) MD: to 3.36 (2H, t, J=5,1 Hz), of 3.95 (3H, s) and 4.65 (2H, t, J=5,1 Hz), 7,56 (1H, t, J=8.0 Hz), 8,10 (1H, d, J=8.1 Hz), 8,23 (1H, d, J=8.1 Hz), 8,30 (3H, Shir. C).

Example 23.

3-(2-aminoethoxy)-4-carbarnoyl-1,2-benzisoxazole hydrochloride and 3-(2-aminoethoxy)-7-carbarnoyl-1,2-benzisoxazole hydrochloride

(a) 3-(2-(N-tert.-butoxycarbonylamino)ethoxy)-4-carbarnoyl-1,2 - benzisoxazole and 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-7 - carbarnoyl-1,2-benzisoxazol.

To a solution of 3-(2-(N-tert.-butoxycarbonylamino)ethoxy) the ri stirring at -70oC in nitrogen atmosphere, and then the resulting mixture was stirred at the same temperature for 15 minutes. In the reaction mixture is injected gaseous carbon dioxide for 10 minutes, and the temperature was raised to 0oC. the Reaction mixture was poured into ice-cold water (40 ml) and washed with diethyl ether (twice 40 ml). The aqueous layer was allocated, after the pH was adjusted to 4 by potassium dihydrophosphate, then extracted with ethyl acetate (twice 40 ml). Obyedinennye extracts dried over anhydrous magnesium sulfate, filtered and the solvent is evaporated under reduced pressure to obtain 3-(2-(N-tert.-butoxycarbonylamino) ethoxy)-4-carboxy-1,2-benzisoxazole and 3- (2-(N-tert. -butoxycarbonylamino)ethoxy)-7-carboxy-1,2-benzisoxazole in the form of a colorless oily mixture of 0.48 g).

The resulting mixture was dissolved in tetrahydrofuran (30 ml) and to this solution add isobutylparaben (0,23 g) and triethylamine (0.18 g) under stirring at 5oC, and then the resulting mixture is stirred for 15 minutes followed by the addition of a solution of tetrahydrofuran saturated with ammonia (saturated at room temperature, 5 ml) and stirred for 15 minutes. The reaction mixture was poured into ice water (40 ml), extrat. The solvent is evaporated under reduced pressure and the residue is purified on a chromatographic column with silica gel, elwira with a mixture of cyclohexane/ethyl acetate (4: 1) to obtain 3-(2-(M-tert.-butoxycarbonylamino)ethoxy)- 4-carbarnoyl-1,2-benzisoxazole (0,30 g, 47%) and 3-(2-(N-tert. - butoxycarbonylamino)ethoxy)-7-carbarnoyl-1,2-benzisoxazole (0.17 g, 26%), respectively, in the form of colorless powder.

Results for 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-4 - carbarnoyl-1,2-benzisoxazole:

Melting point: 119-120oC

IR spectrum (KBr)maxcm-1: 3488, 3443, 3358, 3196, 1688, 1663, 1610, 1592, 1533;

The NMR spectrum (CDCl3) MD: of 1.42 (9H,c), 3,70 (2H, q, J=5,1 Hz), to 4.62 (2H, t, J= 5,1 Hz), is 4.93 (1H, Shir.C) 5,91 (1H, Shir.C), 7,60-of 7.70 (2H,m), 7,79 (1H, Shir.C) to 8.14 (1H, d, J=7,0 Hz).

Results for 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-7 - carbarnoyl-1,2-benzisoxazole:

Melting point: 151-153oC;

IR spectrum (KBr)maxcm-1: 3463, 3396, 3353, 3304, 3232, 3182, 1716, 1680, 1618, 1544;

The NMR spectrum (CDCl3) MD: of 1.46 (9H,c) to 3.67 (2H, q, J=5,1 Hz), of 4.54 (2H, t, J= 5,1 Hz), equal to 4.97 (1H, Shir.C) 5,95 (1H, Shir.C) 7,14 (1H, Shir.C), 7,44 (1H, t, J=7.0 Hz), 7,83 (1H, d, J=7,0 Hz), 8,35 (1H, d, J=7,0 Hz).

(b) 3-(2-aminoethoxy)-4-carbarnoyl-1,2-benzisoxazole hydrochloride

Specified in the title compound (0.08 g, 100%) (0.10 g) and a solution of 4n hydrochloric acid/dioxane (1.0 ml) in the reactions and treatments by way of example 17 (C).

Melting point: 210-213oC (decomposition);

IR spectrum (KBr)maxcm-1: 3383, 3300-2400, 1656, 1605, 1590, 1543;

NMR spectrum (DMSO-d6) MD: of 3.57 (2H, t, J=5,1 Hz), with 4.64 (2H, t, J=5,1 Hz), 7,58 (1H, d, J=7,0 Hz), 7,71 (1H, Shir.C) 7,73 (1H, DD, J=9.0 Hz, J=7,0 Hz), 7,79 (1H, d, J=9.0 Hz), to 7.99 (1H, Shir.C), 8,21 (3H, Shir.C).

(C) 3-(2-aminoethoxy)-7-carbarnoyl-1,2-benzisoxazole hydrochloride

The specified connection (0.04 g, 100%) was obtained as colorless powder from 3-(2-(N-tert.-butoxycarbonylamino)ethoxy)-7-carbarnoyl - 1,2-benzisoxazole (0.05 g) and the solution

4h. hydrochloric acid/dioxane (1.0 ml) in the reactions and treatments by way of example 17 (C).

Melting point: 227-230oC (decomposition);

IR spectrum (KBr)maxcm-13461, 3180, 3300-2400, 1675, 1618, 1596, 1547;

NMR spectrum (DMSO-d6) MD: to 3.34 (2H, t, J=5,1 Hz) and 4.65 (2H, t, J=5,1 Hz) to 7.50 (1H, t, J=7.0 Hz), to 7.77 (1H, Shir.C), 7,83 (1H, Shir.C) to 7.95 (3H, d, J=7,0 Hz), with 8.05 (1H, d, J= 7,0 Hz), 8,31 (3H, Shir.C).

Example 24.

3-(2-aminoethoxy-4-cyano-1, 2-benzisoxazole hydrochloride

(a) 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-4-cyano-1,2 - benzisoxazol

To a solution of 3-(2-(N-tert-butoxycarbonylamino)ethoxy)-4 - carbarnoyl-1,2-benzisoxazole (0.15 g) in 1.5 ml diethylformamide added phosphorus oxychloride (0.09 g) in paramushiru mixture was poured into ice-cold water (20 ml), extracted with ethyl acetate (twice 20 ml), and the combined extracts dried over anhydrous magnesium sulfate. After filtration the solvent is evaporated under reduced pressure and the residue is purified on a chromatographic column with silica gel, elwira with a mixture of cyclohexane/ethyl acetate (4:1) to obtain specified in the title target compound (0,13 g, 93%) as colorless powder.

Melting point: 116-117oC;

IR spectrum (KBr)maxcm-1: 3370, 2232, 1701, 1601, 1530;

The NMR spectrum (CDCl3) MD: of 1.45 (9H,s), of 3.69 (2H, q, J=5,1 Hz), 4,55 (2H, T,J=5,1 Hz), to 5.08 (1H, Shir.C), 7,60 to 7.75 (3H, m).

(b) 3-(2-aminoethoxy)-4-cyano-1,2-benzisoxazole hydrochloride

Specified in the title compound (0.08 g, 100%) was obtained as colorless powder from 3-(2-(N-tert. - butoxycarbonylamino)ethoxy)-4-cyano-1,2-benzisoxazole (0.10 g) and a solution of 4n. hydrochloric acid/dioxane (1.0 ml) in the reactions and treatments by way of example 17 (C).

Melting point: 210-213oC (decomposition);

IR spectrum (KBr)maxcm-1: 3400-2400, 2234, 1601, 1538;

NMR spectrum (DMSO-d6) MD: the 3.35 (2H, t, J=5,1 Hz), 4.72 in (2H, t, J=5,1 Hz), 7,87 (1H, t, J=8.1 Hz), 7,98 (1H, d, J=8.1 Hz), of 8.09 (1H, d, J=8.1 Hz), compared to 8.26 (3H, Shir.C).

Example 25.

3-(2-aminoethoxy)-7-cyano-1,2-benzisoxazole hydrochloride

(a) 3-(2-(N-Tamino) ethoxy)-7-carbarnoyl-1,2-benzisoxazole (0.10 g) in dimethylformamide (1.0 ml) is added phosphorus oxychloride (0.06 g) under stirring at 5oC, and the resulting mixture was stirred at the same temperature for 15 minutes. The reaction mixture was poured into ice water (20 ml), extracted with ethyl acetate (twice 20 ml) and the combined extracts dried over anhydrous magnesium sulfate. After filtration the solvent is evaporated under reduced pressure and the residue is purified on a chromatographic column with silica gel, elwira with a mixture of cyclohexane/ethyl acetate (4: 1) to obtain the title compound (0.09 g, 90%) as colorless powder.

Melting point: 91-92oC;

IR spectrum (KBr)maxcm-1: 3437, 3349, 3316, 2238, 1719, 1701, 1688, 1621, 1607, 1546, 1528;

The NMR spectrum (CDCl3) MD: of 1.45 (9H,c), 3,66 (2H, q, J=5,1 Hz), of 4.54 (2H, t, J= 5,1 Hz) to 4.92 (1H, Shir.C), 7,40 (1H, t, J=8.0 Hz), 7,86 (1H, d, J=8.0 Hz), of 7.90 (1H, d, J=8.0 Hz).

(b) 3-(2-aminoethoxy)-7-cyano-1,2-benzisoxazole hydrochloride

Specified in the title compound (0.05 g, 100%) was obtained as colorless powder from 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-7-cyano - 1,2-benzisoxazole (0.07 g) and a solution of 4n. hydrochloric acid/dioxane (1.0 ml) in the reactions and treatments by way of example 17 (C).

Melting point: 205-208oC (decomposition);

IR spectrum (KBr)maxcm-1: 3241, 3400-2400, 2239, 1623, 1607, 154, ,34 (3H, Shir.C).

Example 26.

3-(2-aminoacetic)-5-fluoro-1,2-benzisoxazole hydrochloride

(a) 3-chloro-5-fluoro-1,2-benzisoxazol

To a solution of 5-fluoro-3-hydroxycarbazole (1.0 g) 0.53 ml of pyridine added phosphorus oxychloride (0,89 ml) and the resulting mixture is refluxed for 8 hours. The reaction mixture was poured into ice water, extracted with ethyl acetate and the combined extracts washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration the solvent is evaporated under reduced pressure and the residue is purified on a chromatographic column with silica gel to obtain the title compound (0.85 grams,.77%) as a colourless oil.

(b) 3-(2-(N-tert.-butoxycarbonylamino)ethylthio)-5-fluoro-1,2 - benzisoxazol

To a solution of 3-chloro-5-fluoro-1,2-benzisoxazole (0,83 g) in 8 ml of dimethylformamide is added 2-tert. -butoxycarbonylmethyl (0,86 g) and potassium carbonate (0,67 g) under stirring in nitrogen atmosphere, and the mixture was stirred at 80oC for 3 hours. The reaction mixture was poured into ice water, extracted with ethyl acetate, and the combined extracts washed with brine and dried over anhydrous magnesium sulfate. After filtration Rastro obtain the title compound (1,21 g, 80%) as a colorless powder.

The NMR spectrum (CDCl3) MD: the 1.44 (9H,s) to 3.41 (2H, t, J=6.2 Hz), to 3.58 (2H, TD, J=6.2 Hz, J=6.2 Hz), to 4.98 (1H, Shir.C), 7,21-7,51 (3H,m).

(C) 3-(2-aminoacetic)-5-fluoro-1,2-benzisoxazole hydrochloride

To a solution of 3-(2-(N-tert. -butoxycarbonylamino) ethylthio)-5-fluoro-1,2-benzisoxazole (0.20 g) in 2 ml of dioxane is added a solution of 4n hydrochloric acid/dioxane (0.8 ml) under stirring at 5oC, and the resulting mixture was stirred at room temperature for 30 minutes. After completion of the reaction the solvent is evaporated under reduced pressure and the residue is recrystallized from ethanol and ethyl acetate to obtain the title compound (0.14 g) as colorless needles.

Melting point: 202-206oC (decomposition);

IR spectrum (KBr)maxcm-1: 2992, 2955, 2915, 1594, 1511, 1493;

NMR spectrum (DMSO-d6) MD: of 3.25 (2H, t, J=7,1 Hz), 3,53 (2H, t, J=7,1 Hz), 7,60-7,86 (3H,m), by 8.22 (3H, Shir.C).

Example 27.

3-(2-aminoacetic)-7-chloro-1,2-benzisoxazole hydrochloride

(a) 3,7-dichloro-1,2-benzisoxazol

Specified in the title compound (0.73 g, 78%) was obtained from 7-chloro-3-hydroxy-1,2-benzisoxazole (0.85 grams) in the reactions and treatments by way of example 26 (a).

(b) 3-(2-(N-tert. -butokukai-1,2-benzisoxazole (0.20 g) in the reactions and treatments by way of example applications 26 (b).

The NMR spectrum (CDCl3) MD: USD 1.43 (9H,s), 3,42 (2H, t, J=6.2 Hz), 3,60 (2H, TD, J=6.2 Hz, J=6.2 Hz), free 5.01 (1H, Shir.C) of 7.24 (1H, t, J=9.1 Hz), of 7.48 (1H, d, J=9.1 Hz), 7,56 (1H, d, J=9.1 Hz).

(C) 3-(2-aminoacetic)-7-chloro-1,2-benzisoxazole hydrochloride

Specified in the title compound (0.12 g quant) is obtained from 3-(2-(N-tert. - butoxycarbonylamino) ethylthio)-7-chloro-1,2-benzisoxazole (0.15 g) in the reactions and treatments by way of example 26 (C).

Melting point: 196-201oC (decomposition);

IR spectrum (KBr)maxcm-1: 2971, 2909, 1592, 1502, 1492;

NMR spectrum (DMSO-d6) MD: 3,26 (2H, t, J=7,1 Hz), of 3.56 (2H, t, J=7,1 Hz), was 7.45 (1H, t, J=7.9 Hz), 7,79 (1H, d, J= 7.9 Hz), 7,86 (1H, d, J=7.9 Hz), to 8.20 (3H, Shir.C).

Example 28.

3-(2-aminoacetic)-7-methyl-1,2-benzisoxazole hydrochloride

(a) 3-chloro-7-methyl-1,2-benzisoxazol

Specified in the title compound (0,30 g, 77%) was obtained from 3-hydroxy-7-methyl - 1,2-benzisoxazole (0.35 g) in the reactions and treatments by way of example 26 (a).

(b) 3-(2-(N-tert. -butoxycarbonylamino)ethylthio)-7-methyl-1,2 - benzisoxazol

Specified in the title compound (0.24 g, 55%) was obtained from 3-chloro-7-methyl-1,2 - benzisoxazole (0.24 g) in the reactions and treatments by way of example 26 (b).

The NMR spectrum (CDCl3) MD: USD 1.43 (9H,s), 2,52 (3H,s), 3,42 is ylthio)-7-methyl-1,2-benzisoxazole hydrochloride

Specified in the title compound (0.08 g) is obtained from 3-(2-(N-tert.-butoxycarbonylamino)ethylthio)-7-methyl-1, 2 - benzisoxazole (0.10 g) in the reactions and treatments by way of example 26 (C).

Melting point: 198-203oC (decomposition);

IR spectrum (KBr)maxcm-1: 2985, 2913, 1598, 1501;

NMR spectrum (DMSO-d6) MD: of 2.51 (3H,s), 3,24 (2H, t, J=7,1 Hz), of 3.54 (2H, t, J=7,1 Hz), 7,33 (1H, t, J=7.4 Hz), 7,52 (1H, d, J=7,4 Hz), 7,58 (1H, d, J=7,4 Hz), by 8.22 (3H, Shir.C).

Example 29.

3-(2-aminoacetic)-5, 7-dichloro-1,2-benzisoxazole hydrochloride

(a) 3,5,7-trichloro-1,2-benzisoxazol

Specified in the title compound (1,81 g, 83%) is obtained from 5,7-dichloro-3-hydroxy-1,2-benzisoxazole (2.00 g) in the reactions and treatments by way of example 26 (a).

(b) 3-(2-(N-tert.-butoxycarbonylamino)ethylthio)-5,7-dichloro-1,2 - benzisoxazol

Specified in the title compound (0.25 g, 68%) is obtained from 3,5,7 - trichloro-1,2-benzisoxazole (0,23 g) in the reactions and treatments by way of example 26 (b).

The NMR spectrum (CDCl3) MD: USD 1.43 (9H,s), 3,42 (2H, t, J=6.2 Hz), to 3.58 (2H, TD, J=6.2 Hz, J=6.2 Hz), to 5.03 (1H, Shir.C) of 7.48 (1H,s), 7,56 (1H,s).

(C) 3-(2-aminoacetic)-5,7-dichloro-1,2-benzisoxazole hydrochloride

Specified in the title compound (0.18 g) obtained from 3-(2-(N - tert.-bout the EPA 26 (C).

Melting point: 199-202oC (decomposition);

IR spectrum (KBr)maxcm-1: 3003, 2970, 2915, 1590, 1480;

NMR spectrum (DMSO-d6) MD: 3,25 (1H, t, J=6.9 Hz), of 3.54 (2H, t, J=6.9 Hz), 8,00 (1H,s), of 8.06 (1H,s), 8,18 (3H, Shir. C).

Example 30.

3-(2-aminoacetic)-7-nitro-1,2-benzisoxazole hydrochloride

(a) 3-chloro-7-nitro-1, 2-benzisoxazol

Specified in the title compound (0,93 g, 80%) derived from 3-hydroxy-7-nitro - 1,2-benzisoxazole (1,05 g) in the reactions and treatments by way of example 26 (a).

(b) 3-(2-(N-tert. -butoxycarbonylamino)ethylthio)-7-nitro - 1,2-benzisoxazol

Specified in the title compound get (0.20 g, 51%) of 3-chloro-7-nitro-1,2-benzisoxazole (0,23 g) in the reactions and treatments by way of example 26 (b).

The NMR spectrum (CDCl3) MD: USD 1.43 (9H,s), of 3.48 (2H, t, J=6.2 Hz), 3,62 (2H, TD, J=6.2 Hz, J=6.2 Hz), to 4.98 (1H, Shir.C) to 7.50 (1H, t, J=9.1 Hz), 7,94 (1H, d, J=9.1 Hz), 8,44 (1H, d, J=9.1 Hz).

(C) 3-(2-aminoacetic)-7-nitro-1,2-benzisoxazole hydrochloride

Specified in the title compound (0.14 g) obtained from 3-(2-(N-tert.-butoxycarbonylamino)ethylthio)-7-nitro-1,2 - benzisoxazole (0.18 g) in the reactions and treatments by way of example 26 (C).

Melting point: 193-196oC (decomposition);

IR spectrum (KBr)man, t, J=7.9 Hz), 8,24 (3H, Shir.C) 8,29 (1H, d, J=7.9 Hz), to 8.57 (1H, d, J=7.9 Hz).

Example 31.

3-(2-aminoacetic)-7-methoxy-1,2-benzisoxazole hydrochloride

(a) 3-chloro-7-methoxy-1,2-benzisoxazol

Specified in the title compound (0,61 g, 69%) was obtained from 3-hydroxy-7-methoxy-1,2-benzisoxazole (0,80 g) in the reactions and treatments by way of example 26 (a).

(b) 3-(2-(N-tert.-butoxycarbonylamino)ethylthio)-7-methoxy-1,2 - benzisoxazol

Specified in the title compound (0.25 g, 54%) was obtained from 3-chloro-7-methoxy-1,2-benzisoxazole (0.26 g) as a result of reactions and treatments by way of example 26 (b).

The NMR spectrum (CDCl3) MD: the 1.44 (9H,s), 3,42 (2H, t, J=6.2 Hz), to 3.58 (2H, TD, J= 6.2 Hz, J=6.2 Hz), Android 4.04 (3H, s), 5,02 (1H, s, C), 6,98 (1H, d, J=9.1 Hz), to 7.15 (1H, d, J=9.1 Hz), 7.23 percent (1H, t, J=9.1 Hz).

(C) 3-(2-aminoacetic)-7-methoxy-1,2-benzisoxazole hydrochloride

Specified in the title compound (90 mg), obtained from 3-(2-(N-tert.- butoxycarbonylamino)ethylthio)-7-methoxy-1,2-benzisoxazole (120 mg) as a result of reactions and treatments by way of example 26 (C).

Melting point: 232-237oC (decomposition);

IR spectrum (KBr)maxcm-1: 3019, 2969, 2907, 1619, 1600, 1512;

NMR spectrum (DMSO-d6) MD: of 3.25 (2H, t, J=7,1 Hz), of 3.54 (2H, t, J=7,1 Hz), 3,98 (3H,s), 7,27-7,40 (3H,m), 8,21 (3H, Shir. (C)oxycarbonyl)ethylthio)-7-amino - 1,2-benzisoxazol

To a solution of 3-(2-(N-tert. - butoxycarbonylamino)ethylthio)-7-nitro-1,2-benzisoxazole (250 mg) in 90% aqueous acetic acid (2 ml) is added powdered zinc (250 mg) under stirring and ice cooling, and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was filtered through celite and the resulting filtrate concentrated under reduced pressure. To the residue water is added, then extracted with ethyl acetate. The combined extracts washed with brine and dried over anhydrous magnesium sulfate. After filtration the solvent is evaporated under reduced pressure and the residue is purified on a chromatographic column with silica gel, elwira with ethyl acetate to obtain the title compound (230 mg).

The NMR spectrum (CDCl3) MD: USD 1.43 (9H,s) to 3.41 (2H, t, J=6.2 Hz) and 3.59 (2H, TD, J=6.2 Hz, J=6.2 Hz), 4,08 (2H, Shir.C) 5,02 (1H, Shir.C) PC 6.82 (1H, d, J= 8.7 Hz), of 6.96 (1H, d, J= 8.7 Hz), 7,12 (1H, t, J= 8.7 Hz).

(b) 3-(2-aminoacetic)-7-amino-1,2-benzisoxazole hydrochloride

Specified in the title compound (120 mg), obtained from 3-(2-(N-tert.-butoxycarbonylamino) ethylthio)-7-amino-1,2-benzisoxazole (140 mg) as a result of reactions and treatments by way of example 26 (C).

Melting point: 157-160o6
) MD: 3,24 (2H, t, J=7.0 Hz), 3,52 (2H, t, J=7.0 Hz), 4,05 to 5.35 (2H, Shir.C) to 6.88 (2H, d, J=7.9 Hz), 7,12 (1H, t, J=7.9 Hz), 8,23 (3H, Shir.C).

Example 33.

3-(2-aminoacetic)-5-methoxy-1,2-benzisoxazole hydrochloride

(a) 3-chloro-5-methoxy-1,2-benzisoxazol

Specified in the title compound (730 mg, 71%) was obtained from 3-hydroxy-5-methoxy-1,2-benzisoxazole (920 ml) in the reactions and treatments by way of example 26 (a).

(b) 3-(2-(N-tert. -butoxycarbonylamino)ethylthio)-5 - methoxy-1,2-benzisoxazol

Specified in the title compound (280 mg, 61%) obtained from the reactions and treatments by way of example 26 (b) from 3-chloro-5-methoxy-1,2-benzisoxazole (260 mg).

The NMR spectrum (CDCl3) MD: USD 1.43 (9H,s), 3,40 (2H, t, J=6.2 Hz), to 3.58 (2H, TD, J= 6.2 Hz, J=6.2 Hz), 3,86 (3H,s), 5,02 (1H, Shir.C) 6,91 (1H,s), 7,18 (1H, d, J=9.1 Hz), the 7.43 (1H, d, J=9.1 Hz).

(C) 3-(2-aminoacetic)-5-methoxy-1,2-benzisoxazole hydrochloride

Specified in the title compound (190 mg) obtained from 3-(2-(N-tert.- butoxycarbonylamino)ethylthio)-5-methoxy-1,2-benzisoxazole (240 mg) as a result of reactions and treatments by way of example 26 (C).

Melting point: 213-217oC (decomposition);

IR spectrum (KBr) maxcm-1: 2997, 2947, 2883, 1592, 1514, 1495;

NMR spectrum (DMSO-d6) MD: 3,23 (2H, t, J=7,1 Hz), 3,52 (ethylthio)-5-methyl-1,2-benzisoxazole hydrochloride

(a) 3-chloro-5-methyl-1,2-benzisoxazol

Specified in the title compound (0,81 g, 71%) was obtained from 3-hydroxy-5-methyl-1,2-benzisoxazole (1,02 g) in the reactions and treatments by way of example 26 (a).

(b) 3-(2-(N-tert-butoxycarbonylamino) ethylthio)-5-methyl - 1,2-benzisoxazol

Specified in the title compound (90 mg, 56%) was obtained from 3-chloro-5-methyl-1,2-benzisoxazole (90 mg) as a result of reactions and treatments by way of example 26(b).

The NMR spectrum (CDCl3) MD: the 1.44 (9H,s) to 2.46 (3H,s), 3,40 (2H, t, J=6.2 Hz), to 3.58 (2H, TD, J=6.2 Hz, J= 6.2 Hz), 5,02 (1H, Shir.C), 7,38 (2H, d, J= 9.1 Hz), 7,42 (1H,s).

(C) 3-(2-aminoacetic)-5-methyl-1,2-benzisoxazole hydrochloride

Specified in the title compound (60 mg) obtained from 3- (2-(N-tert.-butoxycarbonylamino)ethylthio)-5-methyl-1,2 - benzisoxazole (80 mg) as a result of reactions and treatments by way of example 26 (C).

Melting point: 132-135oC (decomposition);

IR spectrum (KBr)maxcm-1: 2996, 2919, 1600, 1592, 1497;

NMR spectrum (DMSO-d6) MD: 2,44 (3H,s), 3,24 (2H, t, J= 7,1 Hz), 3,53 (2H, t, J=7,1 Hz), 7,54 (1H, d, J=8.5 Hz), 7,55 (1H,s), the 7.65 (1H, d, J=8.5 Hz), 8,21 (3H, Shir.C).

Example 35.

3-(2-aminoacetic)-5-nitro-1,2-benzisoxazole hydrochloride

(a) 3-chloro-5-nitro-1,2-benzisoxazol

Specified in sahlawi the method of example 26 (a).

(b) 3-(2-(N-tert. -butoxycarbonylamino)ethylthio)-5-nitro-1,2 - benzisoxazol

Specified in the title compound (560 mg, 58%) was obtained from 3-chloro-5-nitro-1,2-benzisoxazole (560 mg) as a result of reactions and treatments by way of example 26 (b).

The NMR spectrum (CDCl3) MD: the 1.44 (9H,s), 3,47 (2H, t, J=6.2 Hz), 3,62 (2H, TD, J=6.2 Hz, J=6.2 Hz), 4,96 (1H, Shir.C) to 7.64 (1H, A,J=9.1 Hz), 8,48 (1H, d, J=9.1 Hz), 8,56 (1H,s).

(C) 3-(2-aminoacetic)-5-nitro-1,2-benzisoxazole hydrochloride

Specified in the title compound (200 mg) obtained from 3-(2-(N-tert.-butoxycarbonylamino)ethylthio-5-nitro-1,2 - benzisoxazole (250 mg) as a result of reactions and treatments by way of example 26 (C).

Melting point: 183-186oC (decomposition);

IR spectrum (KBr)maxcm-1: 3013, 2971, 2892, 1619, 1594, 1530;

NMR spectrum (DMSO-d6) MD: 3,26 (2H, t, J=7,1 Hz) and 3.59 (2H, t, J=7,1 Hz), 8,03 (1H, d, J=9.1 Hz), 8,24 (3H, Shir.C) 8,56 (1H, d, J=9.1 Hz), 8,72 (1H,s).

Example 36.

3-(2-aminoacetic)-5-amino-1,2-benzisoxazole

(a) 3-(2-(N-tert.-butoxycarbonylamino)ethylthio-5-amino-1,2-benzisoxazol

Specified in the title compound (140 mg) obtained from 3-(2-(N - tert.-butoxycarbonylamino)ethylthio)-5-nitro-1,2-benzisoxazole (150 ml) in the reactions and treatments by way of example 32 (a).

(b) 3-(2-aminoacetic)-5-amino-1,2-benzisoxazole

Specified in the title compound (200 mg) obtained from 3-(2-(N-tert.-butoxycarbonylamino)ethylthio)-5-amino-1,2 - benzisoxazole (200 mg) as a result of reactions and treatments by way of example 26 (C).

Melting point: 201-205oC (decomposition);

IR spectrum (KBr)maxcm-1: 3045, 3021, 2964, 2885, 1628, 1582, 1494;

NMR spectrum (DMSO-d6) MD: 3,26 (2H, t, J=7.0 Hz), 3,35-is 4.85 (2H, Shir. C) 3,55 (2H, t, J=7.0 Hz), 7,54 (1H, d, J= 6.5 Hz), 7,56 (1H,s), of 7.90 (1H, d, J=6.5 Hz), 8,24 (3H, Shir.C).

Example 37.

3-(2-aminoethoxy)-1,2-oil[2,3-e]isoxazol hydrochloride

(a) 3-hydroxy-1,2-oil[2,3-e] isoxazol

Specified in the title compound (3.1 g, 31%) was obtained from 3-hydroxy-2 - naphthoic acid (10.0 g) in the reactions and treatments according to the method of examples 1(a), 1(b) and 1(C).

IR spectrum (KBr)maxcm-1: 3044, 3001, 2940, 2869, 2824, 2746, 2696, 2661, 2623, 1770, 1645, 1618, 1598, 1573, 1521;

NMR spectrum (DMSO-d6) MD: 7,45-the 7.65 (2H,m), 8,01 (1H,s), of 8.04 (1H, d, J=8,4 Hz), 8,15 (1H, d, J=8,4 Hz), 8,43 (1H, s), 12,67 (1H, Shir. C).

(b) 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-1,2-oil-[2,3-e] isoxazol

Specified in the title compound (0,59 g, 72%) was obtained from 3 - hydroxy-1,2-oil[2,3-e] isoxazol (x2">

Melting point: 148-149oC;

IR spectrum (KBr)max ucm-1: 3314, 1707, 1643, 1545, 1535;

The NMR spectrum (CDCl3) CBM: about 1.47 (9H,c), 3,70 (2H, q, J=5,1 Hz), 4,59 (2H, t, J=5,1 Hz), free 5.01 (1H, Shir.C), 7,33-of 7.60 (2H,m), 7,81 (1H,s), 7,94 (1H, d, J=8,4 Hz), 8,00 (1H, d, J=8,4 Hz), by 8.22 (1H,s).

(C) 3-(2-aminoethoxy)-1,2-oil[2,3-e]isoxazol hydrochloride

Specified in the title compound (0.40 g, 99%) was obtained from 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-1,2-oil-[2,3-e] isoxazol (0.50 g) in the reactions and treatments according to the method of example 1(f).

Melting point: 207-213oC (decomposition),

IR spectrum (KBr) maxcm-1: 3300-2400, 1641, 1615, 1545, 1516, 1505;

NMR spectrum (DMSO-d6) MD: 3,39 (2H, q, J=5,1 Hz), 4,71 (2H, t, J=5,1 Hz), 7,50-of 7.70 (2H,m), of 8.09 (1H, d, J=8,4 Hz), 8,13 (1H,s), 8,18 (1H, d, J= 8,4 Hz), at 8.36 (3H, Shir.C) of 8.47 (1H,s).

Example 38.

3-(2-aminoacetic)-5-chloro-1,2-benzisoxazole hydrochloride

(a) 3-(2-(N-tert.-butoxycarbonylamino)ethylthio)-5-chloro-1,2 - benzisoxazol.

Specified in the title compound (0,63 g, 62%) was obtained from 3,5 - dichloro-1,2-benzisoxazole (0,53 g) in the reactions and treatments by way of example 26 (b).

Melting point: 95-96oC;

IR spectrum (KBr)maxcm-1: 3283, 1687, 1523;

The NMR spectrum (CDCl3) MD: the 1.44 (9H,s), 3(2 aminoacylation)-5-chloro-1,2-benzisoxazole hydrochloride

Specified in the title compound (0,41 g, 97%) was obtained from 3-(2-(N-tert. -butoxycarbonylamino)ethylthio)-5-chloro-1,2 - benzisoxazole (0.52 g) in the reactions and treatments by way of example 22 (C).

Melting point: 201-206oC (decomposition),

IR spectrum (KBr)maxcm-1: 3300-2400, 1588, 1524;

NMR spectrum (DMSO-d6) MD: 3,24 (2H, q, J=7.0 Hz), 3,55 (2H, t, J=7.0 Hz), of 7.75 (1H, DD, J=8,9 Hz, J=2.0 Hz), 7,83 (1H, d, J=8,9 Hz), 7,95 (1H, d, J=2.0 Hz), 8,23 (3H, Shir, C).

Example 39.

3-(2-aminoacetic)-5-fluoro-4-methyl-1,2-benzisoxazole hydrochloride

(a) 3-(2-(N-tert. -butoxycarbonylamino) ethylthio)-5-fluoro-4-methyl-1,2-benzisoxazol

Specified in the title compound (0.10 g, 91%) was obtained from 3-(2-(N-tert. -butoxycarbonylamino)ethylthio)-5 - fluoro-1,2-benzisoxazole (0.11 g) in the reactions and treatments by way of example 17(b).

The NMR spectrum (CDCl3) MD: the 1.44 (9H,s) to 2.55 (3H,s), 3,42 (2H, t, J=6,1 Hz) to 3.58 (2H, TD, J=6,1 Hz, J=6,1 Hz), 5,02 (1H, Shir.C), 7,19-7,34 (2H,m).

(b) 3-(2-aminoacetic)-5-fluoro-4-methyl-1,2-benzisoxazole hydrochloride

Specified the title compound (0.07 g) is obtained from 3-(2-(N-tert.- butoxycarbonylamino)ethylthio)-5-fluoro-4-methyl-1,2-benzisoxazole (0.09 g) in the reactions and treatments according to the method of example 1(f).

Temperature plvl the O-d6) MD: 2,53 (3H,s), 3,26 (2H, t, J=6.9 Hz), 3,55 (2H, t, J=6.9 Hz), 7,53-the 7.65 (2H,m), to 8.20 (3H, Shir. C).

Example 40.

3-(2-aminoacetic)-5-fluoro-4-cyano-1,2-benzisoxazole hydrochloride

(a) 3-(2-(N-tert. -butoxycarbonylamino) ethylthio)-5-fluoro-4-carbarnoyl-1,2-benzisoxazol.

3-(2-(N-tert. - butoxycarbonylamino)ethylthio)-5-fluoro-4-carboxy-1,2-benzisoxazol (0.25 g, 74%) was obtained from 3-(2-(N-tert.-butoxycarbonylamino) ethylthio-5-fluoro-1,2-benzisoxazole (0,30 g) in the reactions and treatments by way of example 18 (a).

Then specified in the title compound (0.16 g, 70%) was obtained from 3-(2-(N-tert.- butoxycarbonylamino)ethylthio)-5-fluoro-4-carboxy-1,2 - benzisoxazole (0,23 g) in the reactions and treatments by way of example 18 (b).

The NMR spectrum (CDCl3) MD: USD 1.43 (9H,s) to 3.35 (2H, t, J=6,1 Hz) to 3.58 (2H, TD, J=6,1 Hz, J=6,1 Hz), to 5.03 (1H, Shir.C) of 6.02 (1H, Shir.C) of 6.29 (1H, Shir. C) 7,37 (1H, t, J= 8,9 Hz), a 7.62 (1H, DD, J=3.8 Hz, J=8,9 Hz).

(b) 3-(2-(N-tert. -butoxycarbonylamino)ethylthio)-5-fluoro-4-cyano - 1,2-benzisoxazol

Specified in the title compound (0.12 g, 92%) was obtained from 3-(2- (N-tert. -butoxycarbonylamino)ethylthio)-5-fluoro-4-carbarnoyl-1,2 - benzisoxazole (0.14 g) as a result of reactions and treatments by way of example 19 (a).

The NMR spectrum (CDCl3) MD: of 1.45 (9H,s), of 3.46 (2H, t, J=6.0 Hz), 3,60 (2H, A-1,2-benzisoxazole hydrochloride

Specified in the title compound (0.09 g) is obtained from 3-(2-(N-tert.-butoxycarbonylamino)ethylthio)-5-fluoro-4-cyano-1,2 - benzisoxazole (0.11 g) in the reactions and treatments according to the method of example 1(f).

Melting point: 215-219oC (decomposition);

IR spectrum (KBr)maxcm-1: 3436, 3090, 3005, 1494;

NMR spectrum (DMSO-d6) MD: of 3.27 (2H, t, J=6.9 Hz) and 3.59 (2H, t, J=6.9 Hz), 7,94 (1H, t, J=9.4 Hz), 8,19 (3H, Shir. C) 8,30 (1H, DD, J=3,9 Hz, J= 9.4 Hz).

Example 41.

3-(2-aminoethoxy)-7-methoxy-1,2-benzisoxazole hydrochloride

(a) 3-(2-(N-tert.-butoxycarbonylamino)ethoxy)-7-methoxy - 1,2-benzisoxazol

Specified in the title compound (0.39 g, 63%) was obtained from 3-hydroxy-7-methoxy-1,2-benzisoxazole (0.33 g) in the reactions and treatments according to the method of example 1(e).

Melting point: 98-99oC;

IR spectrum (KBr)maxcm-1: 3348, 1708, 1683, 1624, 1615, 1542, 1533, 1509;

The NMR spectrum (CDCl3) MD: of 1.46 (9H,c) to 3.64 (2H, q, J=5,1 Hz), a 4.03 (3H, s), 4,51 (2H, t, J=5,1 Hz), equal to 4.97 (1H, Shir.C), 6,95-7,00 (1H,m), 7,15-7,20 (2H,m).

(b) 3-(2-aminoethoxy)-7-methoxy-1,2-benzisoxazole hydrochloride

Specified in the title compound (0,23 g, 96%) was obtained from 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-7 - methoxy-1,2-benzisoxazole (0,30 g) in the reaction and processing the O-d6) MD: 3,30 (2H, t, J=5,1 Hz), of 3.97 (3H, s), br4.61 (2H, t, J=5,1 Hz), 7,20-of 7.25 (1H,m), 7,30-to 7.35 (2H,m), 8,29 (3H, Shir.C).

IR spectrum (KBr)maxcm-1: 3022, 2983, 2909, 2840, 1627, 1614, 1546, 1509;

Example 42.

3-(2-aminoethoxy)-5-methoxycarbonyl-1,2-benzisoxazole hydrochloride

(a) 5-bromo-3-(2-(N-tert.-butoxycarbonylamino)ethoxy)-1,2 - benzisoxazol

Specified in the title compound (4,80 g, 67%) was obtained from 5-bromo-3-hydroxy-1,2-benzisoxazole (4,30 g) and 2-(N - tert. -butoxycarbonylamino)of ethanol in the reaction and treatments by way of example 13(e).

Melting point: 123-124oC;

IR spectrum (KBr)maxMD: 3313, 1699, 1683, 1611, 1545;

The NMR spectrum (CDCl3) MD: of 1.46 (9H,c) to 3.64 (2H, q, J=5,1 Hz), 4,50 (2H, t, J= 5,1 Hz) to 4.92 (1H, Shir.C), 7,33 (1H, d, J=8,9 Hz), a 7.62 (1H, DD,J = 8,9; and 1.9 Hz), 7,80 (1H, d, J=1.9 Hz).

(b) 3-(2-(N-tert.-butoxycarbonylamino)ethoxy)-5 - methoxycarbonyl-1,2-benzisoxazol

Specified in the title compound (0.27 g, 29%) was obtained from 5-bromo-3-(2-(N-tert. - butoxycarbonylamino)ethoxy)-1,2-benzisoxazole (1,00 g) in the reactions and treatments by way of example 22 (b).

Melting point: 154-155oC;

IR spectrum (KBr)maxcm-1: 3326, 1720, 1702, 1687, 1629, 1611, 1547;

The NMR spectrum (CDCl3) MD: of 1.46 (9H,c), 3,66 (2H, q, J=5,1 Hz), of 3.96 (3H, s), a 4.53 (2H, dicarbonyl-1,2-benzisoxazole hydrochloride

Specified in the title compound (0.16 g, 98%) was obtained from 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-5 - methoxycarbonyl-1,2-benzisoxazole (0.20 g) in the reactions and treatments by way of example 22 (C).

Melting point: 211-213oC;

IR spectrum (KBr)maxcm-1: 3300-2400, 1718, 1625, 1610, 1544;

NMR spectrum (DMSO-d6) MD: 3,37 (2H, q, J=5,1 Hz), 3,91 (3H,s), 4,63 (2H, t, J= 5,1 Hz), 7,80 (1H, d, J=8,8 Hz), compared to 8.26 (1H, DD, J=8,8 Hz, J=1.6 Hz), 8,44 (1H, d, J=1.6 Hz).

Example 43.

3-(2-aminoethoxy)-5-methylamino-1,2-benzisoxazole and 3-(2-aminoethoxy)-5-dimethylamino-1,2-benzisoxazole

(a) 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-5-methylamino-1,2 - benzisoxazole and 3-(2-(N-tert.-butoxycarbonylamino)-ethoxy)-5 - dimethylamino-1,2-benzisoxazol

To a solution of 5-amino-3-(2-(N-tert. - butoxycarbonylamino)ethoxy)-1,2-benzisoxazole (0.88 g) in 10 ml of tetrahydrofuran, add sodium borohydride (0.66 g) under stirring at 5oC. was added dropwise 37% aqueous formaldehyde solution (0,99 g) and 3M sulfuric acid (1.0 ml) in 10 ml of tetrahydrofuran, and stirred for 15 minutes with 5oC. After stirring at room temperature for 1.5 hours, the reaction mixture is cooled to 5oC and added 37% aqueous solution formaldegidov in ice-cold water (100 ml) and extracted with ethyl acetate (twice 50 ml). The organic layer is dried over anhydrous magnesium sulfate and filtered. The solvent is evaporated under reduced pressure and the residue is purified on a chromatographic column with silica gel, elwira with a mixture of cyclohexane/ethyl acetate (4: 1) to obtain 3-(2-(N-tert.-butoxycarbonylamino)ethoxy)-5 - methylamino-1,2-benzisoxazole (0,49 g, 53%) and 3-(2-(N-tert. - butoxycarbonylamino)ethoxy)-5-dimethylamino-1,2-benzisoxazole (0.14 g, 15%).

Results for 3-(2-(N-tert.-butoxycarbonylamino) ethoxy)-5-methylamino-1,2-benzisoxazole:

Melting point: 122-123oC;

IR spectrum (KBr)maxcm-1: 3392, 5317, 1695, 1673, 1636, 1611, 1548, 1538, 1523;

The NMR spectrum (CDCl3) MD: of 1.46 (9H,c), is 2.88 (3H,c) to 3.64 (2H, q, J=5,1 Hz), with 3.79 (1H, Shir.C) of 4.49 (2H, t, J=5,1 Hz), 4,99 (1H, Shir.C), only 6.64 (1H, d, J= 2.3 Hz), 6.87 in (1H, DD, J=8,9 Hz, J=2.3 Hz), 7.23 percent (1H, d, J=8,9 Hz).

Results for 3-(2-(N-tert.- butoxycarbonylamino)ethoxy)-5-dimethylamino-1,2-benzisoxazole:

IR spectrum (KBr)maxcm-1: 3387, 2979, 2934, 1703, 1547, 1526, 1507;

The NMR spectrum (CDCl3) MD: of 1.46 (9H,c), of 2.97 (6H,c), 3,65

(2H, m), of 4.49 (2H, t, J=5,1 Hz), 4,99 (1H, Shir.C) is 6.78 (1H, d, J=2.4 Hz), 7,10 (1H, DD, J=9,2 Hz, J=2.4 Hz), 7,30 (1H, d, J=9,2 Hz).

(b) 3-(2-aminoethoxy)-5-methylamino-1,2-benzisoxazole

Specified in the title compound (0.27 g, 99%) receive the developments according to the method of example 1(f).

Melting point: 240-250oC (decomposition);

IR spectrum (KBr)maxcm-1: 3030, 2961, 2889, 2841, 2756, 2720, 2683, 2646, 2609, 2579, 2535, 2506, 2479, 2421, 2379, 1623, 1604, 1567, 1544, 1528;

NMR spectrum (DMSO-d6) MD: 2,84 (3H,c) to 3.34 (2H, q, J= 5,1 Hz), br4.61 (2H, t, J=5,1 Hz), the 7.43 (1H, Shir.C), 7,49 (1H, d, J=8,9 Hz), to 7.64 (1H, d, J= 8,9 Hz), 8.34 per (3H, Shir.C).

(C) 3-(2-aminoethoxy)-5-dimethylamino-1,2-benzisoxazole

Specified in the title compound is obtained from 3-(2-(N-tert.-butoxycarbonylamino)ethoxy)-5 - dimethylamino-1, 2-benzisoxazole in the reactions and treatments according to the method of example 1(f).

Melting point: 150-160oC (decomposition);

IR spectrum (KBr)maxcm-1: 3500-3200, 3100-2800, 2700- 2400, 1626, 1551, 1467, 1434;

NMR spectrum (DMSO-d6) MD: a 3.06 (6H,s) to 3.34 (2H, DD, J= a 10.6 Hz, J=5.5 Hz), to 4.62 (2H, t, J=5.5 Hz), 7,8 - to 7.5 (3H,m), of 8.37 (2H, Shir.C).

Example 44.

3-(2-aminoethoxy)-5-deformedarse-1,2-benzisoxazole

(a) 5-hydroxy-3-(2-(N-tert.-butoxycarbonylamino)ethoxy)-1,2 - benzisoxazol

Specified in the title compound (0,60 g, 62%) was obtained from 3,5-dihydroxy-1,2 - benzisoxazole (0.50 g) in the reactions and treatments according to the method of example 1(e).

Melting point: 152-153oC;

IR spectrum (KBr)maxcm-1: 3286, 1672, 1543, 7,42 (1H, d, J=8,9 Hz) 9,68 (1H,s).

(b) 3-(2-(N-tert.-butoxycarbonylamino)ethoxy)-5-deformedarse-1,2 - benzisoxazol

To a solution of 5-hydroxy - 3-(2-(N-tert.-butoxycarbonylamino)ethoxy)-1,2-benzisoxazole (100 mg) in 4 ml of dimethylformamide added sodium methoxide (90 mg) and the resulting mixture was stirred at room temperature for 10 minutes, then injected gas Chlorodifluoromethane for 20 minutes. The reaction mixture was poured into ice water (30 ml), extracted with ethyl acetate (twice 30 ml) and the combined extracts dried over anhydrous magnesium sulfate and filtered. The solvent is evaporated under reduced pressure and the residue is purified on a chromatographic column with silica gel, elwira with a mixture of cyclohexane/ethyl acetate (9:1) to obtain the title compound (19 mg, 16%) as a colorless powder.

Melting point: 155-156oC;

IR spectrum (KBr)maxcm-1: 3322, 1699, 1683, 1541;

The NMR spectrum (CDCl3) MD: of 1.46 (9H,c), the 3.65 (2H, q, J=5,1 Hz), 4,51 (2H, t, J=5,1 Hz), 4,94 (1H, Shir.C) of 6.52 (1H, t, J=73,4 Hz), 7,30 is 7.50 (3H,m).

(C) 3-(2-aminoethoxy)-5-deformedarse-1,2-benzisoxazole

Specified in the title compound (20 mg, 95%) was obtained from 3-(2-(N-tert. -butoxycarbonylamino) ethoxy)-5-deformedarse-1,con: 162-164oC (decomposition);

IR spectrum (KBr) maxcm-1: 3300-2400, 1618, 1599, 1544, 1497;

NMR spectrum (DMSO-d6) MD: to 3.34 (2H, q, J=5,1 Hz), 4,63 (2H, t, J=5,1 Hz), to 4.62 (1H, Shir.C), 7,27 (1H, d, J=76,6 Hz), 7,54 (1H, DD, J=9.0 Hz, J= 2.3 Hz), 7,58 (1H, d, J=9.0 Hz), 8,29 (3H, Shir.C).

Example 45.

3-(2-aminoethoxy)-7-amino-1,2-benzisoxazole

(a) 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-7-nitro-1,2 - benzisoxazol

Specified in the title compound (2.20 g, 68%) was obtained from 3-hydroxy-7-nitro-1,2-benzisoxazole (1.80 g) as a result of reactions and treatments according to the method of example 1(e).

Melting point: 116-117oC;

IR spectrum (KBr)maxcm-1: 3359, 3307, 1718, 1700, 1691, 1628, 1604, 1553;

The NMR spectrum (CDCl3) MD: of 1.46 (9H,c) to 3.67 (2H, q, J=5,1 Hz), of 4.57 (2H, t, J= 5,1 Hz), is 4.93 (1H, Shir.C) 7,46 (1H, t, J=8.1 Hz), to 7.99 (1H, d, J=8.1 Hz), to 8.41 (1H,d, J=8,1 Hz).

(b) 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-7-amino-1,2 - benzisoxazol

Specified in the title compound (1.26 g, 93%) was obtained from 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-7-nitro - 1,2-benzisoxazole (1.50 g) in the reactions and treatments by way of example 32 (a).

Melting point: 107-108oC;

IR spectrum (KBr)maxcm-1: 3438, 3349, 1700, 1640, 1604;

The NMR spectrum (CDCl3) MD: of 1.46 (9H,c), 3,64 (aminoethoxy)-7-amino-1,2-benzisoxazole

Specified in the title compound (0,23 g, 98%) was obtained from 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-7-amino - 1,2-benzisoxazole (0.26 g) as a result of reactions and treatments according to the method of example 1(f).

Melting point: 185-195oC (decomposition);

IR spectrum (KBr) maxcm-1: 3300-2400, 3026, 2870, 2583, 1640, 1611, 1582, 1553, 1525, 1509;

NMR spectrum (DMSO-d6) MD: to 3.33 (2H, q, J=5,1 Hz), 4,59 (2H, t, J=5,1 Hz), to 6.88 (1H, d, J=7.9 Hz), 6,97 (1H, d, J=7.9 Hz), 7,10 (1H, t, J=7.9 Hz), with 8.33 (3H, Shir.C).

Example 46.

3-(2-aminoethoxy)-7-carboxy-1,2-benzisoxazole hydrochloride

Specified in the title compound (0.036 g, 14%) was obtained from 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-1,2-benzisoxazole (0.28 g) in the reactions and treatments by way of example 18 (a), then the reactions and treatments according to the method of example 1(f).

Melting point: 123-126oC (decomposition);

IR spectrum (KBr)maxcm-1: 3140, 3081, 3024, 2960, 2896, 1714, 1620, 1615, 1553, 1548, 1495;

NMR spectrum (DMSO-d6) MD: to 3.36 (2H, t, J=5,1 Hz) and 4.65 (2H, t, J=5,1 Hz), 7,53 (1H, t, J=7,1 Hz), with 8.05 (1H, d, J=7,1 Hz), 8,18 (1H, d, J=7,1 Hz), 8,32 (3H, Shir.S.).

Example 47.

3-(2-aminoethoxy)-5-hydroxy-1,2-benzisoxazole

Specified in the title compound (0.16 g, 97%) was obtained from 3- (2-(N-tert. - the example 1(f).

Melting point: 205-209oC (decomposition);

IR spectrum (KBr)maxcm-1: 3467, 3388, 3112, 3024, 2932, 1617, 1541, 1528, 1503;

NMR spectrum (DMSO-d6) MD: of 3.32 (2H, t, J=5,1 Hz), of 4.57 (2H, t, J=5,1 Hz), 7,01 (1H, d, J=2.5 Hz), 7,13 (1H, DD, J= 9.0 Hz, J=2.5 Hz), was 7.45 (1H, d, J=9.0 Hz), compared to 8.26 (3H, Shir.C) 9,84 (1H, s).

Example 48.

3-(2-aminoethoxy)-5-acetoxy-1,2-benzisoxazole

(a) 5-acetoxy-3-(2-(N-tert. -butoxycarbonylamino)ethoxy) -1,2-benzisoxazol

To a solution of 3-(2-(N-tert.-butoxycarbonylamino)ethoxy)- 5-hydroxy-1,2-benzisoxazole (100 mg) in 5 ml of tetrahydrofuran added triethylamine (44 mg) and acetylchloride (34 mg) under stirring at 5oC, then stirred at the same temperature for 15 minutes. The reaction mixture was poured into ice water (40 ml), extracted with ethyl acetate (twice 40 ml) and the combined extracts dried over anhydrous magnesium sulfate and filtered. The solvent is evaporated under reduced pressure and the residue is purified on a chromatographic column with silica gel, elwira with a mixture of cyclohexane/ethyl acetate (9:1) to obtain the title compound (101 mg, 88%) as colorless powder.

Melting point: 108-110oC (decomposition);

IR spectrum (KBr) maxcm-1: is), of 7.25 (1H, DD, J=9.0 Hz, J=2.2 Hz), 7,39 (1H, d, J=2.2 Hz), the 7.43 (1H, d, J=9.0 Hz).

(b) 3-(2-aminoethoxy)-5-acetoxy-1,2-benzisoxazole

Specified in the title compound (59 mg, 98%) was obtained from 5-acetoxy-3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-1,2 - benzisoxazole (80 mg) as a result of reactions and treatments according to the method of example 1(f).

Melting point: 168-170oC (decomposition);

IR spectrum (KBr)maxcm-1: 3064, 3002, 2962, 2891, 2741, 1748, 1726, 1618, 1592, 1545, 1510;

NMR spectrum (DMSO-d6) MD: 2,31 (3H,c), and 3.31 (2H, q, J=5,1 Hz), to 4.62 (2H, t, J= 5,1 Hz), 7,46 (1H, DD, J=9.0 Hz, J=2.2 Hz), 7,55 (1H, d, J=2.2 Hz), 7,71 (1H, d, J=9.0 Hz), 8,27 (3H, Shir.C).

Example 49.

3-(2-aminoethoxy)-7-methylamino-1,2-benzisoxazole

(a) 3-(2-(N-tert.-butoxycarbonylamino)ethoxy)-7-methylamino-1,2 - benzisoxazol

Specified in the title compound (0.12 g, 13%) derived from 7-amino - 3-(2-(N-tert. -butoxycarbonylamino) ethoxy)-1,2-benzisoxazole (0.88 g) in the reactions and treatments by way of example 43(a).

Melting point: 162-164oC;

IR spectrum (KBr)maxcm-1: 3346, 3312, 1709, 1639, 1626, 1550, 1514;

The NMR spectrum (CDCl3) MD: of 1.46 (9H,c) to 2.99 (3H, d, J=5.0 Hz), 3,63 (2H, q, J= 5,1 Hz), 3,63 (1H, q, J=5.0 Hz), of 4.49 (2H, t, J=5,1 Hz), to 4.98 (1H, Shir. C), only 6.64 (1H, d, J=7.8 Hz), 6,92 (1H, d, J=7.8 for the title compound get (72 mg, 99%) of 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-7-methylamino-1,2-benzisoxazole (80 mg) as a result of reactions and treatments according to the method of example 1(f).

Melting point: 171-181oC (decomposition);

IR spectrum (KBr) maxcm-1: 3026, 2965, 2912, 2866, 2786, 2730, 2638, 2600, 1573, 1546, 1504;

NMR spectrum (DMSO-d6) MD: 2,82 (3H,s) to 3.33 (2H, q, J=5,1 Hz), 4,59 (2H, t, J=5,1 Hz), of 6.65 (1H, d, J=7.9 Hz), 6.89 in (1H, d, J=7.9 Hz), 7,16 (1H, t, J=7.9 Hz), 8.34 per (3H, Shir.C).

Example 50.

5-amino-3-(2-aminoethoxy)-1,2-benzisoxazole

(a) 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-5-nitro-1,2 - benzisoxazol

Specified in the title compound (3,60 g, 74%) was obtained from 3-hydroxy - 5-nitro-1,2-benzisoxazole (2.70 g) in the reactions and treatments according to the method of example 1(e).

Melting point: 136-137oC;

IR spectrum (KBr)maxcm-1: 3346, 1688, 1624, 1555, 1531;

The NMR spectrum (CDCl3) MD: of 1.46 (9H,s) to 3.67 (2H, q, J=5,1 Hz), 4,55 (2H, t, J=5,1 Hz), of 4.95 (1H, Shir.C), 7,56 (1H, d, J=9,2 Hz), 8,46 (1H, DD, J=9,2 Hz, J=2.2 Hz), to 8.62 (1H, d, J=2.2 Hz).

(b) 5-amino-3-(2-(N-so-butoxycarbonylamino)ethoxy)- 1,2-benzisoxazol

Specified in the title compound (1.65 g, 91%) was obtained from 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-5 - nitro-1,2-benzisoxazole (2.00 g) in the reaction and treatment is m-1: 3470, 3442, 3384, 3360, 3325, 3276, 1699, 1639;

The NMR spectrum (CDCl3) MD: of 1.46 (9H,s), 3,63 (2H, q, J=5,1 Hz), 3,70 (2H, s), 4,47 (2H, t, J=5,1 Hz), of 4.95 (1H, Shir.C) 6,83 (1H, d, J=2.7 Hz), 6,92 (1H, DD, J=8,9 Hz, J=2.7 Hz), 7.23 percent (1H, d, J=8,9 Hz).

(C) 5-amino-3-(2-aminoethoxy)-1,2-benzisoxazole

Specified in the title compound (0.21 g, 99%) was obtained from 5-amino-3-(2-(N-tert.-butoxycarbonylamino)ethoxy)-1,2 - benzisoxazole (0.24 g) in the reactions and treatments according to the method of example 1(f).

Melting point: 182-202oC (decomposition);

IR spectrum (KBr)maxcm-1: 3428, 3379, 2963, 2859, 2726, 2665, 2581, 1656, 1637, 1628, 1609, 1549, 1507;

NMR spectrum (DMSO-d6) MD: of 3.46 (2H, q, J=5,1 Hz), 4,63 (2H, t, J=5,1 Hz), EUR 7.57 (1H, DD, J=8.9 Hz, J=2.0 Hz), to 7.67 (1H, d, J=2.0 Hz), to 7.93 (1H, d, J=8,9 Hz), 8,35 (3H, Shir.C)

Example 51.

3-(2-aminoethoxy)-4,7-dimethyl-1,2-benzisoxazole

(a) 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-4,7-dimethyl-1,2 - benzisoxazol

To a solution of 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-7 - methyl-1,2-benzisoxazole (0.15 g) in 5 ml of tetrahydrofuran, add utility (0.7 ml, 1.6 M solution in hexane) dropwise with stirring at -70oC in nitrogen atmosphere, the resulting mixture was stirred at room temperature for 10 minutes and then the temperature was raised to 0oC. The Settlement Is oC. the Reaction mixture was poured into ice-cold water (40 ml), extracted with ethyl acetate (twice 40 ml) and the combined extracts dried over anhydrous magnesium sulfate and filtered. The solvent is evaporated under reduced pressure and the residue is purified on a chromatographic column with silica gel, elwira with a mixture of cyclohexane/ethyl acetate (9:1) to obtain the title compound (0.12 g, 80%) as a colorless powder.

Melting point: 78-79oC;

IR spectrum (KBr)maxcm-1: 3352, 1694, 1604, 1543, 1517;

The NMR spectrum (CDCl3) MD: of 1.45 (9H,s), is 2.44 (3H,s), of 2.56 (3H,s), 4.26 deaths (2H, q, J=5,1 Hz), of 4.49 (2H, t, J=5,1 Hz), the 4.90 (1H, Shir.C) 6,89 (1H, d, J=7,3 Hz), to 7.15 (1H, d, J= 7,3 Hz).

(b) 3-(2-aminoethoxy)-4,7-dimethyl-1,2-benzisoxazole

Specified in the title compound (0.08 g) is obtained from 3-(2-(N-tert.- butoxycarbonylamino)ethoxy)-4,7-dimethyl-1,2-benzisoxazole (0.10 g) in the reactions and treatments according to the method of example 1(f).

Melting point: 222-225oC (decomposition);

IR spectrum (KBr) maxcm-1: 3300-2400, 1601, 1561, 1542, 1511;

NMR spectrum (DMSO-d6) MD: is 2.40 (3H,s), to 2.57 (3H,s) to 3.35 (2H, t, J=5,1 Hz), 4,60 (2H, t, J=5,1 Hz), 7,01 (1H, d, J=7,3 Hz), 7,31 (1H, d, J=7,3 Hz), 8,31 (3H, Shir.C).

Example 52.

3-(2-aminoethoxy)-4-methoxy (5,00 g) in 50 ml of dimethylformamide (50 ml) is added anhydrous potassium carbonate (6,00 g) and 6.0 ml methyliodide under stirring at room temperature, then intensively stirred for 12 hours. After completion of the reaction, the reaction mixture was diluted with ether, washed with water and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure to obtain the title compound (5,80 g, 98%) as oil.

The NMR spectrum (CDCl3) MD: 3,86 (3H,s), 3,93 (3H, s) 6,70-to 6.80 (2H,m), 7,28-7,37 (1H,m).

(b) 2-fluoro-6-methoxybenzyloxy acid

Specified in the title compound (44%) was obtained from methyl 2-fluoro-6 - methoxybenzoate and hydroxylaminopurine in the reactions and treatments according to the method of example 1(b).

The NMR spectrum (CDCl3+MeOH-d4) MD: to 3.92 (3H,s), 6.75 in-6,86 (2H,m), 7,35-7,45 (1H,m).

(C) 3-Hydroxy-4-methoxy-1,2-benzisoxazol

2-fluoro-6-methoxybenzyloxy acid (2.55 g) and potassium hydroxide (4,50 g) dissolved in 25 ml of butanol and refluxed for 4 hours. After completion of the reaction, the reaction mixture is acidified, extracted with ethyl acetate, and the extract obtained was washed with water and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure and the residue is recrystallized from isopropyl ether to obtain the title compound (2,05 g, 90%).

(d) 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-4-methoxy-1,2 - benzisoxazol

Specified in the title compound (81%) is obtained from 3-hydroxy-4-methoxy-1,2-benzisoxazole in the reactions and treatments according to the method of example 1(e).

The NMR spectrum (CDCl3) MD: of 1.46 (9H,s), the 3.65 (2H,m), of 3.96 (3H,c), 4,50 (2H, t, J=5,1 Hz), is 5.06 (1H, sh.C) of 6.61 (1H, d, J=8,2 Hz), 7,02 (1H, d, J= 8,2 Hz), the 7.43 (1H, t, J=8,2 Hz).

(e) 3-(2-aminoethoxy)-4-methoxy-1,2-benzisoxazole

Specified in the title compound (82%) is obtained from 3-(2-(N-tert.- butoxycarbonylamino)ethoxy)-4-methoxy-1,2-benzisoxazole in the reactions and treatments according to the method of example 1(f).

Melting point: 193-197oC;

IR spectrum (KBr)maxcm-1: 3435, 3220, 2960, 1630, 1615, 1535, 1505;

NMR spectrum (DMSO-d6) MD: to 3.34 (2H, t, J=5,2 Hz) to 3.92 (3H,c), 4,60 (2H, t, J=5,2 Hz) 6,86 (1H, d, J=8,4 Hz), 7,17 (1H, d, J=8,4 Hz), 7,58 (1H, t, J=8,4 Hz).

Example 53.

3-(2-aminoethoxy)-4-methoxy-7-methyl-1,2-benzisoxazole hydrochloride

Specified in the title compound is obtained from 3-(2-(N-tert.- butoxycarbonylamino)ethoxy)-4-methoxy-1,2-benzisoxazole in the reactions and treatments by way of example 51 (a), and then by the method of example 1(f).

Melting point: 208-211oC;
3H, t, J=5.4 Hz), with 3.89 (3H, c), 4,59 (2H, t, J=5.4 Hz), to 6.75 (1H, d, J= 8.1 Hz), 7,37 (1H, d, J=8.1 Hz), 8,30 (3H, Shir.C).

Example 54.

3-(2-aminoethoxy)-4-fluoro-1,2-benzisoxazole hydrochloride

(a) 2,6-differentgalaxy acid

Specified in the title compound are obtained from 65% yield from methyl - 2,6-differentiate and hydroxylaminopurine in the reactions and treatments according to the method of example 1(b).

NMR spectrum (DMSO-d6) MD: 7,14-of 7.25 (2H,m), 7,50-of 7.60 (1H, m), 9,40 (1H, Shir.C) of 11.15 (1H, Shir.C).

(b) 3-hydroxy-4-fluoro-1, 2-benzisoxazol.

Specified in the title compound (36%) derived from 2,6 - differentitation acid in the reactions and treatments by way of example 52(C).

Melting point: 175-178oC;

NMR spectrum (DMSO-d6) MD: to 7.09 (1H, t, J=8.5 Hz), 7,40 (1H, d, J=8.5 Hz), EUR 7.57-the 7.65 (1H,m).

(C) 3-(2-(N-tert.-butoxycarbonylamino)ethoxy-4-fluoro-1,2-benzisoxazol

Specified in the title compound (67%) derived from 3-hydroxy-4-fluoro - 1,2-benzisoxazole in the reactions and treatments according to the method of example 1(e).

The NMR spectrum (CDCl3) CBM: about 1.47 (9H,s), the 3.65 (2H,m), 4,51 (2H,t, J=5,1 Hz), 4,90-of 5.06 (1H, Shir.C) 6,91 (1H, t, J= 8.5 Hz), 7.23 percent (1H, t, J=8.5 Hz), 7,44-7,52 (1H,m).

(d) 3-(2-aminoethoxy)-4-fluoro-1,2-benzisoxazole hydrochloride

Melting point: 230-233oC (decomposition);

IR spectrum (KBr)maxcm-1: 3435, 2970, 1635, 1620, 1545, 1520, 1510;

NMR spectrum (DMSO-d6) MD: to 3.34 (2H, t, J=5,2 Hz), of 4.66 (2H, t, J=5,2 Hz), 7,21 (1H, t, J =8,3 Hz), 7,53 (1H, d, J=8,3 Hz), 7.68 per-7,74 (1H, m), 8,35 (3H, Shir.C).

Example 55.

3-(2-aminoethoxy)-4-fluoro-5-methyl-1,2-benzisoxazole hydrochloride and 3-(2-aminoethoxy)-4-fluoro-7-methyl-1,2-benzisoxazole hydrochloride

3-(2-aminoethoxy)-4-fluoro-5-methyl-1,2-benzisoxazole hydrochloride and 3-(2-aminoethoxy)-4-fluoro-7-methyl-1,2-benzisoxazole hydrochloride is obtained from 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-4-fluoro - 1,2-benzisoxazole in the reactions and treatments by way of example 51(a), and then by the method of example 1(f).

(a) Data for 3-(2-aminoethoxy)-4-fluoro-5-methyl-1,2-benzisoxazol - hydrochloride;

Melting point: 201-208oC;

IR spectrum (KBr)maxcm-1: 3430, 3305, 2840, 1645, 1615, 1540, 1515;

NMR spectrum (DMSO-d6) MD: 2,32 (3H,s) to 3.34 (2H, q, J=5.0 Hz), with 4.64 (2H, t, J=5.0 Hz), 7,42 (2H, d, J=8,4 Hz), 7,60 (1H, t, J=8,4 Hz), 8,27 (3H, Shir,C).

(b) Data for 3-(2-aminoethoxy)-4-fluoro-7-methyl-1,2 - benzisoxazole;

Melting point: 196-202oC;

IR spectrum (KBr)maxcm-1: 2975, 1635, 1550, 1520;

NMR spectrum (DMSO-d6) The P> 3-(2-aminoacetic)-5-chloro-7-methyl-1,2-benzisoxazole hydrochloride

(a) 3-(2-(N-tert. -butoxycarbonylamino)ethylthio)-5-chloro-7-methyl - 1,2-benzisoxazol

Specified in the title compound (0,13 g, 62%) was obtained from 3-(2- (N-tert. -butoxycarbonylamino)ethylthio)-5-chloro-1,2 - benzisoxazole (0.20 g) in the reactions and treatments by way of example 17 (b).

The NMR spectrum (CDCl3) MD: the 1.44 (9H,s), of 2.51 (3H,s), 3,40 (2H, t, J=6.3 Hz), to 3.58 (2H, q, J=6.3 Hz), 5,07 (1H, Shir.C), 7,29 (1H,s), of 7.36 (1H,s).

(b) 3-(2-aminoacetic)-5-chloro-7-methyl-1,2-benzisoxazole hydrochloride

Specified in the title compound (0.10 g,Col) is obtained from 3-(2-(N-tert. -butoxycarbonylamino) ethylamino)-5-chloro-7-methyl-1,2-benzisoxazole (0.12 g) as a result of reactions and treatments according to the method of example 1(f).

Melting point: 205-208oC (decomposition);

IR spectrum (KBr)maxcm-12966, 2927, 2848, 2802, 1481;

NMR spectrum (DMSO-d6) MD: 2,50 (3H,s), 3,23 (2H, t, J=6.9 Hz), 3,53 (2H, t, J=6.9 Hz), a 7.62 (1H,s), 7,74 (1H,s), 8,19 (3H, Shir.C).

Example 57.

3-(2-aminoacetic)-5-chloro-7-cyano-1,2-benzisoxazole hydrochloride

(a) 3-(2-(N-tert. -butoxycarbonylamino)ethylthio)-5-chloro-7-carboxy - 1,2-benzisoxazol

Specified in the title compound (0,42 g, 72%) was obtained from 3-(2-(N-tert. -butoxycarbonylamino)e is(2-(N-tert. -butoxycarbonylamino)ethylthio)-5-chloro-7-carbarnoyl - 1,2-benzisoxazol

Specified in the title compound (0.17 g, 85%) was obtained from 3-(2-(N-tert. -butoxycarbonylamino)ethylthio)-5 - chloro-7-carboxy-1,2-benzisoxazole (0.20 g) in the reactions and treatments by way of example 18(b).

IR spectrum (KBr)maxcm-1: 3471, 3354, 3143, 1693, 1678;

The NMR spectrum (CDCl3) MD: of 1.45 (9H,s), of 3.45 (2H, t, J=6,1 Hz) and 3.59 (2H, q, J= 6,1 Hz), 4,96 (1H, Shir.C) 5,97 (1H, Shir.C), 7,12 (1H, Shir,C), 7,73 (1H,s), a 8.34 (1H,s).

(C) 3-(2-(N-tert.-butoxycarbonylamino)ethylthio)-5-chloro-7-cyano-1,2 - benzisoxazol

Specified in the title compound (0,13 g, 90%) was obtained from 3-(2-(N-tert. -butoxycarbonylamino)ethylthio)-5 - chloro-7-carbarnoyl-1,2-benzisoxazole (0.15 g) in the reactions and treatments by way of example 19(a).

IR spectrum (KBr)maxcm-1: 3366, 2240, 1685;

The NMR spectrum (CDCl3) MD: of 1.45 (9H,s), of 3.46 (2H, t, J =6.2 Hz), of 3.60 (2H, q, J=6.2 Hz), 4,96 (1H, Shir,s), 7.81 (1H,s), to 7.84 (1H, s).

(d) 3-(2-aminoacetic)-5-chloro-7-cyano-1,2-benzisoxazole hydrochloride

Specified in the title compound (0.10 g, Col) is obtained from 3-(2-(N-tert. -butoxycarbonylamino) ethylthio)-5-chloro-7-cyano-1,2-benzisoxazole (0.12 g) as a result of reactions and treatments according to the method of example 1(f).

Melting point: 178-1816) MD: of 3.25 (2H, t, J=7.0 Hz), of 3.57 (2H, t, J=7.0 Hz), 8,23 (3H, Shir,C), 8,42 (1H,c), 8,49 (1H, s).

Example 58.

3-(2-aminoethoxy)-5-chloropyrid[3,2-d]isoxazolidinone

(a) Methyl-2,5-dichloronicotinic.

2,5-dichloronicotinic acid chloride (5.0 g) is dissolved in 30 ml of methanol with stirring under ice cooling, and then stirred at room temperature for 30 minutes. The solvent is evaporated under reduced pressure, and the residue is dissolved in ether, and washed with saturated aqueous sodium bicarbonate and brine. The obtained extract is dried over anhydrous magnesium sulfate, and the residue is purified on a chromatographic column with silica gel, elwira with a mixture of cyclohexane/ethyl acetate (30:1) to obtain the title compound (4,2 g, 86%).

The NMR spectrum (CDCl3) MD: 3,98 (3H,s), 8,16 (1H,c), 8,48 (1H,c).

(b) 2,5-dichloropyridine-3-carbohidrazona acid

Specified in the title compound (3.3 g, 79%) was obtained from methyl-2,5-dichloronicotinic (4,2 g) in the reactions and treatments according to the method of example 10(b).

IR spectrum (KBr)maxcm-1: 3187, 3073, 3058, 2985, 2906, 2851, 1661, 1575, 1553;

NMR spectrum (DMSO-d6) MD: 8,11 (1H,c), 8,58 (1H,s), 9,50 (1H,c), 11,40 (1H,s).

(C) 3-hydroxy-5-chloropyrid[3,2-d]isok is s (1.5 g) as a result of reactions and treatments according to the method of example 10(C).

IR spectrum (KBr)maxcm-1: 3193, 3166, 3069, 3055, 3003, 2919, 2821, 2783, 2734, 2689, 2633, 2587, 2550, 1697, 1615, 1602, 1554, 1508;

NMR spectrum (DMSO-d6) MD: to 8.40 (1H,c), 8,63 (1H,c), 12,90 (1H, Shir.C).

(d) 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-5-chloropyrid[3,2-d] isoxazol

Specified in the title compound (0.27 g, 73%) was obtained from 3-hydroxy-5-chloropyrid[3,2-d] isoxazol (0.20 g) in the reactions and treatments according to the method of example 1(e).

IR spectrum (KBr) maxcm-1: 3360, 1709, 1701, 1599, 1537, 1525;

The NMR spectrum (CDCl3) MD: of 1.46 (9H,s) to 3.64 (2H, q, J=5,2 Hz) to 4.52 (2H, t, J= 5,2 Hz), the 4.90 (1H, Shir.C) 8,03 (1H,c), 8,54 (1H, s).

(e) 3-(2-aminoethoxy)-5-chloropyrid[3,2-d]isoxazolidinone

Specified in the title compound (0,19 g) is obtained from 3-(2-(N-tert.-butoxycarbonylamino)ethoxy)-5 - chloropyrid[3,2-d]isoxazol (0.21 g) as a result of reactions and treatments according to the method of example 1(f).

Melting point: 225-230oC (decomposition);

IR spectrum (KBr)maxcm-1: 3065, 3036, 2978, 2900, 1604, 1598, 1535;

NMR spectrum (DMSO-d6) MD: to 3.34 (2H, t, J=5.0 Hz), with 4.64

(2H, t, J=5.0 Hz), of 8.25 (3H, Shir.C), and 8.50 (1H,s), 8,76 (1H, s).

Example 59.

3-(2-aminoacetic)-5-chloropyrid[3,2-d]isoxazolidinone

(a) 3,5-dichloropurine[3,2-d]isoxazol

Specified in the title what about the method of example 16.

The NMR spectrum (CDCl3) MD: 8,08 (1H,s) 8,64 (1H,s).

(b) 3-(2-(N-tert.-butoxycarbonylamino)ethylthio)-5-chloropyrid [3,2-d]isoxazol

Specified in the title compound (0.12 g, 71%) was obtained from 3,5-dichloropurine[3,2-d] isoxazol (0.10 g) in the reactions and treatments by way of example 26(b).

IR spectrum (KBr)maxcm-1: 3369, 1688, 1530;

The NMR spectrum (CDCl3) MD: of 1.46 (9H,s), 3,44 (2H, t, J =6.3 Hz) and 3.59 (2H, q, J=6.3 Hz), equal to 4.97 (1H, Shir, (C), of 7.95 (1H, s), to 8.57 (1H, s).

(C) 3-(2-aminoacetic)-5-chloropyrid[3,2-d]isoxazol hydrochloride

Specified in the title compound (0.08 g, Colca.) obtained from 3-(2-(N-tert.-butoxycarbonylamino)ethylthio)-5-chloropyrid- [3,2-d]isoxazol (0.10 g) in the reactions and treatments according to the method of example 1(f).

Melting point: 194-198oC (decomposition);

IR spectrum (KBr)maxcm-1: 3040, 3001, 2909, 1586, 1515;

NMR spectrum (DMSO-d6) MD: 3,24 (2H, t, J=7,1 Hz), 3,55 (2H, t, J=7,1 Hz), 8,17 (3H, Shir.C) 8,69 (1H,s), 8,79 (1H, s).

3-(2-aminoethoxy)-4-methoxycarbonyl-7-methyl-1,2 - benzisoxazole hydrochloride

(a) 3-(2-(N-tert-butoxycarbonylamino) ethoxy-4-methoxycarbonyl-7-methyl-1,2-benzisoxazol

Specified in the title compound (91%) is obtained from 3-(2-(N-tert - butoxycarbonylamino)ethoxy)-7-methyl-1,2-benzisoxazole in achiev the crown-rump length (KBr)maxcm-1: 3380, 1715, 1703, 1621, 1591, 1534, 1513;

The NMR spectrum (CDCl3) MD: of 1.46 (9H, s), of 2.56 (3H, s), 3,66-7 (2H, q), of 3.97 (3H, s), 4,51 (2H, t, J=5,1 Hz), 5,33 (1H, Shir. C) to 7.35 (1H, d, J and 7.6 Hz), 7,78 (1H, d, J=7,6 Hz).

(b) 3-(2-aminoethoxy)-4-methoxycarbonyl-7-methyl-1,2-benzisoxazole hydrochloride

Specified in the title compound (97%) is obtained from 3-(2-(N - tert-butoxycarbonylamino)ethoxy-4-methoxycarbonyl-7-methyl-1,2 - benzisoxazole in the reactions and treatments by way of example 17(C).

Melting point: 200-202oC (decomposition);

IR spectrum (KBr)maxcm-1: 3148, 3003, 2953, 1699, 1591, 1534, 1511;

NMR spectrum (DMSO-d6) MD: 2,53 (3H, s) to 3.34 (2H, t, J=5,1 Hz), 3,91 (3H, s), br4.61 (2H, t, J=5,1 Hz), to 7.59 (1H, d, J 7.5 Hz), 7,76 (1H, d, J 7.5 Hz), 8,19 (3H, Shir. C).

Example 61.

3-(2-aminoethoxy)-4-carbarnoyl-7-methyl-1,2-benzisoxazole hydrochloride

(a) 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-4 - carbarnoyl-7-methyl-1,2-benzisoxazol

Specified in the title compound (83%) is obtained from 3-(2-(N-tert.-butoxycarbonylamino) ethoxy)-7-methyl-1,2-benzisoxazole in the reactions and treatments by way of example 23(a).

Melting point: 140-141oC;

IR spectrum (KBr)maxcm-1: 3451, 3351, 3199, 1705, 1675, 1618, 1585, 1539, 1525, 1509;

The NMR spectrum (CDCl3 d, J=7,6 Hz).

(b) 3-(2-aminoethoxy)-4-carbarnoyl-7-methyl-1,2-benzisoxazole

Specified in the title compound (99%) is obtained from 3-(2-(N-tert.-butoxycarbonylamino) ethoxy)-4-carbarnoyl-7-methyl-1,2-benzisoxazole in the reactions and treatments by way of example 17(C).

Melting point: 202-205 areoC (decomposition);

IR spectrum (KBr)maxcm-1: 3435, 3347, 3293, 3203, 2950, 1901, 1687, 1659, 1608, 1581, 1544, 1512;

NMR spectrum (DMSO-d6) MD: 2,50 (3H,c) to 3.34 (2H,t, J=5,1 Hz), with 4.64 (2H, t, J= 5,1 Hz), 7,53 (2H,s), to 7.64 (1H, Shir.C) a 7.92 (1H, Shir.C), by 8.22 (3H, Shir.C).

Example 62. 3-(2-aminoethoxy)-4-cyano-7-methyl-1,2 - benzisoxazole

(a) 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-4-cyano - 7-methyl-1,2-benzisoxazol

Specified in the title compound (95%) is obtained from 3-(2-(N-tert.-butoxycarbonylamino) ethoxy)-4-carbarnoyl-7-methyl-1,2-benzisoxazole in the reactions and treatments by way of example 24(a).

Melting point: 84-85oC.

IR spectrum (KBr)maxcm-1: 3452, 3397, 2231, 1716, 1597, 1552, 1541, 1509;

The NMR spectrum (CDCl3) MD: of 1.45 (9H,c) at 2.59 (3H,c), 3,68 (2H, q, J=5,1 Hz), of 4.54 (2H, t, J=5,1 Hz), 5,10 (1H, Shir.C), 7,40 (1H, d, J=7,4 Hz), 7,54 (1H, d, J=7,4 Hz).

(b) 3-(2-aminoethoxy)-4-cyano-7-methyl-1,2-benzisoxazole

the isoxazol in the reactions and treatments by way of example 17(C).

Melting point: 208-211oC;

IR spectrum (KBr)maxcm-1: 3099, 3036, 2966, 2908, 2873, 2850, 2754, 2733, 2232, 1598, 1542, 1514;

NMR spectrum (DMSO-d6) MD: 2,56 (3H,c), 3,39 (2H, t, J=5,1 Hz), 4,71 (2H, t, J=5,1 Hz), to 7.68 (1H, d, J=7.5 Hz), 7,87 (1H, d, J=7.5 Hz), compared to 8.26 (3H, Shir.C).

Example 63.

3-(2-aminoethoxy)-7-methyl-4-methylthio-1,2-benzisoxazole

(a) 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-7-methyl-4 - methylthio-1,2-benzisoxazol

To a solution of 3-(2-(N-tert. - butoxycarbonylamino)ethoxy)-7-methyl-1,2-benzisoxazole (0.15 g) in 20 ml of tetrahydrofuran, add utility (0.7 ml, 1.6 M solution in hexane) dropwise with stirring at -70oC in nitrogen atmosphere, and then the mixture is stirred at the same temperature for 15 minutes, then add the dimethyl sulfide (0.11 g). The reaction mixture was poured into ice water (40 ml) and the combined extracts dried over anhydrous magnesium sulfate, and then filtered. The solvent is evaporated under reduced pressure and the residue is purified on a chromatographic column with silica gel, elwira with a mixture of cyclohexane/ethyl acetate (9:1) to obtain the title compound (0.15 g, 88%) as colorless powder.

Melting point: 85-86oC;

IR spectrum (KBr)maxcm 5,07 (1H, Shir.C) 6,86 (1H, d, J=7.5 Hz), 7,22 (1H, d, J= 7.5 Hz).

(b) 3-(2-aminoethoxy)-7-methyl-4-methylthio-1,2-benzisoxazole hydrochloride

Specified in the title compound are obtained from 94% yield from 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-7-methyl-4 - methylthio-1,2-benzisoxazole in the reactions and treatments by way of example 17(C).

Melting point: 216-218oC (decomposition);

IR spectrum (KBr)maxcm-1: 2940, 2917, 2883, 1629, 1593, 1541, 1508;

NMR spectrum (DMSO-d6) MD: 2,39 (3H,c), of 2.53 (3H,c) to 3.34 (2H, t, J=5,1 Hz), br4.61 (2H, t, J=5,1 Hz), 7,03 (1H, d, J=7.5 Hz), 7,41 (1H, d, J=7.5 Hz), compared to 8.26 (3H, Shir.C).

Example 64.

3-(2-aminoethoxy)-7-chloro-4-methyl-1,2-benzisoxazole

(a) 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-7-chloro-4-methyl-1,2 - benzisoxazol

Specified in the title compound are obtained from 93% yield from 3-(2- (N-tert. -butoxycarbonylamino)ethoxy)-7-chloro-1,2-benzisoxazole in the reactions and treatments by way of example 51(a).

IR spectrum (KBr)maxcm-1: 3355, 1691, 1605, 1551, 1536;

The NMR spectrum (CDCl3) MD: of 1.45 (9H,s), to 2.57 (3H,s), the 3.65 (2H, q, J=5,1 Hz), 4,50 (2H, t, J=5,1 Hz), to 4.87 (1H, Shir. C) 6,94 (1H, d, J=7.8 Hz), 7,37 (1H, d, J=7,8 Hz).

(b) 3-(2-aminoethoxy)-7-chloro-4-methyl-1,2-benzisoxazole hydrochloride

Specified in the title of septate reactions and treatments by way of example 17(C).

Melting point: 215-218oC (decomposition);

IR spectrum (KBr)maxcm-1: 3194, 2967, 2892, 1606, 1540;

NMR spectrum (DMSO-d6) MD: 2,60 (3H,s) to 3.35 (2H, t, J= 5,1 Hz), 4,63 (2H, t, J=5,1 Hz), 7,18 (1H, d, J=7,7 Hz), 7,66 (1H, d, J=7,7 Hz), 8,24 (3H, Shir.C).

Example 65.

3-(2-aminoethoxy)-5,7-dichloro-4-methyl-1,2-benzisoxazole hydrochloride

(a) 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-5,7-dichloro - 4-methyl-1,2-benzisoxazol

Specified in the title compound are obtained from 95% yield from 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-5,7-chloro-1,2-benzisoxazole in the reactions and treatments by way of example 51(a).

Melting point: 109-111oC;

IR spectrum (KBr)maxcm-1; 3354, 1697, 1616, 1552, 1528;

The NMR spectrum (CDCl3) MD: of 1.46 (9H,c) at 2.59 (3H,c), 3,63 (2H, q, J=5,1 Hz), 4,50 (2H, t, J=5,1 Hz), is 4.93 (1H, Shir.C) 7,58 (1H,s).

(b) 3-(2-aminoethoxy)-5,7-dichloro-4-methyl-1,2-benzisoxazole hydrochloride

Specified in the title compound are obtained from 99% yield from 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)- 5,7-dichloro-4-methyl-1,2-benzisoxazole in the reactions and treatments by way of example 17(C).

Melting point: 222-225oC (decomposition);

IR spectrum (KBr)maxcm-1: 3062, 2970, 2897, 2770, 1618, 1596, 1542, 1521;

3-(2-aminoethoxy)-7-carbarnoyl-5-chloro-1,2-benzisoxazole

(a) 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-7-carbarnoyl-5-chloro-1,2 - benzisoxazol

Specified in the title compound with 88% yield is obtained from 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-5 - chloro-1,2-benzisoxazole in the reactions and treatments by way of example 18(a), and then by way of example 18(b).

IR spectrum (KBr)maxcm-1: 3428, 3375, 3297, 3187, 1691, 1658, 1620, 1560, 1531;

The NMR spectrum (CDCl3) MD: of 1.46 (9H, s), 3,66 (2H, q, J= 5,1 Hz), a 4.53 (2H, t, J= 5,1 Hz), 4,94 (1H, Shir,C) of 5.99 (1H, Shir.C) was 7.08 (1H, Shir,C), 7,80 (1H, d, J=2.1 Hz), 8,31 (1H, d, J=2.1 Hz).

(b) 3-(2-aminoethoxy)-7-carbarnoyl-5-chloro-1,2-benzisoxazole hydrochloride

Specified in the title compound are obtained from 98% yield from 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-7 - carbarnoyl-5-chloro-1,2-benzisoxazole in the reactions and treatments by way of example 17(C).

Melting point: 232-237oC (decomposition);

IR spectrum (KBr)maxcm-1: 3450, 3339, 3290, 3238, 3164, 3082, 3047, 3011, 2952, 2878, 2847, 2818, 2766, 2688, 1672, 1626, 1608, 1594, 1547, 1520;

NMR spectrum (DMSO-d6) MD: 3,47 (2H, t, J= 5,1 Hz), 4,63 (2H, t, J=5,1 Hz), 7,94 (1H, Shir.C) of 7.97 (1H, Shir.C) 8,03 (1H, d, J=2.2 Hz), with 8.05 (1H, d, J=2.2 Hz), with 8.33 (3H, Shir. C).

Example 67.

3-(2-aminoethoxyethanol

Specified in the title compound are obtained from 92% yield from 3-(2- (N-tert. -butoxycarbonylamino)ethoxy)-5-chloro-7-carbarnoyl-1,2 - benzisoxazole in the reactions and treatments by way of example 24(a).

Melting point: 141-143oC;

IR spectrum (KBr)maxcm-1: 3364, 2244, 1684, 1609, 1547, 1527;

The NMR spectrum (CDCl3) MD: of 1.45 (9H,c), 3,62 (2H, q, J=5,1 Hz), a 4.53 (2H, t, J= 5,1 Hz), the 4.90 (1H, Shir,C), 7,81 (1H, d, J=2.2 Hz), 7,88 (1H, d, J=2.2 Hz).

(b) 3-(2-aminoethoxy)-5-chloro-7-cyano-1,2-benzisoxazole

Specified in the title compound are obtained from 94% yield from 3-(2-(N-tert.- butoxycarbonylamino)ethoxy)-5-chloro-7-cyano-1,2 - benzisoxazole in the reactions and treatments by way of example 17(C).

Melting point: 211-214oC (decomposition);

IR spectrum (KBr)maxcm-1: 3070, 3047, 2943, 2878, 2810, 2769, 2739, 2685, 2637, 2243, 1611, 1586, 1548, 1507;

NMR spectrum (DMSO-d6) MD: to 3.34 (2H, t, J= 5,1 Hz) and 4.65 (2H, t, J=5,1 Hz), 8,32 (1H, d, J=2.2 Hz), 8,39 (3H, Shir.C), 8,48 (1H, d, J=2.2 Hz).

Example 68.

3-(2-aminoethoxy-pyrido[2,3-d]isoxazol hydrochloride

(a) 3-(2-(N-tert.-butoxycarbonylamino)ethoxy)pyrido[2,3-d]isoxazol

Specified in the title compound are obtained from 63% yield from 3-hydroxypyridine[2,3-d] isoxazol in regex
cm-1: 3374, 3247, 1754, 1698, 1678, 1587, 1529;

The NMR spectrum (CDCl3) MD: the 1.44 (9H, s), 3,68 (2H, q, J=5,1 Hz), 4,59 (2H, t, J= 5,1 Hz), 5,12 (1H, Shir. C) to 7.50 (1H, DL, J=8.6 Hz, J=4.4 Hz), 7,81 (1H, DD, J=8.6 Hz, J=1.4 Hz), 8,68 (1H, DD, J=4.4 Hz, J=1.4 Hz).

(b) 3-(2-aminoethoxy)pyrido[2,3-d]ioctl hydrochloride

Specified in the title compound are obtained from 89% yield from 3-(2-(N-tert-butoxycarbonylamino) ethoxy)pyrido[2,3-d] isoxazol in the reactions and treatments according to the method of example 1(f).

Melting point: 217-222oC (decomposition);

IR spectrum (KBr)maxcm-1: 3070, 3020, 2980, 2911, 2870, 2783, 2700, 2658, 2601, 1631, 1586, 1541;

NMR spectrum (DMSO-d6) MD: the 3.35 (2H, t, J=5,1 Hz), 4.72 in (2H, t, J=5,1 Hz), 7,73 (1H, DD, J=8.6 Hz, J=4.4 Hz), 8,21 (1H, d, J-8.6 Hz), 8,32 (3H, Shir. C) 8,73 (1H, d, J 4.4 Hz).

Example 69.

3-(2-aminoethoxy)-4-(trifluoromethyl)pyrido[3,2-d]isoxazol hydrochloride

4-triftormetilfosfinov acid (5,00 g) is dissolved in a solution of acetic acid (20 ml) and 31% hydrogen peroxide solution (5 ml) and stirred at 100oC for 10 hours. The solvent is evaporated under reduced pressure to obtain the title compound (5,40 g, Quant.) in the form of a solid substance.

Melting point: 210-215oC (decomposition);

The NMR spectrum (CDCl3) MD: 7th ether

Phosphorus oxychloride (4.0 ml) and Piatigorsky phosphorus (4.0 g) is added to 4-triftormetilfosfinov acid N-oxide (2.00 g) and the resulting mixture was stirred at 100oC for 4 hours. The phosphorus oxychloride is evaporated under reduced pressure. To the residue is added methanol (30 ml) under ice cooling, and stirred at room temperature for 30 minutes. After adding to the reaction mixture of aqueous sodium bicarbonate, pH adjusted to alkaline values, the resulting mixture is extracted with ether, washed with water, the extract is dried over anhydrous magnesium sulfate. After filtration the solvent is evaporated under reduced pressure and the residue is purified on a chromatographic column with silica gel, elwira a mixture of hexane/ethyl acetate (9:1) to obtain the title compound (310 mg, 14%) as oil.

The NMR spectrum (CDCl3) MD: 4,01 (3H,s), 7,54 (1H, d, J=5.3 Hz), 8,65 (1H, d, J=5.3 Hz).

(C) 3-hydroxy-4-triptoreline[3,2-d]isoxazol

An aqueous solution (5 ml) hydroxylaminopurine (450 mg) and sodium hydroxide (520 mg) is added to methyl ether complex of 2-chloro-4-triftormetilfosfinov acid (300 mg) at room temperature, and the mixture was stirred for 5 days at room temperature and the resulting mixture was extracted with ethyl acetate. The combined extracts dried over anhydrous sodium sulfate, the solvent is evaporated under reduced pressure and the residue is recrystallized from ethyl acetate to obtain the title compound (180 mg, 67%) as a solid.

Melting point: 196-202oC;

NMR spectrum (DMSO-d6) MD: 7.81 (1H, d, J=4.9 Hz), 8,88 (1H, d, J=4.9 Hz), 13,30 (1H, Shir.C).

(d) 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-4-triptoreline [3,2-d]isoxazol

Specified in the title compound are obtained from 75% yield from 3-hydroxy-4-triptoreline [3, 2-d] isoxazol and 2-(N - tert.-butoxycarbonylamino)of ethanol in the reaction and treatment according to the method of example 1(e).

The NMR spectrum (CDCl3) MD: of 1.45 (9H,s), the 3.65 (2H, q, J=5,2 Hz), 4,55 (2H, t, J=5,2 Hz), the 4.90 (1H, Shir.C), 7,56 (1H, d, J=4.9 Hz), 8.77 (1H, d, J= 4,9 Hz).

(e) 3-(2-aminoethoxy)-4-triptoreline[3,2-d]isoxazol hydrochloride

Specified in the title compound are obtained from 96% yield from 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-4-triptoreline[3,2-d] isoxazol in the reactions and treatments according to the method of example 1(f).

Melting point: 203-207oC;

IR spectrum (KBr)maxcm-1: 3100, 2970, 1600, 1540;

NMR spectrum (DMSO-d6) MD: 3,34 (NEXI)-7-trifluoromethyl-1,2-benzisoxazole hydrochloride

(a) 2-fluoro-3-triftorperasin acid methyl ester

Specified in the title compound obtained as oil from 2-fluoro-3-triftorperasin acid in the reactions and treatments by way of example 52(a).

The NMR spectrum (CDCl3) MD: of 3.96 (3H,s), 7,31 (1H, t, J=5.0 Hz), 7,79 (1H, t, J=5.0 Hz), 8,18 (1H, t, J=5.0 Hz).

(b) 2-fluoro-3-triftormetilfullerenov acid

Specified in the title compound is obtained from 2-fluoro-3-triftorperasin acid methyl ether complex as a result of reactions and treatments by way of example 52(b).

NMR spectrum (DMSO-d6) MD: 7,46 (1H, t, J=5.0 Hz), 7,82 (2H,m).

(C) 3-hydroxy-7-trifluoromethyl-1,2-benzisoxazol

Specified in the title compound obtained as solid from 2-fluoro-3-triftormetilfullerenov acid in the reactions and treatments by way of example 52(C).

Melting point: 204-207oC;

NMR spectrum (DMSO-d6) MD: rate of 7.54 (1H, t, J=7,6 Hz), 7,98 (1H, d, J=7,6 Hz), of 8.09 (1H, d, J=7,6 Hz), 12,80 (1H, Shir.C).

(d) 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-7-trifluoromethyl - 1,2-benzisoxazol

Specified in the title compound obtained as a solid substance with a 65% yield of 3-hydroxy-7-trifluoromethyl - 1,2-Benzino"ptx2">

The NMR spectrum (CDCl3) MD: of 1.45 (9H,s), the 3.65 (2H, q, J=5,2 Hz), of 4.54 (2H, t, J= 5,2 Hz) to 4.52 (1H, Shir.C), 7,39 (1H, t, J=7,6 Hz), 7,79 (1H,d, J=7,6 Hz), the 7.85 (1H, d, J=7,6 Hz).

(e) 3-(2-aminoethoxy)-7-trifluoromethyl-1,2-benzisoxazole

Specified in the title compound are obtained from 77% yield from 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-7 - trifluoromethyl-1,2-benzisoxazole in the reactions and treatments according to the method of example 1(f).

Melting point: 190-194oC;

IR spectrum (KBr)maxcm-1: 2970, 2905, 1615, 1555, 1510;

NMR spectrum (DMSO-d6) MD: 3,37 (2H, t, J=5,1 Hz), and 4.68 (2H, t, J=5,1 Hz), a 7.62 (1H, t, J=7,6 Hz), of 8.09 (1H, d, J=7,6 Hz), 8,16 (1H, d, J=7,6 Hz), 8,44 (3H, Shir.C).

Example 71.

3-(2-aminoethoxy)-4-chloro-1,2-benzisoxazole hydrochloride

(a) 3-(2-(N-tert.-butoxycarbonylamino)ethoxy)-4-chloro-1,2 - benzisoxazol

Specified in the title compound are obtained from 63% yield from 3-hydroxy-4-chloro-1,2-benzisoxazole and 2-(N-tert.- butoxycarbonylamino)of ethanol in the reaction and treatment according to the method of example 1(e).

Melting point: 110-111oC;

IR spectrum (KBr)maxcm-13357, 1691, 1607, 1537;

The NMR spectrum (CDCl3) MD: of 1.46 (9H,s), 3,66 (2H, q, J=5,1 Hz), 4,51 (2H, t, J= 5,1 Hz), 4,99 (1H, Shir.C) of 7.23 (1H, d,J=7,6 Hz), 7,34 (1H, d, J=8,4 Hz), 7,44 (1H, DD, J=8,4 Hz, J=7,6 are square with 99% yield from 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-4-chloro-1,2 - benzisoxazole in the reactions and treatments by way of example 17(C).

Melting point: 221-226oC (decomposition);

IR spectrum (KBr)maxcm-1: 3440, 3070, 3006, 2969, 2898, 1610, 1538, 1515;

NMR spectrum (DMSO-d6) MD: the 3.35 (2H, t, J=5.4 Hz) and 4.65 (2H, t, J=5.4 Hz), 7,42-7,49 (1H,m), 7,62-7,71 (2H,m), 8,23 (3H, Shir.C).

Example 72.

3-(2-aminoethoxy)-6-methylpyridin[3,2-d]isoxazol hydrochloride

(a) 2-chloro-6-methylnicotinic acid ethyl ester

Specified in the title compound obtained as oil from 2-chloro-6-methylnicotinic acid in the reactions and treatments according to the method of example 1(a).

The NMR spectrum (CDCl3) MD: of 1.41 (3H, t, J=7.2 Hz), at 2.59 (3H,s) to 4.41 (2H, q, J=7.2 Hz), 7,16 (1H, d, J=7,2 Hz), 8,08 (1H, d, J=7,2 Hz).

(b) 2-chloro-6-methylpyridin-3-carbohidrazona acid

Specified in the title compound obtained as powder from 2-chloro-6-methylnicotinic acid ethyl ether complex as a result of reactions and treatments according to the method of example 10(b).

NMR spectrum (DMSO-d6) MD: of 2.51 (3H, s), 7,33 (1H, d, J=7.8 Hz), of 7.75 (1H, d, J=7,8 Hz).

(C) 3-hydroxy-6-methylpyridin[3,2-d]isoxazol

Specified in the title compound obtained as powder from 2-chloro-6-the P> IR spectrum (KBr)maxcm-1: 2985, 2907, 2739, 2559, 1663, 1610, 1595, 1561, 1541;

NMR spectrum (DMSO-d6) MD: 2,60 (3H,c), 7,30 (1H, d, J=8.0 Hz), 8,14 (1H, d, J=8.0 Hz).

(d) 3-(2-(N-tert.-butoxycarbonylamino)ethoxy-6-methylpyridin [3,2-d]isoxazol

Specified in the title compound are obtained from 71% yield from 3-hydroxy-6-methylpyridin[3,2-d] isoxazol and 2-(N-tert, butoxycarbonylamino) of ethanol in the reaction and treatment according to the method of example 1(e).

Melting point: 151-152oC;

IR spectrum (KBr)maxcm-1: 3332, 1718, 1708, 1614, 1609, 1534;

The NMR spectrum (CDCl3) MD: 1,4 (9H,c), 2,69 (3H,c) to 3.64 (2H, q, J=5,1 Hz), 4,51 (2H, t, J=5,1 Hz), 4,94 (1H. Shir.C) to 7.15 (1H, d, J=8.0 Hz), of 7.90 (1H, D, J=8.0 Hz).

(e) 3-(2-aminoethoxy)-6-methylpyridin[3,2-d]isoxazol hydrochloride

Specified in the title compound is obtained from 3-(2-(N - tert.-butoxycarbonylamino)ethoxy)-6-methylpyridin[3,2-d] isoxazol in the reactions and treatments according to the method of example 1(f).

Melting point: 209-213oC (decomposition);

IR spectrum (KBr)maxcm-1: 3426, 3063, 3000, 2938, 1669, 1609, 1565, 1536, 1506;

NMR spectrum (DMSO-d6) MD: 2,63 (3H,c), 3,30 is 3.40 (2H,m), to 4.62 (2H,t, J= 5,1 Hz), 7,40 (1H, d, J=8.0 Hz), 8,18 (1H, d, J=8.0 Hz), 8,29 (3H, Shir.C).

Example 73.

3-(2-aminoethoxy)-5-chloro-4-methyl-1,2-baxterville)ethoxy)-5-chloro-4-methyl-1,2-benzisoxazole and 3-(2-(N-tert.-butoxycarbonylamino)ethoxy)-5-chloro-7-methyl-1,2 - benzisoxazol 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-5 - chloro-4-methyl-1,2-benzisoxazol get 40% yield and 3-(2-(N - tert.-butoxycarbonylamino)ethoxy)-5-chloro-7-methyl-1,2 - benzisoxazol get with the release of 37% from 3-(2-(N-tert. - butoxycarbonylamino)ethoxy)-5-chloro-1,2-benzisoxazole in the reactions and treatments by way of example 17(b).

Data for 3-(2-(N-tert.-butoxycarbonylamino)ethoxy)-5-chloro-4 - methyl-1,2-benzisoxazole:

Melting point: 140-141oC;

IR spectrum (KBr)maxcm-1: 3351, 1688, 1615, 1601, 1537;

The NMR spectrum (CDCl3) MD: of 1.46 (9H,c), 2,62 (3H,c), 3,66 (2H, q, J=5,1 Hz), 4,50 (2H, t, J=5,1 Hz), 4,88 (1H, Shir.C) 7,19 (2H, d, J=8,8 Hz), 8,83 (1H, d, J=8,8 Hz).

Data for 3-(2-(N-tert.-butoxycarbonylamino)ethoxy)-5-chloro-7 - methyl-1,2-benzisoxazole:

Melting point: 94-95oC;

IR spectrum (KBr)maxcm-1: 3333, 1686, 1611, 1539;

The NMR spectrum (CDCl3) MD: of 1.46 (9H,c), 2,48 (3H,c), 3,63 (2H, q, J=5,1 Hz), of 4.49 (2H, t, J=5.1 Hz), 4.94 (1H, Shir. C), 7,29 (1H, d, J=1,8 Hz), 7,44 (1H, d, J=1,8 Hz).

(b) 3-(2 - aminoethoxy)-5-chloro-4-methyl-1, 2-benzisoxazole hydrochloride

Specified in the title compound are obtained from 99% yield from 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-5-chloro-4 - methyl-1,2-benzisoxazole in the reactions and treatments by way of example 17(C).

8, 1605, 1536;

NMR spectrum (DMSO-d6) MD: 2,62 (3H,c) to 3.34 (2H, t, J=5,1 Hz), 4,63 (2H, t, J=5,1 Hz), 7,52 (1H, d, J=8,9 Hz), to 7.68 (1H, d, J=8,9 Hz), 8,23 (3H, Shir.C).

(C) 3-(2-aminoethoxy)-5-chloro-7-methyl-1,2-benzisoxazole hydrochloride

Specified in the title compound are obtained from 98% yield from 3-(2-(N - tert. -butoxycarbonylamino)ethoxy)-5-chloro-7-methyl-1,2-benzisoxazole in the reactions and treatments by way of example 17(C).

Melting point: 208-211oC (decomposition);

IR spectrum (KBr)maxcm-1: 3428, 3056, 2966, 2894, 2770, 1608, 1541, 1517;

NMR spectrum (DMSO-d6) MD: the 2.46 (3H,c) to 3.34 (2H, t, J=5,1 Hz), 4,60 (2H, t, J=5,1 Hz), to 7.59 (1H, d, J=1,8 Hz), 7,69 (1H, d, J=1,8 Hz), 8,32 (3H, Shir.C).

Example 74.

3-(2-aminoethoxy)-5-bromo-4-methyl-1,2-benzisoxazole and 3-(2-aminoethoxy)-5-bromo-7 - methyl-1,2-benzisoxazole

(a) 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-5-bromo-4-methyl - 1,2-benzisoxazole and 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-5-bromo-7 - methyl-1,2-benzisoxazol

3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-5 - bromo-4-methyl-1,2-benzisoxazol receive a 7% yield and 3-(2-

(N-tert. -butoxycarbonylamino)ethoxy)-5-chloro-7-methyl-1,2 - benzisoxazol get with 68% yield from 3-(2-(N-tert.- butoxycarbonylamino)ethoxy)-5-bromo-1,2-benzisoxazole in ritox)-5-bromo-4 - methyl-1,2-benzisoxazole:

Melting point: 140-141oC;

IR spectrum (KBr)maxcm-1: 3350, 1688, 1618, 1595, 1538;

The NMR spectrum (CDCl3) MD: of 1.46 (9H,s) of 2.64 (3H,s), 3,66 (2H, q, J=5,1 Hz), 4,50 (2H, t, J=5,1 Hz), 4,88 (1H,Shir.C) 7,14 (1H, d, J=8,8 Hz), 7,63 (1H, d, J=8,8 Hz).

Data for 3-(2-(N-tert.-butoxycarbonylamino)ethoxy)-5-bromo-7 - methyl-1,2-benzisoxazole:

Melting point: 79-80oC;

IR spectrum (KBr)maxcm-1: 3350, 1692, 1612, 1535;

The NMR spectrum (CDCl3) MD: of 1.46 (9H,s), 2,48 (3H,s), the 3.65 (2H, q, J=5,1 Hz), of 4.49 (2H, t, J=5,1 Hz), of 4.95 (1H, Shir.C), 7,29 (1H, d, J=1,8 Hz), 7,44 (1H, d, J=1,8 Hz).

(b) 3-(2-aminoethoxy)-5-bromo-4-methyl-1,2-benzisoxazole hydrochloride

Specified in the title compound are obtained from 96% yield from 3-(2- (N-tert. -butoxycarbonylamino)ethoxy)-5-bromo-4-methyl-1,2 - benzisoxazole in the reactions and treatments by way of example 17(C).

Melting point: 208-212oC (decomposition);

IR spectrum (KBr)maxcm-1: 3436, 3000, 1615, 1599, 1535;

NMR spectrum (DMSO-d6) MD: of 2.64 (3H,s) to 3.34 (2H, t, J=5,1 Hz), 4,63 (2H, t, J=5,1 Hz), 7,46 (1H, d, J=8,9 Hz), 7,82 (1H, d, J=8,9 Hz), 8,24 (3H, Shir.C).

(C) 3-(2-aminoethoxy)-5-bromo-7-methyl-1,2-benzisoxazole hydrochloride

Specified in the title compound are obtained from 98% yield from 3-(2-(N-tert. -butoxycarbonylamino)autokrator melting point: 212-215oC (decomposition);

IR spectrum (KBr)maxcm-1: 3339, 3054, 2968, 2925, 2892, 1606, 1546, 1516;

NMR spectrum (DMSO-d6) MD: the 2.46 (3H,c) to 3.33 (2H, t, J=5,1 Hz), 4,60 (2H, t, J=5,1 Hz), of 7.70 (1H, d, J=1,8 Hz), 7,82 (1H, d, J=1,8 Hz), 8,28 (3H, Shir.C).

Example 75.

3-(2-aminoethoxy)-4,5-dimethyl-1,2-benzisoxazole hydrochloride

(a) 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-4,5-dimethyl-1,2 - benzisoxazol

Specified in the title compound are obtained from 73% yield from 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-5-methyl - 1,2-benzisoxazole in the reactions and treatments by way of example 51(a).

Melting point: 125-126oC;

IR spectrum (KBr) maxcm-1: 3352, 1694, 1678, 1620, 1609, 1539;

The NMR spectrum (CDCl3) MD: of 1.46 (9H,c), of 2.33 (3H,c), of 2.51 (3H, s), the 3.65 (2H, q, J=5,1 Hz), of 4.49 (2H, t, J=5,1 Hz), the 4.90 (1H, sh.C) 7,13 (1H, d, J= 8.5 Hz), 7,29 (1H, d, J=8,5 Hz).

(b) 3-(2-aminoethoxy)-4,5-dimethyl-1,2-benzisoxazole hydrochloride

Specified in the title compound are obtained from 96% yield from 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-4,5 - dimethyl-1,2-benzisoxazole in the reactions and treatments by way of example 17(C).

Melting point: 180-183oC (decomposition);

IR spectrum (KBr)maxcm-1: 3434, 2971, 2924, 2751, 1643, 1612, 1538;

NMR spectrum (DMSO-demer 76.

3-(2-aminoethoxy)-4-methyl-5-methoxy-1,2-benzisoxazole hydrochloride

(a) 3-(2-(N-tert.-butoxycarbonylamino)ethoxy)-4 - methyl-5-methoxy-1,2-benzisoxazol

Specified in the title compound are obtained from 88% yield from 3-(2-(N-tert. -butoxycarbonylamino) ethoxy)-5-methoxy-1,2-benzisoxazole in the reactions and treatments by way of example 51(a).

Melting point: 137-138oC;

IR spectrum (KBr)maxcm-1: 3361, 1689, 1618, 1538;

The NMR spectrum (CDCl3) MD: of 1.45 (9H,s) to 2.46 (3H,c), the 3.65 (2H, q, J=5,1 Hz), a 3.87 (3H,s), 4,48 (2H, t, J=5,1 Hz), the 4.90 (1H, Shir.C), 7,12 (1H, d, J= 8,9 Hz), 7,18 (1H, d, J=8,9 Hz).

(b) 3-(2-aminoethoxy)-4-methyl-5-methoxy-1,2-benzisoxazole hydrochloride

Specified in the title compound are obtained from 99% yield from 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-4-methyl-5 - methoxy-1,2-benzisoxazole in the reactions and treatments by way of example 17(C).

Melting point: 173-176oC (decomposition);

IR spectrum (KBr)maxcm-1: 3423, 3008, 2971, 2920, 2842, 1617, 1601, 1536, 1500;

NMR spectrum (DMSO-d6) MD: 2,44 (3H,c), the 3.35 (2H, t, J=5,1 Hz), of 3.84 (3H, c), 4,60 (2H, t, J=5,1 Hz), 7,35 (1H, d, J= 9.0 Hz), 7,40 (1H, d, J=9.0 Hz), 8,32 (3H, Shir.C).

Example 77.

3-(2-aminoethoxy)-5-carbarnoyl-1,2-benzisoxazole hydrochloride

(a) 3-(2-(N-tert. 12% yield from 3-(2-(N-tert. -butoxycarbonylamino) ethoxy)-5-bromo-1,2-benzisoxazole in the reactions and treatments by way of example 23(a).

Melting point: 178-180oC;

IR spectrum (KBr)maxcm-1: 3348, 3197, 1717, 1672, 1624, 1599, 1543;

The NMR spectrum (CDCl3) MD: of 1.46 (9H,c), the 3.65 (2H, q, J=5,1 Hz), a 4.53 (2H, t, J= 5,1 Hz) to 5.00 (1H, Shir.C), 5,50-6,50 (2H, Shir.C), 7,49 (1H, d, J=8,8 Hz), of 8.04 (1H, d, J=8,8 Hz), 8,16 (1H,s).

(b) 3-(2-aminoethoxy)-5-carbarnoyl-1,2-benzisoxazole hydrochloride

Specified in the title compound are obtained from 96% yield from 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-5-carbarnoyl-1,2 - benzisoxazole in the reactions and treatments by way of example 17(C).

Melting point: 218-222oC (decomposition);

IR spectrum (KBr)maxcm-1: 3429, 3353, 3317, 3195, 2977, 2901, 1671, 1622, 1596, 1546, 1501;

NMR spectrum (DMSO-d6) MD: to 3.33 (2H, t, J=5,1 Hz), with 4.64 (2H, t, J=5,1 Hz), 7,51 (1H, s), 7,72 (1H, d, J=8.8 Hz), 8,18 (1H,s), 8,21 (1H, d, J=8,8 Hz), 8,31 (3H, Shir.C) to 8.40 (1H,s).

Example 78.

3-(2-aminoethoxy)-5-cyano-1,2-benzisoxazole hydrochloride

(a) 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-5-cyano-1,2 - benzisoxazol

Specified in the title compound are obtained from 92% yield from 3-(2-(N-tert. -butoxycarbonylamino) ethoxy)-5-carbarnoyl-1,2-benzisoxazole in reactions and education cm-1: 3349, 2233, 1717, 1708, 1623, 1605, 1540, 1527;

The NMR spectrum (CDCl3) MD: of 1.46 (9H,c), the 3.65 (2H, q, J=5,1 Hz), a 4.53 (2H, t, J= 5,1 Hz), is 4.93 (1H, Shir.C), 7,56 (1H, d, J=8,8 Hz), 7,79 (1H, d, J=8,8 Hz), of 8.04 (1H,s).

(b) 3-(2-aminoethoxy)-5-cyano-1,2-benzisoxazole hydrochloride

Specified in the title compound are obtained from 96% yield from 3-(2-(N-tert. -butoxycarbonylamino)ethoxy)-5-cyano-1,2 - benzisoxazole in the reactions and treatments by way of example 17(C).

Melting point: 212-216oC (decomposition);

IR spectrum (KBr)maxcm-1: 3171, 3096, 3058, 3029, 2953, 2239, 1624, 1601, 1544, 1518;

NMR spectrum (DMSO-d6) MD: to 3.34 (2H, t, J=5,1 Hz) and 4.65 (2H, t, J=5,1 Hz), to $ 7.91 (1H, d, J=8,8 Hz), 8.12 (1H, d, J=8,8 Hz), 8,35 (3H, Shir.C) 8,43 (1H,s).

Test method 1.

Activity by inhibition of monoamine oxidase

Measurements carried out according to the method described in Biochem, Pharmacol., 12, 1439 (1963) u J. Neurochem., 35, 109 (1980). 210 ál phosphate buffer (pH 7,4) and 30 ál subject test compounds (dissolved in 10% solution of DMSO-water) are added to 30 μl of the crude sample of mitochondria in mouse brain (30 μg protein), and the mixture was pre-incubated for 20 minutes at 38oC. then add14C-2-phenylethylamine (PEA, final concentration: 20 μm) for the concentration: 100 μm) to determine the activity by inhibition of monoamine oxidase A-type; the obtained mixtures provide an opportunity to respond, respectively, for 20 minutes at 38oC. then the reaction mixture was suspended by adding 2n HCl (200 MK1),14C-labeled metabolite formed in the enzymatic reaction, extracted with a solvent (ethyl acetate:toluene=1:1), and measured 14C radioactivity using a scintillation counter to determine the concentration (IC50the connection, which reduces14C radioactive activity by 50%.

The results are shown in table 17.

An example of obtaining 1.

The agent in the form of hard capsules.

Individual capsules get, filling 100 mg of the compound of example 1 in the form of a powder, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate in the relevant standard hard gelatin capsules. Prepared individual capsules are washed, dried, and get the agent in the form of hard capsules.

/Industrial applicability/

Derivatives isoxazol (I) and (II) of the present invention have plenty of B-type monoamine oxidase-inhibitory action and A-type a monoamine oxidase-inhibitory action (especially they differ inhibitory activity against monoamine oxidase B-type), and also have nitesky agents against such neuropathies, as Parkinson's disease, depression, Alzheimer's disease, etc., (especially against Parkinson's disease).

If the compound (I) and (II) of the present invention or their farmatsevticheskii acceptable salts are used as therapeutic agents or preventive agents above nervous diseases, these compounds can be administered orally in the form of tablets, capsules, powders, syrups, granules, etc. or neironalna, through injections or suppositories, as they are or in a mixture with the corresponding pharmaceutically acceptable excipients, diluents, etc.

These agents are prepared in conventional ways, using additives such as excipients (for example, sugar derivatives such as lactose, sucrose, glucose, mannitol and sorbitol; starch derivatives as corn starch, potato starch, a - starch, dextrin and carboximetilkrahmal; such derivatives of cellulose, as crystalline cellulose, hydroxypropylcellulose with a low degree of substitution, hypromellose, carmellose, calcixerollic and nutricology with internal crosslinks; acacia; dextran; pullulan, such derived silicate as light anhydrous silicic acid, A calcium carbonate; such sulfate as calcium sulfate, etc.,), binders (for example, the above-mentioned excipients; gelatin; polyvinylpyrrolidone; macrogol, etc.,), fillers (for example, the above-mentioned excipients, nutricology, natrocarbonatite-starch, such chemically modified starch as crosspovidone, cellulose derivatives, etc), moving (for example, talc, stearic acid; metal stearates such as calcium stearate and magnesium stearate; colloidal silica; natural resins, as beeswax and spermaceti; boric acid; glycol; carboxylic acids, as fumaric acid and adipic acid; carboxylate sodium, as sodium benzoate; sulfates such as sodium sulfate; leucine, such laurylsulfate as nutriceuticals, magnipapillata; such silica as silicic acid anhydride and silicic acid hydrate; such derivatives of starch, as the above excipients), fungicides (for example, such parahydroxybenzoate, as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenethyl alcohol; benzylaniline; phenols such as phenol and cresol; acetic anhydride; and sorbic acid, etc.,), it gives taste and the eating and solvent for injection (for example, water, ethanol, glycerol, etc.,). Used doses vary depending on symptoms, age, etc., but preferably, you should enter the adult minimum 1 mg (preferably 10 mg) and a maximum of 2000 mg (preferably, 400 mg) once a day in oral administration, and a minimum of 0.1 mg (preferably 1 mg) and a maximum of 500 mg (preferably, 300 mg) intravenously; and this dose is administered one to six times a day depending on symptoms.

1. Derivatives isoxazol formula (I)

< / BR>
where R1represents a hydrogen atom; a halogen atom; alkyl group containing from 1 to 6 carbon atoms; an alkyl group containing from 1 to 4 carbon atoms and substituted by a halogen atom; alkoxygroup containing from 1 to 6 carbon atoms; haloalkoxy group with 1 to 6 carbon atoms; a hydroxyl group; allylthiourea containing from 1 to 6 carbon atoms; the amino group; monoalkylamines, the alkyl part of which contains from 1 to 6 carbon atoms; dialkylamino in which each alkyl fragment independently contains from 1 to 6 carbon atoms; alkanoyloxy, containing from 1 to 6 carbon atoms; alkoxycarbonyl group containing from 1 to 6 carbon atoms is at;

m represents an integer from 1 to 3;

n represents an integer from 1 to 6;

ring A represents A phenyl ring fused with isoxazoline ring; naphtalene ring condensed with isoxazoline ring; or an aromatic heterocycle with 5 - or 6-membered ring containing one or two heteroatoms selected from the group consisting of atoms of oxygen, nitrogen and sulfur, fused with isoxazoline ring; and

X represents an oxygen atom or a sulfur atom;

provided that if m represents the integer 2 or 3, the substituents R1the same or different;

or its pharmaceutically acceptable salt.

2. Connection on p. 1, where R1represents a hydrogen atom; a halogen atom; alkyl group containing from 1 to 4 carbon atoms; triptorelin group; alkoxygroup containing from 1 to 4 carbon atoms; dipterocarp; a hydroxyl group; allylthiourea containing from 1 to 4 carbon atoms; the amino group; monoalkylamines, in which the alkyl fragment contains from 1 to 4 carbon atoms; dialkylamino in which each alkyl fragment independently contains from 1 to 4 carbon atoms; alkanoyloxy containing from 1 to 4 atoms uh-huh; the nitro-group or a cyano, or its pharmaceutically acceptable salt.

3. Connection on p. 1, where R1represents a hydrogen atom; a halogen atom; alkyl group containing from 1 to 4 carbon atoms; triptorelin group; alkoxygroup containing from 1 to 4 carbon atoms, dipterocarp; a hydroxyl group; allylthiourea containing from 1 to 4 carbon atoms; the amino group; methylaminopropyl; dimethylaminopropyl; alkoxycarbonyl group containing from 1 to 4 carbon atoms; carboxypropyl; karbamoilnuyu group; a nitro-group or a cyano, or its pharmaceutically acceptable salt.

4. Connection on p. 1, R1represents a hydrogen atom; a fluorine atom, chlorine atom, bromine atom, methyl group, triptorelin group, a methoxy group, dipterocarp, a hydroxyl group, methylthiourea, amino group, methylaminopropyl, dimethylaminopropyl, acetyloxy, methoxycarbonyl group, carboxypropyl, karbamoilnuyu group, a nitrogroup, or cyano, or its pharmaceutically acceptable salt.

5. Connection on p. 1, where R1represents a hydrogen atom; a fluorine atom, chlorine atom, bromine atom, methyl group, methoxy group, methylthiourea, Daya salt.

6. The compound according to any one of paragraphs.1 to 5, where m = 2, or its pharmaceutically acceptable salt.

7. The compound according to any one of paragraphs.1 to 5, where m = 1, or its pharmaceutically acceptable salt.

8. The compound according to any one of paragraphs.1 to 7, where n takes values from 2 to 4, or its pharmaceutically acceptable salt.

9. The compound according to any one of paragraphs.1 to 7 ,where n = 2, or its pharmaceutically acceptable salt.

10. The compound according to any one of paragraphs.1 to 9, where ring A is a phenyl ring, naphtalene ring, peregrinae ring, or its pharmaceutically acceptable salt.

11. The compound according to any one of paragraphs.1 to 9, where ring A is a phenyl ring or peregrinae ring, or its pharmaceutically acceptable salt.

12. The compound according to any one of paragraphs.1 to 9, where ring A is a phenyl ring, or its pharmaceutically acceptable salt.

13. The compound according to any one of paragraphs.1 - 12, where X represents an oxygen atom, or its pharmaceutically acceptable salt.

14. Connection on p. 1, selected from the group consisting of:

3-(2-aminoethoxy)benzisoxazole,

3-(2-aminoethoxy)ferberization,

3-(2-aminoacetic)ferberization,

3-(2-aminoethoxy)fluorine-methoxazole,

3-(2-aminoethoxy)fluorine-methoxycarbonylbenzyl,

3-(2-aminoethoxy)percarbonate,

3-(2-aminoethoxy)fluorine-cyanobenzoate,

3-(2-aminoacetic)fluorine-cyanobenzoate,

3-(2-aminoethoxy)chlorobenzotriazole,

3-(2-aminoacetic)chlorobenzotriazole,

3-(2-aminoethoxy)dichlorobenzothiazole,

3-(2-aminoacetic)dichlorobenzothiazole,

3-(2-aminoethoxy)chlorine-methylbenzotriazole,

3-(2-aminoacetic)chlorine-methylbenzotriazole,

3-(2-aminoethoxy)chlorine-carbamoylaspartate,

3-(2-aminoethoxy)chlorine-cyanobenzoate,

3-(2-aminoacetic)chlorine-cyanobenzoate,

3-(2-aminoethoxy)dichloro-methylbenzotriazole,

3-(2-aminoethoxy)bambusicola,

3-(2-aminoethoxy)bromine-methylbenzotriazole,

3-(2-aminoethoxy)methylbenzotriazole,

3-(2-aminoacetic)methylbenzotriazole,

3-(2-aminoethoxy)dimethylbenzoxazole,

3-(2-aminoethoxy)methyl-methoxybenzothiazole,

3-(2-aminoethoxy)methyl-methylthiosemicarbazone,

3-(2-aminoethoxy)methyl-methoxycarbonylbenzyl,

3-(2-aminoethoxy)methyl-carbamoylaspartate,

3-(2-aminoethoxy)methyl-cyanobenzoate,

3-(2-aminoethoxy)trifluoromethyl>/BR>3-(2-aminoethoxy)differentoccasions,

3-(2-aminoethoxy)hydroxybenzotriazole,

3-(2-aminoethoxy)aminobenzotriazole,

3-(2-aminoacetic)aminobenzotriazole,

3-(2-aminoethoxy)methylaminoethanol,

3-(2-aminoethoxy)dimethylaminobenzoate,

3-(2-aminoethoxy)acetyloxybenzoic,

3-(2-aminoethoxy)carboxylesterase,

3-(2-aminoethoxy)methoxycarbonylbenzyl,

3-(2-aminoethoxy)carbamoylaspartate,

3-(2-aminoethoxy)nitrobenzisoxazole,

3-(2-aminoacetic)nitrobenzisoxazole,

3-(2-aminoethoxy)cyanobenzoate,

3-(2-aminoethoxy)nefteiskateli,

3-(2-aminoethoxy)peridotite,

3-(2-aminoethoxy)chloronicotinate,

3-(2-aminoacetic)chloronicotinate,

3-(2-aminoethoxy)methylpyridoxine, and

3-(2-aminoethoxy)triftoratsetilatsetonom

and their pharmaceutically acceptable salts.

15. Connection on p. 1, selected from the group consisting of:

3-(2-aminoethoxy)-1,2-benzisoxazole,

3-(2-aminoethoxy)-5-fluoro-1,2-benzisoxazole,

3-(2-aminoethoxy)-5-fluoro-4-methyl-1,2-benzisoxazole,

3-(2-aminoacetic)-5-fluoro-1,2-benzisoxazole,

3-(2-aminoethoxy)-5-kvantizatsiya,

3-(2-aminoacetic)-5-chloro-1,2-benzisoxazole,

3-(2-aminoethoxy)-6-chloro-1,2-benzisoxazole,

3-(2-aminoethoxy)-7-chloro-1,2-benzisoxazole,

3-(2-aminoethoxy)-5-bromo-1,2-benzisoxazole,

3-(2-aminoethoxy)-5-methyl-1,2-benzisoxazole,

3-(2-aminoacetic)-5-methyl-1,2-benzisoxazole,

3-(2-aminoethoxy)-6-methyl-1,2-benzisoxazole,

3-(2-aminoethoxy)-7-methyl-1,2-benzisoxazole,

3-(2-aminoethoxy)-5-methoxy-1,2-benzisoxazole,

3-(2-aminoacetic)-5-methoxy-1,2-benzisoxazole,

3-(2-aminoethoxy)-5-deformedarse-1,2-benzisoxazole,

3-(2-aminoethoxy)-5-fluoro-4-methylthio-1,2-benzisoxazole,

3-(2-aminoethoxy)-5-methoxycarbonyl-1,2-benzisoxazole,

3-(2-aminoethoxy)-5-nitro-1,2-benzisoxazole,

3-(2-aminoacetic)-5-nitro-1,2-benzisoxazole,

3-(2-aminoethoxy)-4-cyano-1,2-benzisoxazole and

3-(2-aminoethoxy)pyrido(3,2-a)isoxazol,

and their pharmaceutically acceptable salts.

16. Connection on p. 1, selected from the group consisting of

3-(2-aminoethoxy)-4,7-dimethyl-1,2-benzisoxazole,

3-(2-aminoethoxy)-4-fluoro-7-methyl-1,2-benzisoxazole and

3-(2-aminoethoxy)-4-triptoreline(3,2-a)isoxazol

and their pharmaceutically acceptable salts.

17. Applying at least, one who provide a monoamine oxidase agent:

< / BR>
where R1represents a hydrogen atom; a halogen atom; alkyl group containing from 1 to 6 carbon atoms; an alkyl group containing from 1 to 4 carbon atoms and substituted by a halogen atom or alkoxygroup containing from 1 to 4 carbon atoms; alkoxygroup containing from 1 to 6 carbon atoms; haloalkoxy containing from 1 to 6 carbon atoms; a hydroxyl group; allylthiourea containing from 1 to 6 carbon atoms; the amino group; monoalkylamines, the alkyl part of which contains from 1 to 6 carbon atoms; dialkylamino, in which each alkyl fragment independently contains from 1 to 6 carbon atoms; alkanoyloxy group containing from 1 to 6 carbon atoms; alkanolamines containing from 1 to 6 carbon atoms; alkanoyloxy containing from 1 to 6 carbon atoms; alkoxycarbonyl group containing from 1 to 6 carbon atoms; carboxypropyl; karbamoilnuyu group; monoalkylammonium group, the alkyl part of which contains from 1 to 6 carbon atoms; dialkylamino group, each alkyl part of which independently contains from 1 to 6 carbon atoms; a nitro-group, or cyano;

R2ais monoalkylation ragment which independently contains from 1 to 4 carbon atoms;

m represents an integer from 1 to 3;

n represents an integer from 1 to 6;

ring a represents a phenyl ring fused with isoxazoline ring; naphtalene ring condensed with isoxazoline ring; or an aromatic heterocyclic 5 - or 6-membered ring which contains one or two heteroatoms selected from the group consisting of oxygen atoms, nitrogen atoms and sulfur atoms, condensed with isoxazoline ring; and

X represents an oxygen atom or a sulfur atom;

provided that if m represents the integer 2 or 3, the substituents R1the same or different.

18. Application on p. 17 derived isoxazol formula (II) or its pharmaceutically acceptable salts, where R1represents a hydrogen atom; a halogen atom; alkyl group containing from 1 to 4 carbon atoms; pharmacylow group; deformational group; triptorelin group; 2-foretelling group; 2-chloraniline group; 2,2,2-triptorelin group; methoxymethyl group; methoxyaniline group; alkoxygroup containing from 1 to 4 carbon atoms; formatexpr; chlorotoxin; dipterocarp; dichloromethoxy; cryptometer; trichlormethiazide; allylthiourea containing from 1 to 4 carbon atoms; the amino group; monoalkylamines, in which the alkyl fragment contains from 1 to 4 carbon atoms; dialkylamino in which each alkyl fragment independently contains from 1 to 4 carbon atoms; formyl group; an acetyl group; formylamino; acetylamino; alkanoyloxy containing from 1 to 4 carbon atoms; alkoxycarbonyl group containing from 1 to 4 carbon atoms; carboxypropyl; karbamoilnuyu group; methylcarbamoyl group; ethylcarbazole group; dimethylcarbamoyl group; diethylcarbamoyl group; a nitro-group or cyano.

19. Application under item 17, derived isoxazol formula (II) or its pharmaceutically acceptable salts, where R1represents a hydrogen atom; a halogen atom; alkyl group containing from 1 to 4 carbon atoms; pharmacylow group; deformational group; triptorelin group; 2-foretelling group; 2,2,2-triptorelin group; methoxymethyl group; methoxyaniline group; alkoxygroup containing from 1 to 4 carbon atoms; dipterocarp; a hydroxyl group; allylthiourea containing from 1 to 4 carbon atoms; the amino group; methylaminophenol; acetylamino; alkoxycarbonyl group containing from 1 to 4 carbon atoms; carboxypropyl; karbamoilnuyu group; methylcarbamoyl group; ethylcarbazole group; diethylcarbamoyl group; dimethylcarbamoyl group; a nitro-group or cyano.

20. Application on p. 17 isoxazoline derivative of the formula (II) or its pharmaceutically acceptable salts, where R1represents a hydrogen atom; a fluorine atoms, chlorine, bromine, methyl and ethyl groups, triptorelin group, a methoxy group, ethoxypropan, dipterocarp, a hydroxyl group, methylthiourea, ethylthiourea, amino group, methylaminopropyl, ethylamino, dimethylaminopropyl, formyloxy, acetyloxy, methoxycarbonyl group, ethoxycarbonyl group, carboxypropyl, karbamoilnuyu group, a nitro-group or cyano.

21. Application on p. 17 isoxazoline derivative of the formula II or its pharmaceutically acceptable salts, where R1represents a hydrogen atom; a fluorine atom, chlorine atom, bromine atom, methyl group, methoxy group, dipterocarp, methoxycarbonyl group, a nitro-group or cyano.

22. The use according to any one of paragraphs.17 - 21 derived ISPU, dimethylaminopropyl.

23. The use according to any one of paragraphs.17 - 22 derived isoxazol formula II or its pharmaceutically acceptable salts, where m = 2.

24. The use according to any one of paragraphs.17 - 22 derived isoxazol formula II or its pharmaceutically acceptable salts, where m = 1.

25. The use according to any one of paragraphs.17 - 24 isoxazoline derivative of the formula II or its pharmaceutically acceptable salt, where n takes values from 2 to 4.

26. The use according to any one of paragraphs.17 - 24 isoxazoline derivative of the formula II or its pharmaceutically acceptable salt, where n = 2.

27. The use according to any one of paragraphs.17 - 26 isoxazoline derivative of the formula II or its pharmaceutically acceptable salt, where the ring A represents A phenyl ring, naphtalene ring, foreline ring, a thienyl ring, pyrrolidine ring, imidazolidine ring, pyrazolidine ring, thiazolidine ring, isothiazolinone ring, oxazolidine ring, isoxazolidine ring, peregrinae ring, pyridinoline ring, pyrimidinyl ring or pyridazinyl ring.

28. The use according to any one of paragraphs.17 - 26 derived isoxazol formula II or its pharmaceutically acceptable salt, where the ring A represents Swojego isoxazol of formula II or its pharmaceutically acceptable salt, where ring A represents A phenyl ring or peregrinae ring.

30. The use according to any one of paragraphs.17 - 26 derived isoxazol formula II or its pharmaceutically acceptable salt, where the ring A represents A phenyl ring.

31. The use according to any one of paragraphs.17 - 30 derived isoxazol formula II or its pharmaceutically acceptable salts, where X represents the oxygen atom.

32. The use according to any one of paragraphs.17 - 31 derived isoxazol formula II for inhibition of monoamine oxidase.

33. Pharmaceutical composition having the property of inhibiting the monoamine oxidase type b, including an active ingredient and a pharmaceutically acceptable carrier or diluent, wherein the active ingredient contains an effective amount of the compounds of formula I or the compounds of formula II, or pharmaceutically acceptable salt according to any one of paragraphs.1 - 32.

34. Pharmaceutical composition for p. 33, wherein the active ingredient contains a compound of formula I or its pharmaceutically acceptable salt.

35. Pharmaceutical composition for p. 33, wherein the active ingredient contains the connection is In the treatment of Parkinson's disease, depression and Alzheimer's disease, wherein the administered to a patient in need of such treatment, an effective amount of the compounds of formula (I) or formula (II) according to any one of paragraphs.1 - 17, or pharmaceutically acceptable salt or an effective amount of a composition according to p. 33.

37. Connection on p. 1, representing 3-(2-Aminoethoxy)-4-cyan-5-fluoro-1,2-benzisoxazol.

38. Connection on p. 1, representing 3-(2-Aminoethoxy)-5-fluoro-4-methyl-1,2-benzisoxazol.

39. The compounds of formula I and formula II PP.1 and 17, respectively, with inhibiting the monoamine oxidase activity.

Priority points and features:

30.08.94 on PP. 1 - 13, 15, 17 - 36 with the exception of the compounds of formula (I), where R1is alkoxygroup with 5 to 6 carbon atoms; haloalkoxy with 5 to 6 carbon atoms; alkylthiols with 5 to 6 carbon atoms; mono - and dialkylamino, alkyl fragment which contains 5 to 6 carbon atoms; alkanoyloxy with 1oC 6 carbon atoms; carboxypropyl; m = 3; ring A represents naphtalene ring condensed with isoxazoline ring; X represents a sulfur atom; provided that, if m represents the integer 2 or 3, the substituents R1Odin is ltio)-5-chloro-1,2-benzisoxazol, 3-(2-aminoacetic)-5-methyl-1,2-benzisoxazole, 3-(2-aminoacetic)-5-methoxy-1,2-benzisoxazole, 3-(2-aminoethoxy)-5-fluoro-4-methylthio-1,2-benzisoxazole, 3-(2-aminoacetic)-5-nitro-1,2-benzisoxazole, 3-(2-aminoethoxy)-4-cyano-1,2-benzisoxazol;

16.06.95 on p. 16, where the compound of formula (I) represents a 3-(2-aminoethoxy)-4,7-di-methyl-1,2-benzisoxazol; and items 1 - 13, 15, 17 - 36, where R1is alkoxygroup with 5 to 6 carbon atoms; haloalkoxy with 5 to 6 carbon atoms, alkylthiols with 5 to 6 carbon atoms; mono - and dialkylamino, alkyl fragment which contains 5 to 6 carbon atoms; alkanoyloxy with 1 to 6 carbon atoms; carboxypropyl; m = 1 or 2; the ring A represents naphtalene ring condensed with isoxazoline ring; X represents a sulfur atom; provided that, if m represents the integer 2 or 3, the substituents R1the same or different; and where the compounds of formula (I) selected from the group of: 3-(2-aminoacetic)-5-fluoro-1,2-benzisoxazole, 3-(2-aminoacetic)-5-chloro-1,2-benzisoxazole, 3-(2-aminoacetic)-5-methyl-1,2-benzisoxazole, 3-(2-aminoacetic)-5-methoxy-1,2-benzisoxazole, 3-(2-aminoethoxy)-5-fluoro-4-methylthio-1,2-benzisoxazol, 3-(2-aminoacetic)-5-nitro-1,2-benzisoxazole, 3-(2-aminoethoxy)-4-cyano-1,2-benzisoxazol.

 

Same patents:

The invention relates to a condensed heterocyclic compounds or their salts and inhibitors of squalene synthetase containing these compounds as an effective component

The invention relates to a derived benzazepine with condensed nitrogen-containing aromatic 5-membered cycle, represented by formula I

The invention relates to new compounds having pharmacological activity, to a method of their preparation and use as pharmaceuticals

The invention relates to androidiani carboxanilides, compositions based on them and the way to deal with arteriotomy and can be used in agriculture

The invention relates to new chemical substances, which have valuable pharmacological properties, more particularly to a nitrogen-containing heterocyclic compounds of General formula I

< / BR>
where X is oxygen or sulfur;

Y is carbon or nitrogen;

Z is carbon or nitrogen, and Y and Z are not simultaneously mean nitrogen;

R1and R2independent from each other and denote hydrogen, alkyl with 1 to 6 carbon atoms, halogen, trifluoromethyl, nitrile, alkoxy with 1 to 6 carbon atoms, a group of CO2R7where R7means hydrogen or alkyl with 1 to 6 carbon atoms, group-C(O)NR8R9where R8and R9not dependent from each other and denote hydrogen, alkyl with 1 to 3 carbon atoms, methoxy or together with the nitrogen form a morpholine, pyrrolidine or piperidine-NR10R11where R10and R11denote hydrogen or alkyl with 1 to 6 carbon atoms, group-C(O)R12where R12means alkyl with 1 to 6 carbon atoms, group-SO2R12where R12has the specified value, -NHC(O)R12where R12has the specified value, -NHSO2R12where R12has a specified value, and-SO2NR13R14where R13and R142R12where R12has the specified value, -NHC(O)R12where R12has the specified value, -NHSO2R12where R12has the specified value, -SO2NR13R14where R13and R14have a specified value, a nitrogroup, 1-piperidinyl, 2-, 3 - or 4-pyridine, morpholine, thiomorpholine, pyrrolidine, imidazole, unsubstituted or substituted at the nitrogen by alkyl with 1 to 4 carbon atoms, 2-thiazole, 2-methyl-4-thiazole, dialkylamino with 1 to 4 carbon atoms in each alkyl group, or alkilany ether with 1 to 4 carbon atoms;

R4an ester of formula-CO2R16where R16means alkyl with 1 to 4 carbon atoms, the amide of formula C(O)NR17R18where R17and R18independent from each other and denote hydrogen, alkyl with 1 to 2 carbon atoms, methoxy or together with the nitrogen form a morpholine, piperidine or pyrrolidine, phenyl, unsubstituted or substituted by residues from the group comprising halogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, 3-methyl-1,2,4-oxadiazol-5-yl, 2 - or 3-thienyl, 2-, 3 - or 4-pyridyl, 4-pyrazolylborate 4 stands, the ketone of the formula C(O)R19'where R19means alkyl with 1 to 3 carbon atoms, phenyl or 1-Mei-2-yl, a simple ester of the formula-CH2OR20where R20means alkyl with 1 to 3 carbon atoms, thioether formula-CH2SR20where R20has the specified value, the group CH2SO2CH3amines of the formula-CH2N(R20)2where R20has the specified value, the remainder of the formula-CH2NHC(O)R21where R21means methyl, amino or methylamino - group-CH2NHSO2Me2where Me denotes methyl carbamate of the formula CH2OC(O)NHCH3;

R5and R6independent from each other and denote hydrogen or methyl;

n is 0,1 or 2,

Provided that the substituents are not simultaneously have the following meanings: Y and Z is carbon, R1or R2hydrogen, halogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, cyano, nitro, trifluoromethyl, R3unsubstituted phenyl and R4group-C(O)OR16'where R16'means hydrogen, alkyl, alkenyl or quinil, group-C(O)N(R18')(R19'), where R18'and R19'denote hydrogen, alkyl with 1 to 6 carbon atoms, phenyl, alkoxy or together with the nitrogen form pyrrolidine, piperidine or morpholine, cyanotic, unsubstituted phenyl and 4-imidazole,

in the form of a racemate or an individual enantiomers and their salts, are inhibitors of leukotriene biosynthesis

The invention relates to a method for 3-{ 2-[4-(6-toranzo[d]isoxazol-3-yl) piperidine-1-yl] ethyl} -2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a] pyrimidine-4-it (I) interaction of 3-(2-amino-ethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a] pyrimidine-4-it (II) isoxazol derivative of the formula (III)where Y and Z represent the deleted group, such as halogen or alkyl - or arylsulfonate, in the presence of a suitable solvent and base

The invention relates to 9-amino-1,2,3,4-tetrahydropyridines and related compounds of the formula I

< / BR>
in which Y is C= O or CHOH; R1is hydrogen or lower alkyl; R2is hydrogen, lower alkyl or phenyl-lower alkyl; R3is hydrogen, OR4in which R4is hydrogen, COR5in which R5is lower alkyl, X is hydrogen, lower alkyl, halogen, lower alkoxy-, hydroxy-group or trifluoromethyl, their geometric or optical isomers, N-oxides, or their pharmaceutically acceptable salts and accessions acids (acid additive salts), which are useful in reducing dysfunction in memory and are thus indicative for the treatment of disease Allgamer

The invention relates to a new method of obtaining derivatives of 3-phenyloxy-5-hydroxyestra[1,9-CD]isoxazol-6-it General formula (I)

< / BR>
where X is hydrogen or halogen, or lower alkyl, which find wide application in the synthesis of derivatives of 7-hydroxy-5,6-califonication [1] used in the aniline-dye industry for dyeing different types of fibers

The invention relates to a new method of obtaining derivatives of 3-phenyloxy-5-hydroxyestra-[1,9-CD] isoxazol-6-it General formula (I)

< / BR>
where X is hydrogen or halogen, or lower alkyl, which find wide application in the synthesis of derivatives of 7-hydroxy-5,6-califonication [1] used in the aniline-dye industry for dyeing different types of fibers

The invention relates to 4-amino-1-piperidinecarbonitrile formula (I):

< / BR>
where R1and R2each independently of one another denote H, A, Ph, Ph-ALK, CO-A, CO-Het, or known of the chemistry of protective peptides for amino group;

R1and R2together also denote alkylene with 4-5 C atoms, and one or two CH2- groups may be replaced by-O-, -S-, -CO-, -NH-, -NA - and/or N-CH2-Ph and, if necessary, the benzene ring may be precondensation so that the formed dihydroindole, tetrahydropyrimidines, tetrahydroisoquinolinium or dehydrobenzperidol the rest;

R3and R4each independently of one another denote H, A, Gal, -X-R5, CN, NO2, CF3CH2-CF3, SOn-R7or SO2-NR5R6;

R5denotes H, A, CF3CH2-CF3Ph, Ph-alk, C5-C7- cycloalkyl or C5-C7-cycloalkyl-alk;

R6denotes H or A, or

R5and R6together also denote alkylene with 4-5 C atoms, and one CH2group can be replaced by-O-, -S-, -NH-or-N-CH2-Ph;

R7denotes A or Romani;

Gal denotes F, Cl, Br or I;

Ph denotes unsubstituted or one-or two-, or three times substituted by A, OA, Gal, CF3, NH2, NHA or NA2phenyl;

Het denotes a saturated or unsaturated five - or six-membered heterocyclic residue with 1 to 4 atoms of nitrogen, oxygen and/or sulfur; and

"n" represents 1 or 2;

and their physiologically acceptable salts
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