Derivative oxazolidin-2-it drug on their basis

 

(57) Abstract:

Describes the new derivative oxazolidin-2-it General formula I, where R denotes lower alkyl; X denotes cycloalkenyl; bicyclo (2,2,1)hept-2-yl, optionally substituted phenyl-2-oxo-5-ethoxymethyleneamino; bicyclo (2,2,1)hept-5-EN-2-yl; substituted or cycloalkyl or piperidine, optional one - or multiply substituted with halogen, amino, lower alkyl, nitrile, exography, hydroxyimino, ethylenedioxythiophene or or1where R1denotes-CH(C6H5)2, -(CH2)nWITH6H5, lower alkyl, hydrogen, -(CH2)nTHE N3-(CH2)nNH2, -(CH2)nSOCH3, -(CH2)nSP, -(CH2)nSCH3,

-(CH2)nSO2CH3-CO-lower alkyl, -SOS6H5, optionally substituted oxazolidinyl group, or substituted =CR2R3where R2denotes hydrogen or lower alkyl; R3denotes hydrogen, nitrile, lower alkyl, phenyl or COO-lower alkyl, or substituted -(CH2)nR4where R4denotes nitrile, amino, -N3-, -SOS6H4Gal, phenyl or hydroxyl group; or SUB>, -O-C/CH3/3or-0-lower alkyl; or substituted-NR6R7where R6denotes hydrogen or-PINES3; R7stands of PINE trees3benzyl or -(CH2)nTHE N6H4Gal; n is 1 to 3; Y1- -CH = or-N= ; Y2-CH= , -C(IT)=- C(NO2)=, -C(NH2) = - C (Gal) - or-N=, and pharmaceutically acceptable salts of basic compounds of formula I with acids. These compounds have the ability to inhibit monoamine oxidase. Describes the medicinal product on the basis of the compounds of formula I, which can be used to treat conditions of depression, States of panic and fear. 2 C. and 21 C.p. f-crystals.

The invention relates to a derivative of oxazolidinone. In particular, it relates to derivative oxazolidin-2-it General formula

< / BR>
where R denotes lower alkyl;

X denotes cycloalkenyl; bicyclo[2,2,1]hept-2-yl, optionally substituted phenyl-2-oxo-5-ethoxymethyleneamino; bicyclo[2,2,1]hept-5-EN-2-yl; substituted; or cycloalkyl or piperidine, optional one - or multiply substituted with halogen, amino, lower alkyl, nitrile, exography, hydroxyimino, ethylenedioxythiophene or1,

where R is-CH(C6H5)2, - 2-(CH2)nSOCH3,-(CH2)nCN, -(CH2)nSCH3, -(CH2)nSO2CH3, -CO-lower alkyl, -COC6H5, optionally substituted oxazolidinyl group;

or substituted on =CR2R3where R2denotes hydrogen or lower alkyl; R3denotes hydrogen, nitrile, lower alkyl, phenyl or COO-lower alkyl;

or substituted -(CH2)nR4where R4denotes nitrile, amino, -NHCOCH3, -COC6H5Gal, phenyl or hydroxyl group;

or substituted on-COR5where R5denotes lower alkyl, -CH=CH-C6H5-C6H5CF3, -O-C(CH3)3or-O-lower alkyl;

or substituted with-NR6R7where R6denotes hydrogen or-COCH3; R7means-COCH3, benzyl or -(CH2)nNHCOC6H4Gal;

n represents 1-3;

Y1represents-CH= or-N=;

Y2denotes-CH=, -C(OH)=, -C(NO2=), -C(NH2)=, -C(Gal)= or-N=,

and to pharmaceutically acceptable salts of basic compounds of formula I with acids.

These compounds and salts are new and different valuable pharmacological properties, as they have matemticas acceptable salts can be used to treat conditions of depression, States of panic and fear, cognitive brain functions and diseases, neuro-degenerative nature as Parkinson's and Alzheimer's disease.

The present invention also aims at obtaining the compounds of General formula I and their pharmaceutically acceptable salts per se and as pharmaceutical active substances for the development of the method of obtaining these compounds and salts on the development of the containing medicines to fight and accordingly prevent a state of depression, States of panic and fear, disease, neuro-degenerative nature as Parkinson's and Alzheimer's disease, and the manufacture of such drugs, the use of compounds of General formula I and their pharmaceutically acceptable salts for combating or preventing diseases, respectively, to improve health, and also the use of compounds of General formula I and their pharmaceutically acceptable salts for the manufacture of medicines to fight and accordingly prevent a state of depression, States of panic and fear, disease, neuro-degenerative nature as Parkinson's and Alzheimer's disease.

Use Horodnya radicals, as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, etc.

The concept of "cycloalkyl" denotes a saturated cyclic hydrocarbons with the number of carbon atoms in the cycle, preferably 3-7, as, for example, cyclopropane, CYCLOBUTANE, cyclopentane, cyclohexane or Cycloheptane.

Halogen denotes fluorine, chlorine, bromine or iodine.

The term "leaving group" means under the present invention such famous groups as halogen, preferably bromine, arylsulfonate, alkylsulfonate etc.

Under reagents, which are carbonyl, in the framework of this proposal can be understood, for example, diethylcarbamyl, phosgene, or their equivalents.

The term "pharmaceutically acceptable salt" includes salts of organic and inorganic acids as hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonate, paratoluenesulfonyl etc.

For the preferred compounds of formula I are those in which X represents a cyclohexyl or substituted cyclohexyl, R obozie, as oxoprop, hydroxyl group, with hydroxyimino, methoxy, and-O-(CH2)2-R8where R8represents-CN or-CH2NH2. Such compounds are, for example, the following:

(RS)-3-(4-cyclohexylphenol)-5-hydroxymethylimidazole-2-he;

(RS)-3-(4-cyclohexylphenol)-5-ethoxyethylacetate-2-he;

(R)-3-(4-cyclohexylphenol)-5-ethoxyethylacetate-2-he;

(RS)-3-[4-(4- oxocyclohexyl)phenyl]-5-ethoxyethylacetate-2-he;

(RS)-3-[4- (TRANS-4-hydroxycyclohexyl)-phenyl]-5-methoxymethyl - oxazolidin-2-he;

(RS)-3-[4-(4- hydroxyindolacetic)phenyl] -5-methoxymethyl-oxazolidin-2-he;

(R)-3-[4-TRANS-4-hydroxycyclohexyl)-phenyl]-5-methoxymethyl - oxazolidin-2-he;

(RS)-3-[4-(TRANS-4-methoxycyclohexyl)-phenyl] -5 - methoxymethyl-oxazolidin-2-he;

(R)-3-[4-(4-oxocyclohexyl)-phenyl] -5-ethoxyethylacetate-2-he;

(RS)-3-[4-[TRANS-4-(2 - cyanoethoxy)cyclohexyl] phenyl]-5-ethoxyethylacetate-2-he;

(RS) -3-[4-(TRANS-4-ecotoxicological)phenyl] -5-methoxyethoxy - solidin-2-he;

(RS)-3-[4-CIS - and TRANS-4-hydroxymethylcellulose)phenyl]- 5-ethoxyethylacetate-2-it; and

(RS)-3-[4-CIS - or TRANS-4 - hydroxy-4-methylcyclohexyl)phenyl]-5-methoxymethyl-oxazolidin-2-it.


3-[(1RS, 2RS, 4SR)-4-bicyclo[2,2,1] hept-2-ylphenyl]-5 - ethoxyethylacetate-2-he

3-[1RS, 2SR,4RS)-4-bicyclo [2,2,1] hept - 5-EN-2-yl-phenyl]-5-ethoxyethylacetate-2-it.

Also preferred are such compounds in which X represents a cyclohexyl or piperidine substituted on the-CH2CN, -COCH=CH-C6H5, -O(CH2)NH2or-OCH2CN, R denotes methyl and Y1and Y2denote CH-group, for example the following compounds:

(RS)-3-[4- (TRANS-4-cyanomethylene) phenyl]-5 - ethoxyethylacetate-2-he

(R)-3-[4-(TRANS-4-cyanomethylene) phenyl] -5-ethoxyethylacetate-2-he

(E)-(RS)-5-methoxymethyl-3-[4-[1-(3- phenylacrylate)piperidine-4-yl]-phenyl] oxazolidin-2-he

(R)-3-[4- (TRANS-4-cyanometallates) phenyl] -5 - ethoxyethylacetate - 2-he

(RS)-3-[4-(TRANS-4 - cyanometallates) phenyl]-5 - ethoxyethylacetate-2-he

hydrochloride, (RS)-3-[4-[TRANS-4-(2 - aminoethoxy)cyclohexyl]phenyl]-5-ethoxyethylacetate-2-she (1:1)

(R)-3-[4-[TRANS-4-(3-aminopropoxy) cyclohexyl] phenyl]-5 - ethoxyethylacetate-2-it.

Compounds of General formula I and their pharmaceutically acceptable salts can be obtained according to sabree values, cyclist using reagent from which emit carbon monoxide, and under certain conditions, alkylate, or

b) the compound of formula I, where R denotes hydrogen, alkylate, or

C) the compound of formula I, where R is benzyl, is subjected to catalytic hydrogenation, or

g) the compound of the formula

< / BR>
where X, Y1and Y2have the above meanings and R3denotes lower alkyl or benzyl, is subjected to the interaction with the compound of the formula

< / BR>
where R4denotes alkyl or benzyl, or

d) the compound of General formula

< / BR>
where R, Y1and Y2have the above meanings and A denotes a leaving group, is treated with a reagent, which emit Deputy X, or

e) a compound of the formula

< / BR>
where X' denotes a (C5-C7)-cycloalkenyl residue, which is decoded in the formula I for cycloalkyl or piperidine, may be substituted,

and Y1, Y2and R have the above values,

subjected to catalytic hydrogenation to the corresponding saturated cycloalkyl connection, or

g) the compound of formula I, where X is replaced by Ethylenedioxy cycloalkyl, hydronaut, or

C) soy-CN, =CH-CN or-CH2CN, hydronaut to amino compounds, or

and the connection formula I, where X is replaced by oxopropoxy cycloalkenyl or piperidinyl balance, transform, namely:

translate oxoprop in hydroxyisopropyl, or

restore it to a hydroxyl group, or

translate it with suitably substituted amines in-NH(CH2)nNHCOC6H4R3group, where R3and n have the above values, or

translate it into methylene group, benzylidene group, dimethylmethylene group, methylnitrosourea group or methoxycarbonylmethylene group, or

transform it in Ethylenedioxy, or

translate it into the amino group, or

translate it using the appropriate phosphonate =CH-CN group, or

K) the compound of formula I, where X denotes a substituted hydroxyl group cycloalkenyl or piperidinyl the rest,

translate hydroxyl group using Acrylonitrile in-O(CH2)2CN-group, or

alkylate or acelerou it with the appropriate alkyl-, aryl - or allelochemical, or

halogenous appropriate halogenation means, or

transfee to Sultanovich or Sultanovich compounds, or

l) in the compound of formula I, where X is substituted with a hydroxyl group cycloalkenyl balance, digitalout this last to cycloalkenyl residue, or

m) in the compound of formula I, where X is replaced by-O(CH2)n-SOCH3group cycloalkenyl or piperidinyl the rest,

translate the group-O(CH2)nCN-group, or

h) a compound of formula I, where X denotes cycloalkyl balance, piperidinyl balance or protected piperidinyl balance, not linked to a nitrogen atom,

acelerou with appropriate alleluya funds, or

(o) the compound of formula I, where X is substituted on the methylene group cycloalkenyl or piperidinyl the rest,

translate this group in hydroxymethylene group or convert it to 4-hydroxy-4-methyl group, and

p) if desired, the compound of formula I is transferred by using the appropriate acid in a pharmaceutically acceptable salt.

The compound of formula II according to variant (a) of the method according to the invention can be cyklinowanie in the compound of formula I by treatment with a reagent which emit carbon monoxide. Preferably the cyclization carried out potorac in the solvent, for example toluene, is treated with diethylmalonate and after the addition of a methanol solution of sodium methylate was stirred under heating for several hours. The conditions of the reaction, namely the temperature, duration, solvents, etc. may vary depending on the specific reactive derivative.

According to variant b) of the method according to the invention alkylate the hydroxyl group. This alkylation can be carried out by known methods. For methylation, it is advisable to apply as alkylating tools dimethylsulfate. You can work so that alkilirutmi connection is first dissolved in an appropriate solvent, for example toluene, and then process dimethylsulfate, tetrabutylammonium hydrosulfate and sodium hydroxide solution with vigorous stirring. Reaction conditions can be varied depending on the characteristics of alkylating means, respectively alkilirutego connection.

If R is a benzyl, the catalytic hydrogenation can be performed up to R denoting hydrogen (option) method). As the catalyst can be applied yeah, alcohol, methanol, acetic ether, glacial acetic acid or mixtures of these solvents. Preferably simple benzyl ester is dissolved in alcohol and hydronaut at room temperature using a palladium catalyst. The hydrogenation is carried out with the known methods and apparatus for shaking or autoclave.

Under option d) of the method according to the invention the compounds of formula I can be obtained by the interaction of the compounds of formula III and formula IV.

It is advisable to handle alkilany ether of carbamino acid of the formula III 4-(alkoxymethyl)-1,3-dioxolane-2-one of formula IV and stirred for several hours under heating. Another possibility of obtaining compounds of formula I are represented by option d) method. In this case, the compounds of formula V is treated with a reagent, which emit Deputy X. If A in formula V as tsepliaeva group denotes a halogen atom, in particular bromine or iodine, the exchange reaction it is advisable to implement the following way: the oxazolidinone of formula V in a few hours is subjected to an exchange reaction in dimethylformamide (DMF) with the addition of triphenylphosphine, dichloride bis(triphenylphosphine) palladium (II), chlorido known methods.

Derivatives cycloalkyl formula I can also be obtained, if appropriate cycloalkenyl the compounds of formula Ia subjected to catalytic hydrogenation (option e) method). Suitable for this purpose are primarily a 5-7 membered cyclic system which can be gidrirovanii to cyclohexylamin, cyclopentyloxy or cycloheptyl compounds. The hydrogenation is carried out using known methods, preferably using palladium catalyst at room temperature and under normal pressure.

Under option f) method replaced oxoprop derived cyclohexyl formula I obtained by hydrolysis of compounds of formula I, where X is replaced by Ethylenedioxy cyclohexyl, conducted by well-known methods. Preferably thus prepared solution in tetrahydrofuran, stirred for several hours with hydrochloric acid and treated with sodium lye.

The compound of formula I, where X is replaced by-O-(CH2)2CN-cycloalkyl or piperidine, using known methods may gidrirovaniya in aminosidine (option C) method). Preferably, the suspension of sodium borohydride tetrahydrofur the uly I and stirred for several hours. Then, the processing in the usual manner.

If X is replaced by acetonitrile group cycloalkyl, then hydrogenation to aminoethanol group can be carried out in methanol with ammonia in the presence of Raney Nickel. Another option, which receive aminosidine formula I, is that first replaced by =CH-CN-group cycloalkyl hydronaut using Pd on charcoal, and then, as described above, is converted into aminosidine.

If X in the formula I denotes substituted for oxoprop cycloalkenyl or piperidinyl balance, these compounds can be used as starting materials for the production of other compounds of formula I (option) method).

If X is cycloalkane, oxoprop can be transferred to hydroxyisopropyl. This translation is carried out preferably using known methods as follows: at the appropriate compound of formula I with stirring and cooling, add an aqueous solution of hydroxylamine. Appropriate gidroksiiminobetulonovoi after addition of an aqueous solution of sodium carbonate is precipitated in the form of crystals.

Next OH-substituted derivatives of formula I can be half the, is orovided sodium or lithium, in an inert in the reaction conditions an organic solvent as methanol, ethanol, etc., the Recovery is carried out mainly at room temperature.

Replaced by oxopropoxy derivatives cycloalkyl or piperidine derivatives of formula I may be subject to interaction with amines, for example N-(2-amino-ethyl)-4-chlorobenzamido. Preferably both of the reagent is treated while the monohydrate para-toluenesulfonic acid and dissolved in a mixture of toluene and DMF. Then stirred for several hours under heating and, after cooling, is treated with sodium borohydride and hydrochloric acid.

Further, according to the variant of compounds of formula I, where X is replaced by oxoprop cycloalkenyl or piperidinyl residue, can be translated into methylene, benzylidene, dimethylmethylene, metileritrol or methoxycarbonylmethylene derivatives cycloalkyl or piperidine.

It is advisable to work in the following way: in an argon atmosphere, for example a mixture of bromide methyltriphenylphosphonium and sodium amide, or a mixture of bromide isopropyltriphenylphosphonium and sodium amide, or a mixture of bromide benzyltriphenylphosphonium and amide natut. Then add the corresponding oxocyclohexyl or oxopiperidine compound of formula I and stirred for several hours under heating. Subsequent processing is conducted according to conventional methods. Methylene group, under certain conditions, can then re-gidrirovanii.

Also under option and how you can obtain the compounds of formula I, where X is replaced by Ethylenedioxy cycloalkenyl or piperidinyl balance. In this case, the correspondingly substituted oxocyclohexyl or oxopiperidine compound of formula I is subjected to interaction with ethylene glycol in the presence of the monohydrate para-toluenesulfonic acid in toluene. The final compound is obtained after stirring for several hours at heating and conventional processing.

Substituted on oxoprop cycloalkenyl or piperidinyl balance under option and can be translated into the amino group by the interaction of exocoetidae preferably benzylamine and toluensulfonate and subsequent hydrogenation in a few hours with sodium borohydride at room temperature.

Oxocyclohexyl group according brewing sodium is dissolved in ethanol and the solution treated with an ethanol solution citizen.metropolitan, then perform the transformation using the appropriate oxocyclohexyl the compounds of formula I in the final connection.

If X in the formula I denotes a substituted hydroxyl group cycloalkenyl or piperidinyl the rest, and these compounds can be used as starting materials for the production of other compounds of formula I (option) method). Nitrosamine connection can be obtained, for example, the interaction of derivative hydroxycyclohexyl or piperidine derivatives of the formula I with Acrylonitrile in the presence of tert.-the butyl potassium.

Thus obtained nitrosamine the compounds of formula I under certain conditions can be transformed into the corresponding amino compounds by treatment with dry gaseous ammonia dissolved in methanol, and hydrogenation using Raney Nickel.

The compounds of formula I containing a hydroxyl group, with acid chlorides can be etilirovany in the appropriate carbenoxolone. Preferably when this is substituted by a hydroxyl group cycloalkyl or piperidine compound of formula I is dissolved in a solvent, such as methylene chloride, treated with E. which of several hours at room temperature. Further processing is conducted according to known methods.

Alkylation, respectively acylation of compounds of formula I containing a hydroxy group may be carried out using the corresponding alkyl - or allelochemical, for example, by using under the conditions, benzylbromide or chlorodiphenylmethane. This transformation is carried out by known methods.

Halogenoalkane compounds of formula I containing a hydroxyl group can also be carried out by known methods using the appropriate halogenation means. For example, verticalchange compound of formula I is formed by the interaction of hydroxycyclohexyl connection with a mixture of Diethylenetriamine sulfur and methylene chloride after stirring at room temperature.

Also according to version) method of the compounds of formula I containing a hydroxyl group can be converted into the corresponding sulfanilic connection. This transformation can be carried out so that the first hydroxyl compound dissolved in dimethyl sulfoxide, and then treated with glacial acetic acid and acetic anhydride and stirred for some of the bathrooms of the Japanese chemical society.

Appropriate sulfanilate connection can be obtained under certain conditions after the implementation of the above options by oxidation of sulfanilic connection. As the oxidizing agent for this purpose is particularly suitable periodate sodium.

Appropriate sulfonylurea connection can be obtained by oxidation of sulfanilic connection. Preferably the oxidant is used chloroperbenzoic acid. Suitable for this purpose is the solvent, for example methylene chloride.

Under option l) method of the compounds of formula I, where X is substituted with a hydroxyl group cycloalkenyl balance, digitalout to cycloalkenyl balance. This reaction is preferably carried out by the interaction of the hydroxyl compound with triphenylphosphine and benzoic acid in tetrahydrofuran at room temperature and subsequent treatment of the diethyl ester of azodicarboxylic acid.

Under option m) method, where X is replaced by-O(CH2)n-SO-CH3group cycloalkenyl or piperidinyl balance, this group was transferred to the group-O(CH2)nCN due to the fact that cootie in the presence of zinc iodide and trimethylsilylacetamide. This reaction proceeds for several hours at room temperature.

The compound of formula I, where X is piperidinyl or substituted piperidinyl balance, not linked to a nitrogen atom, or cycloalkenyl the remainder may be allerban under option n) method. This acylation carried out preferably using the appropriate alleluya means, for example using benzylbromide, -chloro-4-verbalization, triftormetilfullerenov, acetic anhydride or chloride, cinnamic acid, by well-known methods. As a solvent it is particularly suitable dimethylformamide or methylene chloride.

The compounds of formula I containing a methylene group as a substituent of cycloalkyl or piperidine, can also be used as a starting substance to obtain other compounds of formula I (variant a) method).

The corresponding compound of formula I, where X denotes a substituted methylene group cycloalkenyl or piperidinyl the rest can be translated in hydroxymethylamino connection by hydroabrasive of this compound, dissolved in a solvent, such as THF, with sodium borohydride in prisonere cycloalkene the compounds of formula I can also be transformed into the corresponding 4-hydroxy-4-methylamine derivatives cycloalkyl or piperidine. To this end, the acetate of mercury dissolved in THF and treated with 4-methylindoline cycloalkenyl compound of formula I. Then stirred at room temperature, treated with sodium liquor and subjected to interaction with sodium borohydride. Further processing is conducted according to conventional methods.

The compound of formula I, where R is benzyl, can be obtained by the interaction of the correspondingly substituted cycloalkyl any piperidinylcarbonyl ether with benzoyloxymethyl-1,3-dioxolane-2 - one using known methods.

Pharmaceutically acceptable salt, given the level of technology and features translated into salt compounds can be obtained using known methods.

Used under variant a) method as starting substances, the compounds of formula II can be obtained in the following way: 4-cyclohexylaniline or other correspondingly substituted anilines and (RS)-2,2-dimethyl-1,3 - dioxolane-4-ymetray broadcast methansulfonate (see Journ. Med. Chem. 27, 1176 [1934]) stand in triethylamine for several hours at a temperature of about 140oIn refractory tube. Then after removal of the solvent the residue is stirred with hydrochloric is in the exchange reaction between 4-cyclohexylaniline or other correspondingly substituted aniline and [(R)-2,2-dimethyl-1,3-dioxolane-4-metamaterial-4-sulfonate] triethylamine at a temperature of about 140oC. Then stirred for several hours and then the resulting product is treated first with HCl, and then after stirring for about 1 h alkalinized sodium lye. Subsequent processing is conducted according to conventional and well-known methods.

Used under option g) method as the starting material the compound of the formula III are known and can be obtained as follows.

4-Cycloalkenyl or other correspondingly substituted anilines is dissolved in a solvent, such as THF and water, treated with sodium bicarbonate, and then subjected to an exchange reaction with ethyl ether of Harborview acid. The reaction temperature should not exceed 20oC.

The compounds of formula IV are known and can be obtained by methods known from existing publications.

Required to implement option d) method of the connection formula V may preferably be obtained in the following way in the example below, the Y2denotes nitrogen.

A mixture of ethyl ether pyridine-3-ylcarbamate acid, methoxymethyl - 1,3-dioxolane-2-she and potassium carbonate are heated and stirred for neskolkih which the compound obtained 5-methoxymethyl-3-(1-oxypyridine-3-yl) oxazolidin-2-he bromilow and then with a reducing agent, for example, tribromide phosphorus transfer in compound of formula V. This compound can then, as described above, be subjected to interaction with the reagent from which emit Deputy X. Suitable for this purpose are such tools that are as radical containing, for example, tributylstannyl group. Obtaining these compounds is carried out using known methods.

Substituted cycloalkene the compounds of formula Ia can be obtained by treating compounds of formula V, where A denotes tsepliaeva group, for example halogen, reagent, which emit Deputy X', where X' denotes a (C5-C7)-cycloalkenyl residue, which is decoded in the formula I for cycloalkyl, may be substituted. The reactive group may represent, for example, tributylstannyl group. Preferably the exchange reaction is carried out in an argon atmosphere in the presence dichloride bis(triphenylphosphine) palladium (II) in THF using known methods. Compounds used in options b), C), e), g), h), I), K) l) m) n) o) p) as a source of substances that fall under the formula I and in accordance with this can be obtained by the methods described to obtain this connection is adut, as noted above, activity, inhibiting the monoamine oxidase (MAO). Thanks to this activity the compounds of formula I and their pharmaceutically acceptable salts can be used in the treatment of States of depression, States of panic and fear, cognitive brain functions and diseases, neuro-degenerative nature. Examples of such diseases are hypomnesia associated with Parkinson's disease, primary and secondary dementia, such as dementia type Alzheimer's disease or dementia due to multiple heart attacks, cerebral vascular disease and consequences of traumatic brain injury.

Inhibiting MAO activity of the compounds according to the invention can be determined using standard methods. So tested preparations were subjected to the test described below in vitro according to the method similar to that described by R. J. Wurtmann and J. A. Axelrod in Biochem. Pharmacol. 12, 1439- 1441 (1963).

The selected rat brain homogenized in a ratio of 1:9 (weight/volume) in 0.1 molar buffer solution of potassium phosphate (pH 7,4), then the homogenates were diluted in the ratio 1:4 (volume/volume) in the same buffer solution and kept at -20oC. For incubation was applied a mixture of the following softwaretechnologie;

50 μl of homogenate of rat brain;

and as the substrate 50 ál14C-serotonin (5-HT), respectively14C-phenethylamine (pea), respectively 100,000 disintegrations per minute in accordance with the final concentration of 210-4mol/l, respectively 210-5mol/L.

Before addition of the substrate for 30 min hold preliminary incubation at 37oC. Incubation (in the presence of substrate) are also carried out at 37oC and it lasts for 10 minutes the Reaction is stopped by addition of 200 μl of 2n. of hydrochloric acid. For extraction diaminononane products, depending on the application of 5-HT or pea as substrate shaken for 10 min with 5 ml of diethyl ether, respectively with 5 ml n-heptane, and then centrifuged, the aqueous phase is removed by freezing in a bath of dry ice and the organic phase is decanted in counting cups.

On the basis of obtained by using the counter values determine the activity of MAO in comparison with the control homogenates.

In the conditions of the conducted experiments the activity is linear with respect to time and concentration of homogenizate. The values of the IC50defined graphic by as log concentration curve/Akti is and MAO activity using substrate 5HT, accordingly, FAA 50%.

Revealed in this way the activity of some compounds according to the invention are presented in the following table 1, where the values IC50.

The compounds of formula I and their pharmaceutically acceptable additive, acid salts can be used as medicines, for example in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, for example in the form of tablets, lacquered tablets, coated tablets, terdoslavich and megkozeliteni capsules, solutions, emulsions or suspensions. Medications can also be carried out rectally, for example in the form of suppositories, or parenteral, for example in the form of solutions for injection.

For the manufacture of tablets, lacquered tablets, coated tablets and terdoslavich capsules in the compounds of formula I and their pharmaceutically acceptable acid salt additive can be added pharmaceutically inert, inorganic or organic excipients. As such, for example, tablets, pills and terdoslavich capsules can be used lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc.

For the claim, fats, semi-solid and liquid polyols, etc.

In the manufacture of solutions and syrups as excipients can be used water, polyols, saccharose, invert sugar, glucose, etc.

As excipients for injection solutions are suitable, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.

As excipients for suppositories are suitable, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols etc.,

The pharmaceutical preparations may contain, in addition, and preservatives, solvents, stabilizers, wetting agents, emulsifiers, chemicals, improves taste, dyes, flavouring tools, salts for modifying the osmotic pressure, buffers, coating or antioxidants. They can also contain other valuable in therapeutic relationship substance.

According to the invention compounds of General formula I and their pharmaceutically acceptable additive, acid salts can be used to fight and accordingly prevent a state of depression, cognitive brain functions and diseases, neuro-degenerative nature as Parkinson's and Alzheimer's disease is ividually patient. In oral introduction, the daily dose may be administered primarily at the rate of approximately 10 to 100 mg of the compounds of General formula I, and the specified upper limit is not the limit, if this is appropriate.

The invention is explained more in the following examples, which in no way limit it. All temperatures in the examples are in degrees Celsius.

Example 1

(RS)-3-(4-pylogenetic)-5-hydroxymethylimidazole-2-he

2.4 g (9,62 mmol) (RS)-3-(4 - cyclohexyl-phenylamino)-propane-1,2-diol was dissolved in 50 ml of toluene was treated with 1,25 g (10.6 mmol) of diethylmalonate and 0.4 ml of 1M solution of sodium methylate in methanol and stirred overnight at an oil bath temperature of 110oC. the Solvent is kept in a water-jet pump, the residue was treated with water and 1N. hydrochloric acid and was extracted with acetic ester. The organic phase is washed with water, dried over magnesium sulfate and the solvent drove away. From acetic ester/hexane was obtained 1.4 g of product in the form of yellowish crystals. Forth from the mother liquor was given to 0.9 g of pure product. So pl.: 167-167,5o.

Example 2

(RS) -3-(4-cyclohexylphenol was treated with 15 ml of toluene, 1.6 ml of dimethylsulfate (16.3 mmol), 185 mg of tetrabutylammonium hydrosulfate and a solution of 1.09 g (27.2 mmol) of sodium hydroxide in 1.3 ml of water and was intensively stirred for 30 minutes and Then the reaction mixture was poured into ice water and was extracted with acetic ester. The organic phase is washed with water, dried over magnesium sulfate and the solvent drove away. The result was obtained 1.6 g of a yellow oil. After treatment with acetic ether/hexane was obtained 0.7 g of colorless crystals. So pl.: 69-70o.

Example 3

(S)-3-(4-cyclohexylphenol)-5-hydroxymethylimidazole-2-he

A solution of 1.40 g (5.6 mmol) of (S)-3-(4-cyclohexyl-phenylamino)-propane-1,2-diol in 50 ml of toluene was treated with 0.73 g (6.2 mmol) of diethylmalonate and 0.5 ml of 1M solution of sodium methylate and was stirred overnight at an oil bath temperature of 110o. After removal of the solvent was treated with water and 5 ml of 1N. hydrochloric acid, then was extracted with acetic ester. The organic phase is washed with a solution of common salt, dried over magnesium sulfate and the solvent drove away. From acetic ester/hexane received 1.35 g (S) -3-(4-cyclohexylphenol)-5-hydroxymethylimidazole-2-it is in the form of colorless crystals. So pl.: 166-168o. [] is in 2-he

In a solution of 1.0 g (3.63 mmole) of (S)-3-(4-cyclohexylphenol)-5 - hydroxymethylimidazole-2-it in 10 ml of toluene was added 250 mg of tetrabutylammonium hydrosulfate, a solution of 0.73 g of sodium hydroxide (18.2 mmol) in 1 ml of water and 1.1 ml of dimethylsulfate (10.9 mmol) and was stirred for 1 h at 110o. After cooling, was treated with 10 ml of water and was extracted with acetic ester. After concentration of the solvent was obtained 1.2 g of crystalline mixture, which was chromatographically 30-fold amount of silica gel. Homogeneous according to thin the chromatogram (TLC) fraction of acetic ether/hexane (1: 1) were combined and the solvent drove away. The result has been 0,85 g (S)-3-(4-cyclohexylphenol)-5-ethoxyethylacetate-2-it is in the form of colorless crystals. So pl.: 90-92o. []D=39,7o(C=0,7/CHCl3).

Example 5

(R)-3-(4-cyclohexylphenol)-5 - hydroxymethylimidazole-2-he

6.2 g (24.8 mmole) of (R)-3-(4 - cyclohexylaniline)-propane-1,2-diol was converted and processed in the same way as described in example 3. The result obtained 6.3 g (93%) of beige crystals. So pl.: 166-168o. []D=-48,9o(C=0,7/CH3OH).

Example 6

(R)-3-(4-cyclohexylphenol)-5-ethoxyethylacetate amityvale same as described in example 4. The result has been 1,91 g (91%) of (R)-3-(4 - cyclohexylphenol)-5-ethoxyethylacetate-2-it is in the form of colorless crystals. So pl.: 86-88o. []D=-37,7o(C=0,3/CHCl3).

Example 7

(RS)-3-[4-(4-oxocyclohexyl)phenyl]-5-ethoxyethylacetate-2-he

10 g (38.3 mmol) [4-(4-oxocyclohexyl)phenyl] ethoxycarbonyl ether, 10 g (75 mmol) of (RS)-4-(methoxymethyl)-1,3-dioxolane-2-she and 0.5 g of potassium carbonate was intensively stirred for 4 h at an oil bath temperature of more than 160o. After cooling, treated with 50 ml water and was extracted with acetic ester. Obtained after removal of the solvent a yellow oil (15.5 g) was chromatographically 30-fold amount of silica gel. Homogeneous according to TLC (acetic ester/hexane 7:3) fraction of methylene chloride/acetic ether (15:1) were combined and the solvent drove away. The result has been 5,54 g (48%) of colorless product. So pl.: 114-116o.

Example 8

(RS)-3-[4-(TRANS - 4-hydroxycyclohexyl)-phenyl] -5-methoxymethyl - oxazolidin-2-he

5.0 g (16,44 mmol) (RS)-5-methoxymethyl-3-[4-(4-oxocyclohexyl)- phenyl] oxazolidin-2-it was dissolved in 150 ml of ethanol under conditions of heat and after cooling with stirring, was treated with 620 mg (16.4 STATCOM was treated with water and 1N. hydrochloric acid, whereupon the reaction product was dissolved in acetic ether. The organic phase is washed with water, dried over magnesium sulfate and the solvent drove away. The obtained colorless oil (5.3 g) was dissolved in acetic ether, was treated with hexane to turbidity and loose sediment after 1 h was sucked out. The result has been 3,3 g homogeneous according to the NMR spectrum of alcohol. So pl.: 109-110o.

Example 9

(RS)-3-[4- (4-hydroxyindolacetic)phenyl] -5-methoxymethyl-oxazolidin-2-he

Prepared in the usual way from the ketone oxime was recrystallized from acetic ester. So pl.: 146-147o.

Example 10

(RS)-5-benzoyloxymethyl-3-[4-(4-oxocyclohexyl)phenyl]-oxazolidin-2-he

20 g (76.5 mmol) [4- (4-oxocyclohexyl)phenylethanolamine ether of 23.8 g of (RS)-4- (benzyloxyethyl)-1,3-dioxolane-2-she and 0.25 g of potassium carbonate was intensively stirred for 3 h, and then processed and chromatographically similar to that described in example 7. The obtained benzyl ether pererestorani of tert.-butyl methyl ether/hexane. So pl. : 126,5-128o.

Example 11

(RS)-5-hydroxymethyl - 3-[4-(4-oxocyclohexyl)phenyl]-oxazolidin-2-he

4.9 g (12.9 mmol) of (RS)-5-benzyloxy-3-[4-(4-exile at room temperature. After separation of the catalyst the solvent is kept off and the oil obtained was chromatographically 30-fold amount of silica gel. Eluate methylene chloride/acetic ether (1:4) were combined and the solvent drove away. From acetic ester/hexane was obtained 3.2 g of product. So pl.: 151,5-152,5o.

Example 12

(RS)-3-[4-(TRANS-hydroxycyclohexyl)phenyl] -5 - hydroxymethyl-oxazolidin-2-he

0.5 g (1,73 mmole) of (RS)-5 - hydroxymethyl-3-[4-(4-oxocyclohexyl)phenyl] oxazolidin-2-it was dissolved in 500 ml of ethanol and restored and was treated with 65 mg (1,73 mmole) of sodium borohydride analogous to that described in example 8. The result obtained crystalline product (0,38 g). So pl.: 180-182o.

Example 13

(RS)-3-(4-cyclopropylmethyl)-5-ethoxyethylacetate-2-he

3.0 g (10,48 mmol) (RS)-5-methoxymethyl - 3-(4-bromophenyl)-oxazolidin-2-it, of 6.29 g (6,29 mmol) of triphenylphosphine, 0.88 g (1.25 mmole) dichloride bis(triphenylphosphine)palladium (II), of 3.73 g of lithium chloride, a small amount (on the tip of a spatula) of 2,6-di-tert.-butyl-para-cresol and 6,94 g tributyltinchloride in 50 ml of DMF was stirred for 6 h at 120o. The reaction mixture was treated with water and 1N. sodium lye and were extracted using a simple ether. Poloczek, acetic ether/hexane 1:1) extracts were combined and the solvent drove away. From tert.-butyl methyl ether/hexane was obtained 0.3 g of colorless crystals. So pl.: 58-60o.

Example 14

(R)-3-[4-(4-oxocyclohexyl)phenyl]-5 - ethoxyethylacetate-2-he

5.0 g (19,13 mmol) [4-(4 - oxocyclohexyl)phenyl] ethoxycarbonyl ether was subjected to an exchange reaction with 3.0 g of (S)-4-methoxymethyl-1,3-dioxolane-2-it was processed similarly to that described in example 7. From tert.- butyl methyl ether/hexane received a 1.25 g of the product as yellowish crystals. So pl.: 92-93o, []D=-38,1o(C=1, CHCl3)

Example 15

(R)-3-[4-(TRANS-4-hydroxycyclohexyl)phenyl] - 5-methoxymethyl-oxazolidin-2-he

1.0 g of the ketone in the same way as described in example 8, was restored using sodium borohydride in ethanol and processed. From acetic ester/hexane allocated 0.7 g of colorless crystals. So pl.: 133,5-134,5o. [] D=-38,6o(C=0,7, CHCl3).

Example 16

(RS)-3-[4-(TRANS-4-methoxycyclohexyl)phenyl] -5 - methoxymethyl-oxazolidin-2-he

0.5 g (1,64 mmole) of (RS)-3-[4-(TRANS-4 - hydroxycyclohexyl)phenyl]-5-ethoxyethylacetate-2-it was dissolved in 5 ml of dimethylformamide, treated with 0.5>. Then the reaction mixture was poured into ice water and was extracted with simple ether. The organic phase was washed with water, dried over magnesium sulfate and the solvent drove away. The obtained gel was chromatographically 30-fold amount of silica gel using methylene chloride/acetic ether (1:4). After processing of tert.- butylmethylamine ether/hexane precipitated crystals. The result was obtained 0.33 g of the product. So pl.: 82-83o.

Example 17

3-[(1RS, 2RS,4RS)-4-bicyclo[2.2.1]-hept-2-ylphenyl]-5-methoxymethyl - oxazolidin-2-it (R:S=1:1)

A solution of 56 mg of the diacetate bis(triphenylphosphine)palladium (II), 0.5 g of (RS)-3-(4-itfeel)-5 - ethoxyethylacetate-2-it, 0.16 g bicyclo [2,2,1] hept-2-ene, 0.5 ml of piperidine, and 1 ml of dimethylformamide and 0.15 ml of formic acid was stirred for 3 h in argon atmosphere. The reaction mixture was diluted with 50 ml acetic ester and the precipitation was separated. The filtrate was extracted twice respectively with 20 ml water, the organic phase was dried over magnesium sulfate and the solvent drove away. The obtained brown oil was chromatographically 30-fold amount of silica gel with acetic ether/hexane (7: 3). As a result, after crystallization in acetic ether/hexane in the us is .

Example 18

3-[(1RS,2SR,4RS)-4-bicyclo [2.2.1] hept-5-EN-2-yl-phenyl]-5-methoxymethyl-oxazolidin-2-it (R:S = 1:1)

1.0 g of (RS)-3-(4-itfeel)-5-methoxymethyl-oxazolidin-2-she transformed and processed in the same way as described in example 17. The result has been 0,37 g racemic mixture of diastereomers (1:1) in the form of a crystalline product. So pl.: 46-48o.

Example 19

A mixture of (RS)- and (SR)-5-methoxymethyl-3- [4-[(RS)-3-oxocyclopent] phenyl] oxazolidin-2-it

Suspension out of 0.44 g of (RS)-3-(4 - itfeel)-5-methoxymethyl-2-oxazolidinone and 15 mg of tetrakis(triphenylphosphine)palladium 1.1 ml of 2-cyclopentenone and 1.8 ml of triethylamine was stirred in an argon atmosphere for 24 h at 80o. Then the reaction mixture was cooled, and after addition of 100 ml of 2n. hydrochloric acid was extracted with ethyl ester of acetic acid. The organic phase was dried over magnesium sulfate and concentrated. The residue (0.6 g of brown oil) was chromatographically on silica gel 60 using mixtures of ethyl ester of acetic acid/hexane (1: 3-1: 1), after which he obtained 0.26 g of (RS)- and (SR)-5-methoxymethyl-3-[4-[(RS)-3 - oxocyclopent] phenyl] oxazolidin-2-it is in the form of a colorless oil.1H-NMR (CDCl3) ppm: 7,53 (d, 2H), 7,26 (d, 2H), amounts to 4.76 (m, 1H), 4,06 (t, 1H), 3,93 (t, 1H), 1-yl)-phenyl] -oxazolidin-2-he

In an argon atmosphere for 3 h was heated to 160oa mixture of 6.0 g of ethyl ester of 4-(4-oxopiperidin-1-yl)- phenylcarbamoyl acid, 5.0 g of 4-methoxymethyl-1,3-dioxolane-2-she and 0.6 g of potassium carbonate. Then the reaction mixture was cooled, and treated with methylene chloride and water and the phases were separated. The organic phase was dried over magnesium sulfate and concentrated. The residue (7.8 g) was chromatographically using the ethyl ester of acetic acid as solvent over silica gel 60. The result was obtained 0.6 g of (RS)-5-methoxymethyl-3-[4- (4-oxopiperidin-1-yl)phenyl] oxazolidin-2-it.1H-NMR (CDCl3) ppm: 7,46 (d, 2H), 6,98 (d, 2H), amounts to 4.76 (m, 1H), 3,99 (t, 1H), 3,88 (t, 1H), 3,64 (d, 2H), only 3.57 (t, 4H), 3,44 (s, 3H), of 2.56 (t, 4H).

Example 21

(RS)-3-[4-(4-hydroxypiperidine-1-yl)phenyl] -5 - methoxymethyl-2-oxazolidin-2-he

In a solution of 0.6 g of (RS)-5 - methoxymethyl-3-[4-(4-oxopiperidin-1-yl)-phenyl] oxazolidin-2-it in 25 ml of methanol and 2.5 ml of water was added 0.3 g of sodium borohydride. This mixture was stirred for 24 h at room temperature and then concentrated. The residue was dissolved in methylene chloride and washed with 10% aqueous ammonia solution. The organic phase was dried over magnesium sulfate and concentrated. The residue (0.6 g) was chromatographically on silicagel is and acetic acid was obtained 0.1 g (RS)-3-[4-(4-hydroxypiperidine-1 - yl)phenyl]-5-methoxymethyl-2-oxazolidin-2-it. So pl.: 149-152o.

Example 22

(RS)-3-[5-(1,4-dioxaspiro [4,5] Decan-8-yl)-pyridine-2 - yl]-5-ethoxyethylacetate-2-he

A solution of 0.9 g (RS)-3-[5-(1,4- dioxaspiro[4,5]Dec-7-EN-8-yl)-pyridine-2-yl] -5 - ethoxyethylacetate-2-she and 0.4 g of palladium on coal (10%) in 150 ml of methanol was first made at room temperature and under normal pressure. After filtering off the catalyst was concentrated and the residue was recrystallized from diethyl ether. The result was obtained 0.35 g (RS)-3-[5-(1,4-dioxaspiro [4,5] Decan-8-yl)-pyridine - 2-yl]-5-ethoxyethylacetate-2-it. So pl. 117-121o.

Example 23

(RS)-5-methoxymethyl-3-[5-(4-oxocyclohexyl)-pyridine-2-yl] - oxazolidin-2-he

A solution of 0.5 g of (RS)-3-[5-(1,4- dioxaspiro[4,5]Decan-8-yl)-pyridine-2-yl] -5-methoxymethyl-oxazolidin - 2-it in 20 ml of tetrahydrofuran and 5 ml of 2n. hydrochloric acid was stirred for 4 h at room temperature. Then added 10 ml of 2n. sodium liquor and was extracted several times with ethyl ether, acetic acid. The organic phases were combined, dried over magnesium sulfate and concentrated. After chromatography with ethyl ester of acetic acid on silica gel was obtained 0.4 g of (RS)-5 - methoxymethyl-3-[5-(4-oxocyclohexyl) pyridine-2-yl(s, 3H), is 3.08 (m, 1H), of 2.51 (m, 4H), 2,04 (width, 4H).

Example 24

(RS)-3-[5-TRANS-4-hydroxycyclohexyl)pyridine-2-yl]-5 - ethoxyethylacetate-2-he

A solution of 0.4 g of (RS)-5-methoxymethyl - 3-[5-(4-oxo-cyclohexyl)-pyridin-2-yl] -oxazolidin-2-it in 25 ml of methanol and 2.5 ml of water was treated with 0.2 g of sodium borohydride and stirred for 16 h at room temperature. Then concentrated, the residue was dissolved in methylene chloride and washed with water. The aqueous phase was extracted with methylene chloride, the organic phases were combined, dried over magnesium sulfate and concentrated. The residue (0.4 g) was recrystallized from acetic ester and as a result was obtained 0.2 g of (RS)-3-[5-(TRANS-4 - hydroxycyclohexyl)pyridine-2-yl]-5-ethoxyethylacetate-2-it. So pl.: 142-143o.

Example 25

(RS)-3-[6-(1.4-dioxaspiro [4.5] Decan - 8-yl)pyridine-3-yl]-5-ethoxyethylacetate-2-he

A solution of 0.8 g of (RS)-3-[6-(1,4-dioxaspiro[4,5]Dec-7-EN-8-yl)-pyridin-3-yl] -5 - ethoxyethylacetate-2-she and 1.1 g of palladium on coal (10%) in 250 ml of methanol was first made at room temperature and under normal pressure. After filtering off the catalyst was concentrated. The result was obtained 1.2 g (RS)-3-[6-(1,4-dioxaspiro [4,5]Decan-8-yl)-pyridin-3-yl]- 5 - methoxypyridazine clear sample which is then boiled with diethyl ether. So pl.: 93-94o.

Example 26

(RS)-5-methoxymethyl - 3-[6-(4-oxocyclohexyl)-pyridine-3-yl] -oxazolidin-2-he

A solution of 0.8 g (RS)-3-[6-(1,4-dioxaspiro[4,5]Decan-8-yl-pyridine-3-yl] -5 - methoxymethyl-oxazolidin-2-it in 32 ml of tetrahydrofuran and 8 ml of 2n. hydrochloric acid was stirred for 4 h at room temperature. Then added 15 ml of 2n. sodium liquor and was extracted several times with ethyl ether, acetic acid. The organic phases were combined, dried over magnesium sulfate and concentrated. The result was obtained 0.7 g of (RS)-5-methoxymethyl-3- [6-(4-oxo-cyclohexyl)-pyridin-3-yl] -oxazolidin-2-it.1H-NMR (CDCl3) ppm: 8,49 (s, 1H), 8,19 (d, 1H), 7.23 percent (d, 1H). to 4.81 (m, 1H), 4.09 to (t, 1H), 3,98 (t, 1H), 3,66 (m, 2H), 3,44 (s, 3H), 3,19 (m, 1H), 2,52 (m, 4H), 2,28 (m, 2H), 2.06 to (m, 2H).

Example 27

(RS)- 3-[6-TRANS-(4-hydroxycyclohexyl)-pyridine-3-yl]-oxazolidin-2-he

A solution of 0.7 g of (RS)-5-methoxymethyl-3-[6-(4-oxocyclohexyl)pyridine - 3-yl] -oxazolidin-2-it in 40 ml of methanol and 4 ml of water was treated with 0.3 g of sodium borohydride and stirred for 16 h at room temperature. Then concentrated, the residue was dissolved in methylene chloride and washed with water. The aqueous phase was dried over magnesium sulfate and then boiled with hexane. The result was obtained 0.2 g of (RS)-3-[6-TRANS- (4-hydroxycyclohexyl)pyridine-3-yl]-oxazolidin-2-it. So pl.: 134 - 136o.

Example 28

(RS)-3-[(4-cycloheptyl)phenyl]-5-ethoxyethylacetate-2-he

4,18 g (16.0 mmol) of ethyl ester of 4-cycloheptatriene acid was treated with 1.3 g (16.0 mmol) of pyridine and 18 g (0,136 mol) of (RS)-4-methoxymethyl-1,3-dioxolane-2-it was stirred at bath temperature 160owithin 20 hours After cooling, the reaction mixture was chromatographically on 400 g of silica gel 60 using a simple ether. After recrystallization from isopropyl ether was received of 2.05 g of (RS)- 3-[(4-cycloheptyl)phenyl]-5-ethoxyethylacetate-2-it is in the form of white kristalliset. So pl.: 70-72o.

Example 29

(RS)-3-[(4-adamantane-1 - yl) phenyl]-5-ethoxyethylacetate-2-he

5,42 g (18.1 mmol) of ethyl ester of 4-adamantane-1-yl-phenylcarbamoyl acid was treated 1,43 g (18.1 mmol) of pyridine and 18.0 g (0,136 mol) of (RS)- 4-methoxymethyl-1,3-dioxolane-2-it, and when the bath temperature 160owas stirred for 20 hours After cooling, the reaction mixture was chromatographically on 500 g of silica gel 60 using a simple ether. After recrystallization from methylene chloride/simple ether there was obtained 1.4 g of (RS)-3-[(4-adamantane-1-0

(RS)-3-[4-[TRANS-4-(2-cyanoethoxy)cyclohexyl] phenyl] -5-ethoxyethylacetate-2-he

3,05 g (10.0 mmol) of (RS)-3-[4-TRANS-4 - hydroxycyclohexyl)phenyl]-5-ethoxyethylacetate-2-it was dissolved in 150 ml of methylene chloride and successively treated with 0.64 g (12.0 mmol) of Acrylonitrile and 1.35 g (12.0 mmol) of tert.-the butyl potassium. The reaction mixture was stirred for 18 h at room temperature, after which it was washed with water, the organic phase was dried over sodium sulfate, filtered and evaporated. The residue (4.0 g) was chromatographically on 120 g of silica gel 60 using acetic ether/n-hexane (6: 4). After recrystallization from acetic ester was obtained 1.8 g of (RS)-3-[4-[TRANS-4-(2-cyanoethoxy)cyclohexyl]phenyl]-5 - ethoxyethylacetate-2-it. So pl.: 82-84o.

Example 31

Hydrochloride, (RS)-3-[4-[TRANS-4-(3 - aminopropoxy)cyclohexyl]-phenyl]-5-ethoxyethylacetate-2-she (1:1)

545,3 mg (14.4 mmol) of sodium borohydride suspended in 20 ml of absolute tetrahydrofuran, and treated with 1.64 g (14.4 mmol) triperoxonane acid for 5 min at room temperature. Then for 15 min at room temperature was added dropwise 1.29 g (3.6 mmole) of (RS)-3-[TRANS-4-[4-(5-methoxymethyl-2-oxo - oxazolidin-3-yl)-phenyl] -qi is of 18 h, the reaction mixture was evaporated, the remainder were distributed on the water and methylene chloride, the organic phase is washed with water, dried over sodium sulfate, filtered and evaporated. The residue (1.4 g) was chromatographically 39 g of silica gel 60 using methylene chloride (feast upon. NH3)/methanol (98: 2). The product was washed in methylene chloride water, dried over sodium sulfate, filtered and the filtrate was acidified using ethereal hydrochloric acid. After recrystallization from methylene chloride/simple ester was obtained 1.13 g of the hydrochloride of (RS)- 3-[4-[TRANS-4-(3-aminopropoxy)cyclohexyl] phenyl]-5 - ethoxyethylacetate-2-she (1:1). So pl.: 173-175o.

Example 32

(RS)-3-[4-[TRANS-4-[2-(4,5-dihydrooxazolo-2-yl)benzoyloxy] - cyclohexyl] phenyl]-5-ethoxyethylacetate-2-he

In the suspension of 690 mg (15.8 mmol) of a 55% dispersion of sodium hydride in 20 ml of absolute dimethylformamide in an argon atmosphere for 25 min was added dropwise a solution of 4,58 g (15.0 mmol) of (RS)-3-[4-TRANS-4 - hydroxycyclohexyl)phenyl] -5-ethoxyethylacetate-2-she's in 30 ml of absolute dimethylformamide and stirred for 3 h at room temperature. Then was added dropwise a solution of 3,81 g (15.0 mmol) of N-(2-bromoethyl)phthalimide in 20 ml of absolute dimethylformamide and stirred at room who you and evaporated. The residue was dissolved in glacial acetic acid, washed with water, dried over sodium sulfate, filtered and evaporated. After recrystallization from acetic ester was obtained 4.9 g of (RS)-3-[4-[TRANS - 4-[2-(4,5-dihydrooxazolo-2-yl)benzoyloxy]-cyclohexyl] phenyl]-5 - ethoxyethylacetate-2-it. So pl.: 182-184o.

Example 33

(RS)-3- [4-(TRANS-4-ecotoxicological)phenyl] -5-ethoxyethylacetate - 2-he

In a solution of 0.5 g (1,639 mmole) of (RS)-3-[4-TRANS-4-hydroxycyclohexyl) phenyl] -5-ethoxyethylacetate-2-it in 20 ml of methylene chloride and 5 ml of pyridine was added dropwise with stirring a solution of 0.58 ml acetylchloride (8,195 mmol) in 10 ml of methylene chloride and continued to stir for 3 h at room temperature. Then the reaction mixture was poured into ice water, using 3h. hydrochloric acid was acidified and extracted with methylene chloride. The organic phase is washed with water, dried over magnesium sulfate and the solvent drove away. Acetate crystallized in the processing of tert. - butylmethylamine ether. The result was obtained 0.35 g (62%) of (RS)-3-[4- (TRANS-4-ecotoxicological)phenyl] - 5 - ethoxyethylacetate-2-it. So pl.: 78-79o.

Example 34

(RS)-3-[4-(TRANS-4 - benzyloxyindole the Nile] -5-ethoxyethylacetate-2-it in 20 ml of methylene chloride and 5 ml of pyridine was treated dropwise with a solution of 0.95 ml (8,195 mmol) of benzoyl chloride in 10 ml of methylene chloride and continued to stir for 3 h at room temperature. Then the reaction mixture was poured into ice water, using 3h. hydrochloric acid was acidified and extracted with methylene chloride. The organic phase is washed with water, dried over magnesium sulfate and the solvent drove away. Benzoate crystallized in the processing of tert. - butylmethylamine ether. The result obtained 0.52 g (77%) of (RS)-3-[4- (TRANS-4-benzyloxyphenyl)phenyl] -5-ethoxyethylacetate-2 - it. So pl.: 104-105o.

Example 35

5-methoxy-3-[4-[5-Exo-[4-(5-methoxymethyl-2 - oxoacridine-3-yl)-phenyl]-bicyclo [2.2.1] hept-2-amsoil] phenyl]- oxazolidin-2-he

When the connection is obtained from example 18 as a by-product formed by the above-mentioned compound, which was isolated by chromatography (silica gel, acetic ether/hexane (1:1)). So pl.: 152-154o.

Example 36

Hydrochloride, (RS)-3-[4-[TRANS - 4-[2-(4-chlorobenzylamino)ethylamino]-cyclohexyl] phenyl]-5 - ethoxyethylacetate-2-she (1:1)

A solution of 1.31 g (4.3 mmole) of (RS)-3-[4-(4-oxocyclohexyl)phenyl]-5-ethoxyethylacetate-2-it, 2.0 g (10 mmol) of N-(2-amino-ethyl)-4-chlorobenzamide and 37 mg (0.2 mmole) of the monohydrate of para-toluenesulfonic acid in 20 ml of toluene and 6 ml of dimethylformamide was heated for 7 h in the water separator. When peremeci the Jana acid. The organic phase was separated. The aqueous phase was extracted twice with methylene chloride. Then the organic phase was dried over sodium sulfate, concentrated and chromatographically on silica gel using methylene chloride/methanol (9: 1). The obtained solid was recrystallized from ethanol/simple ether. In the received 200 mg of white crystals. So pl.: 233-235o.

Example 37

(RS)- 5-methoxymethyl-3-[4-(4-methylenechloride)phenyl]-oxazolidin-2-he

In an argon atmosphere 5,76 g (13.8 mmol) of a mixture of bromide methyltriphenylphosphonium and sodium amide in 170 ml of tetrahydrofuran was stirred for 1 h at room temperature. Then for 5 min was added dropwise a solution of 4,20 g (13.8 mmol) (RS)-3-[4-(4- oxocyclohexyl)phenyl]-5-ethoxyethylacetate-2-it. After boiling under reflux during the night was poured into water and was extracted with methylene chloride. After drying over sodium sulfate and concentration was chromatographically using acetic ether/n-hexane (1:2) on silica gel. The result has been 3,47 g (83%) solids. Then a small sample recrystallized from hexane. So pl.: 63-65o.

Example 38

(RS)-3- [4-(CIS - and TRANS-dimetil-3-[4-(4-methylenechloride)phenyl]oxazolidin-2-it in 250 ml of tetrahydrofuran was added to 0.19 g (5.0 mmol) of sodium borohydride and was added dropwise and 0.46 ml (5.0 mmol) of dimethylsulfate. After stirring for 4 h at a temperature of approximately 40owas cooled to 5oand added to 1.5 ml of 2n. sodium lye. Next was slowly added dropwise 0,77 ml of 30% H2O2(7.5 mmol). Then was poured into 100 ml of saturated common salt solution, separating the organic phase and the aqueous phase was extracted with methylene chloride. The organic phase was dried over sodium sulfate, concentrated and chromatographically on silica gel using methylene chloride/methanol. As a result received 350 mg of colorless oil. MS: m/e (% basic peak): 319 (M+, 73), 246 (16), 233 (16), 170 (30), 158 (16), 144 (86), 118 (60), 95 (19), 91 (25), 77 (24), 71 (60), 45 (100).

Example 39

(RS)-3-[4-(CIS - or TRANS-4-hydroxy - 4-methylcyclohexyl)phenyl]-5-methoxymethyl-oxazolidin-2-he

A solution of 525 mg (1.6 mmole) of the acetate of mercury in 10 ml of water was treated with 10 ml of tetrahydrofuran. After stirring for 15 min the suspension was added dropwise a solution of 500 mg (1.7 mmole) of (RS)-5-methoxymethyl - 3-[4-(4-methylenechloride)phenyl] oxazolidin-2-it in 10 ml of tetrahydrofuran. Then was stirred for 1.5 h at room temperature. Next was added first, 10 ml of 2n. sodium lye and after stirring for 10 min was added Rast who was agarawala with methylene chloride, the organic phase was washed with saturated sodium chloride solution and dried over sodium sulfate. After removal of the solvent was chromatographically on silica gel with acetic ether/hexane (1:2). As a result received 150 mg of white crystals. So pl.: 118-119o.

Example 40

(RS)-3-[4-(1,4-dioxaspiro [4.5] Dec-8 - yl)-phenyl]-5-methoxymethyl]-oxazolidin-2-he

A solution of 0.60 g (2 mmole) (RS)-3-[4-(4-oxocyclohexyl)phenyl]-5 - ethoxymethyleneamino, 0.15 mg (2.4 mmole) of ethylene glycol and 30 mg of the monohydrate of para-toluenesulfonic acid in 20 ml of toluene was heated for 7 h in the water separator. Then the toluene was filtered, the residue is suspended in 10 ml of 2n. sodium liquor and was extracted with methylene chloride. After drying over sodium sulfate the solvent drove away. After chromatography on silica gel using a simple ether and recrystallization using a simple ether there was obtained 0.4 g of white crystals. So pl.: 120-123o.

Example 41

(RS)-3-[4-(CIS - 4-forcelogix)phenyl]-5-methoxymethyl-oxazolidin-2-he

0.5 g of (RS)- 3-[4-(TRANS-4-hydroxycyclohexyl)phenyl]-5-methoxymethyl-oxazolidin - 2-it was dissolved in 10 ml of methylene chloride and at room temperature for 30 min were treated with a mixture of th temperature the mixture was poured into 50 ml ice water and was extracted twice with methylene chloride. The organic phase is washed with sodium chloride solution, sodium hydrogen carbonate solution and again with a solution of sodium chloride, then dried over magnesium sulfate and concentrated. The remainder, 0.6 g of yellow honey, chromatographically 30-fold amount of silica gel using methylene chloride/acetic ether (19:1) and as a result received 80 mg of (RS)-3-[4-(CIS-4-forcelogix)phenyl]-5 - ethoxyethylacetate-2-it is in the form of a colorless oil.1H-NMR (CDCl3) part./million: 7,47 (d, 2H), 7,24 (d, 2H), 4,88 (width, 1H), 4,74 (m, 1H), Android 4.04 (t, 1H), 3,91 (m, 1H), 3,64 (d, 2H), 3.43 points (s, 3H), 2,53 (m, 1H), 2,16 (m, 2H), 1,72 (m, 6H).

Example 42

Hydrochloride, (RS)-3-[4-(TRANS-4-aminocyclohexane)phenyl]-5 - ethoxyethylacetate-2-she (1:1)

a) a Mixture of 1.0 g (RS)-3-[4-(4- oxocyclohexyl)phenyl]-5-methoxymethyl-oxazolidin-2-she, 0.1 g of para - toluenesulfonic acid and 0.43 ml of benzylamine in 100 ml of toluene was heated for 3 h in the water separator. The solvent was removed, the residue was dissolved in 50 ml of methanol and stirred with 150 mg of sodium borohydride over night at room temperature. The solvent was removed, the residue was treated with 1H. hydrochloric acid and washed with acetic ether. The aqueous phase was podslushivaet sodium lye and extracted with methylene chloride. Chloridometer/hexane was obtained 0.6 g painted beige crystals of a mixture (1:1) of (RS)-3-[4-CIS - and (RS)-3-[4-(TRANS - benzylaminocarbonyl)phenyl]-5-ethoxyethylacetate-2-it. So pl. 93 - 94o.

b) 0.5 g of a mixture of (RS)-3-[4-CIS - and (RS)-3-[4-(TRANS - benzylaminocarbonyl)phenyl] - 5-ethoxyethylacetate - 2-it was dissolved in 50 ml of ethanol with the addition of one equivalent of 1N. hydrochloric acid and was first made in the presence of palladium on coal (10%) as catalyst at room temperature and normal pressure. After addition of diethyl ether was dropped 0.3 g of hydrochloride (RS)-3-[4- (TRANS-4-aminocyclohexane)phenyl]-5-ethoxyethylacetate-2-she (1: 1) as colorless crystals. So pl.: > 250o.1H-NMR (DMSO) ppm million: 8,12 (width, 3H), 7,47 (d, 2H), 7,25 (d, 2H), to 4.81 (m, 1H), 4.09 to (t, 1H), of 3.77 (m, 1H), to 3.58 (m, 2H), 3,32 (s, 3H), 3,03 (m, 1H), 2,47 (m, 1H), to 2.06 (m, 2H), 1,80 (m, 2H), 1,50 (m, 4H).

Example 43

(RS)-3-[4-(TRANS-4 - benzhydrylidene)phenyl] -5-methoxymethyl-oxazolidin-2-he

0.5 g of (RS)-3-[4-(TRANS-4-hydroxy-cyclohexyl)-phenyl] -5 - ethoxyethylacetate-2-it was heated in 5 ml of ethyldiethanolamine to 0.35 ml chlorodiphenylmethane to 100oand was stirred for 7 h at this temperature. Then the reaction mixture was cooled, acidified 1H. hydrochloric acid and was extracted with acetic ester. The organic phase was neutralized by washing with water, dried over magnesium sulfate and concentrated. The remainder of chromatographical result was obtained 0.3 g of (RS)-3-[4-(TRANS-4-benzhydrylamine-cyclohexyl)phenyl] -5 - ethoxyethylacetate-2-it is in the form of colorless crystals. So pl.: 146 - 148o.

Example 44

A mixture (9:1) of (RS)-3-[4-(TRANS - and CIS-4 - benzyloxycarbonyl)-phenyl] -5-ethoxyethylacetate-2-it

1.0 g of (RS)-3-[4-(hydroxycyclohexyl)phenyl]- 5-ethoxyethylacetate - 2-she was treated in 10 ml of dimethylformamide 0.21 g of sodium hydride and at room temperature. After addition of 50 ml of ethyl ether, acetic acid, washed three times with water. The aqueous phase was extracted with ethyl ester of acetic acid. The organic phases were combined, dried over magnesium sulfate and concentrated. After chromatography of the residue (1.6 g) on 30-fold amount of silica gel using mixtures of methylene chloride/acetic ester was obtained 0.8 g of yellow oil which crystallized from tert.-butyl methyl ether. The result was obtained 0.6 g of a mixture (9:1) (RS)-3-[4-(TRANS - and CIS-4 - benzyloxycarbonyl)phenyl] -5-methoxymethyl-oxazolidin-2-it is in the form of colorless crystals. So pl.: 82-84o.1H-NMR (CDCl3) part./million: 7,46 (d,2H), 7,35 (m, 5H), of 7.23 (d, 2H), 4,74 (m, 1H), 4,60 (s, 2H), 3,99 (t, 1H), 3,90 (m, 1H), 3,63 (d, 2H), 3.43 points (s, 3H), 3,40 (m, 1H), 2,50 (m, 1H), 2,22 (m, 2H), 1.91 a (m, 2H), 1,46 (m, 4H).

Example 45

(R)-3-[4-(TRANS-4-methoxycyclohexyl)phenyl] -5 - methoxymethyl-oxazolidin-2-he

1.4 g of (R)-3-[4-(TRANS-4 - hydroxycyclohexyl)phenyl]-5-methoxy who ing the mixture was stirred overnight at 40o. After addition of 100 ml of diethyl ether three times washed with water. The aqueous phase was extracted with diethyl ether. The organic phases were combined, dried over magnesium sulfate and concentrated. After chromatography was carried out of the residue (1.5 g) on 30-fold amount of silica gel using mixtures of methylene chloride/acetic ester was obtained 1.3 g of colorless oil, which crystallized from tert.-butyl methyl ether. The result was obtained 1.1 g of (R)-3-[4-(TRANS-4 - methoxycyclohexyl)phenyl]-5-ethoxyethylacetate-2-it is in the form of colorless crystals. So pl.: 73-74o.

Example 46

(RS)-3-(4 - cyclohex-1-enalpril)-5-ethoxyethylacetate-2-he

A solution of 410 mg of the diacetate bis(triphenylphosphine)palladium (II), 2.0 g of (RS)-3-(4 - itfeel)-5-ethoxyethylacetate-2-she and 1.8 ml of 1-tributyl-stannyl - 1-cyclohexene in 10 ml of dimethylformamide was stirred for 18 h at 80o. Then the reaction mixture was poured into 100 ml of water and was extracted three times with ethyl ether, acetic acid. The organic phase was washed with a saturated solution of potassium fluoride, a saturated solution of sodium chloride and water, dried over magnesium sulfate and concentrated. After chromatography of the residue (2.0 g) at 30 times the number is crystallized from ethyl ether acetic acid/hexane. The result was obtained 0.3 g of (RS)-3-(4-cyclohex-1-enyl-phenyl)-5 - ethoxyethylacetate-2-it is in the form of colorless crystals. So pl.: 106 - 108o.

Example 47

A mixture of (RS)-and (SR)-3-[(RS)-4-cyclohex-3-enyl - phenyl]-5-ethoxyethylacetate-2-it

A solution of 2.0 g of (RS)-3- [4-(hydroxycyclohexyl)phenyl]-5-ethoxyethylacetate-2-it, 2.1 g of triphenylphosphine and 1.8 g of benzoic acid in 80 ml of tetrahydrofuran was treated at room temperature for 15 min, 1.2 ml of diethyl ester of azodicarboxylic acid in 20 ml of tetrahydrofuran and stirred for 22 h at room temperature. Then the reaction mixture was concentrated, the residue was dissolved in 100 ml of acetic ether, twice washed with 10% sodium carbonate solution and twice with a saturated solution of sodium chloride, dried over magnesium sulfate and concentrated. After chromatography was carried out residue (7.0 g) in a 30-fold amount of silica gel using mixtures of methylene chloride/hexane as a by-product was obtained 0.6 g of oil which crystallized from ethyl ester of acetic acid/hexane. The result was obtained 0.4 g of a mixture of (RS)- and (SR)-3-[(RS)-4-cyclohex-3 - enalpril] - 5-ethoxyethylacetate - 2-it is in the form of colorless crystals. So pl.: 74-75o.

Example 48

(RS)-3-[4-(4-cyanometallates)-phenyl] -5-ethoxyethylacetate-2-he

and 0.46 g of sodium was dissolved in argon atmosphere in 50 ml of ethanol. Then at 20oadded 3.5 g (=3,1 ml) citizen.metropolitan dissolved in 10 ml of ethanol. Then continued to stir for 30 min at room temperature, after which was added 2.0 g of (RS)-5-methoxymethyl-3-[4-(4 - oxocyclohexyl)phenyl]-oxazolidin-2-it. Next was stirred for 1 hour while heating under reflux, then cooled to room temperature, with approximately 0.7 ml of acetic ether was established pH 6 and the reaction mixture was evaporated in vacuum. The crude mixture of 4.2 g) was chromatographically on 200 g of silica gel. Using dichloromethane/ethyl acetate (9:1) was suirable of 1.65 g (RS)-3- [4-(4-cyanometallates) -phenyl]-5 - ethoxyethylacetate - 2-it is in the form of white crystals. After recrystallization of a sample from ethyl acetate/hexane was obtained white crystals with so pl. 121-125o.

Example 49

(RS)-3-[4-(TRANS-4-cyanomethylene)-phenyl] -5 - methoxymethyl-Catholicon-2-he

of 1.65 g of a mixture of (a) (R)-[4-[4-[(R)-, b) (R)-[4-[4-[(S)-, b) (S)-[4-[4-[(R) and g) (S)-[4-[4-[(8)-5- methoxymethyl-2-oxoacridine-3-yl]phenyl]- cyclohexylidene] the normal pressure and at room temperature until theoretical uptake (approximately 16 hours). Then was filtered by suction from the catalyst and evaporated in vacuum. The residue (1.6 g) was dissolved in ethyl acetate and washed with saturated 10% sodium hydrogen carbonate solution and sodium chloride solution. After drying and evaporation was obtained 1.6 g of crystals that cleaning was chromatographically on 30 g of silica gel. Elution was performed using dichloromethane/ethyl acetate in a ratio of 9: 1. After compound obtained according to thin the chromatogram of the pure fractions and recrystallization from ethyl acetate/hexane got to 0.72 g of (RS)-3-[4-(TRANS-4 - cyanomethylene)-phenyl] -5-ethoxyethylacetate-2-it is in the form of white crystals with so pl. 118-120o.

Example 50

(R)-3-[4-(TRANS-4 - cyanomethylene) -phenyl] -5-ethoxyethylacetate - 2-he

1.1 g (R)-[4-[4-(5-methoxymethyl-2-oxo-oxazolidin-3-yl)-phenyl]- cyclohexylidene]acetonitrile was dissolved in 50 ml of methanol, was treated with 0.2 g of Pd/C (10%) and was first made at room temperature and under normal pressure until theoretical uptake of hydrogen. Then was filtered by suction from the catalyst and evaporated in vacuum. Oily residue was chromatographically on 15 g of silica gel. Elution was performed using dichloromethane/ethyl acetate (9: 1). The floor is on. The result was obtained 0.64 g (R)-3-[4-(TRANS-4 - cyanomethylene-hexyl)-phenyl] -5-ethoxyethylacetate-2-it is in the form of white crystals with so pl. 90-91o.

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Example 51

A mixture (1: 1) hydrochloride CIS - hydrochloride and TRANS-(RS)-3-[4-[4-(2-aminoethyl)cyclohexyl] phenyl]-5 - ethoxyethylacetate-2-it

2.1 g of the mixture of (a) (R)-[4-[4-[(R)-, b) (R)-[4-[4-[(S)-, b) (S)-[4-[4-[(R) and g) (S)-[4-[4-[(8)-5- methoxymethyl-2-oxoacridine-3-yl]-phenyl]- cyclohexylidene] acetonitrile (ratio:b=: g=1:1) was first made in 200 ml of methanol with ammonia (20% (weight/volume) and 3.0 g of Raney Nickel for approximately 40 h at normal pressure and room temperature until theoretical uptake of hydrogen. Then was filtered by suction from the catalyst and evaporated in vacuum. The crude product (1.8 g) was chromatographically on 15 g of silica gel. Next was suirable using dichloromethane/methanol/ammonia(25% (250:5:1)) and dichloromethane saturated with ammonia (25%) and methanol (5%). Obtained according to thin-layer chromatography the pure fractions were combined and evaporated. The result was obtained 1.4 g of the base in the form of a turbid oil. 0.7 g of this oil was transferred into the hydrochloride (ethanol hydrochloric acid/simple ether). In this way received 0.5 g of a mixture (1:1) of the hydrochloride of the CIS and hydrochloride 203-207o.

Example 52

(RS)-3-[4-[4-(2-acetylamino) cyclohexyl] phenyl] -5 - ethoxyethylacetate-2-he

0,57 g of a mixture (1:1) of CIS - and TRANS-(RS)-3-[4-[4-(2-aminoethyl)- cyclohexyl] phenyl]-5-ethoxyethylacetate-2-it was dissolved in 2 ml of pyridine was treated with 0.21 g of acetic anhydride. Then was stirred for 3.5 h at room temperature, after which the reaction mixture was dissolved in dichloromethane. The organic phase was washed for 1H. hydrochloric acid, water, sodium bicarbonate and saturated saline, then was dried and evaporated. As a residue was obtained 0.75 g turbid oil, which was led from ethyl acetate/tert. -butyl ether. The result was obtained 0.25 g (RS)-3-[4-[4-(2-acetylamino) cyclohexyl]phenyl]-5-ethoxyethylacetate-2-it is in the form of white crystals with so pl. 120-122o.

Example 53

(RS)-3-[4-(1-tert. - butoxycarbonylamino-4-yl)phenyl]-5-ethoxyethylacetate-2-he

5.5 g (15.0 mmol) of tert.-butyl ester of 4-(4-ethoxycarbonyl-phenyl)piperidine-1-carboxylic acid and 20 grams (0.15 mole) of (RS)-4-(methoxymethyl)-1,3-dioxolane-2-it is intensely stirred in the presence of 2.37 g (30 mmol) of pyridine for 18 hours at a temperature of oil bath of 160o. PEFC is received 3.4 g (RS)-3-[4-(1-tert. -butoxycarbonylamino - 4-yl)phenyl]-5-ethoxyethylacetate-2-it is in the form of a yellowish oil.1H-NMR (CDCl3) part./million: of 7.48 (d, 2H), 7,22 (d, 2H), amounts to 4.76 (m, 1H), 4,25 (width, 2H), of 4.05 (t, 1H), 3,92 (t, 1H), 3,64 (d, 2H), 3.43 points (s, 3H), 2,80 (t, 2H), 2.64 (m, 1H), 1,78 (width, 2H), 1.61 of (m, 2H), 1,49 (s, 9H).

Example 54

Hydrochloride, (RS)-5-methoxymethyl-3-(4-piperidine-4-yl-phenyl)-oxazolidin-2-she (1:1)

of 2.51 g (6.4 mmol) of tert.-butyl ether (RS)-4-[4-(5-methoxymethyl-2-oxoacridine-3 - yl)phenyl]piperidine-1-carboxylic acid was dissolved in 40 ml of acetic ether, and with stirring, was treated at room temperature with 40 ml of 2.2 M of saturated hydrogen chloride solution of acetic ether. After 90 min, the suspension was evaporated and drove with toluene. The result has been 1.47 g of the hydrochloride of (RS)-5-methoxymethyl-3-(4 - piperidine-4-yl-phenyl)-oxazolidin-2-she (1:1). So pl.: 161-163o. 1H-NMR (DMSO) ppm million: 8,98 (width, 2H), 7,52 (d, 2H), 7,24 (d, 2H), to 4.81 (m, 1H), 4,10 (t, 1H), 3,79 (t, 1H), to 3.58 (m, 2H), 3.35 (m. 2H), 3,32 (s, 3H), 2,97 (width, 2H), 2,80 (m, 1H), 1,87 (width, 4H).

Example 55

Hydrochloride, (RS)-3-[4-(1-benzylpiperidine-4-yl)-phenyl] -5 - ethoxyethylacetate-2-she (1:1)

290,4 mg (1.0 mmol) (RS)-4-[4- (5-methoxymethyl-2-oxo-oxazolidin-3-yl) phenyl] piperidine was dissolved in 5 ml of absolute dimethylformamide and treated at priston at 60o. After that, the mixture was evaporated, the residue was distributed in acetic ether and 3n. the ammonia solution, the organic phase is washed with water, dried over sodium sulfate, filtered and evaporated. The base was dissolved in ethanol, acidified ethereal hydrochloric acid and again drove with toluene. After recrystallization from ethanol/simple broadcast received 291,2 mg hydrochloride (RS)-3-[4-(1-benzylpiperidine-4-yl)-phenyl] -5 - ethoxyethylacetate-2-she (1:1). So pl.: 175-177o.

Example 56

Hydrochloride, (RS)-3-[4-[1-[4-(4-forefeel)-4-oxobutyl]-piperidine - 4-yl] -phenyl]-5-ethoxyethylacetate-2-she (1:1)

253,0 mg (of 0.87 mmole) (RS)-4-[4-(5-methoxymethyl-2-oxoacridine-3-yl) phenyl] piperidine was dissolved in 15 ml of absolute dimethylformamide and treated in the presence 352,7 mg (3,485 mmole) of triethylamine 174,8 mg (of 0.87 mmole) -chloro-4-verbalization. The reaction mixture was stirred for 5 h at 100o. Then the mixture was evaporated, the residue was distributed in acetic ether and 3n. the ammonia solution, the organic phase is washed with water, dried over sodium sulfate, filtered and evaporated. The residue was dissolved in ethanol and acidified ethereal hydrochloric acid. After recrystallization from alcohol/simple ether got to 135.9 mg hydrochlo>.

Example 57

(RS)-5-methoxymethyl-3- [4-[1-(4- trifloromethyl) -piperidine-4-yl] -phenyl]- oxazolidin-2-he

273,1 mg (0,94 mmole) of the hydrochloride (RS)-4-[4-(5-methoxymethyl-2 - oxoacridine-3-yl)phenyl] -piperidine was dissolved in 20 ml of methylene chloride and treated in the presence 380,7 mg (3,76 mmole) of triethylamine 196,2 mg (0,94 mmole) of 4-triftormetilfullerenov. The reaction mixture was stirred for 17 h at room temperature. Then the mixture was treated with acetic ether, washed 1H hydrochloric acid and water and dried over sodium sulfate. After recrystallization from acetic ester/simple broadcast received 356,3 mg of (RS)-5-methoxymethyl-3-[4-[1-(4-trifloromethyl)-piperidine-4-yl]- phenyl] -oxazolidin-2-it. So pl.: 164-166o.

Example 58

(RS)-3-[4- (1-acetylpiperidine-4-yl)- phenyl]-5-ethoxyethylacetate - 2-he

177,1 mg (0,61 mmole) (RS)-4-[4-(5-methoxymethyl-2-oxo-oxazolidin-3-yl)-phenyl] -piperidine was dissolved in 20 ml of methylene chloride and treated in the presence 53,1 mg (0.67 mmole) of pyridine and 68.5 mg (0.67 mmole) of acetic anhydride. After stirring for 18 h at room temperature, washed with water and the organic phase was dried over sodium sulfate. After filtration and evaporation filtermeister-2-it is in the form of a yellowish oil.1H-NMR (CDCl3) frequent. /million: 7,49 (d, 2H), 7,20 (d, 2H), 4,80 (m, 2H), of 4.05 (t, 1H), 3,92 (m, 2H), 3,64 (d, 2H), 3.43 points (s, 3H), 3,21 (m, 1H), 2,68 (m, 2H), and 2.14 (s, 3H), of 1.85 (m, 2H), 1,60 (m, 2H).

Example 59

(E)-(RS)-5-methoxymethyl-3-[4-[1-(3- phenylacrylate)piperidine-4-yl]-phenyl] oxazolidin-2-he

201,7 mg (0,695 mmole) of the hydrochloride (RS)-4-[4-(5-methoxymethyl-2-oxoacridine-3 - yl)phenyl] piperidine was dissolved in 15 ml of methylene chloride and in the presence of 281,2 mg (2,78 mmole) of triethylamine under stirring at room temperature was treated dropwise with a solution of 115, 7mm mg (0,695 mmole) of cinnamic acid chloride in 5 ml of methylene chloride. After 17 h, diluted with acetic ether and the organic phase was washed for 1H. hydrochloric acid and water. After recrystallization from acetic ester/simple broadcast received 228,9 mg (E)-(RS)-5-methoxymethyl-3-[4-[1-(3-phenylacrylate)piperidine-4-yl] phenyl] oxazolidin-2-it. So pl.: 136-138o.

Example 60

(RS)-3-[4-(1-ethoxycarbonylpyrimidine-4-yl)phenyl] -5 - ethoxyethylacetate-2-he

1.12 g (3.5 mmole) of ethyl ester of 4-(4-atomiconline-phenyl)-piperidine-1-carboxylic acid were treated in the presence 276,8 mg (3.5 mmole) of pyridine, 4.0 g (30,28 mmol) (RS)-4-(methoxymethyl)-1,3 - dioxolane-2-it, and for 18 h were intensively mixed at a temperature of oil vampira. After recrystallization from methylene chloride/isopropyl ether was received 976 mg (RS)-3-[4-(1-ethoxycarbonylpyrimidine-4-yl) phenyl]-5-ethoxyethylacetate-2-it. So pl.: 86-88o.

Example 61

(R)- 5-methoxymethyl-3-[4-(TRANS-4-methylsulfonylmethane - cyclohexyl)phenyl]oxazolidin-2-he

9.5 g (31,11 mmole) of (R)-3-[TRANS- (4-hydroxycyclohexyl)phenyl]-5-ethoxyethylacetate-2-it was dissolved in 120 ml of dimethyl sulfoxide and sequentially treated with 2 ml of water, 25 ml of acetic ether and 80 ml of acetic anhydride. The reaction mixture was stirred for 22 h at room temperature. Then the mixture was added in portions to a cooled with ice, a solution of 130 g of sodium carbonate in 2 liters of water. After the addition the mixture was stirred for 1 h Then the product was extracted with methylene chloride, the organic phase is washed with water, dried over sodium sulfate, filtered and evaporated. The result was obtained 11.2 g of a yellowish oil, from which the processing of simple ether/n-hexane was obtained crystalline (R)-5 - methoxymethyl-3-[4-(TRANS-4-methylsulfonylmethane)phenyl] oxazolidin-2-it. So pl.: 54-56o, []D= -30,8o(C=1,0, CHCl3). 1H-NMR (COCl3) frequent. /million: 7,47 (P> Example 62

(R)-3- [4-(TRANS-4-methanesulfonylaminoethyl)phenyl]-5 - ethoxyethylacetate-2-he (S-oxide R:S=1:1 mixture of diastereomers)

10.7 g (29,28 mmol) of (R)-5-methoxymethyl-3-[4-(TRANS-4-methylsulfonylmethane) phenyl] oxazolidin-2-it was dissolved in 500 ml of methanol, cooled to 0oand for 90 min with stirring, was treated dropwise with a solution of 4.7 g (22.0 mmol) of periodate of sodium in 150 ml of water. The reaction mixture was stirred in a refrigerator at a temperature of 4-5ofor 19 hours Then the mixture was diluted with 1 l of water and was extracted with methylene chloride. The organic phase is washed with water, dried over sodium sulfate and filtered. The filtrate was filtered through 400 g of silica gel 60 as a buffer and sequentially, separately washed with acetic ether (800 ml), methanol (1 l) and tetrahydrofuran (800 ml). After evaporation of acetic ether eluate was given to 3.16 g of educt. After evaporation of methanol and tetrahydrofurane eluates were received 8,11 g (R)-3-[4- (TRANS-4-methanesulfonylaminoethyl) -phenyl] -5-methoxymethyl - oxazolidin-2-it (S-oxide R:S=1:1 mixture of diastereomers) as a yellow oil. So Kip.: 205o/0.02 mbar, []D= -32,2o(C=1,0%, DMSO).

Example 63

(R)-3-[4-(t is sulfadimethoxine) phenyl] -5 - ethoxyethylacetate - 2-it (S-oxide, RS=1:1 mixture of diastereomers) was dissolved in 200 ml of absolute tetrahydrofuran and in the presence of 420 mg (1,32 mmole) of zinc iodide under stirring for 30 min, treated dropwise with a solution of 17,73 g (0,179 mole) of tributyltinchloride in 40 ml of absolute tetrahydrofuran. The reaction mixture was stirred for 24 h at room temperature. Then the mixture was evaporated, the residue was distributed in acetic ether and water, the organic phase is washed with water, dried over sodium sulfate, filtered and evaporated. The remainder (of 7.75 g) was chromatographically 320 g of silica gel 60 using acetic ether/n-hexane (1:1). As a result received 2.64 g of (R)-3-[4-( TRANS-4 - cyanometallates)phenyl]-5-ethoxyethylacetate-2-it is in the form of a colourless oil; So bales.: 210o/0.02 mbar;] []D= -32,2o(C = 1.0% in CHCl3).1H-NMR (COCl3) part./million: of 7.48 (d, 2H), 7,20 (d, 2H), and 4.75 (m, 1H), 4,32 (d, 2H), was 4.02 (t, 1H), 3,93 (t, 1H), 3,64 (d, 2H), 3,61 (m, 1H), 3.43 points (s, 3H), by 2.55 (m, 1H), 2,39 (m, 2H), 1,95 (m, 2H), 1,50 (width, 4H).

After recrystallization from a simple ether/hexane was obtained white crystals with so pl. 43-45o.

Example 64

(RS)-5-methoxymethyl-3- [4-(TRANS-4-methylsulfonylmethane) phenyl]oxazolidin-2 - he

305,4 mg (1.0 mmol) of (RS)-3-[TRANS-4 - hydroxycyclohexyl)phenyl]relatively 186,9 mg (1.1 mmole) of silver nitrate, 121,4 mg (1.2 mmole) of triethylamine and 115.9 mg (1.2 mmole) of chlorotrimethylsilane. The reaction mixture was stirred for 20 hours Then the mixture was filtered from silver chloride through dicalite, the filtrate was washed with saturated sodium bicarbonate, the organic phase was dried over sodium sulfate, filtered and evaporated. The result has been 354.5 TWh excluding mg of (RS)-5-methoxymethyl-3-[4-(TRANS-4 - methylsulfonylmethane)-phenyl]oxazolidin-2-it is in the form of a yellowish oil.

Example 65

(RS)-3-[4-(TRANS-4 - methanesulfonylaminoethyl)phenyl]-5-ethoxyethylacetate - 2-he (mixture of diastereomers)

1,71 g (4,68 mmole) of (RS)-5-methoxymethyl-3-[4-(TRANS-4 - methylsulfonylmethane) phenyl] oxazolidin-2-it was dissolved in 100 ml of methanol, cooled to 0oand under stirring for 40 min was treated dropwise with a solution of 1.0 g (4,68 mmole) of metaperiodate sodium dissolved in 40 ml of water. The reaction mixture was stirred for 24 h at a temperature of about 4oC. Then the mixture was diluted with water and the product was extracted with methylene chloride. The organic phase is washed with water, dried over sodium sulfate and filtered. The filtrate was filtered through 50 g of silica gel 60 and separately washed methexis) phenyl]-5-ethoxyethylacetate-2-she was led from benzene. So pl.: 98-100o.

Example 66

(RS)-3-[4-(TRANS-4 - cyanometallates)phenyl] -5-ethoxyethylacetate-2-he

536,3 mg (1,40 mmole) of (RS)-3-[4-(TRANS-4 - methanesulfonylaminoethyl) phenyl] -5-ethoxyethylacetate - 2-it (mixture of diastereomers) was dissolved in 25 ml of absolute tetrahydrofuran, and with stirring, was treated with 50 mg of zinc iodide and 465 mg (2,81 mmole) of trimethylsilylacetamide. After stirring for 21 h at room temperature the reaction mixture was diluted with 40 ml of methylene chloride and 40 ml of water, the organic phase is washed with water, dried over sodium sulfate, filtered and evaporated. The residue (517,5 mg) was chromatographically on 25 g of silica gel 60 using acetic ether/n-hexane (1: 1). As a result received 90 mg of (RS)-3-[4-(TRANS-4 - cyanometallates) phenyl]-5-ethoxyethylacetate-2-it is in the form of a colorless oil.1H-NMR (CDCl3) part./million: of 7.48 (d, 2H), 7,20 (d, 2H), and 4.75 (m, 1H), 4,32 (d, 2H), of 4.05 (t, 1H), 3,92 (t, 1H), 3,65 (d, 2H), 3,60 (m, 1H), 3.43 points (s, 3H), of 2.50 (m, 1H), 2,20 (d, 2H), 1,95 (d, 2H), 1,47 (width, 4H).

Example 67

(RS)-3-[4-(TRANS-4-methanesulfonylaminoethyl)phenyl] -5-ethoxyethylacetate-2-he

320,1 mg (from 0.88 mmole) of (RS)-5-methoxymethyl-3-[4-(TRANS-4 - methylsulfonylmethane) phenyl] oxazolidin-2-Rast the air traffic management for 3 h at room temperature the reaction mixture was washed with sodium hydrogen carbonate solution and water, the organic phase was dried over sodium sulfate, filtered and evaporated. The residue (343,2 mg) was chromatographically on 20 g of silica gel 60 using acetic ether. After recrystallization from methylene chloride/simple broadcast received 136,7 mg of (RS)-3-[4-(TRANS-4-methanesulfonylaminoethyl)phenyl] - 5-ethoxyethylacetate-2-it is in the form of white kristalliset with so pl. 145-147o.

Example 68

Hydrochloride, (RS)-3-[4-[TRANS-4-(2 - aminoethoxy)cyclohexyl] phenyl]-5-ethoxyethylacetate-2-she (1:1)

189,7 mg (0,5508 mmole) of (RS)-[TRANS-4-[4-(5-methoxymethyl-2 - oxo-oxazolidin-3-yl)phenyl]cyclohexyloxy] acetonitrile was dissolved in 15 ml saturated with dry ammonia methanol and was first made in the presence of 300 mg of Raney Nickel (type 113 W Degussa). After 30 min was filtered from the catalyst and the filtrate was evaporated. The residue was dissolved in methylene chloride, washed with water, dried over sodium sulfate, filtered and evaporated. The base was dissolved in ethanol and acidified ethereal hydrochloric acid. After recrystallization from alcohol/simple broadcast received of 186.0 mg hydrochloride (RS)-3-[4- [TRANS-4-(2-aminoethoxy)cyclohexyl]phenyl]-5-ethoxyethylacetate - 2-she (1:1). So pl.: 204-206o.

Example 69

(RS)-3-[4- [TRANS-4-(3-acetylamino-2-oxoacridine-3 - yl)phenyl]cyclohexyloxy] propylacetamide was dissolved in 5 ml methylene chloride and treated in the presence 87,01 mg (1.1 mmole) of pyridine and 43.2 mg (0.55 mmole) of acetylchloride. After 3 h, washed with water, the organic phase was dried over sodium sulfate, filtered and evaporated. After recrystallization from acetic ester/simple broadcast received 175,8 mg of (RS)-3-[4-[TRANS-4-(3 - acetylaminofluorene) cyclohexyl] phenyl]-5 - ethoxyethylacetate-2 - it. So pl.: 72-74o.

Example 70

(R)-3-[4-[TRANS-4-(2 - cyanoethoxy)cyclohexyl] phenyl]-5-ethoxyethylacetate-2-he

4,58 g (15.0 mmol) of (R)-3-[TRANS-(4-hydroxycyclohexyl)phenyl]-5 - ethoxyethylacetate-2-it was dissolved in 400 ml of methylene chloride and successively treated with 0.96 g (18.0 mmol) of Acrylonitrile and 2.02 g (18.0 mmol) of tert.-the butyl potassium. The reaction mixture was stirred for 16 h at room temperature, then treated with water, was filtered from nerastvorim components through dicalite, the organic phase is washed with water, dried over sodium sulfate, filtered and evaporated. The residue (5.1 g) was chromatographically in 204 g of silica gel 60 using acetic ether/n-hexane (6: 4). After recrystallization from tert.-butyl methyl ether was obtained 1.6 g of (R)- 3-[4-[TRANS-4-(2-cyanoethoxy)cyclohexyl] phenyl]-5 - ethoxyethylacetate - 2-it. So pl.: 57-59o. []D= -30,0o(C = 0.7 in CHCl3).

Example 71
mmole) of (R)-3-[TRANS-4-[4-(5-methoxymethyl-2-oxo - oxazolidin-3-yl)phenyl] cyclohexyloxy]propionitrile was dissolved in 60 ml saturated with dry ammonia methanol and was first made in the presence of 0.9 g of Raney-Nickel (type B 113 W Degussa). After 3 h was filtered by suction of the catalyst and the filtrate was evaporated. The residue was dissolved in methylene chloride, washed with water, dried over sodium sulfate, filtered and evaporated. The base was dissolved in ethanol and acidified ethereal hydrochloric acid. After recrystallization from alcohol/simple broadcast received 825,2 mg of the hydrochloride of (R)-3-[TRANS-4-[3- (aminopropoxy)cyclohexyl] phenyl] -5-ethoxyethylacetate-2-it. So pl.: 178-180o. []D= -29,78o(C=1% in CHCl3).

Example 72

(R)-5-methoxymethyl-3-[4-(4 - methylenechloride)phenyl]oxazolidin-2-he

2.0 g (7.7 mmol) [4-(4 - methylenechloride)phenyl]ethoxycarbonyl ether was stirred overnight at 160owith 1,02 g (7.7 mmol) of (S)-4-methoxymethyl-1,3-dioxolane-2-she and 170 mg of potassium carbonate. The residue was dissolved in 50 ml of dichloromethane and extracted with 50 ml of water. The organic phase was dried over sodium sulfate and concentrated. After chromatography on silica gel with acetic ether/hexane (1:99) and recrystallization from hexane was obtained 1.04 g (45%) of (R)-5 - methoxymethyl-3-[4-(4-methylenechloride)phenyl]oxazolidin-2-it is in the form of white crystals with so pl. 64o.

Example 73

(R)-3-[4-(CIS - or TRANS-4 - hydroxy-4-methylcyclohexyl 18 ml of tetrahydrofuran. After stirring for 30 min at room temperature the suspension was added dropwise a solution of 900 mg (3 mmole) of (R)-5-methoxymethyl-3-[4-(4 - methylenechloride)phenyl]oxazolidin-2-it in 18 ml of tetrahydrofuran. After conditioning in a refrigeration Cabinet in the next few days were added first 18 ml of 2n. sodium liquor, and then after stirring for 30 min, a solution of 360 mg (9.5 mmol) of sodium borohydride in 12 ml of 2n. sodium lye. After stirring for 30 min were extracted with methylene chloride, the organic phase is washed with water and dried over sodium sulfate. After removal of the solvent was chromatographically on silica gel with acetic ether/dichloromethane (1:1). In the received 200 mg (21%) of (R)-3-[4-(CIS-4-hydroxy-4-methyl-cyclohexyl)phenyl] -5 - ethoxyethylacetate-2-it is in the form of white crystals with so pl. 122-123oand 500 mg of a mixture of CIS - and TRANS-isomers.

Example 74

(R)-TRANS-5-methoxymethyl-3-[4-(4-cyanocyclohexyl)phenyl] -oxazolidin-2-he

A suspension of 500 mg (of 1.84 mmole) of TRANS-[4-(4-cyanocyclohexyl)phenyl] ethoxycarbonyl acid, 365 mg (2.8 mmole) of (S)-4-methoxymethyl-1,3-dioxolane-2-she and 185 mg of potassium carbonate was stirred for 16 h at 160o. The reaction small recrystallized from acetic ester. As a result received 165 mg (29%) of (R)-TRANS-5-methoxymethyl-3-[4-(4-cyanocyclohexyl)phenyl]- oxazolidin-2-it is in the form of white crystals with so pl. 174o.

Example 75

(RS)-5-methoxymethyl-3-[4-(4-dimethylaminoethoxy)-enyl] - oxazolidin-2-he

1,60 g (3.3 mmole) of the mixture of the bromide isopropyltriphenylphosphonium and sodium amide in 30 ml of tetrahydrofuran was stirred for 1 h at room temperature. Then was added dropwise a solution of 1.0 g (3.3 mmole) of (RS)-3-[4-(4- oxocyclohexyl)phenyl] - 5-ethoxyethylacetate - 2-it in 25 ml of tetrahydrofuran. After boiling under reflux for weekend reliabale in 100 ml of water and was extracted three times respectively with 50 ml dichloromethane. After chromatography on silica gel with acetic ether/hexane (1:2) and recrystallization from n-hexane was obtained 120 mg (11%) (RS)-5 - methoxymethyl-3- [4-(4-dimethylmethylene-cyclohexyl)phenyl] oxazolidin-2 - it is in the form of white crystals with so pl. 89-91o.

Example 76

A mixture of (RS)- and (SR)-3-[4-[(RS)-4-benzimidazolinyl]phenyl]-5-methoxymethyl oxazolidin-2-it

5.0 g (10 mmol) of a mixture of bromide benzyltriphenylphosphonium and sodium amide in 100 ml of tetrahydrofuran was stirred for 1 h at room temperature. C-she's in 150 ml of tetrahydrofuran and for 20 h was heated under reflux. After removal of the solvent was dissolved in 150 ml of water and was extracted four times respectively with 80 ml dichloromethane. After chromatography on silica gel with acetic ether/hexane (1:2) and recrystallization from acetic ester/hexane received 250 mg (7%) of white crystals with so pl. 65-69o.

Example 77

(RS)-3-[4-(CIS - and TRANS-4-benzyltoluene)phenyl]-5-methoxymethyl - oxazolidin-2-he

290 mg stock solution in 40 ml of ethanol was treated with 100 mg of 10% palladium on coal and was first made for 20 h at room temperature. After chromatography on silica gel with acetic ether/hexane (1:2) was obtained 110 mg of resin. MS: m/e (% basic peak): 379 (M+, 100), 246 (23), 144 (31), 118 (26), 91 (55), 71 (26), 45 (28).

Example 78

(RS)-3-[4-(4- methoxycarbonylaminophenyl)phenyl] -5-ethoxyethylacetate - 2-he

10.0 g (33 mmole) of (RS)-3-[4-(4-oxocyclohexyl)-phenyl]-5 - ethoxyethylacetate-2-it, and 11.0 g (33 mmole) methoxycarbonylmethylene-triphenylphosphorane in 500 ml of benzene was heated for 24 h under reflux. After removal of the solvent in vacuo was chromatographically on silica gel with acetic ether/hexane (1:1). The result was obtained 3.6 g (43%) of white crystals with so pl. 62-64o.

o. After chromatography on silica gel with acetic ether/hexane (2:3) and recrystallization from acetic ester/simple broadcast received 0,94 g (34%) of beige crystals with so pl. 105-106o.

Example 80

(RS)-3-(3-amino-4-cyclohexylphenol)-5 - ethoxyethylacetate-2-he

0.5 g (1.5 mmole) of (RS)-3-(4-cyclohexyl - 3-nitrophenyl)-5-ethoxyethylacetate-2-she (from the mother liquor in the previous reaction) in 75 ml of ethanol was treated with 100 mg of 10% palladium on coal and was first made for 5 h at room temperature. After filtration, concentration and recrystallization from acetic ester was obtained 150 mg of white crystals with so pl. 130-132o.

Example 81

(RS)-3-(4-cyclohexyl-3-itfeel)-5-ethoxyethylacetate - 2-he

180 mg (0.6 mmole) of (RS)-3-(3-amino-4-cyclohexyl-enyl)-5 - ethoxyethylacetate-2-she (from the mother liquor in the previous reaction) suspended in a mixture of 0.32 ml of water, 0.32 g of 37% hydrochloric acid and 0.64 g of ice and treated at a temperature of 0-5othe solution to 41.4 mg (0.6 mmole) of sodium nitrite in 0.3 ml of water. After stirring for 30 min at this temperature was added a solution of 0.1 g (0.6 mmole) of potassium iodide in 0.3 ml of water. Then was stirred over night while on mg of oil. MS: m/e (% basic peak): 415 (M+, 100), 372 (5), 346 (9), 289 (9), 245 (12), 143 (15), 71 (22).

Example 82

(RS)-3-(4 - cyclohexyl-3-hydroxyphenyl)-5-ethoxyethylacetate-2-he

200 mg (0.7 mmole) of (RS)-3-(3-amino-4-cyclohexylphenol)-5 - ethoxyethylacetate-2-it is suspended in a mixture of 0,86 ml of water, to 0.72 g of ice and 0,235 ml of concentrated sulfuric acid and then treated at a temperature of 0-5oa solution of 45 mg (0,66 mmole) of sodium nitrite in 0.4 ml of water. After boiling under reflux for 3 h and was extracted with dichloromethane, dried over sodium sulfate and drove the solvent. After chromatography on silica gel with acetic ether/hexane (1:2) was obtained 120 mg (60%) of white crystals with so pl. 207-208o.

Example 83

(RS)-3-(3-chloro-4-cyclohexylphenol)-5-ethoxyethylacetate-2 - he

0.45 g (1.6 mmole) of 3-chloro-4-cyclohexylphenol)ethoxycarbonyl ether and 0.84 g (6.4 mmol) of (RS)-4-methoxymethyl-1,3-dioxolane-2-she and 200 mg of potassium carbonate was stirred for 24 h at 160o. After chromatography on silica gel using dichloromethane received 0,57 g of oil containing some number of dioxolane. This dioxolane was removed by molecular distillation at 100o/0.2 mbar. In d>The production of intermediate products

Example 84

(RS)-3-(4-cyclohexylaniline)-propane-1,2-diol

with 8.05 g (44.6 mmol) of 4-cyclohexylaniline, 12.0 g (57 mmol) of (RS)-2,2-dimethyl-1,3-dioxolane - 4-yl-methyl ester of methansulfonate and 11.2 ml (80 mmol) of triethylamine was kept for 4 h in a refractory tube at 140o. The solvent is kept in a water-jet pump, oily brown residue was treated with 50 ml of 3n. hydrochloric acid and was stirred for 1 h at 50o. After cooling were extracted twice respectively in portions of 250 ml simple ether, the aqueous phase was podslushivaet using 2n. sodium liquor and the product was dissolved in acetic ether. The organic phase is washed with water, dried over magnesium sulfate and the solvent drove away. Oily residue crystallized upon treatment with acetic ether/hexane. The result was obtained 2.2 g of the crystal (RS)-3-(4-cyclohexylaniline)- propane-1,2-diol. So pl.: 121-122 (decomposition).

From the mother liquor was further obtained 0.65 g of crystalline product.

Example 85

a) (S)-3-(4-cyclohexylaniline)-4-(2,2-dimethyl-1,3-dioxolane)

5.0 g (28.5 mmol) of 4-cyclohexylaniline, 10.0 g (34,9 mmole) of (R)-2,2-dimethyl-1,3-Dionne 140o. The brown oil obtained after the distillation of volatile components in a water-jet pump, and treated with a saturated solution of sodium carbonate and was extracted with acetic ester. The organic phase is washed with saline, dried over magnesium sulfate and the solvent drove away. The result was obtained 9.5 g of brown oil, which was chromatographically 30-fold amount of silica gel. Obtained after elution with acetic ether/hexane (1: 3) by TLC (acetic ester/hexane 1:2) homogeneous fractions were combined and the solvent drove away. The result was obtained 9.4 g of a yellowish oil. So Kip.: 140o/0.01 mbar. []D= +1,43 (C=1, CHCl3).

b) (S)-3-(4-cyclohexylamino)propane-1,2-diol

4.5 g (S)-3-(4 - cyclohexylaniline)-4-(2,2-dimethyl-1,3-dioxolane) was treated with 50 ml of 3n. hydrochloric acid and was stirred for 1 h at 50o. After cooling with 3h. sodium liquor with ice cooling was podslushivaet that fell into the residue oil was dissolved in acetic ether, washed with common salt solution, dried over magnesium sulfate and the solvent drove away. The obtained pale-brown oil (4.1 g) was chromatographically 30-fold kalichsteinlaredo received 1.5 g of product in the form of beige crystals. So pl.: 116o. []D= is 12.5o(or=0.6, CHCl3).

Example 86

a) (R)-3-(4-cyclohexylaniline)-4-(2,2-dimethyl-1,3-dioxolane)

10.0 g (57 mmol) of 4-cyclohexylaniline, similar to that described in example 42a), transformed and processed 20,0 g (70 mmol) of (S)-2,2-dimethyl-1,3-dioxolane-4 - metamaterial-4-sulfonate. The result has been an 11.7 g (71%) of a yellowish oil. []D= -2,4o(C=1,0, CHCl3).

b) (R)-3-(4-cyclohexylamino) propane-1,2-diol

11.5g (R)-3-(4-cyclohexylaniline-methyl)-4-(2,2-dimethyl-1,2 - dioxolane), similar to that described in example 42B), transformed and treated with 100 ml of 3n. of hydrochloric acid. As a result received 6.25 g of product in the form of beige crystals. So pl.: 118-120o. -12,75o(=0,4, CHCl3).

Example 87

[4-(4-oxocyclohexyl)phenyl]ethoxycarbonyl ether

10.0 g (52,8 mmole) of 4-(4-AMINOPHENYL)cyclohexanone was dissolved in 150 ml of tetrahydrofuran. After addition of 10 ml of water and of 6.65 g (79.2 mmol) of sodium carbonate was intensively stirred for 15 min, then for 20 min was added dropwise a solution of 5.5 ml of ethyl ether of Harborview acid (58,1 mmol) in 25 ml of tetrahydrofuran, and the temperature should not balanitis the residue was treated with water and the reaction product was extracted with acetic ester. The organic phase is washed with water, dried over magnesium sulfate and the solvent drove away. The result obtained 13.8 g (100%) of the carbamate. So pl.: 160-162o.

Example 88

a) 1-(4-AMINOPHENYL)-4-piperidinol

5.6 g of 1-(4-nitrophenyl)-4-piperidone suspended in an argon atmosphere in 60 ml of dioxane, and treated with 2.6 ml of triethylamine and 0.6 g of palladium on coal (5%) and was first made at room temperature and under normal pressure. After filtration and concentration was obtained 5.0 g of 1-(4-AMINOPHENYL)-4-piperidinol.

b) Ethyl ester of 4-(4 - oxopiperidin-1-yl) phenylcarbamate acid

4.9 g of 1-(4-AMINOPHENYL)- 4-piperidinol suspended in the atmosphere of argon in a mixture of 30 ml of tetrahydrofuran and 9 ml of water and treated with 3.3 g of sodium bicarbonate. Then with vigorous stirring at room temperature was added dropwise a solution of 2.7 ml of ethyl ether of Harborview acid in 20 ml of tetrahydrofuran and after the addition was continued to stir for 1 h After adding water and ethyl ester of acetic acid, the phases were separated and the aqueous phase was extracted with ethyl ester of acetic acid. The organic phases were combined, dried over magnesium sulfate and concentrated. OST is 1:0). After crystallization from diethyl ether there was obtained 3.8 g of ethyl ester of 4-(4-oxopiperidin-1-yl)phenylcarbamate acid in the form of grey crystals. So pl.: 145-146o.

Example 89

a) (RS)-3-(5-bromopyridin-2-yl)-5-ethoxyethylacetate-2-he

A mixture of 9.3 g of ethyl ester of 5-bromopyridin-2-yl-carbamino acid, 7.5 g of 4-methoxymethyl-1,3-dioxolane-2-it, 1.0 g of potassium carbonate and 10 ml of decahydronaphthalene was heated for 6 h to 160o. The mixture is then cooled and treated with ethyl ether, acetic acid and water. The phases were separated, the aqueous phase was extracted with ethyl ether, acetic acid and the organic phase was washed with a saturated solution of sodium chloride. The organic phases were combined, dried over magnesium sulfate and then concentrated. After chromatography of the residue (20.2 g) using mixtures of ethyl ester of acetic acid/hexane (1: 2-1: 1) on silica gel was obtained 6.4 g of (RS)-3-(5-bromopyridin-2-yl)-5 - ethoxyethylacetate-2-it, which was recrystallized from diethyl ether. So pl.: 90-92o.

b) (RS)-3-[5-(1,4-dioxaspiro[4,5]Dec - 7-EN-8-yl)-pyridine-2-yl]-5-ethoxyethylacetate-2-he

In an argon atmosphere for 18 h at 70owas stirred suspension of 1.4 g of 3-(5-bromopyridin-2 is nilpotent) palladium (II) in 20 ml of tetrahydrofuran. Then the suspension was cooled, and treated with 150 ml ethyl ester of acetic acid and 150 ml of saturated solution of potassium fluoride and stirred for 30 minutes the Mixture was filtered through Celitebuffer, the phases were separated and the aqueous phase was extracted with ethyl ester of acetic acid. The organic phases were combined, dried over magnesium sulfate, concentrated and chromatographically using diethyl ether as solvent on silica gel 60. The result was obtained 0.6 g (RS)-3-[5-(1,4- dioxaspiro[4,5]Dec-7-EN-8-yl)-pyridine-2-yl]-5 - ethoxyethylacetate-2-it.1H-NMR (CDCl3) part./million: to 8.41 (s, 1H), 8,03 (d, 1H), 7,89 (d, 1H), between 6.08 (t, 1H), 4,82 (m, 1H), 4,21 (t, 1H), 3,91 (t, 1H), 3,92 (s, 4H), of 3.60 (m, 2H), 3,23 (s, 3H), of 2.54 (m, 2H), of 2.38 (m, 2H), equal to 1.82 (t, 2H).

Example 90

a) 1.4-dioxaspiro[4.5]Dec-7-EN-8-silt broadcast triftoratsetata.

48 ml of Diisopropylamine and 210 ml of a 1.6 M solution of n-utility in hexane were prepared in 1 l of absolute tetrahydrofuran in an argon atmosphere a solution of diisopropylamide lithium. In this solution at -70owas added dropwise a solution of 50 g of 1,4-cyclohexanedimethanol in 200 ml of tetrahydrofuran. After removing the cooling bath, the temperature of the mixture was raised to -20othen again on the donkey removal of the cooling bath, the temperature of the mixture was raised to room temperature and the mixture was concentrated. The residue (215 g) was filtered with ethyl ether acetic acid/hexane (1:9) through silica gel 60. The result was obtained with a quantitative yield of 1,4-dioxaspiro[4,5]Dec-7-EN-8-silt ether triftoratsetata.1H-NMR (CDCl3) part./million: to 5.66 (m, 1H), 3,99 (s, 4H), of 2.53 (m, 2H), 2,42 (m, 2H), 1,90 (t, 2H).

b) 8-tributylstannyl-1.4-dioxa-Spiro[4,5]Dec-7-EN

From 13 ml of Diisopropylamine and 59 ml of a 1.6 M solution of n-utility in hexane were prepared in 400 ml of absolute tetrahydrofuran in an argon atmosphere a solution of diisopropylamide lithium. At -70oto this solution was added dropwise 21 ml of anti-hydride and stirred for 2 hours After the addition of 3.5 g of copper cyanide (I) the mixture was allowed to warm to -50oand then quickly added dropwise a solution of 10.4 g of 1,4-dioxaspiro[4,5]Dec-7-EN-8-silt ether triftoratsetata in 80 ml of tetrahydrofuran. Under stirring for 2 h at -30othe reaction mixture was slowly fading to red. Then remove the cooling bath and the mixture was treated with saturated solution of chloride of ammonia and hexane. After filtration through Celitebuffer the aqueous phase was separated and the organic phase was washed successively with water and a saturated solution of chloride is silt ether acetic acid, was treated with 18 g of silver acetate and stirred in the air. Next, the mixture was filtered through Celite-buffer and the filtrate was washed with water and saturated sodium chloride solution. The organic phase was dried over magnesium sulfate, concentrated and chromatographically on silica gel 60 (decontamination using triethylamine). The result has been a 8.9 g of 8-tributylstannyl-1,4-dioxa-Spiro[4,5] Dec-7-ene. 1H-NMR (CDCl3) part./million: 5,70 (m, 1H), 3,98 (s, 4H), 2,36 (width, 4H), 1,74 (t, 2H), 1,45 (m, 6H), of 1.30 (m, 6H), to 0.88 (m, 9H).

Example 91

a) (RS)-5-methoxymethyl-3-pyridin-3-isoxazolidine-2-he

The mixture of 16.8 g of ethyl ester of pyridine-3-ylcarbamate acid, 20 g of 4-methoxymethyl-1,3-dioxolane-2-she and 2.8 g of potassium carbonate was heated for 3 h to 160o. The mixture is then cooled and treated with ethyl ether, acetic acid and water. The phases were separated, then the aqueous phase was extracted with ethyl ether, acetic acid, and the organic phase was washed with a saturated solution of sodium chloride. The organic phases were combined, dried over magnesium sulfate and concentrated. After chromatography of the residue (21 g) using mixtures of ethyl ester of acetic acid/methanol (1:0-20:1) on silica gel was obtained by 17.6 g of (RS)-5-methoxymethyl-3 - pyridine-5 - methoxymethyl-3-(1-oxypyridine-3-yl)oxazolidin-2-he

In an argon atmosphere to a solution of 16.5 g (RS)-5-methoxymethyl-3-pyridin-3 - isoxazolidine-2-it in 250 ml of methylene chloride was added and 33.4 g of 3-chloroperbenzoic acid and the mixture was stirred for 4 h at room temperature. The mixture is then washed with water and the aqueous phase was extracted with methylene chloride. The organic phases were combined, dried over magnesium sulfate, concentrated and chromatographically on silica gel using mixtures of methylene chloride/methanol (50: 1-20:1). The product, 15.9 g of (RS)-5-methoxymethyl-3-(1-oxypyridine-3-yl)oxazolidin - 2-it, boiled for subsequent treatment with diethyl ether. So pl.: 82 - 83o.

in) (RS)-3-(6-bromo-1-oxopyridine-3-yl)-5-ethoxyethylacetate-2-he

At room temperature in a solution of 25.5 g of (RS)-5 - methoxymethyl-3-(1-oxypyridine-3-yl)-oxazolidin-2-it in 300 ml of methylene chloride in the atmosphere of argon was added dropwise to 5.9 ml of bromine dissolved in 35 ml of methylene chloride. The mixture continued to stir for 3 h, then was treated with 350 ml of sodium bicarbonate, after which the phases were separated. The aqueous phase is several times was extracted with methylene chloride. The organic phases were combined, dried over magnesium sulfate, concentrated and chromatograph the 2.5 g of (RS)-3-(6-bromo-1-oxopyridine-3-yl)-5-ethoxyethylacetate-2 - it.1H-NMR (CDCl3) frequent. /million: 8,54 (s, 1H), 7,74 (d, 1H), to 7.59 (d, 1H), 4,82 (m, 1H), 4.00 points (t, 1H), 3,90 (t, 1H), 3,66 (m, 2H), 3.43 points (s, 3H).

g) (RS)-3-(6-bromopyridin-3-yl)-5-ethoxyethylacetate-2-he

In a boiling solution of 22.5 g of (RS)-3-(6-bromo-1-oxopyridine-3-yl)-5 - ethoxyethylacetate-2-she's in methylene chloride in the atmosphere of argon was added dropwise to 10.5 ml tribromide phosphorus and the mixture is boiled overnight. The mixture is then cooled and vigorous stirring was poured into 300 ml of 2n. sodium lye. The aqueous phase was extracted several times with methylene chloride, the organic phases were combined, dried over magnesium sulfate and concentrated. The residue (11.3 g) was chromatographically on silica gel 60 using methylene chloride as solvent. After chromatography got to 9.9 g of (RS)-3-(6-bromopyridin-3-yl)-5-ethoxyethylacetate-2-it, which is boiled for subsequent treatment with diethyl ether. So pl.: 108-110o.

Example 92

(RS)-3-[6-(1,4-dioxaspiro [4.5]Dec-7-EN-8-yl)pyridine-3-yl]-5-ethoxyethylacetate-2-he

In an atmosphere of argon for 22 h at 85owas stirred suspension of the 8.9 g of (RS)-3-(6-bromopyridin-3-yl)-5-ethoxyethylacetate-2-it, 6.5 g of 8-tributylstannyl-1,4-dioxa-Spiro[4,5]Dec-7-ene and 1,4 g of dichloride bis (trifter, the filter residue was washed by a large amount of ethyl ester of acetic acid and the organic phase is repeatedly washed polysystem solution of sodium chloride. The aqueous phase was extracted with ethyl ester of acetic acid, the organic phases were combined, concentrated to a volume of 250 ml, was treated with 250 ml of saturated solution of potassium fluoride and stirred for 30 minutes Then the mixture is again filtered through Celitebuffer, the phases were separated and the aqueous phase was extracted with ethyl ester of acetic acid. The organic phases were combined, dried over magnesium sulfate, concentrated and chromatographically on silica gel 60 using diethyl ether as solvent. The result was obtained 1.2 g (RS)-3-[6-(1,4-dioxa-Spiro[4,5]Dec-7-EN-8-yl)-pyridin - 3-yl] -5-ethoxyethylacetate-2-it.1H-NMR (CDCl3) part./million: 8,48 (s, 1H), 8,19 (d, 1H), 7,56 (d, 1H), 6,50 (m, 1H), 4,79 (m, 1H), 4,12 (t, 1H), was 4.02 (s, 4H), 3.98 (t, 1H), to 3.64 (m, 2H), 3,44 (s, 3H), 2,80 (m, 2H), 2,52 (m, 2H), 1,96 (t, 2H).

Example 93

Ethyl ester of 4-cycloheptylamine acid

for 6.81 g (36.0 mmol) of 4-aminophenylalanine was dissolved in 60 ml of methylene chloride and was treated with 3.13 g (39.6 mmol) of pyridine. The reaction mixture under stirring p is loratafine acid in 15 ml of methylene chloride. After 2 h, washed with water, the organic phase was dried over sodium sulfate, filtered and evaporated. Ethyl ester of 4-cycloheptylamine acid was obtained by distillation at 165-170oand a pressure of 0.3 mbar.

Example 94

Ethyl ester of 4-(adamantane-1-yl)-phenylcarbamoyl acid

5,28 g (20 mmol) of the hydrochloride of 4-adamantane-1-ilfenomeno were placed in 100 ml of methylene chloride and treated 3,22 g (42,0 mmole) of pyridine. To this suspension with stirring at room temperature for 15 min was added dropwise a solution of 2,39 g (22,0 mmole) ethyl ether of Harborview acid in 15 ml of methylene chloride. The reaction mixture was stirred for 2 h at room temperature. Then washed with water, the organic phase was dried over sodium sulfate, filtered and evaporated. The residue was recrystallized from methylene chloride/n-hexane. The result was obtained 5.6 g of ethyl ester of 4-adamantane-1 - infininininini acid as a white kristalliset. So pl.: 132 - 134o.

Example 95

A mixture of (R)- and (S)-[4-[4-[(R)-5-methoxymethyl-2 - oxoacridine-3-yl]-phenyl]cyclohexylidene]acetonitrile

0.66 g of sodium was dissolved in argon atmosphere in 70 ml of ethanol. Then at 20oadded 5 is matney temperature, then was added 2.9 g of (R)-5-methoxymethyl-3-[4-(4-oxo-cyclohexyl) phenyl] oxazolidin-2-it. Next was stirred for 1 hour while heating under reflux, cooled to room temperature, was established, using about 1 ml of acetic ether pH 6 and the reaction mixture was evaporated in vacuum. The residue was dissolved in dichloromethane and washed three times with water, then dried and evaporated. Excess phosphate ester, is still present in the residue, kept at the temperature of the bath 100oand the vacuum of 0.03 mm (So Kip. 0,0334o). The resulting residue (3.2 g) was chromatographically on 250 g of silica gel under medium pressure. Elution was performed using dichloromethane and dichloromethane/ethyl acetate (20: 1). Obtained according to thin the chromatogram of the pure fractions were combined and concentrated in vacuum. The result was obtained 2.6 g of a mixture of (R)- and (S)-[4-[4-[ (R)-5-methoxymethyl-2-oxoacridine-3-yl)] phenyl]cyclohexylidene] acetonitrile (approximately 1:2 E/Z or Z/E) in the form of a slightly cloudy oil, which was directly used for recovery.

Example 96

Tert.-butyl ester of 4-(4-nitrophenyl)piperidine-1-carboxylic acid

of 7.36 g (37,0 mmol) of 4-(4 - nitrophenyl)piperidine and 8,88 g (40.7 mmol) di-tert.-BU the organic phase was dried over sodium sulfate, filtered and evaporated. After recrystallization from n-hexane was obtained 11.2 g of tert.-butyl ester of 4-(4-nitrophenyl)- piperidine-1-carboxylic acid. So pl.: 60-62o.

Example 97

Tert.-butyl ester of 4-(4-AMINOPHENYL) piperidine-1-carboxylic acid

11,03 g (36.0 mmol) of tert.-butyl ester of 4-(4-nitrophenyl)-piperidine-1 - carboxylic acid was dissolved in 200 ml of alcohol and was first made in the presence of 1 g of palladium on coal (10%) at room temperature and under normal pressure. After filtering off the catalyst, the filtrate was concentrated and the residue (10.0 g) was washed in methylene chloride with water. After recrystallization from a simple ether/n-hexane was obtained 8.0 g of tert.-butyl ester of 4-(4-AMINOPHENYL)piperidine-1-carboxylic acid. So pl.: 114-116o.

Example 98

Tert. -butyl ester 4-(4 - ethoxycarbonylmethyl)piperidine-1-carboxylic acid

8,84 g (32.0 mmole) of tert.-butyl ester of 4-(4-AMINOPHENYL)piperidine-1-carboxylic acid was dissolved in 150 ml of methylene chloride and treated in the presence 2,78 g (35.2 mmol) of pyridine and 3,82 g (35.2 mmol) of the ethyl ether of Harborview acid. The reaction mixture was stirred for 16 h at room temperature, then washed with water, g of silica gel 60 using a simple ether/n-hexane (4: 6). After recrystallization from a simple ether/n-hexane received 6,15 g of tert.-butyl ester of 4-(4 - ethoxycarbonylmethyl)piperidine-1-carboxylic acid. So pl.: 126 - 128o.

Example 99

Ethyl ester of 4-(4-ethoxycarbonylmethyl) piperidine-1 - carboxylic acid

3,01 g (14.6 mmol) of 4-(4-AMINOPHENYL)piperidine was dissolved in 100 ml of methylene chloride and stirring was treated in the presence 11,55 g (146 mmol) of pyridine and of 1.74 g (16,06 mmol) of the ethyl ether of Harborview acid. After 3 h the mixture was evaporated, the residue was distributed in acetic ether/water, the organic phase is washed with water, dried over sodium sulfate, filtered and evaporated. The residue (2.7 g) was chromatographically on 85 g of silica gel 60 using methylene chloride/methanol (98:2). After recrystallization from a simple ether/n-hexane was obtained 0.9 g of ethyl ester of 4-(4 - ethoxycarbonylmethyl)piperidine-1-carboxylic acid. So pl.: 105 - 107o.

Example 100

[4-(4-methylenechloride)phenyl]ethoxycarbonyl ether

Suspension of 15,95 g of a mixture of bromide methyltriphenylphosphonium and sodium amide (38.3 mmol bromide methyldiphenylphosphine) in 300 ml was stirred for 1 h at room temperature. Then was added a solution of 10.0 is their night under reflux. The solvent is kept off and the residue was chromatographically on silica gel with acetic ether/hexane (1: 3). The result has been 6,1 g(61%) [4-(4-methylenechloride)phenyl]ethoxycarbonyl ether in the form of white crystals with so pl. 98o.

Example 101

CIS - and TRANS-4-(4-peniciclovir)aniline

In the suspension of 278 mg (1.5 mmole) of 4-(4 - oxocyclohexyl)aniline and 370 mg (1.9 mmole) of toluene-4 - sulfonylmethane in 5 ml of 1,2-dimethoxyethane and 0.15 ml of ethanol at -10oC portions were added 392 mg (3.5 mmole) of tert.-the butyl potassium. After stirring for 1 h at -5oC and over the next 70 hours at room temperature was added 25 ml of water and 10 ml of saturated sodium chloride solution and was extracted three times respectively with 40 ml dichloromethane. The organic phase was dried over sodium sulfate and concentrated. After chromatography on silica gel with acetic ether/hexane (1: 2) received 165 mg (56%) of 4-(4-cyanocyclohexyl)-aniline with so pl. 132-140o.

Example 102

CIS-[4-(4-cyanocyclohexyl)phenyl] ethoxycarbonyl ether and TRANS-[4-(4-cyanocyclohexyl)phenyl] ethoxycarbonyl ether

In a solution of 2.75 g (14 mmol) of CIS - and TRANS-4-(4-cyanocyclohexyl)-aniline in 50 ml tetrahydropyranol ether Harborview acid, dissolved in 5 ml of tetrahydrofuran. After stirring for 4 days at room temperature the solvent is kept off, the residue is suspended in 100 ml of dichloromethane and extracted with water and saturated common salt solution. The organic phase was dried over sodium sulfate and concentrated. After chromatography of the residue on silica gel with acetic ether/hexane (1:2) received 630 mg (17%) TRANS-[4-(4 - cyanocyclohexyl)phenyl]-ethoxycarbonyl ether in the form of white crystals with so pl. 145oand 80 mg (2%) of CIS-[4-(4-cyanocyclohexyl) phenyl]ethoxycarbonyl ether in the form of white crystals with so pl. 110oand 2.5 g (67%) mixed CIS-TRANS fraction.

Example 103

4-cyclohexyl-3-nitrophenylacetylene ether

A mixture of 1.97 g (8.9 mmol) of 4-cyclohexyl-3-nitroaniline and 1.13 g (13.4 mmol) of sodium bicarbonate in 25 ml of tetrahydrofuran and 1.7 ml of water was treated with 1.07 g (9.9 mmol) of the ethyl ether of Harborview acid, dissolved in 5 ml of tetrahydrofuran. After stirring over night at room temperature the solvent is kept off and the residue was chromatographically on silica gel with acetic ether/hexane. The result has been 2,44 g (93%) of a yellow oil. MS: m/e (% basis
A mixture of 1.0 g (5.0 mmol) of 4-cyclohexylmethanol and 0.1 g of iron chloride (III) was heated to 60o. After melting cyclohexylmethanol in well mixed and the mixture was filed within 15 min of gaseous chlorine, after which was added 20 ml of ice water and was extracted using a simple 5 ether. Then the ether is kept off and the residue was dissolved in 60 ml of methanol. Next was treated with 2.5 g (25 mmol) of copper chloride (I) and portions of 1.6 g (29 mmol) of potassium borohydride. After stirring for 30 min reliabale in 0.5 g of water and was extracted with simple ether. After drying over sodium sulfate, removal of the ether and chromatography on silica gel using hexane/acetic ether (9:1) was obtained 0.68 g butter. MS: m/e (% basic peak) = 209 (M+, 75), 166 (100), 140 (78), 131 (62).

Example 105

(3-chloro-4-cyclohexylphenol) ethoxycarbonyl ether

The mixture of 0.59 g (2.8 mmole) of 3-chloro-4-cyclohexylaniline and 0.36 g (4.2 mmole) of sodium bicarbonate in 10 ml of tetrahydrofuran and 0.75 ml of water was treated with 0.34 g (3.1 mmole) of ethyl ether of Harborview acid dissolved in 1 ml of tetrahydrofuran. After 5 hours stirring at room temperature was poured into 25 ml water and was extracted with dichloromethane. After chromatography on with the 38 (18), 225 (12), 212 (34), 192 (23), 166 (19), 140 (20).

An example of A

(RS)-3-(4-cyclohexylphenol)-5-hydroxymethylimidazole-2-it can be used as active substances in the manufacture by known methods of the pharmaceutical preparations of the following composition:

1. Capsules 100 mg

Active substance 100.0 mg

Lactose phoroshop. - 104,7 mg

Talc - 12.0 mg

Magnesium stearate - 3.0 mg

Corn starch - 70.0 mg

The hypromellose - 10.0 mg

Sulfosuccinate dictinary - 0.3 mg- _________ - 300 mg

2. Tablets 50 mg

Active substance 50.0 mg

Lactose phoroshop. - 50.0 mg

Microcrystalline cellulose - 82,0 mg

Na-karboksimetilirovaniya starch - 15,0 mg

Magnesium stearate - 3.0 mg- _________ - 200 mg

3. Suppositories 500 mg

The active substance is 500 mg

The weight of the suppository Up to 2000 mg

4. Suppositories 500 mg

The active substance is 500 mg

The weight of the suppository Up to 2000 mg

5. Megkozeliteni capsules 100 mg

Active ingredient 100 mg

Triglyceride - 300 mg- _________ - 400 MGE

1. Derivative oxazolidin-2-it General formula

< / BR>
where R denotes lower alkyl;

X denotes cycloalkenyl; bicyclo[2,2,1]hept-2-yl, not necessarily the piperidine, not necessarily one - or multiply substituted with halogen, amino, lower alkyl, nitrile, exography, hydroxyimino, ethylenedioxythiophene or1where R1denotes-CH(C6H5)2, -(CH2)nC6H5, lower alkyl, hydrogen, -(CH2)nNHCOCH3, -(CH2)nNH2,

-(CH2)nSOCH3, -(CH2)nCN, -(CH2)nSCH3, -(CH2)nSO2CH3, -CO-lower alkyl, -COC6H5not necessarily substituted oxazolidinone group or substituted =CR2R3where R2denotes hydrogen or lower alkyl; R3denotes hydrogen, nitrile, lower alkyl, phenyl or -- COO-lower alkyl; or substituted -(CH2)nR4where R4denotes nitrile, amino, -NHCOCH3, -COC6H4Gal, phenyl or hydroxyl group; or substituted-COR5where R5denotes lower alkyl, -CH= CH-C6H5, -C6H5CF3, -O-C(CH3)3or-O-lower alkyl; or substituted-NR6R7where R6denotes hydrogen or-COCH3; R7means-COCH3, benzyl or -(CH2)nNHCOC6H4Gal;

n denotes 1 - 3;

Y1obsenations acceptable salts of basic compounds of formula I with acids.

2. Connection on p. 1, where R denotes lower alkyl; X denotes cycloalkyl or piperidine, not necessarily substituted lower alkyl, methylene, Ethylenedioxy, halogen, hydroxyl group, lower alkoxy, hydroxyimino or exography, -O-(CH2)2- R8, -O-CO-R9or-NH(CH2)nNHCOC6H4R10or-CH2OH; bicyclo[2,2,1] hept-2-yl, does not necessarily substituted phenyl-2-oxo-5-ethoxymethyleneamino; bicyclo[2,2,1]hept-5-EN-2-yl or substituted; one of Y1and Y2denotes a CH group and the other represents a nitrogen atom or both represent CH-group; R8represents-CN or-CH2NH2; R9denotes lower alkyl, phenyl or substituted oxazolidinones a phenyl group; R10denotes halogen and n represents 1 to 3.

3. Connection on p. 2, where X denotes a cyclohexyl or substituted by exography, a hydroxyl group, hydroxyimino, a methoxy group, -O(CH2)2CN group or-O(CH2)3NH2-cyclohexyl group, R denotes methyl and Y1and Y2denote CH-group.

4. The compound according to any one of paragraphs.1 to 3, characterized in that it represents the (RS)-3-(4-cyclohexylphenol)-5-methoxyethoxymethyl)-5-ethoxyethylacetate-2-it.

6. The compound according to any one of paragraphs.1 to 3, characterized in that it is a (R)-3-[4-(4-oxocyclohexyl)-phenyl] -5-ethoxyethylacetate-2-it.

7. The compound according to any one of paragraphs.1 to 3, characterized in that it represents the (RS)-3-[4-[TRANS-4-(2-cyanoethoxy)-cyclohexyl]-phenyl]-5-ethoxyethylacetate-2-it.

8. The compound according to any one of paragraphs.1 to 3, characterized in that it represents the (RS)-3-[4-(CIS - or TRANS-4-hydroxy-4-methylcyclohexyl)-phenyl] -5-ethoxyethylacetate-2-it.

9. The compound according to any one of paragraphs.1 to 3, characterized in that it represents the (RS)-3-[4-(CIS - or TRANS-4-hydroxymethylcellulose)-phenyl]-5-ethoxyethylacetate-2-it.

10. The compound according to any one of paragraphs.1 to 3, characterized in that it represents the (RS)-3-(4-cyclohexylphenol)-5-hydroxymethylimidazole-2-he;

(RS)-3-[4-(4-oxocyclohexyl)-phenyl]-5-ethoxyethylacetate-2-he;

(RS)-3-[4-(TRANS-4-hydroxycyclohexyl)-phenyl] -5-ethoxyethylacetate-2-he;

(RS)-3-[4-(4-hydroxyindolacetic)-phenyl] -5-ethoxyethylacetate-2-he;

(R)-3-[4-(TRANS-4-hydroxycyclohexyl)-phenyl] -5-ethoxyethylacetate-2-he;

(RS)-3-[4-(TRANS-4-methoxycyclohexyl)-phenyl] -5-ethoxyethylacetate-2-he;

X denotes a bicyclo[2.2.1]hept-2-yl or bicyclo[2.2.1]hept-5-EN-2-yl.

12. The compound according to any one of paragraphs.1 - 11, characterized in that it is a 3-[(1RS,2RS,4SR)-4-bicyclo[2.2.1]hept-2-yl-phenyl]-5-ethoxyethylacetate-2-it 3-[(1RS,2SR,4RS)-4-bicyclo[2.2.1]hept-5-EN-2-yl-phenyl] -5-ethoxyethylacetate-2-it.

13. Compounds according to any one of paragraphs.1 - 12, where X denotes a cyclohexyl or piperidine, substituted-CH2CN, -COCH=CH-C6H5, -O(CH2)NH2or-OCH2CN, R denotes methyl and Y1and Y2denote CH-group.

14. The compound according to any one of paragraphs.1 - 13, characterized in that it represents the (RS)-3-[4-(TRANS-4-cyanomethylene)-phenyl]-5-ethoxyethylacetate-2-it.

15. The compound according to any one of paragraphs.1 - 13, characterized in that it represents (R)-3-[4-(TRANS-4-cyanomethylene)-phenyl]-5-ethoxyethylacetate-2-it.

16. The compound according to any one of paragraphs.1 - 13, characterized in that it represents (E)-(RS)-5-methoxymethyl-3-[4-[1-(3-phenylacrylate)-piperidine-4-yl]-phenyl]-oxazolidin-2-it.

17. The compound according to any one of paragraphs. 1 - 13, characterized in that it is a hydrochloride, (RS)-3-[4-[TRANS-4-(2-aminoethoxy)-cyclohexyl]-phenyl]-5-ethoxyethylacetate-2-it.

18. The compound according to any one of paragraphs. 1 - 13, characterized in that ptx2">

19. The compound according to any one of paragraphs.1 - 13, characterized in that it represents the (RS)-3-[4-(TRANS-4-cyanometallates)-phenyl] -5-ethoxyethylacetate-2-it.

20. The compound according to any one of paragraphs.1 - 13, characterized in that it represents (R)-3-[4-[TRANS-4-(3-aminopropoxy)-cyclohexyl]-phenyl]-5-ethoxyethylacetate-2-it.

21. Compounds according to any one of paragraphs.1 - 20 and their pharmaceutically acceptable salts, having the ability to inhibit monoamine oxidase.

22. Compounds according to any one of paragraphs.1 - 20 and their pharmaceutically acceptable salts inhibiting the monoamine oxidase to fight or prevent conditions of depression, States of panic and fear, mental disorders of brain function and diseases of the neuro-degerativnye character as Parkinson's and Alzheimer's disease.

23. Drug, monoamine oxidase inhibitory to fight or prevent conditions of depression, States of panic and fear, mental disorders of brain function and diseases of the neuro-degerativnye character as Parkinson's and Alzheimer's disease containing the active substance and a therapeutically inert excipient, characterized in that as acti alkyl; X - bicyclo[2,2,1]hept-2-yl, does not necessarily substituted phenyl-2-oxo-5-ethoxymethyleneamino; bicyclo[2,2,1]hept-5-EN-2-yl; substituted; or cycloalkyl or piperidine, not necessarily one - or multiply substituted with halogen, lower alkyl, exography, hydroxyimino, ethylenedioxythiophene or1where R1is lower alkyl, hydrogen, -(CH2)3NH2, -(CH2)2CN, -CO-lower alkyl, -COC6H5, optionally substituted oxazolidinyl group; or substituted = CR2R3where R2and R3represent hydrogen; or substituted by a group-CH2OH; or is substituted by-NR6R7where R6denotes hydrogen; R7represents -(CH2)nNHCOC6H4Gal; n = 1 to 3; Y1represents-CH= or-N=; Y2represents-CH= or-N=, and pharmaceutically acceptable salts of basic compounds of formula I with acids;

27.09.94 - when R is lower alkyl; X is cycloalkenyl; or cycloalkyl or piperidine, optional single - or multi-substituted amino, nitrile, or-OR1where R1denotes-CH(C6H5)2, -(CH2)nC6H5where n = 1 to 3, -(CH2)nNHCOCH3where n = 1 to 3, -(CH2)nNH2where n = 1, 2; -(CH2nSO2CH3where n = 1 to 3; or a substituted =CR2R3where R2denotes hydrogen or lower alkyl; R3denotes nitrile, lower alkyl, phenyl or -- COO-lower alkyl; or substituted -(CH2)nR4where R4denotes nitrile, amino, -NHCOCH3, -COC6H5Gal, phenyl, n = 1 - 3, or R4- hydroxyl group when n = 2, 3; or substituted-COR5where R5denotes lower alkyl, -CH=CH-C6H5, -C6H5CF3, -O-C(CH3)3or-O-lower alkyl; or substituted-NR6R7where R6denotes hydrogen or-COCH3; R7means-COCH3or benzyl; Y1represents-CH= or-N= ; Y2denotes-C(OH)=; -C(NO2)=; -C(NH2)=; -C(Gal)=, as well as pharmaceutically acceptable salts of basic compounds of formula I with acids.

 

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