Derivatives of 5-(hydroxymethyl)-oxazolidin-2-it, methods for their production, medicine and pharmaceutical composition

 

(57) Abstract:

Described derivatives of 5-(hydroxymethyl)oxazolidin-2-it formula I, where X represents an atom of oxygen, sulphur or the group NR wherein R is hydrogen or C1-C4-alkyl, normal or branched; R1represents a hydrogen atom or methyl group; R2represents (i) a group R3O, in which R3is either a hydrogen atom or a benzyl group, possibly substituted by hydrogen atom or a benzyl group, possibly substituted by a halogen atom or nitro or methylendioxyphenyl, or is a group methoxyethyl, butyl, 4,4,4-tripcomputer, 4,4,4-Cryptor-3-hydroxybutyl or 4,4,4-triflorum-2-enyl, or (ii) the group-CH= CH-R4or-CH2-CH2-R4in which R4represents a hydrogen atom or a phenyl group, 3,3,3-cryptochromes or 3,3,3-Cryptor-2-hydroxypropyl, in the form of enantiomers or diastereomers, or mixtures of these various forms, including racemic mixtures. Also disclosed as methods of obtaining the described compounds, the drug and pharmaceutical composition thereof. The invention can be used to obtain medications used to treat Dept is concerned derivative isoindole, more specifically, derivatives of 5-(hydroxymethyl)oxazolidin-2-it is substituted in position 3 indazol, benzisoxazole or benzisothiazolin cycle, method of their production and their use in therapy.

Known (patent application EP-A-0425209) derivatives of naphthylacetamide active inhibitors of monoamine oxidase (MAO).

The present invention relates to new compounds corresponding to General formula (I)

< / BR>
in which X represents an oxygen atom, a sulfur atom or the group NR wherein R is hydrogen or C1-C4the alkyl, normal or branched,

R1represents a hydrogen atom or methyl group, and

R2is:

(i) a group R3O, in which R3is either a hydrogen atom or a benzyl group, possibly substituted by a halogen atom, or nitro - or methylenedioxy group, or a group methoxyethyl, butyl, 4,4,4-tripcomputer, 4,4,4-Cryptor-3-hydroxybutyl or 4,4,4-triflorum-2-enyl, or

(ii) the group-CH=CH-R4or-CH2-CH2-R4in which R4represents a hydrogen atom or a phenyl group, 3,3,3-cryptochromes or 3,3,3-Cryptor-2-hydroxypropyl.

The connection form is tomarow or diastereoisomers. These different forms as well as mixtures thereof, including racemic mixtures, form part of the invention.

The compounds of formula (I) in which X is an oxygen atom and R2represents a group-CH=CH-R4with the exception of compounds in which R4is a hydrogen atom, are in the form of CIS or TRANS isomers. These forms, as well as their mixtures, are part of this invention.

The compounds of formula (I) in which R2represents a group R3O, where R3is a group of 4,4,4-triflorum-2-enyl, exist in the form of CIS and TRANS isomers. These forms, as well as their mixtures, are part of this invention.

The preferred compounds are those for which:

X represents an oxygen atom, a sulfur atom or a group NR, and R is a hydrogen or C1-C4the alkyl, normal or branched.

R1represents a methyl group or a hydrogen atom

and R2represents a group R3O, in which R3represents either a hydrogen atom or a benzyl group, possibly substituted by a halogen atom, or nitro - or methylendioxyphenyl or group methoxyethyl, butyl, 4,4,4-trile mixtures of these different forms, including racemic mixtures.

Other preferred compounds are those for which:

X represents an oxygen atom, a sulfur atom or a group NR, and R is a hydrogen or C1-C4the alkyl, normal or branched,

R1represents a metal group or a hydrogen atom, and

R2represents a group-CH=CH-R4or-CH2-CH2-R4and in which R4represents a hydrogen atom or a phenyl group, 3,3,3-cryptochromes or 3,3,3-Cryptor-2-hydroxypropyl,

in the form of enantiomers or diastereoisomers or mixtures of these different forms, including racemic mixtures.

The most preferred compounds are those for which:

X represents an oxygen atom,

R1represents a methyl group or a hydrogen atom, and

R2is:

(i) a group R3O, in which R3represents either a hydrogen atom or benzyl group, in some cases substituted by a halogen atom, or

(ii) the group-CH=CH-R4or-CH2-CH2-R4and in which R4represents a hydrogen atom or phenyl group, 3,3,3-cryptochromes or 3,3,3-three the racemic mixture.

Among these compounds can be lead compounds for which:

X represents an oxygen atom,

R1represents a methyl group or a hydrogen atom and

R2represents either a hydroxyl group or phenylmethoxy group, in some cases substituted by a halogen atom or nitro or methylenedioxy group, or 4,4,4-triptorelin group, or 4,4,4-Cryptor-3-hydroxyethoxyphenyl group

in the form of enantiomers or diastereoisomers or mixtures of these different forms, including racemic mixtures,

and in particular, can be called (S)-5-methoxymethyl-3-[6-(4,4,4 - triptoreline)-1,2-benzisoxazol-3-yl]oxazolidin-2-it.

The compounds of formula (I) in which R1is a methyl group, and R2is the group R3can be obtained by the method indicated in Appendix 1, according to this method process the isoindole derivative of the formula (II) one of the isomers of 4(R) - or 4(S) 4-methoxymethyl-1,3-dioxolane of the formula (IIIa) in the presence of potassium carbonate to obtain 5(S) or 5(R) isomer of the compounds of formula (Ia) according to this invention. You can then dibenzylamine compound (Ia) by catalytic hydrogenation in the classic for specialist conditions according to this invention. Then you can process the compound (Ib) or a compound of formula R3Y, in which R3defined as in formula (I) above, except for the values of hydrogen and unsubstituted benzyl, and Y is a leaving group such as chlorine atom or bromine or tailorshop, in the presence of potassium carbonate or the compound of the formula R3OH, in which R3defined as previously, in the presence of triphenylphosphine and diethyl ester of azodicarboxylic acid, to obtain the 5(S) or 5(R) isomers of compounds of formula (Ic) in accordance with this invention in which R3defined as previously. In each of the compounds of formula (II), (Ia), (Ic), mentioned here, X has one of the meanings given in the formula (I), and Bn represents a benzyl group. The compounds of formula (I) for which X represents the group NH, can be obtained for example compounds of formula (Ic), where

X represents a group NCH3using benzoyl peroxide.

The compounds of formula (I) in which R1is a methyl group and R2is a group-CH=CH-R4or a group-CH2-CH2-R4can be obtained by the method presented in Appendix 2. According to this method handles the connection formue formula (IV) result in interaction with tributylammonium in the presence of lithium chloride and tetrakis(triphenylphosphine) palladium. Then treated with a compound of formula (Id) according to the invention with ozone, followed by dimethyl sulfide, in dichloromethane, and the resulting compound of formula (V) result in interaction with iodide triphenylphosphine formula R4CH2PPh3+I-in which R4defined as above in formula (I), except for the value of hydrogen, in the presence of potassium carbonate. Then restore the connection of the formula (Ie) according to the invention, in which R4defined as previously, with hydrogen in the presence of a catalyst to obtain the compounds of formula (If) according to the invention, in which R4defined as previously. In each of the compounds (Ib), (IV), (Id), (V), (Ie) and (If), such as X defined above in formula (I).

The compounds of formula (I) in which R1is a hydrogen atom and R2is a group OR3where R3defined as in formula (I) above can be obtained by the method presented in Appendix 3. According to this method processes the compound of formula (II) one of the isomers of 4(R) - or (4S) 4-phenylmethoxy-1,3-dioxolane-2-it (IIIb) in the presence of potassium carbonate to obtain isomer 5(S) or (R) compounds of the formula (VI). Dibenzyline isomer of the formula (VI) by catalytic hydrogenation with semi-join of the formula R3Y, in which R3defined as above in formula (I), except for the value of hydrogen, and Y represents a leaving group such as chlorine atom or bromine or tosyloxy group, with the receipt of the isomers of 5(S) or 5(R) compounds of the formula (Ic), respectively invention, in which R3defined as before. All the compounds (II), (Ib), (Ic), (VI) defined above, X is defined as in formula (I) above.

Compound (Ig), for which R1represents a hydrogen atom and R2is a group-CH=CH-R4or-CH2-CH2-R4get the demethylation of compounds (If) respectively invention using tribromide boron, according to the method described in Annex 2.

The compound of formula (II) are obtained according to the method presented in Appendix 4. According to this method, treated with 2-fluoro-4-hydroxybenzonitrile benzylbromide in the presence of potassium carbonate. Then process the thus obtained 2-fluoro-4-phenylmethanesulfonyl in three different ways corresponding to the value X:

when X represents an oxygen atom: treated with 2-fluoro-4-phenylmethanesulfonyl the acetone oxime in the presence of tert-butanolate potassium, obtaining 2-[[(1-methylethylidene)Aminta in ethanol,

when X represents a sulfur atom: treated with 2-fluoro-phenylmethanesulfonyl sulphur and ammonia propanol,

when X represents a group NR, and R is C1-C4the alkyl, normal or branched: treated with 2-fluoro-4-phenylmethanesulfonyl by R5NHNH2where R5is C1-C4the alkyl, normal or branched, in ethanol.

Each of these methods leads to the production of the compounds of formula (VII), where X represents an oxygen atom, a sulfur atom or a group NR, and R is C1-C4alkyl chain, a normal or branched. The compound of formula (VII) is treated with ethyl ether chloroformate in the presence of sodium bicarbonate to obtain the compounds of formula (II) in which X is defined as before.

Isomer 4(S) compounds of the formula (IIIa) is a known compound, the receipt of which is described in the patent EP-0511031.

Its isomer 4(R) are obtained in the same manner, on the basis of (R)-2,2-dimethyl-1,3-dioxolane-4-methanol.

Isomer 4(S) compound (R)-phenylmethoxy-1,3-dioxolane-2-she is of the formula (IIIb) is a known compound, the receipt of which is described in Helvetica Chimica Acta, 66, Nola.

The following examples illustrate the present invention.

Example 1: (S)-5-methoxymethyl-3-[1-methyl-6-(phenylmethoxy)-1H - indazol-3-yl]oxazolidin-2-he

1.1 (R)-4-methoxymethyl-3-[1-methyl-6-(phenylmethoxy)-1H-indazol-3 - yl]oxazolidin-2-he

In the reactor 6 l, equipped with a refrigerator, a temperature sensor and additional capacity, introduce 420 g (of 10.5 mol) of sodium hydroxide in pellets. To the solution, stirred at 20oC add a 2.3 liter dichloromethane, 396 g (of 3.00 mol) of (R)-2,2-dimethyl-1,3-dioxolane-4-methanol ([]2d0= -11; c = 4; methanol) and 20.5 g (0,090 mol) of the chloride of benzyltriethylammonium. Then add 567 g (4,50 mol) dimethylsulfate for 50 min, keeping the temperature below 30oC. the Mixture is stirred for 18 h, then add 1 liter of water. Separate the organic phase and washed it with 0.5 l of water. Extravert the aqueous phase with 3 l of dichloromethane, then combine the organic phases, filtered and concentrated by distillation under reduced pressure. Get 496 g of the product.

1.2. (S)-3-methoxypropane-1,2-diol

Heated at 60oC, under stirring, a mixture of 496 g of the product obtained in the previous step, in 220 ml of demineralized water, then add 1.5 ml of 36% solenostomidae is evaporated at a pressure of 5.2 kPa, at temperatures below 70oC, then distilled else if 61oC at a pressure of 13 PA. Get 246 g of product.

[]2d0= +5,8(c = 4; methanol).

1.3. (R)-4-methoxymethyl-1,3-dioxolane-2-he

In a flask equipped with additional capacity and installation for the distillation, enter 245 g (3,31 mol) of (S)-3-methoxypropane-1,2-diol and 560 ml (4,62 mol) of diethylmalonate. The mixture is heated at 95oC, then add a solution of sodium methylate, obtained from 10 ml of methanol and 0.5 g (0,02 mol) of sodium. Distilled for 2 hours, the ethanol formed during the reaction (the temperature of the mass: from 95 to 112oC; column temperature: from 82 to 78oC), then the mixture is cooled and distilled at a pressure of 13 PA separating excess diethylmalonate. Get 267 g of the product.

[]2d0= +30,3(c = 1; dichloromethane).

1.4. 2-fluoro-4-(phenylmethoxy)benzonitrile

To a solution of 13.3 g (0,106 mol) of 2-fluoro-4-hydroxybenzonitrile in 150 ml of acetonitrile add to 15.2 ml (to 0.127 mol) of benzylbromide and 29.3 g (0,212 mol) of potassium carbonate. The mixture is stirred at the boil under reflux for 1 h 30 min, then filter, concentrate the filtrate under reduced pressure and diluted with receiving the filtering and drying gain of 20.3 g of the product.

Melting point: 87oC.

1.5. 1-methyl-6-(phenylmethoxy)-1H-indazol-3-amine

Heated at the boil under reflux for 20 g (0,088 mol) of 2-fluoro-4-(phenylmethoxy)benzonitrile with 60 ml of ethanol and 15,45 ml (to 0.29 mol) of a solution of methylhydrazine for 11 hours the Mixture is cooled to 0oC, then collect the precipitate by filtration. The residue is washed with ethanol, then ether. Get a 20.2 g of product.

Melting point: 150oC.

1.6. Ethyl ester [1-methyl-6-(phenylmethoxy)-1H-indazol-3-yl]carbamino acid

To a solution of 19.7 g (0,078 mol) of 1-methyl-6-(phenylmethoxy)-1H-indazol-3-amine in 200 ml of a mixture of tetrahydrofuran/water (9/1) type of 9.8 g of sodium bicarbonate (0,117 mol), then add, dropwise, maintaining the temperature at 25oC, 8,9 ml (0,093 mol) ethylchloride. Get milky white suspension, which continue to stir for 30 min, then the solvent is evaporated under reduced pressure. The residue is treated with dichloromethane and water. The organic phase is decanted, dried over sodium sulfate and concentrate under reduced pressure. The product is crystallized from diisopropyl ether. Get to 20.1 g of the product.

Melting point: 204oC.

C mixture of 1.03 g (7.8 mmol) of (R)-4-methoxymethyl-1,3-dioxolane-2-she and 82 mg (0.6 mmol) of potassium carbonate in 30 ml of anhydrous dimethylformamide, then add in the continuation of 20 min a solution of 1.95 g (6 mmol) of ethyl ester [1-methyl-6-(phenylmethoxy)-1H-indazol-3-yl]carbamino acid in 30 ml of dimethylformamide. The reaction mixture is stirred at 135oC for 45 min, then cooled and the solvent is distilled off under reduced pressure. The residue is purified on a column of silica using a mixture of ethyl acetate/cyclohexane 50/50. Highlight the product in the form of oil, which crystallized and which pound in diisopropylate ether. Get 1.5 g of product.

Melting point: 116-117oC

[]2d0= +26,1 (c = 1; methanol)

Example 2: (S)-3-(6-hydroxy-1-methyl-1H-indazol-3-yl)- 5-(methoxymethyl)oxazolidin-2-he

Hydronaut 3.1 g (8.4 mmol) of (S)-5-(methoxymethyl)-3-[1-methyl - 6-(phenylmethoxy)-1H-indazol-3-yl] oxazolidin-2-it in 40 ml of tetrahydrofuran and 40 ml of ethanol, in the presence of 500 mg of 10% palladium on coal (containing 50% moisture). After filtration of the catalyst and evaporation of the solvent under reduced pressure the residue is purified chromatographically on a column of silica using dichloromethane and obtain 2.1 g SUP> (c = 1, methanol)

Example 3: (S)-5-methoxymethyl-3-[1-methyl-6-(4,4,4-triptoreline)- 1H-indazol-3-yl]oxazolidin-2-he

Stirred at the boil under reflux for 3 h the mixture 524 mg (2 mmol) of (S)-3-(6-hydroxy-1-methyl-1H-indazol-3-yl)- 5-(methoxymethyl)oxazolidin-2-it, 478 mg (2.5 mmol) of 4,4,4-Cryptor-1-bromobutane and 552 mg (4 mmol) of potassium carbonate in 10 ml of acetonitrile. Then the mixture is cooled, it is filtered, the solvent is distilled off under reduced pressure and purify the residue by recrystallization from a mixture of isopropanol-diisopropyl ether. Obtain 0.4 g of the product as a white powder.

Melting point: 103-104oC

[]2d0= +25,6(c = 1, methanol)

Example 4: (S)-5-methoxymethyl-3-[6-(4,4,4-triptoreline)-1H - indazol-3-yl]oxazolidin-2-he

A mixture of 0.30 g (of 0.77 mol) of (S)-5-methoxymethyl-3-[1-methyl-6-(4,4,4 - triptoreline)-1H-indazol-3-yl]oxazolidin-2-it, of 0.47 g (to 1.9 mol) of benzoyl peroxide in 10 ml of dichloromethane is refluxed for 12 hours, the Solvent is evaporated under reduced pressure, collecting the residue with methanol and filtered off the insoluble part. Then add 4 ml of 1 N. hydrate of sodium oxide. Stirred for 15 minutes are filtering the product and UP>2d0= +11,6(c = 1; dimethylsulfoxide)

Example 5: (S)-5-methoxymethyl-3-[6-(phenylmethoxy)-1,2 - benzisoxazol-3-yl]oxazolidin-2-he

5.1. 2-[[(1-methylethylidene)amino]oxy]-4-(phenylmethoxy)benzonitrile

The solution 7,83 g (0,107 mol) of acetone oxime in 200 ml of dimethylformamide is stirred for 30 min in the presence of 12 g (of 0.11 mol) 95% tert-butanolate potassium. Then added within 15 min, a solution of 20.3 g (0,089 mol) of 2-fluoro-4-(phenylmethoxy)benzonitrile in 100 ml of dimethylformamide. The mixture is stirred for 2 h, then poured into ice water. The crystallized product is filtered, dissolving it in dichloromethane, then dry the solution over sodium sulfate and concentrate under reduced pressure. Gain of 21.2 g of the product.

Melting point: 102oC.

5.2. 6-(phenylmethoxy)-1,2-benzisoxazol-3-ylamine

Lead in the interaction of 20.2 g (0,072 mol) of 2-[[(1-methylethylidene)amino] oxy]-4-(phenylmethoxy)benzonitrile with 340 ml solution of 4 N. chloroethanol acid in ethanol for 20 h, then the solvent is evaporated, after which the solvent is evaporated. Then crystallized product is triturated in dichloromethane, then filtered and dissolved solids in a minimum amount of warm Metrology obtain 16.3 g of product.

Melting point: 166oC.

5.3. Ethyl ester [6-(phenylmethoxy)-1,2-benzisoxazol-3 - yl]carbamino acid

To a solution of 10.1 g (0,042 mol) 6-(phenylmethoxy)-1,2-benzisoxazol-3-amine in 100 ml of a 9/1 mixture of tetrahydrofuran and water is added to 8.8 ml (0,092 mol) ethylchloride and 10.6 g (0,126 mol) of sodium bicarbonate. The mixture is stirred for 18 h, then the solvent is evaporated and the residue is treated with dichloromethane and water. Decanted organic phase is dried over sodium sulfate and concentrate under reduced pressure. After crystallization from isopropyl alcohol and recrystallization from n-butanol gain of 11.5 g of the product.

Melting point: 144-146oC.

5.4. (S)-5-methoxymethyl-3-[6-(phenylmethoxy)-1,2-benzisoxazol-3 - yl]oxazolidin-2-he

Heated to 140oC mixture of 5.4 g (0,034 mol), 4(R)-methoxymethyl-1,3-dioxolane-2-she and 0.24 g (1.7 mmol) of potassium carbonate in 35 ml of anhydrous dimethylformamide, and then added, over 20 min, a solution of 5.5 g (18 mmol) of ethyl ester of 6-(phenylmethoxy)-1,2-benzisoxazol-3-carbamino acid in 20 ml of dimethylformamide. The reaction medium is stirred at 140oC for 40 min, then cooled and the solvent is evaporated under reduced pressure is stallization from isopropyl ether to obtain 4.1 g of product.

Melting point: 92,0 to 92.1oC.

[]2d0= -8,6 (c = 1; dichloromethane).

Example 6: (S)-3-(6-hydroxy-1,2-benzisoxazol-3-yl)- 5-(methoxymethyl)oxazolidin-2-he

A solution of 3.9 g (to 0.011 mol) of (S)-5-methoxymethyl-3-[6-(phenylmethoxy)- 1,2-benzisoxazol-3-yl]oxazolidin-2-it in 60 ml of tetrahydrofuran and 60 ml of ethanol hydronaut for 30 min in the presence of 1.1 g of 5% palladium on coal (containing 50% moisture). Then the catalyst is filtered off and the filtrate is evaporated under reduced pressure. Obtain 2.3 g of the product.

Melting point: 148, 7mm-148, 8 personsoC.

[]2d0= 14,2(c = 1; dimethyl sulfoxide).

Example 7: (S)-5-methoxymethyl-3-[6-(4,4,4-triptoreline)-1,2 - benzisoxazol-3-yl]oxazolidin-2-he

A mixture of 1.3 g (4.9 mmol) of (S)-3-(6-hydroxy-1,2-benzisoxazol-3 - yl)-5-methoxymethyl-oxazolidin-2-it, of 1.4 g (7.3 mmol) of 4-bromo-1,1,1-triptorelin and 1.4 g (9.8 mmol) of potassium carbonate in 20 ml of acetonitrile is stirred at the boil under reflux for 30 minutes and Then the mixture is cooled, filtered, evaporated under reduced pressure, the solvent and purify the residue is chromatographically on a column of silica, elwira dichloromethane. After processing flora>[]2d0= +8,7(c = 1; dichloromethane).

Example 8: (R)-5-methoxymethyl-3-[6-(phenylmethoxy)-1,2 - benzisoxazol-3-yl]oxazolidin-2-he

Heated to 140oC a mixture of 1.4 g (0,010 mol), 4(S)-methoxymethyl-1,3-dioxolane-2-she and 0.1 g (0,0073 mol) of potassium carbonate in 35 ml of anhydrous dimethylformamide, and then for 20 min add a solution of 2.5 g (0,0080 mol) of ethyl ester of 6-(phenylmethoxy)-1,2-benzisoxazol-3-carbamino acid in 10 ml of dimethylformamide. The reaction mixture was stirred at 140oC for 35 min, then the mixture is cooled and the solvent is evaporated under reduced pressure. The residue is purified on a column of silica, using a mixture of 25/75 ethyl acetate and cyclohexane. After crystallization from isopropyl ether to obtain 1.65 g of the product.

Melting point: 92,0-92,2oC.

[]2d0= -9,6(c = 1; dichloromethane).

Example 9: (R)-3-(6-hydroxy-1,2-benzisoxazol-3-yl)- 5-(methoxymethyl)oxazolidin-2-he

A solution of 21 g (0,059 mol) of (R)-5-methoxymethyl-3-[6-(phenylmethoxy)- 1,2-benzisoxazol-3-yl] oxazolidin-2-it in 310 ml of tetrahydrofuran and 310 ml of ethanol hydronaut for 30 min in the presence of 6 g of 5% palladium on coal (containing 50% moisture). Then silica using a mixture of 2% methanol in dichloromethane. Obtain 2.3 g of the product.

Melting point: 151,4-151,5oC.

[]2d0= 14,2(c = 1; dimethyl sulfoxide).

Example 10: (R)-5-methoxymethyl-3-[6-(4,4,4-Cryptor-3(R)- hydroxyethoxy)-1,2-benzisoxazol-3-yl]oxazolidin-2-he

A mixture of 1.0 g (2.8 mmol) of (R)-3-(6-hydroxy-1,2-benzisoxazol-3 - yl)-5-(methoxymethyl)oxazolidin-2-it, 1.8 g (6.2 mmol) of 4,4,4-Cryptor-3(R)-hydroxybutyrate and 1.0 g (7.6 mmol) of potassium carbonate in 25 ml of acetonitrile is stirred for 3 hours while boiling under reflux. The mixture is then cooled, the solvent is evaporated under reduced pressure, collecting the residue using ethyl acetate, then washed with water. The organic phase is dried over sodium sulfate, concentrate it under reduced pressure and the resulting product chromatografic on a column of silica, elwira 1% mixture of methanol in dichloromethane. After recrystallization from a mixture of ethyl acetate and diisopropyl ether obtain 0.6 g of product.

Melting point: 147oC.

[]2d0= +16,6(c = 1; dichloromethane).

Example 11: (S)-5-hydroxymethyl-3-[6-(4,4,4-triptoreline)-1,2 - benzisoxazol-3-yl]oxazolidin-2-he

11.1. (S)-5-FeNi is (0,02 mol) of (R)-4-phenylmethoxy-1,3-dioxolane-2-she and 0.14 g (1.0 mmol) of potassium carbonate in 50 ml of dry dimethylformamide, then added dropwise within 10 min a solution of 3.1 g (1.0 mmol) of the ethyl ester of 6-(phenylmethoxy)-1,2-benzisoxazol-3-carbamino acid in 10 ml of dimethylformamide. The reaction mixture was stirred at 140oC for 30 min, then cooled and the solvent is evaporated under reduced pressure. The residue is purified on a column of silica, elwira a mixture of 20% ethyl acetate in hexane. Obtain 2.0 g of product.

Melting point: 98-99oC.

[]2d0= -1,0(c = 1; dichloromethane).

11.2. (S)-5-hydroxymethyl-3-(6-hydroxy-1,2-benzisoxazol-3 - yl)oxazolidin-2-he

During 50 min hydronaut a solution of 1.7 g (0,040 mol) of (S)-5-phenylmethoxy-3-[6-(phenylmethoxy)-1,2-benzisoxazol-3 - yl]oxazolidin-2-it, in 20 ml of tetrahydrofuran and 2 ml of a 3 n solution chloroethanol acid in ethanol, in the presence of 0.5 g of 5% palladium on coal (containing 50% moisture). Then the catalyst is filtered off and the filtrate is evaporated under reduced pressure. After trituration of the residue in dichloromethane gain of 0.85 g of the product.

Melting point: 226-228oC.

[]2d0= +18,1(c = 1; dimethyl sulfoxide).

11.3. (S)-5-hydroxymethyl-3-[6-(4,4,4-tricornutum a mixture of 0.75 g (ě 0.030 mol) of (S)-5-hydroxymethyl-3-(6-hydroxy-1,2 - benzisoxazol-3-yl)oxazolidin-2-it, 0,63 g (3.3 mmol) of 4-bromo-1,1,1-triptorelin and 0,83 g (6.0 mmol) of potassium carbonate in 12 ml of dimethylformamide and 2.5 ml of acetonitrile, then cooled, poured into water and the precipitate is filtered off. After washing with water and then with petroleum ether and chromatography on a column of silica with eluent of 50% mixture of ethyl acetate and dichloromethane, get 0,70 g of the product.

Melting point: 159,6-159,9oC.

[]2d0= +12,1(c = 1; dichloromethane).

Example 12: (R)-5-(methoxymethyl)-3-(6-ethynyl-1,2-benzisoxazol-3 - yl)oxazolidin-2-he

12.1. (R)-5-(Methoxymethyl)-2-oxo-3-oxazolidinyl-1,2 - benzisoxazol-6-yl triftorbyenzola

To a solution of 11 g (0,042 mol) of (R)-5-(methoxymethyl)-3-(6-hydroxy-1,2 - benzisoxazol-3-yl)oxazolidin-2-it in 110 ml of pyridine added at 0oC for 10 min and 8.4 ml (0,050 mol) triftormetilfullerenov anhydride. The solution is stirred for 18 h, then poured into 2 N. ice-cold aqueous solution of hydrochloric acid. The product is extracted with ethyl acetate, then the organic phase is dried over sodium sulfate and concentrate under reduced pressure. Obtain 16.5 g of product.

Melting point: 94oC.

12.2. (R)-5-(methoxymethyl)-3-(6-ethynyl-1,2-benisons mol) of [(R)-5-(methoxymethyl)-2-oxo-3-oxazolidinyl]- 1,2-benzisoxazol-6-yl triftoratsetata, 12.3 g (of 0.038 mol) tributyltinhydride, 765 mg (0.66 mmol) of tetrakis(triphenylphosphine) palladium and 4.8 g (of 0.11 mol) of lithium chloride in 160 ml of dioxane. Then evaporated under reduced pressure, the solvent, collect the residue with ethyl acetate, filtered on silica, the organic phase is washed with water, dried over sodium sulfate and concentrate under reduced pressure. The oil obtained is again dissolved in acetonitrile, washed with hexane and the solution concentrated. Chromatography of the residue on a column of silica using 30% mixture of ethyl acetate in cyclohexane obtain 16.5 g of product.

Melting point: 79,2-79,4oC.

[]2d0= -5,4(c = 1; dichloromethane).

Example 13: TRANS-(R)-5-(methoxymethyl)-3-[6-(5,5,5-Cryptor-4(R)- hydroxyben-1-enyl)-1,2-benzisoxazol-3-yl]oxazolidin-2-he

13.1. (R)-5-methoxymethyl-3-(6-formyl-1,2-benzisoxazol-3 - yl]oxazolidin-2-he

In a solution of 8.0 g (0,029 mol) of (R)-5-(methoxymethyl)-3-(6-ethynyl-1,2 - benzisoxazol-3-yl)oxazolidin-2-she's in 210 ml of dichloromethane miss at -40oC current ozone, then replacing the ozone current of argon and add to 10.7 ml of 0.15 mol) of dimethyl sulfide. Stirred for 3 h, allowing the temperature to rise to room, ZAT is omashu 30% mixture of ethyl acetate in cyclohexane obtain 5.0 g of the product.

Melting point: 116oC.

13.2. TRANS-(R)-5-(methoxymethyl)-3-[6-(5,5,5-Cryptor-4(R)- hydroxyben-1-enyl)-1,2-benzisoxazol-3-yl]oxazolidin-2-he

Stirred at the boil under reflux for 2 h in a mixture of 1.8 g (6.5 mmol) of (R)-5-methoxymethyl-3-(6-formyl-1,2 - benzisoxazol-3-yl)oxazolidin-2-it, 4.0 g (17.8 mmol) (4,4,4-Cryptor-3(R)-hydroxybutyl)triphenylphosphonium iodide and 1.25 g (9.1 mmol) of potassium carbonate in 1.4 ml of formamide and 18 ml of dioxane, the mixture is then poured into ice water. Then extracted the product with ethyl acetate, the organic phase is dried over sodium sulfate and concentrate it under reduced pressure. After chromatography was carried out of the residue on a column of silica with a mixture of 30% ethyl acetate in cyclohexane and trituration in diisopropyl ether obtain 1.2 g of product.

Melting point: 141,1-141,6oC.

[]2d0= +15,8(c = 1; dichloromethane).

Example 14: (R)-5-(methoxymethyl)-3-[6-(5,5,5-Cryptor-4(R)- hydroxyphenyl)-1,2-benzisoxazol-3-yl]oxazolidin-2-he

Within 30 min hydronaut a mixture of 1.0 g (0,0026 mol) of TRANS-(R)-5-(methoxymethyl)-3-[6-(5,5,5-Cryptor-4(R)-hydroxy-1 - pentenyl-1,2-benzisoxazol-3-yl] oxazolidin-2-she's in 30 ml of ethanol, in the presence 0,22 g 5% nigromaculata residue on a column of silica with a mixture of 1.5% methanol in dichloromethane and rubbing in a mixture of petroleum ether and diisopropyl ether obtain 0.88 g of product.

Melting point: 129,0-129,4oC.

[]2d0= +4,9(c = 1; dichloromethane).

Example 15: (R)-5-hydroxymethyl-3-[6-(5,5,5-Cryptor-4(R)- hydroxyphenyl)-1,2-benzisoxazol-3-yl]oxazolidin-2-he

To a solution of 0,495 g (1,27 mmol) of (R)-5-(methoxymethyl)-3-[6-(5,5,5- Cryptor-4(R)-hydroxyphenyl-1,2-benzisoxazol-3-yl] oxazolidin-2-it in 5 ml of dichloromethane is added dropwise, at 0oC, and 3.8 ml (3.8 mmol) of 1 M solution tribromide boron in dichloromethane. After 2 h of interaction reaction medium is diluted with dichloromethane and treated with a hydroxide of ammonia, diluted to slightly alkaline pH. The organic phase is separated, dried over sodium sulfate and evaporated. Chromatography on a column of silica with a mixture of ethyl acetate and cyclohexane, and then rubbing in ethyl acetate to obtain 0.12 g of the product.

Melting point: 135,1-136,2oC.

[]2d0= 0,0(c = 1; methanol).

Example 16: (S)-5-methoxymethyl-3-[6-(phenylmethoxy)-1,2 - benzisothiazol-3-yl]oxazolidin-2-he

16.1. 6-(phenylmethoxy)-1,2-benzisothiazol-3-amine

In an autoclave at 100oC for 5 h withstand a mixture of 13.2 g (0,058 mol) of 2-fluoro-4-(phenylmethoxy)benzonitrile and 1.85 g (0,058 mol) of sulfur in the Ute dichloromethane, the insoluble part is filtered, then the solvent is evaporated under reduced pressure. The product was then purified chromatographically on a column of silica using cyclohexane and ethyl acetate in the ratio of 60/40. Then carry out a second cleaning of 1.7 g of the product by chromatography on a column of silica with a mixture of diisopropyl ether and methanol in the ratio of 99/1.

Melting point: 158oC.

16.2. Ethyl ester [6-(phenylmethoxy)-1,2-benzisothiazol-3 - yl]carbamino acid

According to the method of example 1.6 obtain 1.19 g of ethyl ether [6-(phenylmethoxy)-1,2-benzisothiazol-3-yl] carboxylic acid on the basis of 1.28 g (0,005 mol) 6-(phenylmethoxy)-1,2-benzisothiazol-3-amine.

Melting point: 149-150oC.

16.3. (S)-5-methoxymethyl-3-[6-(phenylmethoxy)-1,2-benzisothiazol-3 - yl] oxazolidin-2-he

According to the method of example 1.7 obtain 0.4 g (S)-5-methoxymethyl-3-[6-(phenylmethoxy)-1,2-benzisothiazol-3 - yl] oxazolidin-2-it is based on 0,57 g (1,73 mmol) ethyl ether [6-(phenylmethoxy)-1,2-benzisothiazol-3-yl]carboxylic acid, 0.20 g (2.2 mmol) of (R)-4-methoxymethyl-1,3-dioxolane-2-she and 24 mg (0,17 mmol) of potassium carbonate.

Melting point: 105-106oC

[]2d0= +9.9 ridin-2-he

17.1. (S)-5-methoxymethyl-3-(6-hydroxy-1,2-benzisothiazol-3 - yl)oxazolidin-2-he

To a solution of 2.10 g (5,67 mmol) of (S)-5-methoxymethyl-3-[6-(phenylmethoxy)-1,2-benzisothiazol-3 - yl]oxazolidin-2-Il in 76 ml of dichloromethane, cooled to -8oC add for 4 h in three portions of 8.7 ml (68 mmol) of dimethylaniline and 6.9 g (0,051 mol) of aluminium chloride. The mixture is then poured into ice water and the product extracted with dichloromethane. The organic phase is dried over sodium sulfate and concentrate under reduced pressure. After purification by chromatography on a column of silica using a mixture of dichloromethane and methanol in the ratio of 99/1 and trituration in diisopropyl ether obtain 1.4 g of product.

Melting point: 142oC

17.2. (S)-5-methoxymethyl-3-[6-(4,4,4-triptoreline)-1,2 - benzisothiazol-3-yl]oxazolidin-2-he

According to the method of example 3, get 0,42 g (S)-5-methoxymethyl-3-[6-(4,4,4-triptoreline)-1,2-benzisothiazol-3 - yl]oxazolidin-2-it, on the basis of 0.4 g (1,43 mmol) of (S)-5-methoxymethyl-3-(6-hydroxy-1,2-benzisothiazol-3-yl)oxazolidin-2-it, 0.34 g (1.25 mmol) of 4,4,4-triphosphorylated and 0.42 g (3.1 mmol) of potassium carbonate in 8 ml of acetonitrile.

Melting point: 78-79oC

[]2d0= +8,9(c = 1; methanol).

Configuration, marked R and/or S, as well as the 5 ' and/or 5S, refers to a heterocyclic oxazolidinone, and the configuration marked 3R, 4R 3S and belongs to the chain R2.

Compounds in accordance with the invention have been the subject of pharmacological tests to determine their ability to inhibit monoamine oxidase A and monoamine oxidase B.

Measuring the activity of MAO-A and MAO-B in vitro were carried out using as the source of enzyme homogenate of rat brain, according to a known method (C. Fowler and M. Strolin-Benedetti J. Neurochem., 40, 1534-1541 (1983)).

Standard dosing is that homogenize the rat brain in 20 volumes of 0.1 M (pH of 7.4) phosphate buffer and preincubated 100 μl of homogenate (5 mg tissue) at 37oC for 20 min in the absence or presence of different concentrations of the studied inhibitor. The reaction is initiated by addition of [14C] serotonin ([14C] 5HT, the final concentration of 125 μm) for measuring the activity of MAO-A or [14C]phenethylamine ([14C]PEA, the final concentration of 8 μm) for measuring the activity of MAO-B, in the final volume of 500 ál. After 5 min incubation of [14C]5HT and 1 min incubation of [14C]PEA, the reaction stopped by the addition of 200 who have unspent substrate extraction in the organic phase, and their number is determined by counting the radioactivity.

Inhibitory activity against MAO-A and MAO-B are expressed respectively by the inhibition constants Ki (MAO-A) and Ki (MAO-B).

For compounds according to the invention Ki (MAO-A) varies between 15 nm and more than 1 μm, and Ki (MAO-B) is between 1 nm and more than 1 microns.

Some compounds according to the invention are selective inhibitors of MAO-B, and the ratio of Ki (MAO-A)/Ki (MAO-B) may be of the order of 103.

Others, however, are mixed inhibitors of MAO-A and MAO-B, and the ratio of Ki (MAO-A)/Ki (MAO-B) may be less than 10.

The results obtained show that the compounds according to this invention can be used to obtain drugs that are selective inhibitors of MAO-B or mixed inhibitors of MAO-A and MAO-B, and these medicaments find their use in therapy, namely in the treatment of depressive States of any origin, senile depressive psychosis, hypobole, social phobias, irritability, to improve the overall working of the brain, for the prevention and treatment of neurodegenerative diseases such as Parkinson's disease Alzheimer and all Nar is receiving tobacco, alcohol and/or drugs, and loss of appetite.

Compounds according to this invention can be represented, in combination with excipients, in the form of compositions intended for administration orally, parenterally or rectally, for example in the form of tablets, pills, capsules, solutions, suspensions or suppositories.

Oral dose of the main active input substances can reach up to 50 mg/kg/day, in one or several stages. When parenteral and rectal routes this dose can be up to 10 mg/kg/day, in one or more methods.

Injection

Active substance 5 mg

Glucose is 250 mg

Water for injection as needed up to 5 ml

one vial of 5 ml

The ingredients in the traditional way mix and prepare a solution for injection.

Gelatin capsule

Active ingredient 100 mg

Talc - 24 mg

Silica gel - 1 mg

one capsule - 125 mg

The ingredients in the traditional way mix and prepare gelatin capsules.

Tablet

Active substance - 400 mg

Silica gel 10 mg

Stearic acid - 20 mg

Corn starch - 45 mg

one is Syrup

The active substance is 5 grams

Methyl ester of 4-hydroxybenzoic acid - 150 mg

Saccharose - 50 grams

Distilled water as required up to 100 ml

One bottle of 100 ml

The ingredients in the traditional way mix and prepare the syrup.

1. Derivatives of 5-(hydroxymethyl)oxazolidin-2-it General formula I

< / BR>
in which X represents an oxygen atom, a sulfur atom or the group NR wherein R is hydrogen or C1- C4-alkyl, normal or branched;

R1represents a hydrogen atom or methyl group;

R2represents (i) a group R3O, in which R3is either a hydrogen atom or a benzyl group, possibly substituted by a halogen atom or nitro or methylendioxyphenyl, or is a group methoxyethyl, butyl, 4,4,4-tripcomputer, 4,4,4-Cryptor-3-hydroxybutyl or 4,4,4-triflorum-2-enyl, or (ii) the group-CH=CH-R4or-CH2-CH2-R4in which R4represents a hydrogen atom or a phenyl group, 3,3,3-cryptochromes or 3,3,3-Cryptor-2-hydroxypropyl,

in the form of enantiomers or diastereoisomers, or mixtures of these various forms, including racemic mixtures.

2. P is an oxygen atom, the sulfur atom or the group NR wherein R is hydrogen or C1- C4-alkyl, normal or branched, R1represents a methyl group or a hydrogen atom, R2represents a group R3O, in which R3O is either a hydrogen atom or a benzyl group, possibly substituted by a halogen atom or nitro or methylendioxyphenyl or group methoxyethyl, butyl, 4,4,4-tripcomputer, 4,4,4-triflorum-2-enyl, 4,4,4-Cryptor-3-hydroxybutyl, in the form of enantiomers or diastereoisomers, or mixtures of these different forms, including racemic mixtures.

3. Derivatives of 5-(hydroxymethyl)oxazolidin-2-it General formula I on p. 1, characterized in that X represents an oxygen atom, a sulfur atom or the group NR wherein R is hydrogen or C1- C4-alkyl, normal or branched; R1represents a methyl group or a hydrogen atom; R2represents a group-CH= CH-R4or-CH2-CH2-R4in which R4represents a hydrogen atom or a phenyl group, 3,3,3-cryptochromes, and 3,3,3-Cryptor-2-hydroxypropyl, in the form of enantiomers or diastereoisomers, or mixtures of these different forms, including racemic mixtures.

1represents a methyl group or a hydrogen atom, R2represents (i) a group R3O, in which R3represents either a hydrogen atom or a benzyl group, possibly substituted by a halogen atom or nitro or methylendioxyphenyl or group methoxyethyl, butyl, 4,4,4-tripcomputer, 4,4,4-Cryptor-3-hydroxybutyl or 4,4,4-triflorum-2-enyl, or (ii) the group-CH=CH-R4or-CH2-CH2-R4in which R4represents a hydrogen atom or a phenyl group, 3,3,3-cryptochromes or 3,3,3-Cryptor-2-hydroxypropyl, in the form of enantiomers or diastereoisomers, or mixtures of these different forms, including racemic mixtures.

5. Derivatives of 5-(hydroxymethyl)oxazolidin-2-it General formula I on p. 1, wherein X is an oxygen atom, R1represents a methyl group or a hydrogen atom, and R2represents either a hydroxyl group or phenylmethoxy group, possibly substituted by a halogen atom or nitro or methylendioxyphenyl or group, 4,4,4-triptoreline or group, 4,4,4-Cryptor-3-hydroxybutanal, in the form of enantiomers or diastereoisomers, or mixtures of these different forms, including racemic mixtures.

6. (soedinenii formula I in which X represents an oxygen atom, or sulfur atom or the group NR, and R is a hydrogen or C1- C4-alkyl, normal or branched; R1represents a methyl group, R2represents a group R3O, in which R3represents either a hydrogen atom or a benzyl group, possibly substituted by a halogen atom or nitro or methylendioxyphenyl or group methoxyethyl, butyl, 4,4,4-tripcomputer, 4,4,4-Cryptor-3-hydroxybutyl or 4,4,4-triflorum-2-enyl, characterized in that the compound of formula II

< / BR>
process one of the isomers of 4(R) - or 4(S) 4-methoxymethyl-1,3-dioxolane-2-it formula IIIa

< / BR>
in the presence of potassium carbonate to obtain isomer 5(S) or 5(R) compounds of the formula Ia

< / BR>
which dibenzyline catalytic hydrogenation or by using a Lewis acid to obtain isomer 5(R) or 5(R) the compounds of formula(Ib), R1= CH3)

< / BR>
which process or the compound of the formula R3Y, in which R3defined as in formula I, except for the values of hydrogen and unsubstituted benzyl, and Y is a leaving group such as chlorine atom or bromine or tailorshop, in the presence of potassium carbonate or the compound of the formula is the receiving of the isomers of 5(S) or 5(R) compounds of formula(Ic), R1= CH3)

< / BR>
and, if necessary, process connections, such as X = NCH3where X = NH, benzoyl peroxide with formation of compounds of formula Ih

< / BR>
8. Method of producing compounds of the formula I, in which R1represents a hydrogen atom, and the substituents X and R2have the same value as before, characterized by the fact that the ethyl ester of 6-phenylmethoxy-1,2-benzisoxazol-3-carbamino acid of the formula II

< / BR>
process one of the isomers of 4(S) or 4(R) 4-phenylmethoxy-1,3-dioxolane-2-it formula IIIb

< / BR>
in the presence of potassium carbonate to obtain isomer 5(R) or 5(S) of compounds of formula VI

< / BR>
which dibenzyline catalytic hydrogenation to obtain isomer 5(R) or 5(S) the compounds of formula(Ib), 1= H)

< / BR>
which is then treated with a compound of the formula R3Y, in which R3defined as in formula I, except for the value of hydrogen, and Y is a leaving group such as chlorine atom or bromine or tailorshop, in the presence of potassium carbonate to obtain the isomers of 5(R) or 5(S) the compounds of formula(Ic), R1= H)

< / BR>
9. Method of producing compounds of the formula I, in which X represents an atom of the acid is extensive, R1represents a hydrogen atom or methyl group, and R2represents a group-CH=CH-R4or-CH2-CH2-R4where R4represents a hydrogen atom or a phenyl group, 3,3,3-cryptochromes or 3,3,3-Cryptor-2-hydroxypropyl, characterized in that it consists in processing the compounds of formula(Ib), R1= CH3)

< / BR>
triftormetilfullerenov anhydride, the interaction of the thus obtained compounds of formula IV

< / BR>
with tributylamine in the presence of lithium chloride and tetrakis(triphenylphosphine)palladium, treatment of compounds of formula (Id)

< / BR>
ozone, then dimethyl sulfide, the interaction of the compounds of formula V

< / BR>
with triphenylphosphonium formula R4CH2PPh3+I-in which R4defined as in formula I above, with the exception of the values of the hydrogen, in the presence of potassium carbonate, and recovering the compounds of formula Ie

< / BR>
with hydrogen in the presence of a catalyst to obtain the compounds of formula If

< / BR>
in which R4defined as previously, and treatment of this compound with tribromide boron obtaining the compounds of formula Ig

< / BR>
10. Medicine, inhibiting the monoamine oxidase B or mules I on p. 1.

11. The pharmaceutical composition inhibiting the monoamine oxidase B or inhibiting the monoamine oxidase B and monoamine oxidase A, characterized in that it contains a compound of formula I under item 1 in combination with any suitable excipient.

 

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< / BR>
where X denotes O, S, NH or NA;

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< / BR>
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