Derivatives of diarylamino containing alicyclic group, showing antagonism against serotonin-2 receptors and/or inhibitory activity against squalene synthase, a composition for treatment and prevention of cardiovascular diseases

 

(57) Abstract:

Derivatives of diarylamino formula I, where R1unsaturated heterocyclic group with 5 ring atoms, one of which is nitrogen, possibly substituted on one carbon atom IT or1-20alkanoyloxy and nitrogen atoms possibly substituted C1-6by alkyl; R2a, R2b, R2c-H, methyl, methoxy, F, Cl, Br; R3a, R3b, R3c, R3d- H, C1-6alkoxy or halogen atom, and their pharmaceutically acceptable salts and esters. The compounds of formula I are antagonists of the serotonin-2 receptors and have the ability to inhibit the activity of squalene synthase. 2 C. and 16 h.p. f-crystals, 4 PL.

The invention relates to a series of new derivatives of diarylamino containing acyclic group. These compounds are antagonists of the serotonin-2 receptors and have the ability to inhibit the activity of squalene synthase. The invention also provides methods of using these compounds, compositions containing these compounds, and methods for producing these compounds.

Serotonin, which is the classic physiologically active substance, also known as neurotransmitter and games is tonine has several subtypes of receptors. Among them serotonin-2 receptors, which are distributed in endothelial cells of blood vessels and platelets and is closely associated with narrowing of the blood vessels and platelet aggregation tS. J. Peroutka et al. Fed. Proc., 42, 213 (1983)]. Thus, antagonists of serotonin acting at serotonin receptors-2, are useful to prevent compression of blood vessels and platelet aggregation. Known ketanserin, exerting an antagonistic effect on serotonin-2 receptors [J. I. S. Robertson,Curr. Opinion Cardiol., 3, 702 (1988)], but its usefulness is limited to its strong anti-hypertensive effect and therefore this drug was originally created as an antagonist of adrenaline 1. Recently appeared diarylamino derivative as inhibitor of platelet aggregation with an antagonistic effect relative to the serotonin-2 receptors [J. Med. Chem., 35, 189 (1992); ibid 33 1818 (1990); EP 600717]. However, it was shown that these two compounds have the ability to inhibit squalene synthase.

One of the three major risk factors of ischemic heart diseases such as arteriosclerosis, is hyperlipidemia. You know, what is heart disease can be prevented by reducing excessively elevated sod is-reductase in the system of cholesterol synthesis, this enzyme has no effect on the course of synthesis of derivatives of isoprene. Therefore, the biosynthesis of cholesterol can inhibit blocking squalene synthase without any inhibitory effect on the biosynthesis of ubiquinone, dolichol and other important compounds metabolism [Nature, 343, 425 (1990)] . This indicates that inhibitors of squalene synthase very useful as a therapeutic and preventive medicines to fight with hyperlipidemia. Current inhibitors of squalene synthase are isoprenoid (povinelli) phosphate, saragossie acid containing as the main structure dioxabicyclo ring, and others (U.S. patent N 4871721; U.S. patent N 5102907).

Connection, providing as antagonistic action regarding serotonin-2 receptors, and inhibitory effect on squalene synthase, can not only prevent and inhibit the emergence and development of atherosclerosis due to its antihyperlipidemic effect (inhibitory effect on squalene synthase), but also to inhibit thrombosis in atherosclerotic lesions lesions due to its antagonistic action on the serotonin receptors-2 and improve hamod is ractice and therapy of these diseases.

A brief description of the invention.

In accordance with the present invention offers a number of new alicyclic derivatives, which are preferably alicyclic amines, and their pharmacologically acceptable salts, which are useful for prevention and therapy of cardiovascular diseases (including thrombotic, arteriosclerotic or gipolipidemicheskie diseases, particularly thrombotic diseases), have a strong antagonistic effect on serotonin-2 receptors and an additional inhibitory effect on squalene synthase and have extended an antagonistic effect on serotonin-2 receptors in vivo.

Compounds of the present invention are those compounds of formula (1):

< / BR>
where R represents a saturated heterocyclic group attached to a link or a group represented by the symbol A, via a ring carbon atom, with the specified saturated heterocyclic group has from 3 to 6 ring atoms, of which one or two are heteroatoms selected from the group consisting of heteroatoms of nitrogen, oxygen and sulphur and is substituted by at least one carbon atom on is unsubstituted on the nitrogen atom or substituted on the nitrogen atom by at least one Deputy, selected from the group consisting of the substituents defined below;

R2a, R2band R2cthe same or different from each other and each represents a hydrogen atom, metallum group, ethyl group, methoxy group, ethoxypropan, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a cyano or a nitro-group, and at least one of the radicals R2a, R2band R2crepresents a group or atom other than(th), from hydrogen;

R3a, R3band R3dthe same or different from each other and each represents a hydrogen atom, alkyl group having from 1 to 6 carbon atoms, halogenation group having from 1 to 6 carbon atoms, alkenylphenol group having from 2 to 6 carbon atoms, alkylamino group having from 2 to 6 carbon atoms, a hydroxy-group, alkoxygroup having from 1 to 6 carbon atoms, halogenlampe having from 1 to 6 carbon atoms, alkoxycarbonyl having from 2 to 6 carbon atoms, alkanoyloxy having from 1 to 6 carbon atoms, carbamoyloximes, alkylcarboxylic, in which the alkyl part has from 1 to 6 carbon atoms, dialkylammonium, in which each alkyl part has
A represents A single bond or alkilinity group having from 1 to 6 carbon atoms;

these substituents selected from the group consisting of hydroxy groups, alkoxycarbonylmethyl, in which CNS part has from 1 to 20 carbon atoms, alkanoyloxy having from 1 to 20 carbon atoms, alkanoyloxy having from 2 to 7 carbon atoms and substituted by carboxypropyl, carbamoyloximes, alkylcarboxylic having from 1 to 6 carbon atoms, and dialkylammonium in which each alkyl part has from 1 to 10 carbon atoms;

these substituents selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, alkyl groups having from 1 to 6 carbon atoms and substituted by at least one aryl group, as defined below, aryl groups defined below, and alkoxycarbonyl groups having from 2 to 10 carbon atoms;

these aryl groups are carbocyclic aromatic groups having from 6 to 10 carbon atoms and which is unsubstituted or substituted by at least one Deputy, selected from the group consisting of the substituents defined below;

shown is p, having from 1 to 6 carbon atoms, and halogen atoms; and their pharmaceutically acceptable salts and esters.

In accordance with the present invention it is also proposed composition for the prevention and treatment of cardiovascular diseases, containing antagonist of the serotonin-2 receptors, which specified the antagonist of the serotonin-2 receptors also shows inhibitory activity against squalene-synthase and is an active compound selected from the group consisting of such as defined above, compounds of formula (1) and their pharmaceutically acceptable salts.

Also, in accordance with the present invention proposes a method of preventing or treating cardiovascular disease in affected mammal, comprising the introduction of a given mammal, which may be human, an effective amount of the active compounds exhibiting antagonistic activity against serotonin-2 receptors and inhibitory activity against squalene-synthase, and the specified active compound selected from the group consisting of such as defined above, compounds of formula (1) and their pharmaceutically acceptable salts.

And e is written in more detail below.

Detailed description of the invention.

In the compounds of the present invention R1represents a saturated heterocyclic group attached to a link or a group represented by the symbol A, via a ring carbon atom. Saturated heterocyclic group has from 3 to 6 ring atoms, of which one or two are heteroatoms selected from the group consisting of heteroatoms of nitrogen, oxygen and sulfur. The group, represented by the radical R1preferably contains one nitrogen heteroatom in the ring and no longer contains no heteroatoms or contains one heteroatom selected from the group consisting of heteroatoms of nitrogen, oxygen and sulfur, and the remaining ring atoms are carbon atoms. The group is substituted with at least one of its carbon atoms by at least one Deputy, selected from the group consisting of the substituents defined above and shown in the examples below. When a group contains (which is preferred) a nitrogen atom, this nitrogen atom is unsubstituted or may be substituted by at least one Deputy, selected from the group consisting of the substituents defined above and privdenniro, pyrrolidinyloxy, piperidino, piperazinilnom, morpholinyl, thiomorpholine, imidazolidinyl, pyrazolidinone, triazinyl and tetrazolyl group, of which preferred are azetidinone, pyrrolidinyl, piperideine, piperazinilnom, morpholinyl and thiomorpholine group, and more preferred are 2-pyrrolidinyl, 3-pyrrolidinyl, 2-piperideine, 3 - piperideine, 4-piperideine, 1-piperazinilnom, 2 - morpholinyl and 3-morpholinyl group. Even more preferred groups are 2-pyrrolidinyl, 3 - pyrrolidinyl, 2-piperideine, 3-piperideine and 4 - piperideine group, and particularly preferred groups are 2-pyrrolidinyl and 3-piperideine group. The most preferred group is 2-pyrrolidinyl group.

These groups are substituted. There are no particular restrictions on the number of substituents, except for the limitations imposed by the number of substitutable positions, and possibly by steric (spatial) constraints. Usually used preferably 3 Deputy, and more preferably 2 to the Deputy.

When R3a, R3b, R3cor R3dis alkyl is about from 1 to 4, carbon atoms, and examples include methyl, ethyl, sawn, ISO-propyl, boutelou, isobutylene, second-boutelou, tert-boutelou, pentelow, isopentanol, neopentyl, 2-methylbutyl, 1-ethylpropyl, 4-methylpentyl, 3 - methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3 - dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1, 3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, hexoloy and isohexyl group. Of them, preferred are alkyl groups having from 1 to 4 carbon atoms, preferably methyl and ethyl group, and most preferably a methyl group.

When R3a, R3b, R3cor R3dis halogenating group, it can be a group with an unbranched or branched chain, having from 1 to 6, preferably from 1 to 4, carbon atoms, and its examples include formeterol, deformational, triptorelin, chlormethine, bromatology, otmetilo, 2-foretelling, 2-chloraniline, 2-bromo-ethyl, 2-iodation, 3-forproperty, 4-terbutaline, 5-forinternal and 6-perhexiline group. Of these are preferred permetrina, deformity Milna, deformational, triptoreline, 2-florachilena and 2-chloraniline group and the most preferred triptorelin group.

When R3a, R3b, R3cor R3dis alkenylphenol group, it can be a group with an unbranched or branched chain, having from 2 to 6, preferably 3 or 4, carbon atoms, and examples include the vinyl, allyl, metallinou, 1-propenyloxy, Isopropenyl, 1 battiloro, 2-butenyloxy, 3-butenyloxy, 1-pentanediol, 2 - pentanediol, 3-pentanediol, 4-pantanillo), 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl groups, which are the preferred vinyl, allyl, metalllica, 2-bucinellina, 2-penttila and 2-examilia group, more preferred allyl and metalllica group and the most preferred allyl group.

When R3a, R3b, R3cor R3dis alkylamino group, it can be a group with an unbranched or branched chain, having from 2 to 6, preferably 3 or 4, carbon atoms, and its examples include etinilnoy, propargyl (2-propenyloxy), 1-propenyloxy, 1-butenyloxy, 2-butenyloxy, 3 - butenyl the preferred etinilnoy, propargyl, 2-Butyrina, 2-penicilina and 2-hexylamine group, more preferred propargyl and 2-Butyrina group and the most preferred propargyl group.

When R3a, R3b, R3cor R3dis alkoxygroup, it can be a group with an unbranched or branched chain, having from 1 to 6, preferably from 1 to 4, carbon atoms, and examples include methoxy, ethoxy-, propoxy-, isopropoxy, butoxy, isobutoxy-, second -, butoxy-, tert-butoxy-, pentyloxy, isopentylamine, neopentylene-, 2-methylbutoxy-, 1 ethylpropoxy-, 4-methylpentane-, 3-methylpentane-, 2-methylpentane-, 1 methylendioxy-, 3,3-Dimethylbutane-, 2,2-Dimethylbutane-, 1,1 - Dimethylbutane-, 1, 2 Dimethylbutane-, 1, 3 Dimethylbutane-, 2,3-Dimethylbutane-, 2-ethylbutane, hexyloxy and isohexadecane. Of them, preferred are alkoxygroup having from 1 to 4 carbon atoms, preferably methoxy and ethoxypropan and most preferably a methoxy group.

When R3a, R3b, R3cor R3dis halogenlampe, it can be a group with an unbranched or branched chain, having from 1 to 6, preferably from 1 methoxy-, admetox-, 2-floratone-, 2-chloroethoxy-, 2-bromoethoxy-, 2-iodoxy-, 3-forproperty-, 4 - forbooks-, 5-perpetrate - and 6-perhexiline. Of these are preferred formatosi, deformedarse, triptoreline, chloromethoxy-, 2-floratone - and 2 - choreography, more preferred formatosi, deformedarse, triptoreline-, 2-floratone - and 2-choreography and most preferred triptoreline and dipterocarp.

When R3a, R3b, R3cor R3dis alkoxycarbonylmethyl having from 2 to 7 carbon atoms, its CNS part can be a group with an unbranched or branched chain, having from 1 to 6, preferably from 1 to 4, carbon atoms, and its examples include methoxycarbonylamino, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxyethene-, second -, butoxycarbonylamino-, tert-butoxycarbonylamino, ventilatsioonile, isobutylacetophenone, neopentecostalism-, 2-metallocarborane-, 1 ethylpropylamine-, 4-methylbenzyloxycarbonyl-, 3 - methylbenzyloxycarbonyl-, 2 methylbenzyloxycarbonyl-, 1-methylpentyl is oxy, 1, 2 diethylpyrocarbonate-, 1, 3 diethylpyrocarbonate-, 2,3-dimethylbutadiene-, 2-tilbetciiiolis, hexyloxyethoxy and isohexadecane. Of them, preferred are alkoxycarbonylmethyl having from 1 to 4 carbon atoms, preferably of methoxycarbonylamino and ethoxycarbonylmethoxy and most preferably methoxycarbonylamino.

When R3a, R3b, R3cor R3dis alkanoyloxy, it alcoolica part can be a group with an unbranched or branched chain, having from 1 to 6, preferably from 2 to 5, carbon atoms, and its examples include formyloxy-, acetoxy-, propionyloxy, butyryloxy, isobutyryloxy, valeriote, pivaloyloxy and hexaniacinate, of which preferred are acetoxy, propionyloxy, butyryloxy , isobutyryloxy, valerianic and pivaloyloxy. More preferred are acetoxy and propionyloxy, and most preferred is acetoxygroup.

When R3a, R3b, R3cor R3dis alkylcarboxylic, the alkyl part of this group may be a group with Nera include methylcarbamoyl-, ethylcarbamate, propylgallate, isopropylcarbamate, butylcarbamoyl, isobutylbarbituric-, second -, butylcarbamoyl-, tert-butylcarbamoyl, intercorporate, isobutylbarbituric, neopentanoate-, 2-methylbutylamine-, 1 ethylpropylamine-, 4-methylphenylcarbinol-, 3 - methylphenylcarbinol-, 2-methylphenylcarbinol-, 1 methylphenylcarbinol-, 3, 3 dimethylbutylamine-, 2,2-dimethylbutanoate-, 1,1-dimethylbutylamino-, 1,2 - dimethylbutylamino-, 1,3-dimethylbutylamine-, 2,3 - dimethylbutyramide-, 2 ethylbutylamine, hexylberberine and isohexanoate. Of them, preferred are alkylcarboxylic having from 1 to 4 carbon atoms in the alkyl part, preferably methylcarbamoyl and ethylcarboxylate and most preferably methylcarbamoylmethyl.

When R3a, R3b, R3cor R3dis dialkylammonium, each alkyl part of this group (which may be the same or different from each other) may be a group with an unbranched or branched chain, having from 1 to 6, is molotsi, N-isopropyl-N-methylcarbamoyl-, N,N - diethylcarbamoyl-, N,N-dipropylamino-, N, N-diisopropylcarbodiimide-, N,N-dibutylbarbituric-, N, N - diisobutylamine-, N,N-di-sec-butylcarbamoyl-, N, N-di-tert-butylcarbamoyl-, N,N-dimetilkarbamida-, N,N-diisopentylphthalate-, N,N-lineapellebologna- , N,N-dihexylfluorene - and N,N-deisohexanizer. Of them, preferred are dialkylammonium having from 1 to 4 carbon atoms in each alkyl part, preferably N,N-dimethylcarbamoyl-, N - ethyl-N-methylcarbamoyl - and N,N-diethylcarbamoyl and most preferably N,N-dimethylcarbamoyl.

When R3a, R3b, R3cor R3drepresents a halogen atom, it may be a fluorine atom, chlorine atom, bromine atom or iodine atom, preferably fluorine atom or chlorine atom.

When R3a, R3b,R3cor R3drepresents an aryl group, it represents a carbocyclic aromatic group which has from 6 to 10 carbon atoms and which is unsubstituted or substituted by at least one Deputy, selected from the group consisting of substituents set the number of substituents, in addition to restrictions imposed by the number of substitutable positions, and possibly by steric constraints. Examples of such groups include phenyl, 2 - methylphenyl, 3-methylphenyl, 4-methylphenyl, 2 - metoksifenilny, 3-metoksifenilny, 4-metoksifenilny, 2 - ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 2 - propoxyphenyl, 3-propoxyphenyl, 4-propoxyphenyl, 2 - florfenicol, 3-florfenicol, 4-terfenadine, 2-chloraniline, 3-chloraniline, 4-chloraniline, 2-bromperidol, 3 - bromperidol, 4-bromperidol, 2-itfinally, 3-itfinally, 4-itfinally, 2,4-dimethylaniline, 2,4-dichloraniline, 2,4 - differenly, 1-naftalina, 2-naftalina, 2-methyl-1-naftalina, 3-methyl-1-naftalina, 4-methyl-1-naftalina, 5-methyl-1-naftalina, b-methyl-1-naftalina, 7-methyl-1-naftalina, 8-methyl-1-naftalina, 2-methoxy-1-naftalina, 3-methoxy-1-naftalina, 4-methoxy-1 - naftalina, 2-ethoxy-1-naftalina, 3 ethoxy-1-naftalina, 4 - ethoxy-1-naftalina, 2-propoxy-1-naftalina, 3-propoxy-1-naftalina, 4-propoxy-1-naftalina, 2-fluoro-1-naftalina, 3-fluoro-1-naftalina, 4-fluoro-1-naftalina, 2-chloro-1-naftalina, 3 - chloro-1-naftalina, 4-chloro-1-naftalina, 2-bromo-1-naftalina, -

3-bromo-1-naftalina, 4-bromo-1-naftalina, 2-iodine-1 - naftalina, 3-iodine-1-n, 6-methyl-2-naftalina, 7-methyl - 2-naftalina, 8 - methyl-2-naftalina, 2-methoxy-2-naftalina, 3-methoxy-2-naftalina, 4-methoxy-2-naftalina, 2-ethoxy-2-naftalina, 3 ethoxy-2 - naftalina, 4-ethoxy-2-naftalina, 2-propoxy-2-naftalina, 3 - propoxy-2-naftalina, 4-propoxy-2-naftalina, 2-fluoro-2 - naftalina, 3-fluoro-2-naftalina, 4-fluoro-2-naftalina, 2-chloro-2 - naftalina, 3-chloro-2-naftalina, 4-chloro-2-naftalina, 2-bromo-2 - naftalina, 3-bromo-2-naftalina, 4-bromo-2-naftalina, 2-iodine-2 - naftalina, 3-iodine-2-naftalina and 4-iodine-2-naftalina group. Of them, preferred are phenyl, methylphenylene, metoksifenilny, Fortunella, chloraniline and naftalina group, and most preferred is a phenyl group.

When A represents alkylenes group, it has from 1 to 6, preferably from 1 to 4, carbon atoms and may be a group with an unbranched or branched chain. Examples of such groups include methylene, ethylene, propylene, trimethylene, tetramethylene, pentamethylene and hexamethylene group. Of these are preferred methylene, ethylene and trimethylene group, more preferred methylene and ethylene groups and the most preferred ethylene g is or branched chain, having from 1 to 6, preferably from 1 to 4, carbon atoms, and examples include methyl, ethyl, sawn, ISO-propyl, boutelou, isobutylene, second-boutelou, tert-boutelou, pentelow, isopentanol, neopentyl, 2-methylbutyl, 1-ethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethyl boutelou, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2, 3-dimethylbutyl, 2 - ethylbutyl, hexoloy and isohexyl group. Of them, preferred are alkyl groups having from 1 to 4 carbon atoms, preferably methyl and ethyl group, and most preferably a methyl group.

When the Deputy is alkoxycarbonyl group, its CNS part can be a group with an unbranched or branched chain, having from 1 to 20 carbon atoms (i.e., alkoxycarbonylmethyl generally has from 2 to 21 carbon atoms), and examples include methoxycarbonylamino, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxyethene-, second -, butoxycarbonylamino-, tert-butoxycarbonylamino, pentyloxybenzoyl is elextronics-, undecalactone, dodecyloxyethoxy, treeselectionmodel, tetradecylammonium, pentadecanedioic, hexadecyltrichlorosilane, heptadecadiene, octadecyltrichlorosilane, nondestructively and casinosecureonlinegamb. Of them, preferred are alkoxycarbonylmethyl, in which CNS part has from 1 to 6 or from 8 to 18 carbon atoms, and more preferably from 1 to 4 or from 8 to 18 carbon atoms. Specific preferred groups include ethoxycarbonyl, isopropoxycarbonyl-, tert-butoxycarbonylamino, octyloxybenzoate, hexadecyltrichlorosilane and octadecyltrichlorosilane, more preferably, ethoxycarbonyl, isopropoxycarbonyl-, tert-butoxycarbonylamino, octyloxybenzoate and hexadecyltrichlorosilane and most preferably octyloxybenzoate.

When the Deputy represents alkanoyloxy, it can be a group with an unbranched or branched chain, having from 1 to 20 carbon atoms, and its examples include formyloxy-, acetoxy-, propionyloxy, butyryloxy, isobutyryloxy, valeriote-, drink the sea, palmitoleic, staralliance and casanovaspa. Of them, preferred are groups having from 2 to 5 or 10 to 18 carbon atoms, more preferably from 10 to 16 carbon atoms. Specific preferred groups include decanoate, eurolocs, myristoleic and palmitoylated and most preferably decanoate and euroelixir.

When the Deputy represents alkanoyloxy, replaced by carboxypropyl, it is a remnant of the dicarboxylic acid. The group may be unbranched or branched and has from 2 to 7 carbon atoms in alkanoyloxy part (i.e., from 3 to 8 carbon atoms in all carboxyterminal alkanoyloxy). Examples of such carboxyamides of alkanoyloxy include melonlike, succinylate, glucosyloxy, adipoless, pimeliinae and suberoylanilide. Of them, preferred are alkanoyloxy having from 3 to 6 carbon atoms, most preferably succinylate and glutaredoxin. If desired carboxylic Deputy can be esterificated, for example as described below.

When the Deputy represents alkylcarboxylic, the alkyl part of this propertyh atoms, and its examples include methylcarbamoyl, ethylcarbamate, propylgallate, isopropylcarbamate, butylcarbamoyl, isobutylbarbituric-, second -, butylcarbamoyl-, tert-butylcarbamoyl, intercorporate, isobutylbarbituric, neopentanoate-, 2-methylbutylamine-, 1 ethylpropylamine-, 4-methylphenylcarbinol-, 3-methylphenylcarbinol-, 2-methylphenylcarbinol-, 1-methyl - intercorporate-, 3, 3 dimethylbutylamine-, 2,2-dimethylbutanoate-, 1,1-dimethylbutylamino-, 1,2 - dimethylbutylamino-, 1,3-dimethylbutylamine-, 2, 3 dimethylbutylamine-, 2-ethylbutylamine, hexylberberine and isohexanoate. Of them, preferred are alkylcarboxylic having from 1 to 4 carbon atoms in the alkyl part, preferably methylcarbamoyl and ethylcarboxylate and most preferably methylcarbamoylmethyl.

When the Deputy represents dialkylammonium, each alkyl part of this group (which may be the same or different from each other) may be a group with an unbranched or branched chain is N-ethyl-N-methyl - carbamoyloximes-, N-isopropyl-N-methylcarbamoyl-, N, N-diethylcarbamoyl-, N,N-dipropylacetamide-, N,N-diisopropylcarbodiimide-, N,N-dibutylbarbituric-, N, N-diisobutylamine-, N,N-di-sec-butylcarbamoyl-, N,N - di tertbutylcalix-, N,N-dimetilkarbamida-, N, N-diisopentylphthalate-, N,N-lineapellebologna-, N,N-dihexylfluorene - and N,N-deisohexanizer. Of them, preferred are dialkylammonium having from 1 to 4 carbon atoms in each alkyl part, preferably N,N-dimethylcarbamoyl-, N-ethyl-N - methylcarbamoyl - and N,N-diethylcarbamoyl and most preferably N, N-limitinternalrecursion.

When the Deputy represents an alkyl group, substituted by at least one aryl group, the alkyl part has from 1 to b carbon atoms and may be any of the groups defined and described in the examples above in connection with R3a, R3b, R3cor R3d. Aryl group is preferably phenyl group which may be substituted or unsubstituted. There is no particular limit on the number of aryl groups that are substituents on the alkyl group, in addition to restrictions which could the positive use 1-3 aryl group, and more preferably 1 aryl group. Specific examples of such aryl-substituted alkyl groups include benzyl, o-, m - and p-methylbenzyl, o-, m - and p-methoxybenzyl, o-, m - and p-forbindelse, o-, m - and p-chloraniline, o-, m - and p - bromobenzyl, fenetylline, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentane, 6-phenylhexanoic, benzhydryl, o- , m - and p-methylbenzhydryl, o-, m - and p-methoxybenzylamine, o-, m - and p-farbenspiel, o-, m - and p-chloro-benzhydryl, OO' - mm' and PP'-diferencijalno, OO' - mm' and PP'- dichlorobenzidine and trailing group. Of these are preferred benzyl, o-, m - and p-methylaniline, o-, m - and p-methoxyaniline, o-, m - and p-tormentilla, o-, m - and p - chloraniline, o-, m - and p-brombenzene, penicilina and benzydamine group, and most preferred is a benzyl group.

When the Deputy represents an aryl group, it can be any of the aryl groups defined and described in the examples above in connection with R3a, R3b, R3cor R3dmost preferably the phenyl group.

When the Deputy is alkoxycarbonyl group having from 2 to 10 carbon atoms, its ALCO is about from 1 to 4, 7 or 8, carbon atoms, and examples of these alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxyethanol, second-butoxycarbonyl, tert - butoxycarbonyl, ventilatsioonile, isobutylacetophenone, neopentylglycol, 2-metilbutanoilny, 1-ethylpropylamine, 4-methylbenzyloxycarbonyl, 3-methylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl, 1-methylbenzyloxycarbonyl, 3,3-dimethylbutylamino, 2,2-dimethylbutylamino, 1,1-dimethylbutylamino, 1,2-dimethylbutylamino, 1,3 - dimethylbutylamino, 2,3-dimethylbutylamino, 2 - metilbutanoilny, hexyloxyphenol, isohexadecane, heptyloxybiphenyl, octyloxybiphenyl and nonlexically group. Of them, preferred are alkoxycarbonyl group having from 2 to 5, 8 or 9 carbon atoms, preferably methoxycarbonyl, ethoxycarbonyl and octyloxyphenyl group, and most preferably methoxycarbonyl group.

Deputy represents an alkyl group, the ima as examples above in connection with R3a, R3b, R3cor R3d.

Deputy , which is the Deputy at the carbon atom of the heterocyclic groups represented by the radical R1represents preferably a hydroxy-group, alkoxycarbonyl having from 1 to 6 or from 8 to 18 carbon atoms in the CNS part, alkanoyloxy having from 1 to 20 carbon atoms, carboxyterminal alkanoyloxy having from 3 to 7 carbon atoms in alkanoyloxy part, carbamoyloximes or mono - or dialkylammonium, in which an alkyl group or each alkyl group has 1 or 2 carbon atoms, more preferably a hydroxy-group, alkoxycarbonyl having from 1 to 4 or from 8 to 18 carbon atoms in the CNS part, alkanoyloxy, having from 2 to 5 or 10 to 18 carbon atoms, carboxyterminal alkanoyloxy having from 3 to 6 carbon atoms in alkanoyloxy part, carbamoyloximes or mono - or dialkylammonium, in which alkyl or each alkyl group has 1 or 2 carbon atoms. More preferred groups included in substituents are hydroxymethylbilane, ethoxycarbonyl, isopropoxycarbonyl-, octadecyltrichlorosilane- , acetoxy-, propionyloxy, butyryloxy, valeriote, pivaloyloxy, decanoate, undecanoate, eurolocs, myristoleic, palmitoleic, stearolic, succinylate, glucosyloxy, carbamoylated-, N-methylcarbamoyl-, N-ethyl - carbamoylated-, N, N-dimethylcarbamoyl - and N,N-diethylcarbamoyl. Even more preferred groups are hydroxy, ethoxycarbonyl, isopropoxycarbonyl-, tert - butoxycarbonylamino, octyloxybenzoate, hexadecyltrichlorosilane-, acetoxy-, decanoate, eurolocs, palmitoleic, stearolic, succinylate, carbamoylated - and N,N-dimethylcarbamoyl and most preferred are hydroxy, octyloxybenzoate, decanoate, eurolocs and palmitoylated.

Deputy , which is the Deputy at the nitrogen atom of the heterocyclic groups represented by the radical R1preferably represents an alkyl group having from 1 to 4 carbon atoms, or phenyl group, unsubstituted or substituted with at least one methyl group, a methoxy group, a fluorine atom or a chlorine atom. More preferred groups included in the Deputy is LASS="ptx2">

Preferred compounds of the present invention are those compounds of formula (1) in which R1represents a heterocyclic group having a ring nitrogen atom.

Specific examples of five - or six-membered saturated heterocyclic groups which may be represented by R1include the following groups. In these groups "? " means that the next Deputy may be in any other release position. Such groups include hydroxypyrrolidine, methoxycarbonylpropionyl, ethoxycarbonylpyrimidine, propeciaonlineorder.info, isopropoxycarbonyloxymethyl, butoxycarbonyloxyimino, tert-butoxycarbonyloxyimino, pentyloxyphenylacetylene, exelonzionenergysolutions, octyloxybenzophenone, nonelectrically, lecellcrisismoreconditionsymp, undesirableinflexibilities, dodecyloxybenzoyl, treeselectionlistener, pentadecafluoroheptyl, hexadecyltrichlorosilane, getdecimalseparator, propionoxypiperidine, butyrylcholine, valeriucciobello, pivaloyloxymethyl, hexanoyloxyfucoxanthin, 3,3-dimethylaminopyridinium, heptacarboxyporphyrin, actinomycetemcomitans, nonanoyloxybenzenesulfonate, technologyproviding, andeconomically, lauroylsarcosine, meriterhospitalmadisonwi, polymethylenepolyphenylene, stearoylethanolamine, ecasinojokeronline7, domainverwaltung, succinylcholine, glutamylcysteine, dipolarizations, pelloidoterapiya, carbamoylbiphenyl, N-methylcarbamoylmethyl, N-ethylcarbodiimide, N, N-dimethylcyclohexylamine), N,N-diethylcarbamoyl, N-methyl-N-ethylcarbodiimide, 1 - methyl- ?-hydroxypyrrolidine, 1-methyl-?- methoxycarbonylpropionyl, 1-methyl-? - ethoxycarbonylpyrimidine, 1-methyl-?-propeciaonlineorder.info, 1-methyl - ?-isopropoxycarbonyloxymethyl, 1-methyl-? - butoxycarbonyloxyimino is, 1-methyl-? - heptyloxybiphenyl, 1-methyl-?- octyloxybenzophenone, 1-methyl- ?-nonelectrically, 1-methyl-?- decyloxybenzoyloxybenzylideneamino, 1-methyl-?- undesirableinflexibilities, 1-methyl-?-dodecyloxybenzoyl, 1-methyl-? -treeselectionlistener, 1-methyl-?-pentadecafluoroheptyl, 1-methyl-? -hexadecyltrichlorosilane, 1-methyl-?-getdeclaredannotations, 1-methyl-?- octadecyltriethoxysilane, 1-methyl-?- formyloxyethyl, 1-methyl-?-acetoxypropionyl, 1-methyl-?-propionoxypiperidine, 1-methyl-? - butyrylcholine, 1-methyl-?-valeriucciobello, 1-methyl-?-pivaloyloxymethyl, 1-methyl-? - hexanoyloxyfucoxanthin, 1-methyl-? - (3,3 - dimethylbutyryl) pyrrolidinyl, 1-methyl- ? - heptacarboxyporphyrin, 1-methyl-?- actinomycetemcomitans, 1-methyl-?-nonanoyloxybenzenesulfonate, 1-methyl- ? -decanoylacetaldehyde, 1 - methyl-?-andeconomically, 1-methyl-? -lauroylsarcosine, 1-methyl-?-meriterhospitalmadisonwi, 1 - medinilla, 1 - methyl-? -domainverwaltung, 1-methyl-? -succinylcholine, 1-methyl- ?-glutamylcysteinylglycine, 1 - methyl-?-dipolarizations, 1-methyl-?-pelloidoterapiya, 1-methyl-?-carbamoylbiphenyl, 1 - methyl-?- (N-methylcarbamoyl) pyrrolidinyl, 1-methyl-?-(N - ethylcarbamate) pyrrolidinyl, 1-methyl-?- (N,N-dimethylcarbamoyl) pyrrolidinyl, 1-methyl-?- (N,N-diethylcarbamoyl) pyrrolidinyl, 1-methyl-?- (N-methyl-N-ethylcarbamate) pyrrolidinyl, 1-ethyl- ? -hydroxypyrrolidine, 1-ethyl-? -methoxycarbonylpropionyl, 1-ethyl-? -ethoxycarbonylpyrimidine, 1-ethyl-?- propeciaonlineorder.info, 1-ethyl-? from propeciaonlineorder.info, 1-ethyl-?- butoxycarbonyloxyimino, 1-ethyl-?- tert-butoxycarbonyloxyimino, 1-ethyl-? - pentyloxyphenylacetylene, 1-ethyl-?- exelonzionenergysolutions, 1-ethyl-?- heptyloxybiphenyl, 1-ethyl-? - octyloxybenzophenone, 1-ethyl-?- nonelectrically, 1-ethyl-?- decyloxybenzoyloxybenzylideneamino, 1-ethyl-? - hexadecyltrichlorosilane, 1-ethyl-?- octade is inuu, 1-ethyl-?-butyrylcholine, 1 - ethyl-?-valeriucciobello, 1 - ethyl-? -pivaloyloxymethyl, 1-ethyl-? -actinomycetemcomitans, 1-ethyl-? -nonanoyloxybenzenesulfonate, 1-ethyl-?- decanoylacetaldehyde, 1-ethyl-?-andeconomically, 1-ethyl-?-lauroylsarcosine 1-ethyl-?- meriterhospitalmadisonwi, 1-ethyl-?-polymethylenepolyphenylene, 1-ethyl-?-stearoylethanolamine, 1-ethyl- ? -succinylcholine, 1-ethyl-?-glutamylcysteinylglycine, 1-ethyl-? -dipolarizations, 1-ethyl-? - pelloidoterapiya, 1-ethyl-? -carbamoylbiphenyl, 1-ethyl-? - (N-methylcarbamoyl) pyrrolidinyl, 1-ethyl-? - (N, N-dimethylcarbamoyl) pyrrolidinyloxy, hydroxypiperidine, ethoxycarbonylpyrimidine, ethoxycarbonylpyrimidine, isopropoxycarbonyloxymethyl, tert - butoxycarbonyloxyimino, octyloxybenzophenone, nonelectrically, declaremathoperator, hexadecyltrichlorosilane, octadecyltrichlorosilane and function, acetoxypiperidine, propionoxypiperidine, butylisoxazole, valenciano, palmitoylcarnitine, stearoylethanolamine, succinylcholine, glutamylcysteine, carbamoylbiphenyl, N - methylcarbamoylmethyl, N-ethylcarbodiimide, N, N - dimethylcarbamodithioato, 1-methyl-? - hydroxypiperidine, 1-methyl-?-ethoxycarbonylpyrimidine, 1-methyl-?-ethoxycarbonylpyrimidine, 1-methyl-?- isopropoxycarbonyloxymethyl, 1-methyl-? - tert-butoxycarbonyloxyimino, 1-methyl- ?- octyloxybenzophenone, 1-methyl-?- nonelectrically, 1-methyl-? -declaremathoperator, 1-methyl-?- hexadecyltrichlorosilane, 1-methyl-?- octadecyltrichlorosilane, 1-methyl- ? - acetoxypiperidine, 1-methyl-? - propionoxypiperidine, 1-methyl-?-butylisoxazole, 1-methyl-? -valeriucciobello, 1-methyl-?-pivaloyloxymethyl, 1-methyl -? -technologieberatung, 1-methyl- ?-lauroylsarcosine, 1-methyl-?-ministeriosemanuel.net, 1-methyl-?-palmitoylcarnitine, 1-methyl-? - stearoylethanolamine, 1-methyl-?-succinylcholine, 1-methyl-? -glutamylcysteine, 1-methyl-?- carbamoylbiphenyl is methylcarbamoyl)piperidino, 1-ethyl-? - hydroxypiperidine, 1-ethyl-?-ethoxycarbonylpyrimidine, 1 - ethyl-? -isopropoxycarbonyloxymethyl, 1-ethyl-?-tert - butoxycarbonyloxyimino, 1-ethyl-?-octyloxybenzophenone, 1-ethyl-? -nonelectrically, 1-ethyl-N-declaremathoperator, 1-ethyl-? - hexadecyltrichlorosilane, 1-ethyl-? -octadecyltrichlorosilane, 1-ethyl-? -acetoxypiperidine, 1-ethyl-? -propionoxypiperidine, 1-ethyl-? -butylisoxazole, 1-ethyl-?-valeriucciobello, 1-ethyl-?- pivaloyloxymethyl, 1-ethyl-?-technologieberatung, 1-ethyl-?-lauroylsarcosine, 1-ethyl-? -ministeriosemanuel.net, 1-ethyl-? -palmitoylcarnitine, 1-ethyl-?-stearoylethanolamine, 1-ethyl-?- acryloyloxyhexyloxy, 1-ethyl-?-succinylcholine and 1-ethyl-?-glutamylcysteine group.

Of these groups, preferred are hydroxypyrrolidine, methoxycarbonylpropionyl, ethoxycarbonylpyrimidine, isopropoxycarbonyloxymethyl, tert-butoxycarbonyloxyimino, octyloxybenzophenone, nonyloxypolyethylsiloxane, acetoxypropionyl, propionoxypiperidine, valerianviramune, pivaloyloxymethyl, decanoylacetaldehyde, underageerotica, lauroylsarcosine, ministeriosemanuel.net, polymethylenepolyphenylene, stearoylethanolamine, actinobacteria, glutamylcysteinylglycine, carbamoylaspartate, N-methylcarbamoylmethyl, N,N-dimethylcyclohexylamine, 1-methyl-?-hydroxypyrrolidine, 1-methyl-?- methoxycarbonylpropionyl, 1-methyl-? -ethoxycarbonylpyrimidine, 1-methyl-?- isopropoxycarbonyloxymethyl, 1-methyl-?-tert-butoxycarbonyloxyimino, 1-methyl-? -octyloxybenzophenone, 1-methyl-?-but relaxationisparticularly, 1-methyl-?-decyloxybenzoyloxybenzylideneamino, 1-methyl-?-hexadecyltrichlorosilane, 1-methyl-? -octadecyltriethoxysilane, 1-methyl-? -acetoxypropionyl, 1 - methyl-? -propionoxypiperidine, 1-methyl-?- valerianviramune, 1-methyl-?- pivaloyloxymethyl, 1-methyl-?- decanoylacetaldehyde, 1-methyl -? - undec, -methyl- ? -polymethylenepolyphenylene, 1-methyl-?- stearoylethanolamine, 1-methyl-? -succinylcholine, 1-methyl-?-glutamylcysteinylglycine, 1-methyl-?-carbamoylbiphenyl, 1-methyl-?- (N-methylcarbamoyl)pyrrolidinyl, 1-methyl-? - (N,N - dimethylcarbamoyl) pirapitinga, 1-ethyl-? - hydroxypyrrolidine, 1-ethyl-?-methoxycarbonylpropionyl, 1 - ethyl-?-ethoxycarbonylpyrimidine, 1-ethyl-?- isopropoxycarbonyloxymethyl, 1-ethyl-? -tert - butoxycarbonyloxyimino, 1-ethyl-?- octyloxybenzophenone, 1-ethyl-?- nonelectrically, 1 - ethyl-?-decyloxybenzoyloxybenzylideneamino, 1-ethyl-?-hexadecyltrichlorosilane, 1-ethyl-? - octadecyltriethoxysilane, 1-ethyl-? - acetoxypropionyl, 1-ethyl-? -propionoxypiperidine, 1-ethyl-? -valerianviramune, 1-ethyl-?-pivaloyloxymethyl, 1-ethyl- ?-lauroylsarcosine, 1-ethyl-?-ministeriosemanuel.net, 1-ethyl-?-polymethylenepolyphenylene, 1-ethyl-?-stearoylethanolamine, 1-ethyl-?- succinylcholine, 1-ethyl-?-glutamylcysteinylglycine, 1-ethyl-? -carbamazepina, isopropoxycarbonyloxymethyl, tert-butoxycarbonyloxyimino, octyloxybenzophenone, DeclareCaptionLabelFormat, hexadecyltrichlorosilane, octadecyltrichlorosilane, acetoxypiperidine, propionoxypiperidine, valeriucciobello, pivaloyloxymethyl, technologiemanagement, andeconomically, lauroylsarcosine, ministeriosemanuel.net, palmitoylcarnitine, stearoylethanolamine, succinylcholine, patrilocally, carbamoylbiphenyl, N - methylcarbamoylmethyl, N, N-dimethylcyclohexylamine, 1-methyl-?-hydroxypiperidine, 1-methyl-?- ethoxycarbonylpyrimidine, 1-methyl-?- ethoxycarbonylpyrimidine, 1-methyl-?-isopropoxycarbonyloxymethyl, 1-methyl-?-tert - butoxycarbonyloxyimino, 1-methyl-?- octyloxybenzophenone, 1-methyl-?- declaremathoperator, 1-methyl-? - hexadecyltrichlorosilane, 1-methyl-? - octadecyltrichlorosilane, 1-methyl- ?-acetoxypiperidine, 1-methyl-?-propionoxypiperidine, 1-methyl-? -valeriucciobello, 1-methyl -?- lauroylsarcosine, 1-methyl-?-ministeriosemanuel.net, 1-methyl-? -palmitoylcarnitine, 1-methyl-?- stearoylethanolamine, 1-methyl-?-succinylcholine, 1-methyl-?-patrilocally, 1-methyl-?-carbamoylbiphenyl, 1-methyl-?- (N, N-dimethylcarbamoyl) piperideine, 1-ethyl-?-hydroxypiperidine, 1-ethyl-? - ethoxycarbonylpyrimidine, 1-ethyl-?- ethoxycarbonylpyrimidine, 1-ethyl-? -isopropoxycarbonyloxymethyl, 1-ethyl-? - tert-butoxycarbonyloxyimino, 1-ethyl-?-octyloxybenzophenone, 1-ethyl-? -DeclareCaptionLabelFormat, 1-ethyl-?- hexadecyltrichlorosilane, 1-ethyl-? - octadecyltrichlorosilane, 1-

ethyl-? -acetoxypiperidine, 1-ethyl-? - propionoxypiperidine, 1-ethyl-? -valeriucciobello, 1-ethyl-?-pivaloyloxymethyl, 1-ethyl-? - technologiemanagement, 1-ethyl-? -lauroylsarcosine, 1 - ethyl-? -ministeriosemanuel.net, 1-ethyl-? - palmitoylcarnitine, 1-ethyl-? -stearoylethanolamine, 1-ethyl-?-succinylcholine, 1-ethyl-? - glutamylcysteine and 1-ethyl-? -carbamoylbiphenyl group.

More prefer is carbonyloxy-2-pyrrolidinone, 4-tert - butoxycarbonylamino-2-pyrrolidinone, 4-octyloxybenzoate-2 - pyrrolidinone, 4-decyloxybenzoate-2-pyrrolidinone, 4 - hexadecyltrichlorosilane-2-pyrrolidinone, 4-octadecanoyloxy-2-pyrrolidinone, 4-acetoxy-2-pyrrolidinyl, 4-propionyloxy-2-pyrrolidinone, 4-valeriote-2 - pyrrolidinone, 4-pivaloyloxy-2-pyrrolidinone, 4-decanoate-2 - pyrrolidinone, 4-euroluxe-2-pyrrolidinone, 4-myristoleate-2-pyrrolidinone, 4 palmitoylated-2-pyrrolidinone, 4-stearolic-2 - pyrrolidinone, 4-succinate-2-pyrrolidinone, 4 - glucosyloxy-2-pyrrolidinone, 4-carbamoylated-2-pyrrolidinone, 4 - N-methylcarbamoyl) -2-pyrrolidinyl, 4 - N,N - dimethylcarbamoyl) -2-pyrrolidinone, 1-methyl - 4 - hydroxypyrrolidine, 1-methyl-4-ethoxycarbonyl-2 - pyrrolidinone, 1-methyl-4-isopropoxycarbonyl-2 - pyrrolidinone, 1-methyl-4-tert-butoxycarbonylamino-2 - pyrrolidinone, 1-methyl-4-octyloxybenzoate-2 - pyrrolidinone, 1-methyl-4-decyloxybenzoate-2 - pyrrolidinone, 1-methyl-4-hexadecyltrichlorosilane-2-pyrrolidinone, 1-methyl-4 - octadecanoyloxy-2-pyrrolidinone, 1-methyl-4 - acetoxy-2-pyrrolidinone, 1-methyl-4-prop is Aya, 1-methyl-4 - decanoate-2-pyrrolidinone, 1-methyl-4-euroluxe-2-pyrrolidinone, 1 - methyl-4-myristoleate-2-pyrrolidinone, 1-methyl-4 - palmitoleate-2-pyrrolidinone, 1-methyl-4-stearolic-2 - pyrrolidinone, 1-methyl-4-succinate-2-pyrrolidinone, 1 - methyl-4-glucosyloxy-2-pyrrolidinone, 1-methyl-4-carbamoylated - 2-pyrrolidinone, 1-methyl-4- (N-methylcarbamoyl) -2 - pyrrolidinone, 1-methyl-4- (N, N-dimethylcarbamoyl) -2 - pyrrolidinone, 1-ethyl-4-hydroxy-2-pyrrolidinone, 1-ethyl-4 - ethoxycarbonyl-2-pyrrolidinone, 1-ethyl-4 - isopropoxycarbonyl-2-pyrrolidinone, 1-ethyl-4 - tertbutoxycarbonyl-2-pyrrolidinone, 1-ethyl-4 - octyloxybenzoate-2-pyrrolidinone, 1-ethyl-4 - hexadecyltrichlorosilane-2-pyrrolidinone, 1-ethyl-4 - octadecanoyloxy-2-pyrrolidinone, 1-ethyl-4-acetoxy-2 - pyrrolidinone, 1-ethyl-4-decanoate-2-pyrrolidinone, 1 - ethyl-4-euroluxe-2-pyrrolidinone, 1-ethyl-4-myristoleate-2 - pyrrolidinone, 1-ethyl-4-palmitoleate-2-pyrrolidinone, 1 - ethyl-4-stearolic-2-pyrrolidinone, 1-ethyl-4-succinate-2 - pyrrolidinyl, 4-hydroxy-2-piperideine and 1-methyl-4 - hydroxy-2-piperideine group.

Even more preferred groups irrelatively, 4-tert-butoxycarbonylamino - 2-pyrrolidinone, 4-octyloxybenzoate-2 - pyrrolidinone, 4-hexadecyltrichlorosilane-2-pyrrolidinone, 4-octadecanoyloxy-2-pyrrolidinone, 4-acetoxy-2-pyrrolidinyl, 4-pivaloyloxy-2-pyrrolidinone, 4-decanoate-2-pyrrolidinone, 4-euroluxe-2 - pyrrolidinone, 4-myristoleate-2-pyrrolidinone, 4-palmitoleate - 2-pyrrolidinone, 4-stearolic-2-pyrrolidinone, 4-succinate-2-pyrrolidinone, 4 carbamoylated-2 - pyrrolidinone, 4- (N,N-dimethylcarbamoyl) -2-pyrrolidinone, 1-methyl-4-hydroxy-2-pyrrolidinone, 1-methyl-4-ethoxycarbonyl - 2-pyrrolidinone, 1-methyl-4-isopropoxycarbonyl-2-pyrrolidinone, 1-methyl-4-tert-butoxycarbonylamino - 2-pyrrolidinone, 1-methyl-4-octyloxybenzoate-2 - pyrrolidinone, 1-methyl-4-hexadecyltrichlorosilane-2 - pyrrolidinone, 1-methyl-4-octadecanoyloxy-2-pyrrolidinone, 1-methyl-4-acetoxy-2-pyrrolidinone, 1-methyl-4 - pivaloyloxy-2-pyrrolidinone, 1-methyl-4-decanoate-2 - pyrrolidinone, 1-methyl-1-4-euroluxe-2-pyrrolidinone, 1 - methyl-4-myristoleate-2-pyrrolidinone, 1-methyl-4-palmitoleate - 2-pyrrolidinone, 1-methyl-4-Staropoli-2-pyrrolidinone, 1 molotsi) -2-pyrrolidinyl group.

Much more preferable groups are 4-hydroxy - 2-pyrrolidinone, 4-ethoxycarbonyl-2-pyrrolidinone, 4-isopropoxycarbonyl-2-pyrrolidinone, 4-tert - butoxycarbonylamino-2-pyrrolidinone, 4-octyloxybenzoate - 2-pyrrolidinone, 4-hexadecyltrichlorosilane-2 - pyrrolidinone, 4-octadecanoyloxy-2-pyrrolidinone, 4-acetoxy-2-pyrrolidinyl, 4-decanoate-2-pyrrolidinone, 4-euroluxe-2-pyrrolidinone, 4-myristoleate - 2-pyrrolidinone, 4 palmitoylated-2-pyrrolidinone, 4 - stearolic-2-pyrrolidinone, 4-succinate-2-pyrrolidinone, 4-carbamoylated-2-pyrrolidinone, 1-methyl-4-hydroxy - 2-pyrrolidinyl, -methyl-4-ethoxycarbonyl-2-pyrrolidinone, 1-methyl-4-isopropoxycarbonyl-2-pyrrolidinone, 1-methyl-4-tert-butoxycarbonylamino-2-pyrrolidinone, 1 - methyl-4-octyloxybenzoate-2-pyrrolidinone, 1-methyl-4 - hexadecyltrichlorosilane-2-pyrrolidinone, 1-methyl-4 - octadecanoyloxy-2-pyrrolidinone, 1-methyl-4-acetoxy - 2-pyrrolidinone, 1-methyl-4-decanoate-2-pyrrolidinone, 1 - methyl-4-euroluxe-2-pyrrolidinone, 1-methyl-4-myristoleate - 2-pyrrolidinone, 1-methyl-4-palmitoleate-2-pyrrolidinyl the e is more preferred groups are 4-hydroxy - 2-pyrrolidinone, 4 ethoxycarbonyl-2-pyrrolidinone, 4 - tert-butoxycarbonylamino-2-pyrrolidinone, 4-octyloxybenzoate - 2-pyrrolidinone, 4-hexadecyltrichlorosilane-2-pyrrolidinone, 4-octadecanoyloxy-2 - pyrrolidinone, 4-decanoate-2-pyrrolidinone,4-euroluxe-2 - pyrrolidinone, 4-myristoleate-2-pyrrolidinone, 4 - palmitoleate-2-pyrrolidinone, 4-stearolic-2 - pyrrolidinone, 1-methyl-4-hydroxy-2-pyrrolidinone, 1-methyl - 4-ethoxycarbonyl-2-pyrrolidinone, 1-methyl-4-tert - butoxycarbonylamino-2-pyrrolidinone, 1-methyl-4-octyl - oxycarbonyl-2-pyrrolidinone, 1-methyl-4-hexadecyloxypropyl-2-propylaniline, 1-methyl-4-octadecylamine - carbonyloxy-2-pyrrolidinone, 1-methyl-4-decanoate-2 - pyrrolidinone, 1-methyl-4-euroluxe-2-pyrrolidinone, 1-methyl-4-myristoleate-2-pyrrolidinone, 1-methyl-4 - palmitoleate-2-pyrrolidinone and 1-methyl - 4-stearolic-2-pyrrolidinyl group.

The most preferred groups are 4-hydroxy-2 - pyrrolidinone, 4-decanoate-2-pyrrolidinone, 4-euroluxe - 2-pyrrolidinone, 4-myristoleate-2-pyrrolidinone, 4-palmitoleate-2-pyrrolidinone, 4-stearolic-2 - propylenimine, 1-Milna, 1-methyl-4-myristoleate-2-pyrrolidinone, 1 - methyl-4-palmitoleate-2-pyrrolidinone and 1-methyl-4 - stearolic-2-pyrrolidinyl group.

When R1is pyrrolidinyloxy group, it is preferably substituted 2-pyrrolidinyl group, more preferably 4-hydroxy-3-methyl-2-pyrrolidinyl group or 4-hydroxy-2-pyrrolidinyl group or such a group in which the esterified hydroxy-group.

When the compound of the present invention contains in its molecule a basic group, it can form acid additive salt. Examples of such acid additive salts include salts with mineral acids, in particular halogen acids such as hydrofluoric, Hydrobromic, iododerma or hydrochloric acid), nitric acid, perchloro acid, carbonic acid, sulfuric acid or phosphoric acid; salts with lower alkylsulfonyl acids such as methanesulfonate, triftormetilfullerenov or econsultancy acid; salts with arylsulfonic acids, such as benzolsulfonat or p-toluensulfonate acid; salts with organic carboxylic acids such, for the, Olona, gluconic or citric acid; and salts with amino acids such as glutamic or aspartic acid.

In addition, when the compound of the present invention contains a free carboxypropyl, it can form an ester. There are no special restrictions to the nature of ester, provided that in the case of its use in therapy, he should be farmatsevticheskii, i.e., must not be less active (or not unacceptably less active than the free acid, and not more toxic (or not unacceptably more toxic) than the free acid. Examples of ester groups include:

alkyl groups having from 1 to 20 carbon atoms, more preferably from 1 to 6 carbon atoms, such as shown in the examples above, and higher alkyl groups, are well known in the field of chemistry, such as Reptilia, anjilina, Danilina, decile, Godzilla, redecilla, pentadactyla, octadecyl, Donatella and Casilina group, and more preferably alkyl groups having from 1 to 4 carbon atoms, and most preferably methyl and ethyl groups;

cycloalkyl group having from 3 to 7 carbon atoms, for example, ie group, in which the alkyl part has from 1 to 3 carbon atoms and the aryl part is a carbocyclic aromatic group having from 6 to 14 carbon atoms which may be substituted or unsubstituted and, if substituted, has at least one of the substituents defined and described in the examples above, although preferred are unsubstituted groups; examples of such Uralkalij groups include benzyl, fenetylline, 1 - phenylethylene, 3-phenylpropanol, 2-phenylpropyl, 1-naphthylmethyl, 2-naphthylmethyl, 2- (1-naphthyl) ethyl, 2- (2-naphthyl) ethyl, benzhydryl (i.e. diphenylmethyl), triphenylmethyl, bis (o-nitrophenyl)methyl, 9-antiloitering, 2,4,6-trimethylbenzyl, 4-brombenzene, 2-nitrobenzyl, 4 - nitrobenzyl, 3-nitrobenzyl, 4-methoxybenzyl and piperonyl group;

alkeneamine group having from 2 to 6 carbon atoms, such as vinyl, allyl, 2-methylaniline, 1-protanilla, isopropylene, 1-bucinellina, 2-bucinellina, 3-bucinellina, 1-penttila, 2-penttila, 3-penttila, 4-penttila, 1-examilia, 2-examilia, 3-examilia, 4-examilia and 5-examilia group, of which are predpochtitelnye allyl and 2-methylaniline group;

halogenated alkyl groups having from 1 to 6, preferably from 1 to 4, carbon atoms in which the alkyl part is a group, such as alkyl groups, as defined and described in the examples above, and the halogen atom is a chlorine atom, fluorine, bromine or iodine, such as 2,2,2-trichlorethylene, 2-halogenation (for example, 2 - chloraniline, 2-florachilena, 2-brometalia or 2-idalina), 2,2-dibromoethylene and 2,2,2-tribromaniline group;

substituted serialkiller groups in which the alkyl part is the same as the alkyl groups defined and described in the examples above, and the silyl part has up to 3 substituents, selected from alkyl groups having from 1 to 6 carbon atoms, and phenyl groups which are unsubstituted or have at least one Deputy, selected from the substituents defined and described in the examples above, for example, 2 - trimethylsilylethynyl group;

phenyl group where the phenyl group is unsubstituted or substituted, preferably at least one alkyl group having from 1 to 4 carbon atoms, or allmineral, for example, phenyl, taillow and benzamidopiperidine, defined and described in the examples above, for example, the very Venizelou group or p-brompheniramine group;

cyclic and acyclic terpinolene group, for example geraniou, marilou, lunalilo, matchlock, manilow (in particular, m - and p-manilow), toyellow, marilou, pinarillo, Bardolino, morcerelow, nobinonly, norbornylene, mantenerlo, Campanile and norbornylene group;

alkoxymethyl groups in which the CNS part has from 1 to 6, preferably from 1 to 4, carbon atoms and may itself be substituted by a single unsubstituted alkoxygroup, such as methoxymethyl, ethoxymethylene, propoxymethyl, isopropoxyaniline, butoxymethyl and methoxyethoxymethyl group;

aliphatic aryloxyalkyl groups in which the acyl group is preferably alkanoyloxy group and more preferably alkanoyloxy group having from 2 to 6 carbon atoms, and the alkyl part has from 1 to 6, preferably from 1 to 4, carbon atoms, such as acetoxymethyl, propionylthiocholine, butyrylcholine, isobutylacetophenone, pivaloyloxymethyl, 1-emailarticle, 1-acetoxyethyl, 1-isobut wirelessinternet, 1-isobutylacetophenone, 1-acetoxypropionyl, 1-acetoxy-2-methylpropyl, 1-propionylcarnitine, 1-propionoxypiperidine, 2 - acetoxypropionyl and 1-butyrolacetone group;

cycloalkylation aliphatic aryloxyalkyl groups in which the acyl group is preferably alkanoyloxy group and more preferably alkanoyloxy group having from 2 to 6 carbon atoms, cycloalkenyl substituent has from 3 to 7 carbon atoms and the alkyl part has from 1 to 6, preferably from 1 to 4, carbon atoms, such as (cyclohexylmethoxy)methyl, 1-(cyclohexyloxy) ethyl, 1- (cyclohexylmethoxy) through 2-methyl-1- (cyclohexylmethoxy) through (cyclopentyloxy)methyl, 1- (cyclopentyloxy) ethyl, 1- (cyclopentyloxy), sawn and 2-methyl-1-(cyclopentyloxy)through the group.

alkoxycarbonylmethyl groups, in particular 1- (alkoxycarbonyl)ethyl group, in which CNS part has from 1 to 10, preferably from 1 to 6, and more preferably from 1 to 4 carbon atoms and the alkyl part has from 1 to 6, preferably from 1 to 4, carbon atoms, such as 1-methoxycarbonylmethylene, 1 - e is basilosauridae, 1-msobuttoniconandcaption, 1-second - butoxycarbonyloxyimino, 1-tert-butoxycarbonyloxyimino, 1- (1-ethylpropylamine)ethyl and 1-(1,1 - dipropylenetriamine)ethyl group, and other alkoxycarbonylmethyl group, in which the CNS, and the alkyl groups have from 1 to 6, preferably from 1 to 4, carbon atoms, such as 2-methyl-1- (isopropoxycarbonyl) through 2- (isopropoxycarbonyl)through isopropoxycarbonyloxymethyl, tert - butoxycarbonyloxyimino, methoxycarbonylmethylene and ethoxycarbonylmethylene group;

cycloalkylcarbonyl and cycloalkylcarbonyl groups in which cycloalkyl group has from 3 to 10, preferably from 3 to 7, carbon atoms and is a mono - or polycyclic and optionally substituted by at least one (and preferably only one) alkyl group, having from 1 to 4 carbon atoms (e.g. selected from those alkyl groups, examples of which are given above) and the alkyl part has from 1 to 6, more preferably from 1 to 4 carbon atoms (for example, selected from alkyl groups, examples of which are given above) and most preferably awsecommerceservice, cyclopentanecarboxaldehyde, cyclopentanecarboxaldehyde, 1-cyclohexyloxycarbonyloxy, 1-cyclohexylcarbodiimide, 1 - cyclopentanecarbonitrile, 1-cyclopentanecarbonitrile, 1-cyclohexyloxycarbonyloxy, 1-cyclohexylcarbonyl, 1-methylcyclohexanecarboxylic, 1-methylcyclohexanecarboxylic, 2-methyl-1-(1 - methylcyclohexanecarboxylic) through 1- (1-methylcyclohexanecarboxylic) through 2- (1-methylcyclohexanecarboxylic) through 1- (cyclohexyloxycarbonyloxy) through 2- (cyclohexyloxycarbonyloxy) through 2-methyl-1- (1-methylcyclopentadienyl) through 1- (1-methylcyclopentadienyl) through 2- (1-methylcyclopentadienyl) through 1- (cyclopentanecarbonyl) through 2- (cyclopentanecarbonyl) through 1- (1-methylcyclopentadienyl) ethyl, 1- (1-methylcyclopentadienyl) through adamantanecarboxylic, adamantankarboksilato, 1-adamantanecarboxylic and 1-adamantankarboksilato group;

cycloalkylcarbonyl groups in which the CNS group has only one who does polycyclic, for example, cyclopropanecarboxaldehyde, cyclobutanedicarboxylate, cyclopentanetetracarboxylic, cyclohexyloxycarbonyloxy, 1- (cyclopropylmethoxy) ethyl, 1- (cyclobutanedicarboxylate) ethyl, 1- (cyclopentanecarbonyl) ethyl and 1- (cyclohexyloxycarbonyloxy) ethyl group;

technicianlocation and terminologiemanagement groups in which terpinolene group - such as in the examples above, and preferably is circular terpinolene group, for example 1- (methyloxycarbonyl) ethyl, 1- (methylcarbonate) ethyl, methyloxycarbonyl, methylcarbamoylmethyl, 1- (3 - pennicornis) ethyl, 1- (3-pennicornis) ethyl, 3-pinaysexscandaldownload and 3-pinayscandalblog group;

5-alkyl or 5-phenyl-[which may be substituted by at least one of the substituents defined and described in the examples above] (2-oxo-1,3-dioxolan-4-yl)alkyl groups in which each alkyl group (which may be the same or different) has from 1 to 6, preferably from 1 to 4, y is (5 - isopropyl-2-oxo-1,3-dioxolan-4-yl) methyl, (5-tert-butyl-2-oxo-1, 3-dioxolan-4-yl)methyl and (5-methyl-2-oxo-1,3 - dioxolan-4-yl)ethyl group; and

other groups, in particular groups easily removable in vivo, such as felicilda, indayla and 2-oxo-4,5,6, 7 - tetrahydro-1,3-benzodioxole-4-ilen group.

Compounds of the present invention may exist in the form of various stereoisomers, depending on the presence of asymmetric carbon atoms. The present invention includes both the individual isomers [preferably (2R, 4R) -isomer] and their mixtures, including racemic mixtures.

Compounds of the present invention can absorb water from the atmosphere with the formation of hydrate. The present invention covers such hydrates, in particular the hydrates of some salts of the compounds of formula (1).

Preferred compounds of the present invention are those compounds of formula (1) and their salts and esters, in which:

(1) R1is pyrrolidinyloxy, piperidino, morpholinyl, thiomorpholine or piperazinilnom group, which is substituted at a carbon atom by at least one of substituents (1unsubstituted or substituted on the nitrogen atom by at least one and is oxycarbonate, having from 1 to 6 or from 8 to 18 carbon atoms in the CNS part of alkanoyloxy having from 1 to 20 carbon atoms, carboxyamides of alkanoyloxy having from 3 to 6 carbon atoms in alkanoyloxy part, carbamoyloximes and mono - or dialkylammonium having 1 or 2 carbon atoms in the alkyl or each alkyl part;

these deputies1selected from the group consisting of alkyl groups having 1 to 4 carbon atoms, and phenyl groups which are unsubstituted or substituted by at least one Deputy, selected from the group consisting of methyl groups, methoxypropyl, fluorine atoms and chlorine atoms.

(2) R1is parapedinella, piperidino, morpholinyl or thiomorpholine group, which is substituted at a carbon atom by at least one of the substituents2and unsubstituted or substituted on the nitrogen atom of at least one of the substituents2listed alternates2selected from the group consisting of hydroxy groups, alkoxycarbonyl having from 1 to 4 or from 8 to 18 carbon atoms in the CNS part of alkanoyloxy having from 2 to 5 carbon atoms, Alka narodnih atoms in alkanoyloxy part, carbamoyloximes and mono - or dialkylammonium having 1 or 2 carbon atoms in the alkyl or each alkyl part.

these deputies 2selected from the group consisting of alkyl groups having 1 to 4 carbon atoms.

(3) R1is pyrrolidinyloxy, piperidino, morpholinyl or thiomorpholine group, which is substituted at a carbon atom by at least one of the substituents3unsubstituted or substituted on the nitrogen atom of at least one of the substituents3,

these deputies (3selected from the group consisting of hydroxy, methoxycarbonylamino, ethoxycarbonyl, isopropoxycarbonyl-, tert-butoxycarbonylamino, octyloxybenzoate, decyloxybenzoate, hexadecyltrichlorosilane, octadecyltrichlorosilane-, acetoxy-, propionyloxy, butyryloxy, valeriote, pivaloyloxy, decanoate, undecanoate, eurolocs, myristoleic, palmitoleic, stearolic, succinylate, glucosyloxy, carbamoylated-, N-methylcarbamoyl-, N-ethylcarbamate - and N, N-dimethylcarbamoyl; these deputies3selected from the group consisting of methyl and EDA, which is substituted by coal - native atom of at least one of the substituents4and unsubstituted or substituted on the nitrogen atom of at least one of the substituents 3,

these deputies4selected from the group consisting of hydroxy, ethoxycarbonyl, isopropoxycarbonyl-, tert-butoxycarbonylamino, octyloxybenzoate, hexadecyltrichlorosilane, octadecyltrichlorosilane, decanoate, eurolocs, palmitoleic, sterilox, succinylate, carbamoylated - and N, N-dimethylcarbamoyl;

these deputies 3such as defined above.

(5) R1is 4-hydroxy-2-pyrrolidinyl, 4-ethoxycarbonyl-2-pyrrolidinyl, 4-isopropoxycarbonyl-2 - pyrrolidinyl, 4-tert-butoxycarbonylamino-2-pyrrolidinyl, 4-octyloxybenzoate-2-pyrrolidinyl, 4 - hexadecyltrichlorosilane-2-pyrrolidinyl, 4-octadecanoyloxy-2-pyrrolidinyl, 4-acetoxy-2-pyrrolidinyl, 4 - decanoate-2-pyrrolidinyl, 4-euroluxe-2-pyrrolidinyl, 4-myristoleate-2-pyrrolidinyl, 4-palmitoleate-2 - pyrrolidinyloxy, 4 stearolic-2-pyrrolidinyl, 4 - succinate-2-pyrrolidinone, etinilnoy, 1-methyl-4-isopropoxycarbonyl-2-pyrrolidinyl, 1-methyl-4-tert - butoxycarbonylamino-2-pyrrolidinyl, 1-methyl-4 - octyloxybenzoate-2-parapedinella, 1-methyl - 4 - hexadecyloxypropyl-hydroxy-2-pyrrolidinyl), 1-methyl-4 - octadecanoyloxy-2-pyrrolidinyl, 1-methyl-4-acetoxy - 2-pyrrolidinyl, 1-methyl-4-decanoate-2-pyrrolidinyloxy, 1 - methyl-4-euroluxe-2-pyrrolidinyl, 1-methyl-4-myristoleate - 2-pyrrolidinyl, 1-methyl-4-palmitoleate-2-pyrrolidinyl, 1-methyl-4-stearolic-2-pyrrolidinyl or 1-methyl-4 - succinate-2-pyrrolidinyl group.

(6) R1is 4-hydroxy-2-pyrrolidinyl, 4 - ethoxycarbonyl-2-pyrrolidinyl, 4-tert-butoxycarbonylamino - 2-pyrrolidinyl, 4-octyloxybenzoate-2-parapedinella, 4-hexadecyltrichlorosilane-2-pyrrolidinyl, 4 - octadecanoyloxy-2-pyrrolidinyl, 4-decanoate-2 - pyrrolidinyl, 4-euroluxe-2-pyrrolidinyl, 4-myristoleate - 2-pyrrolidinyl, 4-palmitoleate-2-pyrrolidinyl, 4-stearolic-2-pyrrolidinyloxy, 1-methyl-4-hydroxy-2 - pyrrolidinyl, 1-methyl-4-ethoxycarbonyl-2-pyrrolidinyl, 1-methyl-4-tert-butoxycarbonylamino-2-pyrrolidinyl, 1-methyl-4-octadecanoyloxy-2-pyrrolidinyloxy, 1-methyl-4 - decanoate-2-pyrrolidinyl, 1-methyl-4-euroluxe-2 - pyrrolidinyl, 1-methyl-4-myristoleate-2-pyrrolidinyl, 1 - methyl-4-palmitoleate-2-pyrrolidinyl or 1-methyl-4 - stearolic-2-pyrrolidinyl group.

(7) R1is 4-hydroxy-2-pyrrolidinyloxy), 4 - decanoate-2-pyrrolidinyl, 4-euroluxe-2-pyrrolidinyl 4 myristoleate-2-pyrrolidinyl, 4 - palmitoleate-2-pyrrolidinyl, 4-stearolic-2 - pyrrolidinyl, 1-methyl-4-hydroxy-2-pyrrolidinyl, 1-methyl - 4-decanoate-2-pyrrolidinyl, 1-methyl-4-euroluxe-2 - pyrrolidinyl, 1-methyl-4-myristoleate-2-pyrrolidinyloxy, 1 - methyl-4-palmitoleate-2-pyrrolidinyl or 1-methyl-4 - stearolic-2-pyrrolidinyl group.

(8) R2aand R2bthe same or different from each other, represent each a hydrogen atom, a methyl group, a methoxy group, a fluorine atom, a chlorine atom, a bromine atom, a cyano or a nitro-group, and R2crepresents a hydrogen atom.

(9) R2aand R2bthe same or different from each other, represent each a hydrogen atom, a methyl group, a methoxy group, a fluorine atom, a chlorine atom or bromine atom and R2crepresents a hydrogen atom.

2crepresents a hydrogen atom.

(11) R2arepresents a fluorine atom, and R2band R2cboth represent hydrogen atoms.

(12) R3a, R3band R3cthe same or different from each other, represent each a hydrogen atom, alkyl group having from 1 to 4 carbon atoms, halogen-substituted alkyl group having 1 or 2 carbon atoms, alkenylphenol group having 3 or 4 carbon atoms, alkylamino group having 3 or 4 carbon atoms, a hydroxy-group, alkoxygroup having from 1 to 4 carbon atoms, halogen-substituted alkoxygroup having 1 or 2 carbon atoms, alkoxycarbonyl group having from 1 to 4 carbon atoms in the CNS part, alkanoyloxy having from 2 to 5 carbon atoms, karbamoilnuyu group, mono - or dialkylamino group having 1 or 2 carbon atoms in the alkyl or each alkyl part, a halogen atom, a cyano, a nitro-group or phenyl group which is unsubstituted or substituted by at least one of the substituents1defined below, and R3drepresents a hydrogen atom;

these deputies 1selected from the group consisting of methyl, ethyl, me is to be apart from each other, represent each a hydrogen atom, a methyl or ethyl group, a fluorine or chlorine substituted alkyl group having 1 or 2 carbon atoms, allyl group, propargyl group, a hydroxy-group, a methoxy group, ethoxypropan, fluorine-methoxy group, dipterocarp, chlorotoxin, 2-fluoro-ethoxypropan, 2 - chlorethoxyfos, methoxycarbonyl group, ethoxycarbonyl group, alkanoyloxy having 2 or 3 carbon atoms, karbamoilnuyu group, methylcarbamoyl group, dimethylcarbamoyl group, a fluorine atom, a chlorine atom, a bromine atom, a cyano, a nitro-group or phenyl group, which is unsubstituted or substituted by at least one of the substituents2defined below, and R3drepresents a hydrogen atom;

these deputies2selected from the group consisting of methyl and methoxypropyl and fluorine atoms and chlorine.

(14) R3a, R3band R3cthe same or different from each other, represent each a hydrogen atom, methyl group, ethyl group, formeterol group, triptorelin group, chloromethylene group, a hydroxy-group, a methoxy group, ethoxypropan, formatexpr, dipterocarp, 2-fluoro-etoxylates a hydrogen atom.

(15) R3aand R3bthe same or different from each other, represent each a hydrogen atom, a methyl group, a hydroxy-group, a methoxy group, ethoxypropan, formatexpr, dipterocarp, fluorine atom, chlorine atom, bromine atom or cyano and R3cand R3dboth represent hydrogen atoms.

(16) R3aand R3bthe same or different from each other, represent each a hydrogen atom, a methoxy group or a fluorine atom and R3cand R3dboth represent hydrogen atoms.

(17) represents A single bond or alkilinity group having from 1 to 4 carbon atoms

(18) represents A single bond, methylene group, ethylene group or trimethylene group.

(19) represents A single bond, methylene group or ethylene group.

(20) A represents ethylene group.

Of the above compounds, preferred are those compounds in which R1, such as defined in any of paragraphs (1) to(7), R2a, R2band R2csuch as defined in any of paragraphs (8) to(II), R3a, R3b, R3cand R3dsuch as defined in any of paragraphs (12)-(16), and A - as defined by the crystals (1) and their salts and esters, where:

R1is pyrrolidinyloxy, piperidino, morpholinyl, thiomorpholine or piperazinilnom group, which is substituted at a carbon atom by at least one of the substituents 1unsubstituted or substituted on the nitrogen atom of at least one of the substituents1defined above;

R2aand R2bthe same or different from each other, represent each a hydrogen atom, a methyl group, a methoxy group, a fluorine atom, a chlorine atom, a bromine atom, a cyano or a nitro-group, and R2crepresents a hydrogen atom;

R3a, R3band R3cthe same or different from each other, represent each a hydrogen atom, alkyl group having from 1 to 4 carbon atoms, halogen-substituted alkyl group having 1 or 2 carbon atoms, alkenylphenol group having 3 or 4 carbon atoms, alkylamino group having 3 or 4 carbon atoms, a hydroxy-group, alkoxygroup having from 1 to 4 carbon atoms, halogen-substituted alkoxygroup having 1 or 2 carbon atoms, alkoxycarbonyl group having from 1 to 4 carbon atoms in the CNS part, alkanoyloxy, having from 2 to 5 carbon atoms, each alkyl part, halogen atom, a cyano, a nitro-group or phenyl group which is unsubstituted or substituted by at least one of the substituents1defined above, and R3drepresents a hydrogen atom; and

A represents A single bond or alkilinity group having from 1 to 4 carbon atoms.

(22) Compounds of formula (1) and their salts and esters, in which:

R1is pyrrolidinyloxy, piperidino, morpholinyl or thiomorpholine group, which is substituted at a carbon atom by at least one of the substituents2and unsubstituted or substituted on the nitrogen atom of at least one of the substituents2defined above;

R2aand R2bthe same or different from each other, represent each a hydrogen atom, a methyl group, a methoxy group, a fluorine atom, a chlorine atom, a bromine atom, a cyano or a nitro-group, and R2crepresents a hydrogen atom;

R3a, R3band R3cthe same or different from each other, represent each a hydrogen atom, alkyl group having from 1 to 4 carbon atoms, halogen-substituted alkyl group having 1 or 2 carbon atoms, alkenylphenol group, it is foam, having from 1 to 4 carbon atoms, halogen-substituted alkoxygroup having 1 or 2 carbon atoms, alkoxycarbonyl group having from 1 to 4 carbon atoms in the CNS part, alkanoyloxy having from 2 to 5 carbon atoms, karbamoilnuyu group, mono - or dialkylamino group having 1 or 2 carbon atoms in the alkyl or each alkyl part, a halogen atom, a cyano, a nitro-group or phenyl group which is unsubstituted or substituted by at least one of elastically1defined above, and R3drepresents a hydrogen atom; and

A represents A single bond or alkilinity group having from 1 to 4 carbon atoms.

(23) Compounds of formula (1) and their salts and esters in which:

R1is pyrrolidinyloxy, piperidino, morpholinyl or thiomorpholine group, which is substituted at a carbon atom by at least one of the substituents3and unsubstituted or substituted on the nitrogen atom of at least one of the substituents 3defined above;

R2aand R2bthe same or different from each other, represent each a hydrogen atom, methyl group, IU 3b and R3cthe same or different from each other, represent each a hydrogen atom, a methyl or ethyl group, a fluorine or chlorine substituted alkyl group having 1 or 2 carbon atoms, allyl group, propargyl group, a hydroxy-group, a methoxy group, ethoxypropan, formatexpr, dipterocarp, chlorotoxin, 2-floratone group, 2 - chlorethoxyfos, methoxycarbonyl group, ethoxycarbonyl group, alkanoyloxy having 2 or 3 carbon atoms, karbamoilnuyu group, methylcarbamoyl group, dimethylcarbamoyl group, a fluorine atom, a chlorine atom, a bromine atom, a cyano, a nitro-group or phenyl group, which is unsubstituted or substituted by at least one of the substituents2defined above, and R3drepresents a hydrogen atom; and

A represents A single bond, methylene group, ethylene group or trimethylene group.

(24) Compounds of formula (1) and their salts and esters in which:

R1is pyrrolidinyloxy, piperidino or morpholinyl group, which is substituted at a carbon atom by at least one of the substituents4and unsubstituted or substituted be otherness or different from each other, represent each a hydrogen atom, fluorine atom or chlorine atom and R2crepresents a hydrogen atom;

R3a, R3band R3cthe same or different from each other, represent each a hydrogen atom, methyl group, ethyl group, formeterol group, triptorelin group, chloromethylene group, a hydroxy-group, a methoxy group, ethoxypropan, formatexpr, dipterocarp, 2-floridacheap, fluorine atom, chlorine atom, bromine atom, cyano, karbamoilnuyu group or phenyl group, and R3drepresents a hydrogen atom; and

A represents A single bond, methylene group, ethylene group or trimethylene group.

(25) Compounds of formula (1) and their salts and esters in which:

R1is 4-hydroxy-2-pyrrolidinyl,4-ethoxycarbonyl-2-pyrrolidinyl, 4-isopropoxycarbonyl - 2-pyrrolidinyl, 4-tert-butoxycarbonylamino-2-pyrrolidinyl, 4-octyloxybenzoate-2-pyrrolidinyl, 4-hexadecyltrichlorosilane-2-pyrrolidinyl, 4-octadecylsilane-hydroxy - 2-pyrrolidinyl, 4-acetoxy-2-pyrrolidinyl, 4 - decanoate-2-pyrrolidinyl, 4-euroluxe-2-pyrrolidinyl, 4-myristoleate-2-pyrrolidinyl the Yu, 4 carbamoylated-2-pyrrolidinyl, 1-methyl-4-hydroxy-2-pyrrolidinyl, 1-methyl-4-ethoxycarbonyl-2-pyrrolidinyl, 1-methyl-4-isopropoxycarbonyl-2 - pyrrolidinyl, 1-methyl-4-tert-butoxycarbonylamino-2 - pyrrolidinyl, 1-methyl-4-octyloxybenzoate-2-pyrrolidinyl, 1-methyl-4-hexadecyltrichlorosilane-2-pyrrolidinyl, 1-methyl-4-octadecanoyloxy-2-pyrrolidinyloxy, 1-methyl-4-acetoxy-2-pyrrolidinyl, 1-methyl-4-decanoate - 2-pyrrolidinyl, 1-methyl-4-euroluxe-2-pyrrolidinyl, 1-methyl-4-myristoleate-2-pyrrolidinyl, 1 - methyl-4-palmitoleate-2-pyrrolidinyl, 1-methyl-4-stearolic-2-pyrrolidinyl or 1-methyl-4-succinate - 2-pyrrolidinyl group.

R2aand R2bthe same or different from each other, represent each a hydrogen atom, fluorine atom or chlorine atom and R2crepresents a hydrogen atom.

R3aand R3bthe same or different from each other, represent each a hydrogen atom, a methyl group, a hydroxy-group, a methoxy group, ethoxypropan, formatexpr, dipterocarp, fluorine atom, chlorine atom, bromine atom or cyano and R3sand R3dboth represent hydrogen atoms; and

A) and their salts and esters in which:

R1is 4-hydroxy-2-pyrrolidinyl, 4-ethoxycarbonyl-2-pyrrolidinyl, 4-tert-butoxycarbonylamino-2 - pyrrolidinyl, 4-octyloxybenzoate-2-pyrrolidinyl, 4 - hexadecyltrichlorosilane-2-pyrrolidinyl, 4-octadecanoyloxy-2-pyrrolidinyl, 4-decanoate-2 - pyrrolidinyl, 4-euroluxe-2-pyrrolidinyl, 4-myristoleate-2-pyrrolidinyl, 4-palmitoleate-2-pyrrolidinyl, 4-stearolic-2-pyrrolidinyloxy, 1-methyl-4-hydroxy-2 - pyrrolidinyl, 1-methyl-4-ethoxycarbonyl-2-pyrrolidinyl, 1-methyl-4-tert-butoxycarbonylamino-2-pyrrolidinyl, 1-methyl-4-octyloxybenzoate-2-pyrrolidinyl, 1-methyl-4 - hexadecyltrichlorosilane-2-pyrrolidinyl, 1-methyl-4 - octadecanoyloxy-2-pyrrolidinyl, 1-methyl-4 - decanoate-2-pyrrolidinyl, 1-methyl-4-euroluxe-2 - pyrrolidinyloxy, 1-methyl-4-myristoleate-2-pyrrolidinyl, 1 - methyl-4-palmitoleate-2-pyrrolidinyl or 1-methyl-4 - stearolic-2-pyrrolidinyl group;

R2arepresents a fluorine atom, and R2band R2cboth represent hydrogen atoms;

R3aand R3bthe same or different from each other, represent each a hydrogen atom, metoxy is the UPP.

(27) Compounds of formula (1) and their salts and esters in which;

R1is 4-hydroxy-2-pyrrolidinyl, 4-decanoate-2-pyrrolidinyl, 4-euroluxe-2-pyrrolidinyl, 4 - myristoleate-2-pyrrolidinyl, 4-palmitoleate-2-pyrrolidinyl, 4-stearolic-2-pyrrolidinyl, 1-methyl-4-hydroxy-2-pyrrolidinyl, 1-methyl-4-decanoate-2-pyrrolidinyl, 1-methyl - 4-euroluxe-2-pyrrolidinyl, 1-methyl-4 - myristoleate-2-pyrrolidinyloxy, 1-methyl-4-palmitoleate-2 - pyrrolidinyl or 1-methyl-4-stearolic-2-pyrrolidinyl group:

R2arepresents a fluorine atom, and R2band R2cboth represent hydrogen atoms;

R3aand R3bthe same or different from each other, represent each a hydrogen atom, a methoxy group or a fluorine atom and R3cand R3dboth represent hydrogen atoms; and

A represents an ethylene group.

Specific examples of some of the compounds of the present invention are the compounds of formula (I-1):

< / BR>
In the formula above, substituting groups are groups defined in table 1. The table uses the following abbreviations:

Ac:Acetyl

Adp: Adipoyl

Boc: tert-Butox is Noel

Dod: Dodecyl

Et: Ethyl

Glu: Glutaryl

Hep: Heptanoyl

Hex: Hexanoyl

Hpd: Heptadecyl

Hxd: Hexadecyl

Lau: Lauroyl

Mal: Malonyl

Me: Methyl

Mor: Morpholinyl

Myr: Myristoyl

Non: Nonanoyl

Oc: Octyl

Ocd: Octadecyl

Oct: Octanoyl

Pal: Palmitoyl

Pnd: Pentadecyl

Ph: Phenyl

Pip: Piperidyl

Pir: Piperazinil

Piv:Pivaloyl

Pr: Propyl

iPr: Isopropyl

Prp: Propionyl

Pyr: Pyrrolidinyl

Ste: Stearoyl

Suc: Succinyl

Ttd: Tetradecyl

Trd: Tridecyl

Tmor: Thiomorpholine

Und: Undecyl

Vai: Valerie

Of the above compounds, preferred are compounds NN 1, 2, 7, 8, 12, 17, 19, 22, 26, 28, 34, 37, 44, 46, 67, 77, 81, 114, 118, 125, 126, 152, 154, 159, 162, 196, 198, 202, 203, 204, 224, 225, 226, 227, 230, 234, 236, 240, 246, 250, 252, 266, 267, 268, 284, 285, 286 and 359, and more preferred connection NN 1, 7, 17, 19, 22, 28, 67, 77, 81, 114, 118, 125, 126, 152, 154, 159, 162, 196, 198, 202, 204, 224, 226, 230, 234, 236, 240, 250, 252, 266, 267, 268, 284, 285, 286 and 359.

Even more preferred compounds are compounds NN 1, 7, 17, 19, 22, 67, 77, 81, 114, 118, 125, 126, 152, 154, 159, 162, 196, 198, 202, 204, 226, 236 and 266.

Most preferred are compounds NN:

1. 2-{ 2-[4-fluoro-2-(2-phenylethyl)phenoxy] ethyl}-4-hydroxy - 1-methylphenoxy]ethyl}-4 - euroiksi-1 methylpyrrolidine;

22. 2-[2-[4-fluoro-2- (2-phenylethyl) phenoxy} ethyl]-1-methyl - 4-succinylcholine;

67. 2-[2- [4-fluoro-2-(2- (3 - methoxyphenyl)ethyl]phenoxy]ethyl]-4-hydroxy-1-methylpyrrolidine;

77. 2-[2-{-fluoro-2-[2- (Z - methoxyphenyl)ethyl] phenoxy]ethyl}-4-euroluxe-1 methylpyrrolidine;

81. 2-[2-{4-fluoro-2-[2-(Z-methoxyphenyl) ethyl]phenoxy] ethyl]-1-methyl-4-succinylcholine;

114. 2-[2-{4-fluoro-2-[2-(4-forfinal) ethyl]phenoxy]ethyl] -4-hydroxy-1-methylpyrrolidine;

118. 2- [2-[4-fluoro-2-[2- (4-forfinal) ethyl] phenoxy}ethyl] -4-hydroxypyrrolidine;

125. 2-(2-{ -fluoro-2-[2- (4-forfinal) ethyl] phenoxy}ethyl]-1-methyl-4-palmitoylcarnitine;

126. 2 -[2 -{4 -fluoro - 2 -[2- (4-forfinal) ethyl) phenoxy}ethyl-1-methyl-4-succinylcholine;

152. 2 -[2-{4 -fluoro - 2- [2- (4-fluoro-3-methoxyphenyl)ethyl] phenoxy}ethyl] -4-hydroxy-1-methylpyrrolidine;

154. 2-[2-{4-fluoro-2-[2-(4-fluoro-3-methoxyphenyl)ethyl] phenoxy} ethyl] -4-hydroxypyrrolidine;

159. 2-[2-{ 4-fluoro-2-[2- (4-fluoro-3-methoxyphenyl) ethyl] phenoxy} ethyl}-4-euroluxe-1 methylpyrrolidine;

162. 2-[2-{ 4-fluoro-2-[2- (4-fluoro-3-methoxyphenyl) ethyl] phenoxy} ethyl]-1-methyl-4-succinylcholine;

196. 2-[2-{ 2-[2- (3,4-Differenl) ethyl]-4-fervency}- ethyl] -4-hydroxy-1-methylpyrrolidine;

198. 2-[2-{2-[2-(3,4-Differenl)ethyl]-4-fervency}- ethyl] -4-hydroxypyrrolidine;
and their pharmaceutically acceptable salts.

Compounds of the present invention can be obtained in a variety of ways known in the field of production of compounds of this type. For example, they can be obtained by methods described in EP 600717, or in the manner shown in the following reaction scheme.

< / BR>
In the above formulas:

R1, R2a, R2b, R2c, R3a, R3b, R3c, R3dand A - such as defined above;

R1arepresents any of groups represented by R1except that protects any active nitrogen atom (for example, a heterocyclic ring or amino, alkylaminocarbonyl or alkylcarboxylic - groups included in substituents ) or a hydroxy-group, excluding the case when the Deputy is carboxyterminal alkanoyloxy; R4a, R4b, R4cand R4dsuch as defined for R3a, R3b, R3cand R3daccordingly, except that protect the hydroxy-group; and

Z represents a hydroxy-group, a halogen atom (preferably chlorine atom, bromine or iodine), alkanolammonium having from 1 to 6 carbon atoms, or arylsulfonamides carbon atoms and which is unsubstituted or substituted, at least one Deputy, selected from the group consisting of the substituents defined and described in the example above.

Examples of hydroxy-protective groups for groups introduced in R1a, R4a, R4b, R4c, R4dinclude cyclic ether groups (such as tetrahydrofuranyl and tetrahydropyranyl group), methoxymethyl group, methoxyethoxymethyl group and arylmethylidene and arylethoxysilanes groups in which the aryl part has from 6 to 10 ring carbon atoms and which is unsubstituted or substituted by at least one Deputy, selected from the group consisting of the substituents defined and described in the example above. Of them, preferred are tetrahydropyranyl, methoxymethyl, benzyl, p-methoxybenzyl, p-brombenzene, benzyloxycarbonyl, p-methoxybenzylideneamino and p-bromobenzyloxycarbonyl group.

Examples of protective groups for the nitrogen atom, amino group, monoalkylamines and other heterocyclic rings represented by the symbol R1ainclude alkoxycarbonyl group having from 1 to 6 carbon atoms in alkoxyimino the groups, in which the aryl part has from 6 to 10 ring carbon atoms and which is unsubstituted or substituted by at least one Deputy, selected from the group consisting of the substituents defined and described in the example above. Of them, particularly preferred are tert-butoxycarbonyl, acetyl, benzyl, p-methoxybenzyl, p-brombenzene, benzyloxycarbonyl, p-methoxybenzylideneamino and p-bromobenzyloxycarbonyl group.

Stage 1 shows the scheme of the reactions receive the compound of formula (IV) coordinating the compounds of formula (II) with the compound of the formula (III).

When Z represents a halogen atom, alkanolammonium or arylsulfonate, the reaction can be performed in the presence of a solvent and base.

There are no special restrictions to the nature of the grounds and equivalent can apply any base commonly used in reactions of this type. Examples of such bases include carbonates of alkali metals such as sodium carbonate and potassium carbonate; bicarbonates of alkali metals such as sodium bicarbonate and potassium bicarbonate; alkali metal fluorides, lithium; alkoxides of alkali metals such as sodium methoxide, ethoxide sodium tert-piperonyl potassium and lithium methoxide; and organic amines such as pyridine, picoline, triethylamine, N-methylmorpholine and 4-dimethylaminopyridine. Of them, preferred are carbonates of alkali metals, alkali metal fluorides, hydrides of alkali metals and alkoxides of alkali metals.

The reaction is normally and preferably carried out in the presence of a solvent. There are no special restrictions to the nature of the solvent, provided that it has no adverse effect on the reaction or on the involved reagents and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include hydrocarbons such as hexane, benzene and toluene; halogenated hydrocarbons, such as methylene chloride, chloroform and 1,2-dichloroethane; ethers, such as diethyl ether, tetrahydrofuran and dioxane; ketones, such as acetone and methyl ethyl ketone; NITRILES, such as acetonitrile; amides such as N,N-dimethylacetamide, dimethylformamide, N - organic and hexamethylphosphoric triamide; and sulfoxidov, such as dimethyl sulfoxide; or a mixture of any two or more of these will dissolve Ekati in a wide range of temperatures and the precise reaction temperature is not required for the present invention. The preferred reaction temperature depends upon such factors as the nature of the solvent and the used material and the substrate. However, it is usually advisable to carry out the reaction at a temperature of from 0oC to 100oC, and more preferably from 10oC to 80oC. the Time required for the reaction, can also be changed within wide limits depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent. But if the reaction is carried out at the above preferred conditions, it is usually sufficient period of from 30 minutes to 48 hours, and more preferably from 1 to 24 hours.

When Z represents a hydroxy-group, the reaction can be carried out in the presence of a solvent, triphenylphosphine and di (C1-C4alkyl)azodicarboxylate, such as diethylazodicarboxylate or diethylazodicarboxylate.

The reaction is normally and preferably carried out in the presence of a solvent. There are no special restrictions to the nature of the solvent, provided that it has no adverse effect on the reaction or on the involved reagents and that it can dissolve the reagents, at least to some stephanmatthiesen hydrocarbons, halogenated hydrocarbons or ethers.

The reaction may proceed in a wide range of temperatures and the precise reaction temperature is not required for the present invention. The preferred reaction temperature depends upon such factors as the nature of the solvent and the used starting material or reagent. However, it is usually advisable to carry out the reaction at a temperature of from -20oC to 100oC, and more preferably from 10oC to 80oC. the Time required for the reaction can also be changed within wide limits depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent. But if the reaction is carried out at the above preferred conditions, it is usually sufficient period of from 30 minutes to 48 hours, and more preferably from 1 to 24 hours.

Upon completion of the reaction, the target compound of formula (IV) can be extracted from the reaction mixture by traditional methods. For example, if there are insoluble substance is removed by filtration, when it comes, and then remove the solvent by evaporation under reduced pressure, to the residue water is added and the mixture extrage the aqueous magnesium sulfate and then remove the solvent. If necessary, the target compound can be further cleaned by conventional methods, for example by recrystallization or by column chromatography.

Stage 2 includes the following optional reactions that can be performed in any convenient order:

reaction (a): reaction of removal hydroxyamino group which may be present in R1a, R4a, R4b, R4cor R4d;

reaction (b): the reaction of alkylation, acylation or carbamylcholine hydroxy-group, formed in reaction (a);

reaction (c): the reaction of removing the protective group for the nitrogen atom, amino and other groups that may be present in R1a;

reaction (d): the reaction of transformation of the hydroxy-group in the amino group;

reaction (e): the reaction of transformation alkoxycarbonyl group which may be present in R1a, a methyl group or alkanoyloxy group which may be present in R1ain the alkyl group;

reaction (f): reaction of alkylation of the group =NH, which may be present in R1a;

reaction (g): the reaction of transformation of ceanography in karbamoilnuyu group.

Reaction (a).

This reaction removes the Character reactions change depending on the type of the protective group and the reaction may be carried out by methods well known in the field of organic synthesis.

When hydroxyamino group is arylmethylidene or armletaccessory group, the reaction may be carried out by ensuring cooperation between the protected compound with hydrogen (typically at a pressure of 1-10 atmospheres, and preferably at a pressure of 1-3 atmospheres) in a solvent in the presence of a hydrogenation catalyst. There is no particular restriction on the nature of the used catalyst and can be equivalent to use any catalyst commonly used in reactions of this type. Examples of such catalysts include palladium on charcoal, Raney Nickel, platinum oxide, platinum black, rhodium on alumina and palladium on barium sulphate.

The reaction is normally and preferably carried out in the presence of a solvent. There are no special restrictions to the nature of the solvent, provided that it has no adverse effect on the reaction or on the involved reagents and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include alcohols, such as methanol, ethanol and isopropanol; ethers, such as diethyl ether, tetrahydrofuran and dioxane; aromatic uglev the haunted esters, such as ethyl acetate and butyl acetate; aliphatic acids such as acetic acid; and mixtures of any one or more of these organic solvents with water.

The reaction may proceed in a wide range of temperatures and the precise reaction temperature is not required for the present invention. The preferred reaction temperature depends upon such factors as the nature of the solvent and the used starting material or reagent. However, it is usually advisable to carry out the reaction at a temperature of from 0oC to 100oC, and more preferably from 20oC to 80oC. the Time required for the reaction can also be changed within wide limits depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent. But if the reaction is carried out at the above preferred conditions, it is usually sufficient period of from 30 minutes to 48 hours, and more preferably from 1 to 24 hours.

When the hydroxy-protecting group is methoxymethyl, methoxyethoxymethyl or a cyclic ether group, the reaction can be performed to ensure synergy secure connection with acid is used in reactions of this type. Examples of such acids include inorganic acids, such as acetic acid, triperoxonane acid, methanesulfonate acid and p-toluensulfonate acid; a Lewis acid such as boron TRIFLUORIDE; or strongly acidic cation exchange resin, such as Dow X 50W (trademark). Of them, preferred are inorganic acid or organic acid, and more preferred is hydrochloric acid, sulfuric acid or triperoxonane acid.

The reaction is normally and preferably carried out in the presence of a solvent. There are no special restrictions to the nature of the solvent, provided that it has no adverse effect on the reaction or on the involved reagents and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include hydrocarbons such as hexane and benzene; halogenated hydrocarbons such as methylene chloride and chloroform; esters such as ethyl acetate; ketones, such as acetone and methyl ethyl ketone; alcohols, such as methanol and ethanol; ethers, such as diethyl ether, tetrahydrofuran and dioxane; or a mixture of any one or more of these solvents with vadh">

The reaction may proceed in a wide range of temperatures and the precise reaction temperature is not required for the present invention. The preferred reaction temperature depends upon such factors as the nature of the solvent and the used starting material or reagent. However, it is usually advisable to carry out the reaction at a temperature of from -10oC to 100oC, and more preferably from -5oC to 50oC. the Time required for the reaction can also be changed within wide limits depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent. But if the reaction is carried out at the above preferred conditions, it is usually sufficient period of from 5 minutes to 48 hours, and more preferably from 30 minutes to 10 hours.

If there are two or more hydroxy-protective groups introduced in R1a, R4a, R4b, R4cor R4dthey can be removed selectively by appropriate choice of protective groups and appropriate reaction conditions.

Upon completion of the reaction, the target compound can be extracted from the reaction mixture in the traditional way. For example, one of the suitable methods include rastvorimogo substances by filtration; adding a water-immiscible organic solvent such as ethyl acetate; washing with water and removing the solvent. If necessary, obtained in the manner described, the target compound can be further purified by conventional methods, for example by recrystallization, the resultant deposition rates or chromatography.

Reaction b.

This reaction alkylate, acelerou or carbamoylethyl the hydroxy-group. The reaction can be carried out using methods well known in the field of organic synthesis. However, in General, interact hydroxy group was alkylated with alkylating allermuir or carbamoylation agent.

The reaction is normally and preferably carried out in the presence of a solvent. There are no special restrictions to the nature of the solvent, provided that it has no adverse effect on the reaction or on the involved reagents and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include aromatic hydrocarbons, such as benzene and toluene; halogenated hydrocarbons, such as methylene chloride and chloroform; esters such as ethyl acetate; ethers, such CACR CLASS="ptx2">

The reaction may proceed in the presence or absence of a base. There is no particular restriction on the nature of the used grounds and equivalent can apply any base commonly used in reactions of this type. Examples of such bases include organic tertiary amines such as triethylamine, pyridine, diethylethanolamine and 4-(N,N-dimethylamino)pyridine.

Examples of alkylating, alleluya and carbamoylphenoxy agents that may be used include:

alkylhalogenide having from 1 to 6 carbon atoms, such as methyliodide, ethyliodide, propyliodide, utilidad, pentolite and hexalite;

(C1-C6alkanoyloxy)-(C1-C6alkyl)halides, such as formyloxyethyl, acetoxymethyl, acetoxymethyl, propionylacetate, butyrylacetate, valeriakittynice, pivaloyloxymethyl, pivaloyloxymethyl and pivaloyloxymethyl;

alkylaminocarbonyl having from 1 to 14 carbon atoms in the alkyl part, such as methylcarbonate, methyl-bromocarbons, ethylchloride, propylparaben, isopropylparaben, butylparaben, tert-BUTYLCARBAMATE, intelilitent, vexilla, dodecylmercaptan, tridecylalcohol and tetradecylbenzene;

aryl - and arylalkylamine having from 6 to 10 carbon atoms in the aryl part (which may be unsubstituted or may be substituted by at least one of the substituents defined and described in the example above), such as phenylcarbamoyl, methylphenylcarbinol, forgenerations, chlorphtorcarbon, methoxyphenylacetone and afternarket;

alkanoyl and alkanolamine having from 2 to 20 carbon atoms, such as acetylchloride, propionitrile, butyrylcholine, butylbromide, isobutyrate, valerianic, pivaloyloxy, hexanoate, 3, 3-dimethylbutyramide, heptanoate, octanoate, nonanoate, decanolide, laureillard, myristoylated, palmitoylated, stearolic, ihsanoglue, akriloilkhlorida, methacryloylamido, crotonville and lynaenorfleet;

anhydrides alkanovykh and alkenovich acids having from 2 to 20 carbon atoms, such as a mixed anhydride of formic and acetic acids, acetic, propionic, butane, Valerian, pivaloyl, hexane, heptane, octane, nonane, decanoyl, Lavrinovic acids, having from 6 to 10 carbon atoms in the aryl part (which may be unsubstituted or may be substituted by at least one of the substituents defined and described in the example above), such as benzoyl chloride, benzylbromide, benzoinated, methylbenzoate, methoxybenzophenone, tormentilla, chlorobenzylchloride and aftercare;

anhydrides arylcarboxylic acids having from 6 to 10 carbon atoms in the aryl part (which may be unsubstituted or may be substituted by at least one of the substituents defined and described in the example above), such as benzoic, methylbenzoyl, methoxybenzoyl, fervently, chlorbenzene and naphthoic anhydrides;

the cyclic anhydrides of the acids, such as succinoyl, glutaric, adipic, pillowy and subinoy anhydrides;

isocyanato acid and alkylsulfonate having from 1 to 6 carbon atoms in the alkyl part, such as methyl isocyanate, utilitzant, propositional, utilitzant, penalization and exisitant;

aryl - and aracelitana having from 6 to 10 carbon atoms in the aryl part (which may be unsubstituted or may be substituted, at marlenedesigner, methoxyphenylalanine, forgenerations, charterization and naphthylisocyanate; and

di (C1-C6alkyl) carbamoylated, such as N,N - dimethylcarbamoyl, N-ethyl-N-methylcarbamoylmethyl, N,N - diethylcarbamoyl, N, N-dipropylacetamide, N-ISO - propyl-N-methylcarbamoylmethyl, N,N-dibutylethanolamine, N,N-dependencyresolver and N,N - dihexylfluorene.

The reaction of acylation of the hydroxy-group can also be accomplished by interaction of the corresponding hydroxycodone with carboxylic acid. There are no special restrictions of the nature used carboxylic acids, and the choice of carboxylic acids depends on the input acyl group. Examples of such carboxylic acids include aliphatic carboxylic acids having from 2 to 20 carbon atoms, which can be alcamovia or alkenone acid, such as acetic, propionic, butane, valeric, hexanoic, 3,3-Dimethylbutane, heptane, octane, novanova, cekanova, lauric, myristic, palmitic, stearic, Casanova, acrylic, methacrylic, crotonic and linoleic acid; monoalkyl esters of dicarboxylic acid, such as tert-butylmalonate, tert-butylate, having from b to 10 carbon atoms in the aryl part (which may be unsubstituted or may be substituted by at least one of the substituents defined and described in the example above), such as benzoic, methylbenzene, methoxybenzene, fervently, chlorbenzene and naphthoic acid. The reaction can be performed as in the case when Z in stage 1 represents a hydroxy-group. When the acylation is performed with the use of monoalkylated complex ether dicarboxylic acid, complex obtained tert-butyl ether may be treated with acid as well as in reaction (a) stage 2, and thereby converted into the target C2-C7alkanolamine, replaced by carboxypropyl.

The reaction may proceed in a wide range of temperatures and the precise reaction temperature is not required for the present invention. The preferred reaction temperature depends upon such factors as the nature of the solvent and the used starting material or reagent. However, it is usually advisable to carry out the reaction at a temperature of from -10oC to 50oC, and more preferably from ABOUToC to 30oC. the Time required for the reaction, can be used reagents and solvent. But if the reaction is carried out at the above preferred conditions, it is usually sufficient period of from 15 minutes to 20 hours, and more preferably from 30 minutes to 10 hours.

Upon completion of the reaction, the reaction product can be extracted from the reaction mixture by traditional methods. For example, if insoluble, it is separated, when necessary, from the reaction mixture by filtration, or, if the reaction solution is acidic or alkaline, the reaction mixture was neutralized (when necessary), and then can follow the same procedure which is used in stage 1.

Reaction (c).

This reaction removes the protective group for the nitrogen atom in the group represented by the symbol R1a. This reaction can be carried out by methods well known in the field of organic synthesis, although the nature of the reaction varies depending on the type of the protective group.

When the protective group for the nitrogen atom is arylmethylidene or armletaccessory group, the reaction can be performed as described in relation to reaction (a) stage 2, when the protective group for the hydroxy-group is arylmethylidene group.

When the protective group is wearing the reaction of (a) stage 2, when the protective group for the hydroxy-group is methoxymethyl group.

When the protective group for the nitrogen atom is alkoxycarbonyl group, it can be removed by interaction with the substrate. There is no particular restriction on the nature of the used grounds and equivalent can apply any base commonly used in reactions of this type. Examples of such bases include hydroxides of alkali metals such as lithium hydroxide, sodium hydroxide and potassium hydroxide, and carbonates of alkali metals such as sodium carbonate and potassium carbonate. The reaction is normally and preferably carried out in the presence of a solvent. There is no particular restriction on the nature of the used solvent, provided that it has no adverse effect on the reaction or on the involved reagents and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include alcohols, such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, water or a mixture of water and any one or more of these organic solvents. Then hydrolyzing the product.

The reaction may proceed in a wide range to the reaction temperature depends on factors such as the nature of the solvent and the used starting material or reagent. However, it is usually advisable to carry out the reaction at a temperature of from 0oC to 100oC, and more preferably from room temperature to 60oC. the Time required for the reaction can also be changed within wide limits depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent. But if the reaction is carried out at the above preferred conditions, it is usually sufficient period of from 30 minutes to 48 hours, and more preferably from 1 to 16 hours.

Upon completion of the reaction, the reaction product can be extracted from the reaction mixture in the traditional way, for example as described in relation to stage 1.

Reaction (d).

The reaction of the hydroxy-group is transformed into the amino group. The reaction can be performed in the following sequential stages: the transformation of the hydroxy-group in sulfonyloxy and then turning sulfonyloxy in sidegroup; or the transformation of the hydroxy-group in the halogen atom (preferably chlorine atom, bromine or iodine), the conversion of the halogen atom in sidegroup and then restore sidegroup.

The reaction conversion of the hydroxy-group in the halogen atom can be performed in the presence or absence of a base by processing the halogenation agent. There is also no particular restrictions of the nature used halogenation agents and equivalent can apply any of halogenation agent commonly used in reactions of this type. Examples of such halogenation agents include thionylchloride, such as thionyl chloride or thienylboronic; oxychloride phosphorus, such as oxychloride phosphorus and pentachloride phosphorus and pentabromide phosphorus; arylphosphonate having from 6 to 10 carbon atoms in the aryl part (which may be unsubstituted or may be substituted by at least one of the substituents defined and described in the example above), such as triphenylphosphine, triphenylphosphine or triphenylphosphite; mixtures of triarylphosphine defined and described in the example above [for example, triphenylphosphine], and tetrachloride carbon [e.g., carbon tetrachloride, tetrabromide carbon or tetraiodide carbon]; and mixtures of triarylphosphine defined and described in the example above [for example, triphenylphosphine], and N - halogenating [for example, N-chlorosuccinimide or N - bromosuccinimide] . Of these are preferred thionylchloride, halides of phosphorus and arylphosphonate and most preferred thionyl chloride, trichlorethane, tribromopropane, triphenylmethylchloride, triphenylphosphorane and triphenylphosphite. The reaction can be performed as well as the reaction of (b) stage 2.

The reaction of transformation of sulfonyloxy or halogen atom in sidegroup can be done by ensuring interaction of the corresponding connection asiastar in the presence of a solvent. There are no special restrictions to the nature of the solvent, provided that it has no adverse effect on the reaction or on the involved reagents and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include ethers, such as tetrahydrofuran and dioxane, amides, such as dimethylformamide and N,N - dimethylacetamide. The reaction may proceed in a wide range of temperatures and the precise reaction temperature is not required for the present invention. The preferred reaction temperature depends upon such factors as the nature of the solvent and the used starting material or reagent. However, it is usually advisable to carry out the reaction at a temperature of from 0oC to 150oC, and more preferably from room temperature to 100oC. the Time required for the reaction can also be changed within wide limits depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent. But if the reaction is carried out at the above preferred conditions, it is usually sufficient period of from 30 minutes to 20 hours, and more preferably from 1 to 10 hours.

Re reaction (a) stage 2, when the protective group is arylmethylidene group or others, or as in reaction (e) stage 2.

Upon completion of the reaction, each reaction product can be removed from reaction mixtures in the traditional way, for example as described in relation to stage 1.

Reaction (e).

This reaction alkoxycarbonyl group represented by the symbol R6atransformed into a methyl group or alkanoyloxy group represented by the symbol R6aturn in the alkyl group. This reaction can be accomplished by treatment with a reducing agent (preferably aluminohydrides alkali metal, such as aluminized lithium) in an inactive solvent (preferably simple ether, such as diethyl ether, tetrahydrofuran or dioxane). The reaction may proceed in a wide range of temperatures and the precise reaction temperature is not required for the present invention. The preferred reaction temperature depends upon such factors as the nature of the solvent and the used starting material or reagent. However, it is usually advisable to carry out the reaction at a temperature of from 0oC to 100oC, and more preferably from room temperature to 80o

Upon completion of the reaction, each reaction product can be removed from reaction mixtures in the traditional way, for example as described in relation to stage 1.

Reaction (f).

This reaction alkylate group = NH, which can be entered in the group represented by the symbol R1a. The reaction may be carried out by treatment with alkylating agent in the presence of base as well as in reaction (b) stage 2. There are no special restrictions of the nature used alkylating agents and equivalent can apply any alkylating agent commonly used in reactions of this type. Examples of such alkylating agents include alkylhalogenide having from 1 to 6 carbon atoms, such as methyliodide, ethyliodide, propyliodide, utilidad, pentolite and hexalite. There is also no specific limitations to the nature of the grounds and equivalent can apply any base commonly used in reactions of this type. Examples of such bases include carbonates of alkali metals such as potassium carbonate and carbonate on the ionograph turn in karbamoilnuyu group. The reaction may be carried out by ensuring interaction of the respective connection base. There are no special restrictions to the nature of the grounds and equivalent can apply any base commonly used in reactions of this type. Examples of such bases include hydroxides of alkali metals such as sodium hydroxide and potassium hydroxide, and carbonates of alkali metals such as sodium carbonate and potassium carbonate. The reaction is normally and preferably carried out in the presence of a solvent. There are no special restrictions to the nature of the solvent, provided that it has no adverse effect on the reaction or on the involved reagents and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include aqueous alcohol such as aqueous methanol or aqueous ethanol, water, ethers, such as water and diethyl ether, aqueous tetrahydrofuran or aqueous dioxane, and water. Of them, preferred are water spirits.

The reaction may proceed in a wide range of temperatures and the precise reaction temperature is not required for the present invention. The preferred reaction temperature depends on tselesoobraznym to carry out the reaction at a temperature of from 10oC to 200oC, and more preferably from 50oC to 150oC. the Time required for the reaction can also be changed within wide limits depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent. But if the reaction is carried out at the above preferred conditions, it is usually sufficient period of from 30 minutes to 48 hours, and more preferably from 1 to 20 hours.

Upon completion of the reaction, the target compound can be extracted from the reaction mixture in the traditional way. For example, one of the suitable methods include neutralization of the reaction mixture when it is needed; or, when there is an insoluble substance, removing insoluble substances by filtration; adding a water-immiscible organic solvent such as ethyl acetate; washing with water and then removing the solvent. If necessary, obtained in the manner described, the target compound can be further purified by conventional methods, for example by recrystallization, the resultant deposition rates or chromatography.

The compounds of formula (1) can be converted into their salts, preferably pharmaceutically acceptable salts, putts appropriate acid in a solvent. There are no special restrictions to the nature of the solvent, provided that it has no adverse effect on the reaction or on the involved reagents and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include ethers, such as diethyl ether, tetrahydrofuran and dioxane, alcohols such as methanol and ethanol, or halogenated hydrocarbons, such as methylene chloride and chloroform. The reaction may proceed in a wide range of temperatures and the precise reaction temperature is not required for the present invention. The preferred reaction temperature depends upon such factors as the nature of the solvent and the used starting material or reagent. However, it is usually advisable to carry out the reaction at about room temperature. The time required for the reaction can also be changed within wide limits depending on many factors, particularly the reaction temperature and the nature of the reagents and solvent. But if the reaction is carried out at the above preferred conditions, it is usually sufficient period of from 5 minutes to 1 hour.

An alternative way of obtaining hydrochlori the resins (for example, on a column of CM - Sephadex C-25 [trademark] and elute the column with diluted hydrochloric acid.

Esters of the compounds of the present invention can be obtained by methods well known in the field of chemistry, and no special technology is required.

One of the source materials - compound of the formula (II) can be produced well known manner (EP 1759, EP 398326 and EP 600717).

BIOLOGICAL ACTIVITY

The compounds of formula (1) are as antagonistic effect on serotonin-2 receptors, and inhibitory effect on squalene synthase, are impact resistant and have a prolonged antagonistic effect on serotonin-2 receptors in vivo. They also have a minimum antagonistic effect against the adrenaline1and very low toxicity. Therefore, the compounds of formula (1) useful for therapy or prophylaxis (preferably for the treatment of thrombotic or arteriosclerotic diseases, since these compounds are effective antagonists of the serotonin-2 receptors, which are distributed on endothelial cells of blood vessels or platelets, and platelet aggregation inhibitors. They are also useful for Ter the arteries or blood vessels in the brain) (cerebrovascular), resulting from these diseases. In addition, they are useful for the treatment or prevention hyperlipidemics and arteriosclerotic diseases, because these compounds effectively reduce cholesterol in the blood. In particular, these compounds are very useful for therapy or prophylaxis (preferably, for therapy) arteriosclerotic diseases, because they effectively inhibit the serotonin-2 receptors and effectively reduce cholesterol.

The biological activity of the compounds according to the present invention is illustrated by the following tests.

TEST 1

Experiment with narrowing of blood vessels(vasoconstriction)

Studied the effect on smooth muscle contraction by the method of Van Neuten et al. [J. Pharmacol. Exp. Ther. , 218, 217-230, (1981)]. Were killed by exsanguination rats male SD having a weight of approximately 500 g each, and each animal was dissected tail artery. Removed from the artery accrete to her tissues to obtain spiral strips approximately 2x20 mm Strip was hung in the bath for organs, which had a temperature of 37oC and contained 10 ml of Tyrode saturated with a gas mixture (95% O2/5% CO2), and resulted in tearing of the initial tensile load of 0.5 g and the sensor produced a record of change of voltage on the isometric method. Was added to the bath 310-6M serotonin as inducer of vasoconstriction and after stabilization of the contractile response of the drug (sample) was added to the bath test the connection with a gradual increase in the content of the test compounds in the bath for controlling the tension in the spiral strip. Then added 10-4M papaverine. Assuming that the voltage before the addition of each test compound was 100% and the voltage after 5 minutes after addition of papaverine was 0%, the curve of least squares regression to calculate the concentration of each test compound required to reduce the voltage Ud 50% (IC50. The results are shown in table 2.

TEST 2

Experiment with binding to receptors

Method was used Leysen et al. [Mol. Pharmacol.,21, 301- 314, (1982). In this experiment, we used male rats Wictar (weighing 280-320 g). Cut off the head of each animal was dissected cortex and striatum. These bodies were frozen on dry ice and kept at -80oC. Binding to serotonin receptors was tested using the cortex. For the preparation of suspensions of frozen membranes cloth when 49000xq (rpm) for 10 minutes. The precipitate (pellet) suspended in Tris buffer, centrifuged and re-suspended in Tris-buffer. Protein content was determined in the resulting suspension of membranes and Tris-buffer brought him to 0.57 mg/protein/ml. Suspension of membranes were stored at -80oC.

The reaction of binding to receptors was started by injecting 40 μl of the suspension of membranes in a test tube containing 50 ál of3H-ligand and 10 μl each of the test compounds (dissolved in dimethylsulfoxide). After incubation at 30oC for 1 hour the reaction was stopped by filtration under reduced pressure using a glass filter Whatman GF/b Filter was washed ice Tris-buffer (4 ml x 2 times). The filter is then treated ACS-11 and defined its radioactivity using a liquid scintillation counter. Determined the nonspecific binding in the presence of 20 km of atropine. The percent binding was determined in percent in - generowanie binding to receptors in the presence of each test compound. Along the curve of least squares regression to calculate the concentration of each test compound required to inhibit binding by 50% (IC50). The results are shown in tab the inhibition of squalene synthase was determined by the method described in U.S. patent N 5102907; Anal. Biochem. 203, 310 (1992).

Reaction against squalene-synthase was tested under anaerobic conditions using a test tube sizes h mm, containing the reaction solution having the following composition.

Each 100 μl reaction solution (one analysis) contained 50 mm KH2PO4/H2HPO4(ph 7.5; buffer solution containing potassium dihydrophosphate-phosphate of dicale), 10 mm NaF (sodium fluoride), 10 mm MgCl2(magnesium chloride), 2 mm DTT (dithiotreitol), 50 mm ascorbic acid, 20 units/ml of ascorbic acid oxidase, 1 μm NADPH (nicotinamide adenine dinucleotide phosphate), 10 μm [4-14C] -FPP (farnesylpyrophosphate acid); 58 µci/µmol), 60 µg/ml suspension of microsomes rat liver and inhibitor solution (5 μl each of the test compounds in methanol or water).

The reaction was started by adding microsomal suspensions of rat liver. Then the reaction solution was incubated in a thermostat at 37oC for 20 minutes, after which the reaction was stopped by adding 100 μl of a mixture (1:1 by volume) 40% KOH (aqueous solution of potassium hydroxide) and 95% EtOH (aqueous ethanol). Resulting reaction solution was heated at 65oC for 30 minutes is about layer was mixed with 10 ml of scintillator and radioactivity was determined using liquid scintillation counter.

Inhibitory activity of each of the test compounds against the enzyme was determined through co-incubation of a sample containing the test compound with a sample of the enzyme and substrate in the reaction solution.

Table 4 shows the concentration (IC50each test compound required for 50% inhibition.

From the above data it can be clearly seen that the compounds of the present invention exhibit high activity as antagonists at serotonin-2 receptors in combination with the ability to inhibit the activity of squalene synthase.

When using compounds of formula (1) and their pharmaceutically acceptable salts and esters as a therapeutic or preventive drugs for these diseases can be entered individually or in a mixture with a pharmaceutically acceptable additive such as a filler or diluent any suitable way, for example, by way of oral administration (for example, in the form of tablets, capsules, granules, powder or syrup) or parenteral administration (for example, in the form of an injection solution).

These dosage forms can be izgotov, such as lactose, sucrose, glucose, mannitol and sorbitol; starch derivatives such as corn starch, potato starch, a-starch, dextrin and carboximetilkrahmal; cellulose derivatives such as crystalline cellulose, nizkozameshhennoj hydroxypropylcellulose, hypromellose, carboxymethyl cellulose, calcium carboxymethyl cellulose and cross-linked sodium carboxymethylcellulose; Arabian gum; dextran; pullulan; silicates, such as light silicic acid anhydride, synthetic aluminum silicate and meta-silicate of magnesium aluminate; phosphates such as calcium phosphate; carbonates, such as calcium carbonate; and sulfates such as calcium sulfate), a binder (for example, these fillers, gelatin, polyvinylpyrrolidone, macrogol), loosening the substance (for example, these fillers, chemically modified derivatives of starch or cellulose, such as sodium croscarmellose, sodium carboximetilkrahmal and cross-linked polyvinylpyrrolidone), a substance that facilitates the production (for example, talc; stearic acid; metal stearates such as calcium stearate and magnesium stearate; colloidal silicon dioxide; Laks, such as bi-grams of the acid; the sodium carboxylates such as sodium benzoate; sulfates such as sodium sulfate; leucine; laurilsulfate, such as sodium lauryl sulfate and lauryl sulfate, magnesium; silicic acids such as silicic acid anhydride and silicic acid hydrate; and starch derivatives used in these fillers), stabilizing agent (for example, esters of peroxybenzoate, such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenethyl alcohol; benzylaniline; phenols such as phenol and cresol; thimerosal; acetic anhydride; sorbic acid), corrigent (for example, a widely used sweetener, an acidulant, flavouring substance), the diluent and solvent for injection (for example, water, ethanol, glycerol). The recommended daily dose for adults, though, and depends on the symptoms, age and so on, is in the range from 1 mg (preferably 10 mg to 2000 mg, preferably 400 mg) for oral administration and from 0.1 mg (preferably 1 mg) to 500 mg (preferably 300 mg) for intravenous injection. The dose must be administered one to six separate doses per day, in accordance with the symptoms.

Getting with the of some raw materials, used in these examples is illustrated in the following receipts.

EXAMPLE 1

(2P, 3P) -2 - 2 - 4-fluoro-2 - 2- (3-methoxyphenethyl)-phenoxy ethyl-4-hydroxy-1-methylpyrrolidinone

1(a) (2P, 4P)-1-Etoxycarbonyl-2 - 2 - 4-fluoro-2 - 2-(3-methoxyphenyl)ethyl, phenoxy ethyl-4-hydroxypyrrolidine

399 mg of 4-fluoro-2 - 2-(3-methoxyphenyl)ethyl phenol (obtained as described in obtaining 4) was dissolved in 8 ml of dimethylacetamide and then to the resulting solution were added under ice cooling 363 mg of tert-butoxide potassium and 718 mg (2, 4P) -2- (2-chloroethyl) -1-etoxycarbonyl-4-hydroxypyrrolidine. Then the resulting mixture was stirred at 40oC for 5 hours. At the end of this time was added 50 ml of ethyl acetate and the reaction mixture was washed with water and saturated aqueous sodium chloride, in that order. An ethyl acetate layer was dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The obtained oily substance was purified column chromatography on silica gel using as eluent a mixture of hexane and ethyl acetate to volume ratio of 3: 7 and he got 535 mg (yield 76%) indicated in the title compounds as colorless meet); of 1.75 to 2.3 (3H, multiplet); 2,3-2,6 (1H, multiplet); of 2.75 to 3.0 (4H, multiplet); 3,4-3,8 (1H, multiplet); of 3.45 (1H, doublet of doublets, J= 4,3 and 11.9 Hz); with 3.79 (3H, singlet); 3.9 to a 4.3 (5H, multiplet); 4.35 the-4,5 (1H, multiplet); 6.8 or 6.9 (6H, multiplet); 7,15-of 7.25 (1H, multiplet).

1(b) (2R, 4R)-2-[2-{4-fluoro-2-[2-(3-methoxyphenyl) ethyl]- phenoxy}-ethyl] -4-hydroxy-1-methylpyrrolidine

201 mg (2R, 4R)-2-[2-{4-fluoro-2-[2-(3-methoxyphenyl)ethyl] phenoxy}ethyl] -1-etoxycarbonyl-4-hydroxypyrrolidine [obtained as described in the above stage (a)] was dissolved in 4 ml of tetrahydrofuran and the resulting solution was added dropwise to a suspension of 53 mg sociallyengaged in 4 ml of tetrahydrofuran while cooling with ice and stirring. Then the mixture was heated under reflux for 30 minutes. At the end of this time the reaction mixture was cooled on ice and added to it decahydrate sodium sulfate to decompose excess hydride. Was removed by filtration of the insoluble matter and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography on silica gel using as eluent a mixture of methylene chloride and methanol with a volume ratio of 4:1 and as a result received 139 mg (yield 80%) indicated in the title compounds as colorless iplot); 2,2-2,4 (1H, multiplet); 2.40 a (1H, doublet of doublets, J=4,5 and 10.8 Hz); of 2.51 (3H, singlet); 2,75 was 3.05 (5H, multiplet); 3,62 (1H, doublet of doublets, J= 6,0 and 10.8 Hz); with 3.79 (3H, singlet); 3,9-4,1 (2H, multiplet); 4,4-4,55 (1H, multiplet); 6,7-6,9 (6H, multiplet);7,15-of 7.25 (1H, multiplet).

1 (C) (2R, 4R)-2- [2-{4-fluoro-2- [2- (3-methoxyphenyl) ethyl] phenoxy}-ethyl] -4-hydroxy-1-methylpyrrolidinone

246 mg of (2R, 4R)-2-[2-{4-fluoro-2-[2-(3-methoxyphenyl) ethyl]- phenoxy} ethyl] -4-hydroxy-1-methylpyrrolidine [obtained as described above in stage (b)] was dissolved in 5 ml of ethyl acetate and the resulting solution was added 0.25 ml of 4 n solution of hydrogen chloride in ethyl acetate. Then the mixture was allowed to stand at room temperature for about 10 minutes. The crystals deposited precipitates were collected by filtration and dried under vacuum to obtain 210 mg (yield 78%) indicated in the title compounds as colorless crystals, melting at 128-129oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques: to 2.0-2.2 (1H, multiplet); 2.3 to approximately 2.65 (2H, multiplet); 2,33 (1H, doublet of doublets, J= 5,9 and 13.8 Hz); of 2.75 to 3.0 (4H, multiplet); 2,89 (3H, singlet); 2,99 (1H, doublet, J= 12.3 Hz); of 3.78 (3H, singlet); 3,8-4,2 (4H, multiplet); 4,55 is 4.7 (1H, multiplet); 6,65-6,8 (4H, multiplet); 6.8 or 6.9 (2H, multiplet); 7,15-of 7.25 (1H, multiplet).

2 (a) (2R, 4R)-1-tert-Butoxycarbonyl-4-tert-butyldimethylsilyloxy-2-[2-{4-fluoro-2-[2-(4-forfinal)ethyl]phenoxy}-ethyl]-pyrrolidin

248 mg of 4-fluoro-2-[2-(4-forfinal)ethyl]phenol (obtained as described in obtaining 6) was dissolved in 10 ml of N,N-dimethylacetamide and then to the resulting solution was added with ice cooling to 125 mg of tert-butoxide potassium and 405 mg (2S, 4R)-1-tert-butoxycarbonyl-4-tert-butyldimethylsilyloxy-2-(2-chloroethyl)pyrrolidine. Then the resulting mixture was stirred at room temperature for 3 hours, after which the reaction mixture was added 150 ml of ethyl acetate. The reaction mixture was washed with water and saturated aqueous sodium chloride, in that order. An ethyl acetate layer was dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The obtained oily substance was purified by column chromatography on silica gel using as eluent a mixture of hexane and ethyl acetate to volume ratio of 4:1, and the result was 433 mg (yield 73%) indicated in the title compounds as a colorless oily substance.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques: 0,02 (3H, singlet); 0,03 (3H, singlet); 0,84 (N, singlet);1,46 is ipled); of 3.9 to 4.2 (3H, multiplet); 4.25 in-4,4 (IH, multiplet); 6,7-7,0 (5H, multiplet); 7,05 to 7.2 (2H, multiplet).

2 (b) (2R, 4R)-2-[2-{4-fluoro-2-[2-(4-forfinal)ethyl]phenoxy}ethyl] -4-hydroxy-1-methylpyrrolidine

398 mg (2R, 4R)-1-tert-butoxycarbonyl-4-tert-butyldimethylsilyloxy-2- [2-{4-fluoro-2-[2- (4-forfinal) ethyl] phenoxy}- ethyl]pyrrolidine [obtained as described in the above stage (a)] was dissolved in 10 ml of tetrahydrofuran and the resulting solution was added dropwise to a suspension of 81 mg of sociallyengaged in 10 ml of tetrahydrofuran while cooling with ice and stirring. Then the obtained mixture was heated under reflux for 1 hour. At the end of this time the reaction mixture was cooled on ice and added to it decahydrate sodium sulfate to decompose excess hydride. Was removed by filtration of the insoluble matter and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography on silica gel using as eluent a mixture of methylene chloride and methanol with a volume ratio of 7:3, and the result was 151 mg (yield 59%) indicated in the title compounds as a colorless oily substance.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques: 1,plet); to 3.49 (1H, doublet of doublets, J=6,3 and 10.2 Hz); 3,85 - of 4.05 (2H, multiplet); 4.35 the-4,5 (1H, multiplet); 6,7-6,9 (3H, multiplet); the 6.9 to 7.0 (2H, multiplet); 7,05 to 7.2 (2H, multiplet).

2 (C) (2R, 4R)-2-[2-{4-fluoro-2-[2-(4-forfinal)ethyl]phenoxy} ethyl]-4-hydroxy-1-methylpyrrolidinone

138 mg of (2R, 4R)-2-[2-{4-fluoro-2-[2-(4-forfinal)ethyl]phenoxy}ethyl] -4-hydroxy-1-methylpyrrolidine [obtained as described above in stage (b)] was dissolved in 4 ml of ethyl acetate and then to the resulting solution was added 0.15 ml of 4 n solution of hydrogen chloride in ethyl acetate and concentrating the solution by evaporation under reduced pressure. The obtained oily substance was dissolved in 5 ml of ethyl acetate and the resulting solution was allowed to stand at room temperature for about 10 minutes. The crystals deposited precipitates were collected by filtration and dried under vacuum to obtain 66 mg (yield 43%) indicated in the title compounds as colorless crystals, melting at 70-73oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) m e: of 2.0-2.2 (1H, multiplet); 2,25-to 2.65 (3H, multiplet); 2,78 (4H, singlet); 2,84 (3H, singlet); 2,99 (1H, doublet, J=12,4 Hz); of 3.7-3.9 (1H, multiplet); 3,9-4,2 (3H, multiplet); 4,55 is 4.7 (1H, multiplet); 6,7-7,05 (5H, multiplet); 7,05 to 7.2 (2H, multiplet).

R, 4R) -1-tert-Butoxycarbonyl-2-[2-{4-fluoro-2-[2-(4 - forfinal) ethyl] phenoxy} ethyl]-4-hydroxypyrrolidine

687 mg of 4-fluoro-2-[2-(4-forfinal) ethyl]phenol (obtained as described in obtaining 6) was dissolved in 12 ml of N,N - dimethylacetamide and then to the resulting solution were added under ice cooling 212 mg of tert-butoxide potassium. Then the resulting mixture was stirred for 10 minutes, after which was added to her 687 mg (2S, 4R)-2-(2-chloroethyl)-1-tert-butoxycarbonyl-4-tert - butyldimethylchlorosilane. Then the resulting mixture was stirred at room temperature for 14 hours. At the end of this time the reaction mixture was added 135 mg of tert - butoxide potassium and the mixture was stirred at 40oC for 4 hours, after which was added 300 ml of ethyl acetate. The resulting reaction mixture was washed with water and saturated aqueous sodium chloride, in that order. An ethyl acetate layer was separated and dried over anhydrous magnesium sulfate. Then it was concentrated by evaporation under reduced pressure. The obtained oily substance was purified by column chromatography on silica gel using as eluent a mixture of hexane and ethyl acetate to volume ratio of 2:3 and as a result received 571 mg (yield 74%) indicated resonance (270 MHz, CDCl3) memorial plaques: 1,45 (S, singlet); 1.7 to was 2.05 (2H, multiplet); from 2.1 to 2.25 (1H, multiplet); 2,3-by 2.55 (1H, multiplet); 2,85 (4H, singlet); 3,4-3,7 (1H, multiplet); of 3.42 (1H, doublet of doublets, J=4,4 and 11.9 Hz); 3,9-of 4.05 (2H, multiplet); 4.1 and of 4.25 (1H, multiplet); 4.35 the-4,5 (1H, multiplet); 6,7-6,9 (3H, multiplet); the 6.9 to 7.0 (2H, multiplet). 7,05 to 7.2 (2H, multiplet).

3(b) (2R, 4R)-2-[2-{ 4-fluoro-2-[2-(4-forfinal)ethyl] phenoxy} ethyl]-4-hydroxypyrrolidine

570 mg of (2R, 4R)-1-tert-butoxycarbonyl-2-[2-{4-fluoro-2-[2- (4-forfinal) ethyl] phenoxy}ethyl] -4-hydroxypyrrolidine [obtained as described in the above stage (a)] was dissolved in 5 ml ethyl acetate and then to the resulting solution was added 5 ml of 4 n solution of hydrogen chloride in ethyl acetate. Next, the resulting mixture was stirred at room temperature for 30 minutes. At the end of this time the crystals deposited precipitates were collected by filtration, washed with ethyl acetate and dried under vacuum, resulting in 381 mg (yield 78%) indicated in the title compounds as colorless crystals, melting at 186-187oC.

Spectrum of nuclear magnetic resonance (270 MHz, hexadeuterated dimethyl sulfoxide) M. D.: 1,65-of 1.85 (1H, multiplet); 2,0-2,4 (3H, multiplet); 2,82 (4H, singlet); 3,01 (1H, doublet, J=12,2 Hz); 3,3-of 3.45 (1H, multiplet); 3,8 is, multiplet).

EXAMPLE 4

(2R, 4R) -2-[2-{4-fluoro-2-[2- (4-fluoro-3-methoxyphenyl)ethyl] phenoxy}ethyl] -4-hydroxy-1-methylpyrrolidinone

4 (a) (2R, 4R)-1-Etoxycarbonyl-2-[2-{4-fluoro-2-[2-(4-fluoro-3 - methoxyphenyl) ethyl] phenoxy}ethyl]-4-hydroxypyrrolidine

622 mg of 4-fluoro-2-[2-(4-fluoro-3-methoxyphenyl)ethyl]phenol (obtained as described in obtaining 5) was dissolved in 7 ml of N, N-dimethylacetamide. Cooperated obtained solution of 343 mg of tert-butoxide potassium and 678 mg (2S, 4R) -2- (2-chloroethyl) -1-etoxycarbonyl-4-hydroxypyrrolidine and was extracted with a solution as described in stage (a) of example 1. The obtained oily substance was purified by column chromatography on silica gel using as eluent a mixture of hexane and ethyl acetate to volume ratio of 2:3 and as a result received 552 mg (yield 52%) indicated in the title compounds as a colorless oily substance.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques: 1-1,35(3H, multiplet); 1,7-of 1.95 (1H, multiplet); a 1.96 (1H, doublet of doublets, J=4.9 and 7.2 Hz); 2,05 was 2.25 (1H, multiplet); 2,25-to 2.65 (1H, multiplet); of 2,75 2,95 (4H, multiplet); of 3.45 (1H, doublet of doublets, J=4.3 and 12.0 Hz); 3.45 points and 3.8 (1H, multiplet); a 3.83 (3H, singlet); 3,85-of 4.05 (1H, multiplet); 4,05 of 4.3 (3H, multiplet); tor-3-methoxyphenyl) ethyl] phenoxy} ethyl]-4-hydroxy-1-methylpyrrolidine

Cooperated with each other 551 mg (2R, 4R) - 1-etoxycarbonyl-2-[2-{4-fluoro-2-[2-(4-fluoro-3-methoxyphenyl)ethyl] phenoxy}ethyl]-4-hydroxypyrrolidine [obtained as described in the above stage (a)], 20 ml of tetrahydrofuran and 140 mg of sociallyengaged and then the reaction mixture was treated as in stage (b) of example 1. The concentrate was purified by column chromatography on silica gel using as eluent a mixture of methylene chloride and methanol with a volume ratio of 3:2 and the result was 405 mg (yield 84%) indicated in the title compounds as a colorless oily substance.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques: 1,65-2,1 (3H, multiplet); 2,1-2,3 (1H, multiplet); of 2.25 (1H, doublet of doublets, J=5,2 and 10.3 Hz); 2,39 (3H, singlet); 2,6-2,8 (1H, multiplet); 2.8 to 3.0 (4H, multiplet); 3,50 (1H, doublet of doublets, J=6.2 and 10.3 Hz); of 3.84 (3H, singlet); 3,85-of 4.05 (2H, multiplet); 4.35 the-4,5 (1H, multiplet); 6,65-7,05 (6N, multiplet).

4 (c) (2R, 4R)-2-[2-{4-fluoro-2-[2-(4-fluoro-3-methoxyphenyl) ethyl]phenoxy} ethyl]-4-hydroxy-1-methylpyrrolidinone

399 mg of (2R, 4R)-2-[2-{4-fluoro-2-[2-(4-fluoro-3-methoxyphenyl)ethyl] phenoxy} ethyl] -4-hydroxy-1-methylpyrrolidine [obtained as described above in stage (b)] was dissolved growth. Solvent was removed by evaporation under reduced pressure and the obtained solid substance was dissolved in a small amount (approximately 0.5 ml) of methylene chloride and then to the resulting solution was added 5 ml of ethyl acetate. The resulting mixture was allowed to stand at room temperature for about 10 minutes. Precipitated precipitated crystals were collected by filtration and dried under vacuum, resulting in 359 mg (yield 82%) indicated in the title compounds as colorless crystals, melting at 128-130oC.

Spectrum of nuclear magnetic resonance (400 MHz, hexadeuterated dimethyl sulfoxide +D2O) M. D.: of 1.8-2.0 (1H, multiplet); of 2.0-2.2 (1H, multiplet); 2,20 (1H, doublet of doublets, J=6,0 and 13.7 Hz); 2,4-by 2.55 (1H, multiplet); of 2.7-3.0 (4H, multiplet); 2,89 (3H, singlet); 2,97 (1H, doublet, J= 12,5 Hz); 3,6-3,9 (2H, multiplet); of 3.80 (3H, singlet); 3.95 to to 4.15 (2H, multiplet); the 4.3 is 4.45 (1H, multiplet); 6,7-6,8 (1H, multiplet); 6,9-to 7.15 (5H, multiplet).

EXAMPLE 5

(2R, 4R) -2-{2-[4-fluoro-2- (2-phenylethyl) phenoxy}ethyl]-4-hydroxypyrrolidine

5 (a) (2R, 4R)-1-tert-Butoxycarbonyl-4-tert-butyldimethylsilyloxy-2- { 2- [4-fluoro-2- (2-phenylethyl) phenoxy}ethyl]pyrrolidin

Cooperated with each other 1090 mg of 4-fluoro-2- (2-peneliti is dimethylaminopyridine and 566 mg of tert-butoxide potassium in 10 ml of N,N-dimethylacetamide and the mixture was extracted so as described in stage (a) of example 2. The obtained oily substance was purified by column chromatography on silica gel using as eluent a mixture of hexane and ethyl acetate to volume ratio of 5: 1 and the received 2090 mg (yield 84%) indicated in the title compounds as a colorless oily substance.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques: 0,02 (3H, singlet); 0,03 (3H, singlet); 0,84 (N, singlet); 1,45 (S, singlet); 1.7 to 1,95 (2H, multiplet); a 2.0 to 2.15 (1H, multiplet); 2,25-2,5 (1H, multiplet); 2.8 to 2.95 for (4H, multiplet); 3,3-the 3.65 (1H, multiplet); at 3.35 (1H, doublet of doublets, J= 4,5 and 11.0 Hz); 3,85 to 4.2 (3H, multiplet); 4,25 and 4.4 (1H, multiplet); 6,7-6,9 (3H, multiplet); 7,15-to 7.35 (5H, multiplet).

5(b) (2R, 4R)-2-{2-[4-fluoro-2-(2-phenylethyl)phenoxy]ethyl}-4 - hydroxypyrrolidine

600 mg of (2R, 4R)-1-tert-butoxycarbonyl-4-tert-butylmethacrylate-2-{2- [4-fluoro-2- (2-phenylethyl)phenoxy] ethyl} pyrrolidine [obtained as described in the above stage (a)] was dissolved in 5 ml of dioxane and then to the resulting solution was added ml of 4 n solution of hydrogen chloride in dioxane. Then the mixture was allowed to stand at room temperature for 1 hour. At the end of this time the solvent was removed by evaporation and methanol and the resulting solution was added 10 ml of ethyl acetate, then gave the solution to stand at room temperature for about 10 minutes. Precipitated precipitated crystals were collected by filtration and dried under vacuum, resulting in 270 mg (yield 67%) indicated in the title compounds as colorless crystals, melting at 151-152oC.

Spectrum of nuclear magnetic resonance (270 MHz, CD3OD) M. D.: of 1.8-2.0 (1H, multiplet); 2,1-2,4 (3H, multiplet), of 2.8-3.0 (4H, multiplet); 3,22 (1H, doublet, J=12,4 Hz); 3.46 in (1H, doublet of doublets, J=4,1 and 12.4 Hz); 4,0-4,2 (3H, multiplet); 4,5-4,6 (1H, multiplet); 6,8-7,0 (3H, multiplet); 7,1-7,3 (5H, multiplet).

EXAMPLE 6

(2R, 4R)-2-{ 2-[4-fluoro - 2-(2-phenylethyl)phenoxy]ethyl} -4-hydroxy-1-methylpyrrolidinone

6 (a) (2R, 4R)-1-tert-Butoxycarbonyl-2-{2-[4-fluoro-2-(2 phenylethyl) phenoxy] ethyl}-4-hydroxypyrrolidine

1490 mg of (2R, 4R) -1-tert-butoxycarbonyl-4-tert-butyldimethylsilyloxy-2-{ 2-[4-fluoro-2- (2-phenylethyl) phenoxy] ethyl}pyrrolidine [obtained as described in example 5 (a)] was dissolved in 15 ml of tetrahydrofuran and the resulting solution was added 0,79 ml tetrabutylammonium. Then the resulting mixture was stirred at room temperature for 0.5 hours. At the end of this time the reaction solution was concentrated by evaporation is adopted on silica gel using as eluent a mixture of hexane and ethyl acetate to volume ratio of 1:1 and the received 1115 mg (yield 95%) indicated in the title compounds as a colorless oily substance.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques: 1,45 (S, singlet); 1.7 to was 2.05 (2H, multiplet); 2,05 was 2.25 (1H, multiplet); 2,3-by 2.55 (1H, multiplet); is 2.88 (4H, singlet); 3,4-of 3.75 (1H, multiplet); of 3.42 (1H, doublet of doublets, J=4,4 and 11.9 Hz); 3.9 to 4.5 (2H, multiplet); 4,05-of 4.25 (1H, multiplet); 4,3-of 4.45 (1H, multiplet); 6,7-6,9 (3H, multiplet); 7,1-to 7.35 (5H, multiplet).

6 (b) (2R, 4R) -2-{2-[4-fluoro-2- (2-phenylethyl) phenoxy]ethyl}-4-hydroxy-1-methylpyrrolidine

Cooperated between 1115 mg of (2R, 4R)-1-tert - butoxycarbonyl-2-{ 2-[4-fluoro-2-(2-phenylethyl) phenoxy] ethyl} -4-hydroxypyrrolidine [obtained as described in the above stage (a)] 20 ml of tetrahydrofuran and 200 ml of lithium - aluminiumhydride with subsequent processing as described in stage (b) of example 1. Obtained with the concentrated substance was purified by column chromatography on silica gel using as eluent a mixture of methylene chloride and methanol with a volume ratio of 5:1 and the result obtained 540 mg (yield 61%) indicated in the title compound as a colourless solid.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques: 1,65-2,3 (4H, multiplet); 2,30 (1H, doublet of doublets, J=4.8 and 10.5 Hz); 2,44 (3H, singlet); 2,7-2,95 (1H, multiplet); is 2.88 (4H, singlet); 3,55 (1H, doublet Doo

6 (c) (2R, 4R) -2-{2- [4-fluoro-2- (2-phenylethyl) phenoxy] ethyl}-4-hydroxy-1-methylpyrrolidinone

540 mg of (2R, 4R)-2-{2-[4-fluoro-2-(2 - phenylethyl)phenoxy]ethyl} -4-hydroxy-1-methylpyrrolidine [obtained as described above in stage (b)] was dissolved in 5 ml of ethyl acetate and the resulting solution was added to 0.60 ml of 4 n solution of hydrogen chloride in ethyl acetate. Precipitated precipitated crystals were collected by filtration and dried under vacuum, resulting in 515 mg (yield 86%) indicated in the title compounds as colorless crystals, melting at 121-122oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques: a 2.0 to 2.15 (IH, multiplet); 2,25-2,6 (2H, multiplet); 2,33 (IH, doublet of doublets, J= 5,8 and 13.9 Hz); 2,85 (4H, singlet); 2,87 (3H, singlet); 3,00 (1H, doublet, J= 12,5 Hz); 3,7-4,2 (4H, multiplet); 4,5 with 4.65 (1H, multiplet); 6,7-6,9 (3H, multiplet); 7,1-to 7.35 (5H, multiplet).

EXAMPLE 7

(2R, 4R) -2- [2-{2- [2- (3,4-Differenl) ethyl]-4 - fervency}ethyl]-4-hydroxy-1-methylpyrrolidinone

7 (a) (2R, 4R) -1-tert-Butoxycarbonyl-4-tert-butyldimethylsilyloxy-2-[2-{2-[2-(3,4-differenl) ethyl]-4-fervency} ethyl] -pyrrolidin

Cooperated between 400 mg of 2-[2-(3,4-differenl) ethyl]-4-terfenol (obtained as described in obtaining 7), 690 mg (2S, 4R)-2l N,N-dimethylacetamide and the reaction mixture was extracted in the same way, as described in stage (a) of example 2. The obtained oily substance was purified by column chromatography on silica gel using as eluent a mixture of hexane and ethyl acetate to volume ratio of 5:1 and the result obtained 580 mg (yield 63%) indicated in the title compounds as a colorless oily substance.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques: 0,02 (3H, singlet); 0,04 (9H, singlet); 0,84 (3H, singlet); 1,45 (S, singlet); 1.7 to 1,95 (2H, multiplet); 1,95-2,15 (1H, multiplet); 2,2-to 2.55 (1H, multiplet); of 2.7-3.0 (4H, multiplet); 3.25 to the 3.65 (2H, multiplet); 3,85-of 4.05 (2H, multiplet); 4,05-of 4.25 (1H, multiplet); 4,25 and 4.4 (1H, multiplet); 6,7-7,1 (6N, multiplet).

7(b) (2R, 4R)-1-tert-Butoxycarbonyl-2-[2-{ 2-[2- (3,4- differenl) ethyl]-4-fervency}ethyl]-4-hydroxypyrrolidine

580 mg of (2R, 4R)-1-tert-butoxycarbonyl-4-tert-butyldimethylsilyloxy-2- [2-{2-[2-(3, 4-differenl) ethyl]-4-fervency} ethyl)pyrrolidine [obtained as described in the above stage (a)] was dissolved in 5 ml of tetrahydrofuran and the resulting solution was added at 0.31 ml tetrabutylammonium. Then the resulting mixture was stirred at room temperature for 1 hour. At the end of this time the reaction mixture was concentrated by evaporation of silicagel using as eluent a mixture of hexane and ethyl acetate to volume ratio of 1: 1 and the received 280 mg (yield 61%) indicated in the title compound as a colourless solid.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:1,46 (N, singlet); 1,7-2,0 (2H, multiplet); 1,05-2,3 (1H, multiplet); 2,3 - by 2.55 (1H, multiplet); 2,84 (4H, singlet); 3,4-3,7 (1H, multiplet); 3.43 points (1H, doublet of doublets, J= 4,2 and 11.9 Hz); 3,85-of 4.05 (2H, multiplet); 4,05-of 4.25 (1H, multiplet); 4.35 the-4,5 (1H, multiplet); the 6.7 and 7.1 (6H, multiplet).

7(C) of (2R, 4R)-2-[2-{ 2-[2-(3,4-Differenl)ethyl]-4-fervency} -ethyl] -4-hydroxy-1-methylpyrrolidine

Cooperated between 280 mg of (2R, 4R)-1-tert - butoxycarbonyl-2- [2-{ 2- (3, 4-differenl) ethyl]-4 - fervency}ethyl]-4-hydroxypyrrolidine [obtained as described above in stage (b)], 5 ml of tetrahydrofuran and 50 mg sociallyengaged with subsequent processing as described in stage (b) of example 1. Obtained with the concentrated substance was purified by column chromatography on silica gel using as eluent a mixture of methylene chloride and methanol with a volume ratio of 10:1 and the received 140 mg (yield 63%) indicated in the title compound as a colourless solid.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques: 1,75-2,5 (4H, multiplet); 2,41 (1H, doublet of doublets, J=a 4.3 and 10.8 Hz); of 2.51 (3H, singlet); 2.8 to 3,05 (1H, multiplet); 2,84 (4H, singlet); to 3.64 (1H, double doublet (d) (2R, 4R)-2-[2-{2-[2-(3,4-Differenl) ethyl]-4-fervency}ethyl]-4-hydroxy-l-methylpyrrolidinone

140 mg of (2R, 4R)-2-[2-{2-[2-(3-, 4-differenl)ethyl]-4 - fervency}ethyl] -4-hydroxy-1-methylpyrrolidine [obtained as described above in stage (c)] was dissolved in 5 ml of ethyl acetate and the resulting solution was added 0.15 ml of 4 n solution of hydrogen chloride in ethyl acetate. Precipitated precipitated crystals were collected by filtration and dried under vacuum, resulting in 113 mg (yield 73%) indicated in the title compounds as colorless crystals, melting at 93-94oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques: 2,05-of 2.25 (1H, multiplet); 2,25-2,7 (3H, multiplet); and 2.83 (4H, singlet); 2,9-3,15 (1H, multiplet); 2.91 in (3H, singlet); 3.75 to a 4.3 (4H, multiplet); 4,55-of 4.75 (1H, multiplet); 6,7-7,15 (6N, multiplet).

EXAMPLE 8

(2R, 4R) -2- [2-{ 2-[2- (3, 4-Differenl) ethyl]-4 - fervency}ethyl] 4-hydroxypyrrolidine

83 mg of (2R, 4R)-1-tert-butoxycarbonyl-2-[2-{2-(3,4-differenl) ethyl] -4-fervency} ethyl]-4-hydroxypyrrolidine [obtained as described in example 7(b)] was dissolved in 2 ml of dioxane and the resulting solution was added 2 ml of 4 n solution of hydrogen chloride. Then the mixture was allowed to stand at room temperature in accordance with the vacuum, receiving 55 mg (yield 77%) indicated in the title compounds as colorless crystals, melting at 170-171oC.

Spectrum of nuclear magnetic resonance (270 MHz, CD3OD) M. D.: 1,75-of 1.95 (1H, multiplet); of 2.15 to 2.35 (2H, multiplet); 2,35 is 2.55 (1H, multiplet); 2,85 (4H, singlet); 3,24 (1H, doublet, J=12,6 Hz); 3,49 (1H, doublet of doublets, J= 4,4 and 12.6 Hz); 3.95 to a 4.2 (3H, multiplet); 4,5-4,6 (1H, multiplet); 6,7-7,15. (6N, multiplet);

EXAMPLE 9

(2R, 4R) -2-{ 2- [4-Chloro-2- (2-phenylethyl) phenoxy]ethyl}-4 hydroxy-1-methylpyrrolidine

9 (a) (2R, 4R) -2-{2- [4-Chloro-2- (2-phenylethyl) phenoxy]ethyl}-1-etoxycarbonyl-4-hydroxypyrrolidine

500 mg of 4-chloro-2-(2-phenylethyl)phenol was dissolved in 10 ml of N,N - dimethylacetamide, cooperated obtained solution of 270 mg of tert-butoxide potassium and 520 mg of (2S, 4R-2-(2-chloroethyl)-1 - etoxycarbonyl-4-hydroxypyrrolidine and the reaction mixture was extracted as described in stage (a) of example 1. The obtained oily substance was purified by column chromatography on silica gel using as eluent a mixture of hexane and ethyl acetate to volume ratio of 1:2, and the result obtained 260 mg (yield 29%) indicated in the title compound as an oily substance.

Spectrum of nuclear magnetic Rezo,75 (1H, multiplet); to 3.41 (1H, doublet of doublets, J= 4,2 and 11.9 Hz); 3.9 to a 4.3 (5H; multiplet); a 4.3 and 4.4 (1H, multiplet); of 6.73 (1H, doublet, J=8.6 Hz); 7,05-to 7.35 (7H, multiplet).

9(b) (2R, 4R)-2-{2-[4-Chloro-2-(2 - phenylethyl)phenoxy]ethyl}-4-hydroxy-1-methylpyrrolidine

Cooperated between 260 mg of (2R, 4R)-2-{2-[4- chloro-2- (2-phenylethyl) phenoxy]ethyl}-1-etoxycarbonyl-4-hydroxypyrrolidine [obtained as described in the above stage (a)], 10 ml of tetrahydrofuran and 70 mg of sociallyengaged with subsequent processing as described in stage (b) of example 1. Obtained with the concentrated substance was purified by column chromatography on silica gel using as eluent a mixture of methylene chloride and methanol with a volume ratio of 5:1, and the result was 103 mg (yield 46%) indicated in the title compound as a colourless solid, melting at 65-68oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques: 1,7-2,05 (3H, multiplet); 2,15-2,4 (1H, multiplet); 2,31 (1H, doublet of doublets, J= 4.9 and 10.5 Hz); 2,44 (3H, singlet); of 2,75 2,95 (1H, multiplet); of 2.86 (4H, singlet); 3,55 (1H, doublet of doublets, J=6,l and 10.5 Hz); 3,85 of 4.1 (2H, multiplet); of 4.35-4.5 (1H, multiplet); 6,74 (1H, doublet, J =8,4 Hz); 7,05-to 7.35 (7H, multiplet).

EXAMPLE 10

(2R, 4R) -2-{2- [4-Bromine-xianbei-4-hydroxypyrrolidine

500 mg of 4-bromo-2-(2-phenylethyl) phenol was dissolved in 10 ml of N,N-dimethylacetamide, cooperated obtained solution of 220 mg of tert-butoxide and potassium 440 mg of (2S, 4R)- 2-(2-chloroethyl)-1-etoxycarbonyl-4-hydroxypyrrolidine and the reaction mixture was extracted as described in stage (a) of example 1. The obtained oily substance was purified by column chromatography on silica gel using as eluent a mixture of hexane and ethyl acetate to volume ratio of 1:2, and the result obtained 280 mg (yield 34%) indicated in the title compound as an oily substance.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques: 1.1 to about 1.35 (3H, multiplet); about 1.75 to 2.6 (4H, multiplet); 2,85 (4H, singlet); 3,4-of 3.75 (1H, multiplet); of 3.42 (1H, doublet of doublets, J=4,2 and 11.9 Hz); 3.9 to a 4.3 (5H, multiplet); 4,3-of 4.45 (1H, multiplet); 6,69 (1H, doublet, J=8.5 Hz); 7,15-to 7.35 (7H, multiplet).

10(b) (2R, 4R)-2-{2-[4-Bromo-2-(2-phenylethyl)phenoxy]ethyl} - 4-hydroxy-1-methylpyrrolidine

Cooperated between 280 mg of (2R, 4R) -2-{2- [4-bromo-2- (2-phenylethyl) phenoxy] ethyl} -1-etoxycarbonyl-4 - hydroxypyrrolidine [obtained as described in the above stage (a)], 10 ml of tetrahydrofuran and 70 mg of sociallyengaged with subsequent processing as described in the silica gel, using as eluent a mixture of methylene chloride and methanol with a volume ratio of 5:1, and the result was 113 mg (yield 46%) specified in the title compound as a colourless solid, melting at 63-66oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques: 1,7-2,05 (3H, multiplet); for 2.1 to 2.35 (1H, multiplet); to 2.29 (1H, doublet of doublets, J= 4,9 and 10.4 Hz); to 2.42 (3H, singlet); 2,7-2,95 (1H, multiplet); of 2.86 (4H, singlet); to 3.52 (1H, doublet of doublets, J=6,l and 10.4 Hz); 3,9-of 4.05 (2H, multiplet); 4.35 the-4,5 (1H, multiplet); 6,70 (1H, doublet, J=8,4 Hz); 7,15-to 7.35 (7H, multiplet).

EXAMPLE 11

(2R, 4R) -4-Hydroxy-1-methyl-2-{ 2- [5-methyl-2- (2-phenylethyl) phenoxy] ethyl}pyrrolidinedione

11 (a) (2R, R4) -1-Etoxycarbonyl-4-benzyloxy-2-{2-[5-methyl-2- (2-phenylethyl) phenoxy]ethyl}pyrrolidin

1000 mg 5-methyl-2- (2-phenylethyl) phenol was dissolved in 10 ml of N,N-dimethylacetamide, cooperated obtained solution of 580 mg of tert-butoxide potassium and 1620 mg of (2S, 4R)-4 - benzyloxy-2- (2-chloroethyl) -1-ethoxycarbonylpyrimidine and the reaction mixture was extracted as described in stage (a) of example 2. The obtained oily substance was purified by column chromatography on silica gel using as eluent a mixture of hexane and ethyl acetate to volume ratio of 3:1 and as a result got a 1680 mg (yield 73%) indicated in the title compound as an oily substance.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3 is of doublets, J=4,7 and 11.9 Hz); 3,55 of 4.3 (7H, multiplet); of 4.44 (2H, singlet); 6,6 to 6.75 (2H, multiplet); 6,99 (IH, doublet, J=7,4 Hz); and 7.1 to 7.4 (10H, multiplet).

11 (b) (2R, 4R) -1-Etoxycarbonyl-4-hydroxy-2-{2-[5-methyl-2 -(2-phenylethyl) phenoxy]ethyl}pyrrolidin

1680 mg of (2R, 4R)-1-etoxycarbonyl-4-benzyloxy-2-{2-[5 - methyl-2- (2-phenylethyl) phenoxy]ethyl}pyrrolidine [obtained as described in the above stage (a)] was dissolved in 15 ml of ethanol and then to the resulting solution were added 200 mg of the catalyst in the form of a 10% (weight/weight) of palladium on coal. Then, the resulting suspension was stirred under hydrogen at atmospheric pressure and at 60oC for 1.5 hours. At the end of this time was removed by filtration of the catalyst and the reaction solution was concentrated by evaporation under reduced pressure. The obtained concentrate was purified by column chromatography on silica gel using as eluent a mixture of hexane and ethyl acetate to volume ratio of 1:2 and the result was 1150 mg (yield 85%) indicated in the title compound as an oily substance.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques: 1.1 to about 1.35 (3H, multiplet); 1,7-of 2.25 (3H, multiplet); 2,25-2, 65 (1H, multiplet); 2,32 (3H, singlet); of 2.86 (4H, singlet); and 3.3 to 3.8 (1H, multiplet); 3,44 (1H, DAB (1H, doublet, J=7.5 Hz); 7,1-to 7.35 (5H, multiplet).

11 (C) (2R, 4R)-4-Hydroxy-1-methyl-2-{2-[5-methyl-2-(2 - phenylethyl)phenoxy] ethyl}pyrrolidin

Cooperated between 1150 mg of (2R, 4R)-1 - etoxycarbonyl-4-hydroxy-2-{ 2- [5-methyl-2- (2-phenylethyl) phenoxy] ethyl} pyrrolidine [obtained as described above in stage (b)], 18 ml of tetrahydrofuran and 330 mg of sociallyengaged with subsequent processing as described in stage (b) of example 1. Obtained with the concentrated substance was purified by column chromatography on silica gel using as eluent a mixture of methylene chloride and methanol with a volume ratio of 10:1 and the received 776 mg (yield 80%) indicated in the title compound as a colourless solid.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques is 1.6-1.8 (1H, multiplet); 1.85 to a 2.0 (2H, multiplet); of 2.15 to 2.35 (1H, multiplet); 2,20 (1H, doublet of doublets, J=5.4 and 10.0 Hz); of 2.33 (3H, singlet); of 2.38 (3H, singlet); 2,6-2,8 (1H, multiplet); 2,87 (4H, singlet); 3,47 (1H, doublet of doublets, J=6.4 and 10.0 Hz); 3,9-4,1 (2H, multiplet); 4,35-4,5 (1H, multiplet); 6,6 to 6.75 (2H, multiplet); 7,00 (1H, doublet, J=7,4 Hz); 7,15-to 7.35 (5H, multiplet).

11 (d) (2R, 4R)-4-Hydroxy-1-methyl-2-{ 2- [5-methyl-2- (2 - phenylethyl)phenoxy] ethyl}pyrrolidinedione
o
C.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques: 0-2,2 (1H, multiplet); 2,25-to 2.65 (3H, multiplet); of 2.33 (3H, singlet); 2,84 (4H, singlet); to 2.85 (3H, singlet); 2,98 (1H, doublet, J=12,6 Hz); 3.75 to 4,1 (3H, multiplet); 4.1 and of 4.25 (1H, multiplet); 4,55 with 4.65 (1H, multiplet); 6,66 (1H, singlet); 6.73 x (1H, doublet, J=7,4 Hz); 7,01 (1H, doublet, J=7,4 Hz); 7,1-to 7.35 (5H, multiplet).

EXAMPLE 12

(2R, 4R]-4-Hydroxy-1-methyl-2-{2-[4-methyl-2-(2-phenylethyl) phenoxy] ethyl} pyrrolidinedione

12 (a) (2R, 4R) -1-Etoxycarbonyl-4-benzyloxy-2-{2-[4 methyl-2- (2-phenylethyl) phenoxy] ethyl}pyrrolidin

1200 mg of 4-methyl-2-(2-phenylethyl) phenol was dissolved in 10 ml of N, N-dimethylacetamide, cooperated obtained rinnooy mixture was extracted in the same way, as described in stage (a) of example 2. The obtained oily substance was purified by column chromatography on silica gel using as eluent a mixture of hexane and ethyl acetate to volume ratio of 3:1 and the received 1820 mg (yield 73%) indicated in the title compound as an oily substance.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques: 1.1 to about 1.35 (3H, multiplet); a 1.7-2.1 (2H, multiplet); 2,2-2,6 (2H, multiplet); and 2.26 (3H, singlet); 2,87 (4H, singlet); of 3.42 (1H, doublet of doublets, J=4,7 and 11.9 Hz); 3,55 of 4.3 (7H, multiplet); of 4.44 (2H, singlet); 6,72 (1H, doublet, J=7,8 Hz); the 6.9 to 7.0 (2H, multiplet); of 7.1 to 7.4 (1OH, multiplet).

12 (b) (2R, 4R)-1-Etoxycarbonyl-4-hydroxy-2-[2-[4-methyl-2- (2-phenylethyl) phenoxy] ethyl} pyrrolidin

1820 mg of (2R, 4R)-1-etoxycarbonyl-4-benzyloxy-2-{2-[4 - methyl-2- (2-phenylethyl) phenoxy] ethyl} pyrrolidine [obtained as described in the above stage (a)] was dissolved in 20 ml of ethanol and then to the resulting solution were added 200 mg of the catalyst in the form of a 10% (weight/weight) of palladium on coal. Then the resulting mixture was stirred under hydrogen at atmospheric pressure and at 60oC for 2 hours. At the end of this time was removed by filtration of the catalyst and the reaction mixture was concentrated by cyprianophobia as eluent a mixture of hexane and ethyl acetate to volume ratio of 1:2, and the result obtained 1410 mg (yield 95%) indicated in the title compound as an oily substance.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques: 1.1 to about 1.35 (3H, multiplet); about 1.75 to 2.3 (3H, multiplet); of 2.25 (3H, singlet); 2,3-2,6 (1H, multiplet); of 2.86 (4H, singlet); 3,4-3,8 (1H, multiplet); of 3.42 (1H, doublet of doublets, J= 4,4 and 11.9 Hz); 3,98 (2H, triplet, J=5,9 Hz); 4,05 of 4.3 (1H, multiplet); of 4.12 (2H, Quartet, J=7,1 Hz); 4,3-of 4.45 (1H, multiplet); 6,72 (1H, doublet, J=7.9 Hz); the 6.9 to 7.0 (2H, multiplet); 7,15-to 7.35 (5H, multiplet).

12 (C) (2R, 4R)-4-Hydroxy-1-methyl-2-{2-[4-methyl-2-(2-phenylethyl) phenoxy]ethyl}pyrrolidin

Cooperated between 1410 mg of (2R, 4R)-1 - etoxycarbonyl-4-hydroxy-2-{2-[4-methyl-2- (2-phenylethyl) phenoxy]ethyl}pyrrolidine [obtained as described above in stage (b)], 20 ml of tetrahydrofuran and 400 mg sociallyengaged with subsequent processing as described in stage (b) of example 1. Obtained with the concentrated substance was purified by column chromatography on silica gel using as eluent a mixture of methylene chloride and methanol with a volume ratio of 5:1 and the received 884 mg (yield 73%) indicated in the title compound as a colourless solid.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques: 1,55-1,8 (1H, multiplet); of 1.8-2.0 (2H, multiplet); 2,15-2,3 (1H, multiplet); 2,20 (1H, doublet doublet is Hz); 3,9-4,1 (2H, multiplet); 4.35 the-4,5 (1H, multiplet); 6,74 (1H, doublet, J=8,9 Hz); 6,9-7,00 (2H, multiplet); 7,15-to 7.35 (5H, multiplet).

12(d) (2R, 4R)-4-Hydroxy-1-methyl-2-{2-[4-methyl-2-(2-phenylethyl) phenoxy] ethyl}pyrrolidinedione

884 mg of (2R, 4R)-4-hydroxy-1-methyl-2-{ 2-[4-methyl-2- (2 - phenylethyl)phenoxy] ethyl} pyrrolidine [obtained as described above in stage (c)] was dissolved in 10 ml of ethyl acetate and then to the resulting solution was added to 0.65 ml of 4 n solution of hydrogen chloride in ethyl acetate. Then solvent was removed by evaporation under reduced pressure. The obtained solid substance was dissolved in a small amount of methylene chloride and, after adding 10 ml of ethyl acetate to the resulting solution was allowed to stand at room temperature for about 10 minutes. The crystals deposited precipitates were collected by filtration and dried under vacuum, resulting in 905 mg (yield 92%) indicated in the title compounds as colorless crystals, melting at 136-138oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques: to 2.0-2.2 (1H, multiplet); 2,25-to 2.65 (3H, multiplet); and 2.27 (3H, singlet); and 2.83 (3H, singlet); of 2.86 (4H, singlet); to 2.94 (1H, doublet, J=a 12.7 Hz); of 3.7-3.9 (1H, multiplet); 3,9-4,1 (2H, multiplet); 4.1 and of 4.25 (1H, multiplet); 4,55 with 4.65 (1H, multi-1-methyl-2-{2-[6-methyl-2- (2-phenylethyl) phenoxy]ethyl} pyrrolidinedione

13 (a) (2R, 4R)-1-Etoxycarbonyl-4-benzyloxy-2-{2- [6 methyl-2- (2-phenylethyl)phenoxy]ethyl}pyrrolidin

1200 mg of 6-methyl-2-(2-phenylethyl)phenol was dissolved in 10 NN-dimethylacetamide, cooperated obtained solution of 700 mg of tert-butoxide potassium and 1600 mg of (2S, 4R-4)-benzyloxy-2- (2-chloroethyl) -1-ethoxycarbonylpyrimidine and the reaction mixture was extracted as described in stage (a) of example 2. The obtained oily substance was purified by column chromatography on silica gel using as eluent a mixture of hexane and ethyl acetate to volume ratio of 3:1 and he got 2260 mg (yield 90%) indicated in the title compound as an oily substance.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques: to 1.23 (3H, triplet, J= 7.0 Hz); about 1.75 and 2.1 (2H, multiplet); 2,2 - 2,6 (2H, multiplet); of 2.28 (3H, singlet); 2,90 (4H, singlet); of 3.42 (1H, doublet of doublets, J=4,5 and 11.9 Hz); 3,55 was 3.9 (3H, multiplet); 4,05 of 4.3 (2H, multiplet); of 4.12 (2H, Quartet, J= 7.0 Hz); 4,35-4,6 (2H, multiplet); 6,9-7,1 (3H, multiplet); and 7.1 to 7.4 (10H, multiplet).

13 (b) (2R, 4R) -1-Etoxycarbonyl-4-hydroxy-2-{2-[6-methyl-2- (2-phenylethyl)phenoxy]ethyl}pyrrolidin

2260 mg of (2R, 4R)-1-etoxycarbonyl-4-benzyloxy-2-{2-[6 - methyl-2- (2-phenylethyl) phenoxy] ethyl} pyrrolidine[received telesfora in the form of a 10% (weight/weight) of palladium on coal. Then the resulting mixture was stirred under hydrogen at atmospheric pressure and at 60oC for 1.5 hours. At the end of this time was removed by filtration of the catalyst and the reaction mixture was concentrated by evaporation under reduced pressure. The obtained concentrate was purified by column chromatography on silica gel using as eluent a mixture of hexane and ethyl acetate to volume ratio of 1:2 and as a result got 1840 mg (quantitative yield) specified in the title compound as an oily substance.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques: 1,15-1,2 (3H, multiplet); 1,75-of 2.05 (2H, multiplet); 2,05 was 2.25 (1H, multiplet); of 2.28 (3H, singlet); 2,35-2,6 (1H, multiplet); 2,90 (4H, singlet); 3,4-3,9 (3H, multiplet); of 3.42 (1H, doublet of doublets, J=4,2 and 11.9 Hz); 4,0-of 4.25 (3H, multiplet); 4,3-of 4.45 (1H, multiplet); 6,9-7,1 (3H, multiplet); 7,05-to 7.35 (5H, multiplet).

13 (c) (2R, 4R)-4-Hydroxy-1-methyl-2-{ 2-[6-methyl-2-(2-phenylethyl) phenoxy]ethyl}pyrrolidin

Cooperated between 1840 mg of (2R, 4R)-1 - etoxycarbonyl-4-hydroxy-2-{ 2- [6-methyl - 2- (2-phenylethyl) phenoxy] ethyl}pyrrolidine [obtained as described above in stage (b)], 20 ml of tetrahydrofuran and 530 mg of sociallyengaged followed obrabotkoi chromatography on silica gel using as eluent a mixture of methylene chloride and methanol with a volume ratio of 5:1, and the result was 1050 mg (yield 67%) specified in the title compound as a colourless solid.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques: 1,55-1,75 (1H, multiplet); of 1.8-2.0 (2H, multiplet); to 2.18 (1H, doublet of doublets, J=5,6 and 10.0 Hz); about 2.2 to 2.35 (1H, multiplet)? of 2.30 (3H, singlet); is 2.37 (3H, singlet); 2,6-of 2.75 (1H, multiplet); 2.91 in (4H, singlet); 3,43 (1H, doublet of doublets, J= 6.3 and 10.0 Hz); of 3.78 (2H, triplet, J=6.6 Hz); 4,3-4,55 (1H, multiplet); to 6.95 (1H, doublet of doublets, J=6.0 and 8.6 Hz); to 7.0, and 7.1 (2H, multiplet); 7,15-to 7.35 (5H, multiplet).

13(d) (2R, 4R)-4-Hydroxy-1-methyl-2-{2-[6-methyl-2-(2-phenylethyl)phenoxy] ethyl}pyrrolidinedione

1050 g of (2R, 4R)-4-hydroxy-1-methyl-2-{2-[6-methyl-2-(2 - phenylethyl)phenoxy] ethyl} pyrrolidine [obtained as described above in stage (c)] was dissolved in 10 ml of ethyl acetate and then to the resulting solution was added of 0.77 ml of 4 n solution of hydrogen chloride in ethyl acetate. Then solvent was removed by evaporation under reduced pressure. To the obtained solid substance was added 20 ml of ethyl acetate and the mixture was allowed to stand at room temperature for about 10 minutes. The crystals deposited precipitates were collected by filtration and dried under vacuum, resulting in 1024 mg (yield 88%) indicated in the title compounds as colorless crystals, melting at 114-115oC.

Spectrum of nuclear magnetic resonance (270 Hz); 2,45-to 2.65 (1H, multiplet); of 2.7-3.1 (5H, multiplet); 2,90 (3H, singlet); 3,7-4,0 (3H, multiplet); 4,0-4, 2 (1H, multiplet); 4,5 with 4.65 (1H, multiplet); 6,9-7,1 (3H, multiplet); 7,15-to 7.35 (5H, multiplet).

EXAMPLE 14

(2R, 4R-4-Hydroxy-2-{2- [4-methoxy-2- (2-phenylethyl) - phenoxy]ethyl}-1-methylpyrrolidinone

14 (a) (2R, 4R) -1-Etoxycarbonyl-4-hydroxy-2-{2-[4-methoxy - 2-(2-phenylethyl)phenoxy]ethyl}pyrrolidin

1300 mg of 4-methoxy-2-(2-phenylethyl) phenol was dissolved in 10 ml of N,N-dimethylacetamide, cooperated obtained solution of 610 mg of tert-butoxide and potassium 1000 mg (2S, 4R-2- (2-chloroethyl) -1-etoxycarbonyl-4-hydroxypyrrolidine and the reaction mixture was extracted as described in stage (a) of example 2. The obtained oily substance was purified by column chromatography on silica gel using as eluent a mixture of hexane and ethyl acetate to volume ratio of 1:2 and the result was 448 mg (yield 24%) indicated in the title compound as an oily substance.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques: 1.1 to about 1.35 (3H, multiplet); a 1.7-2.1 (2H, multiplet); from 2.1 to 2.25 (1H, multiplet); 2,25-2,6 (1H, multiplet); is 2.88 (4H, singlet);. 3,44 (iH, doublet of doublets, J= 4,4 and 11.9 Hz); 3.45 points of 3.75 (1H, multiplet); to 3.73 (3H, singlet); of 3.97 (2H, triplet,4R)-4-Hydroxy-2-{2- [4-methoxy-2- (2-phenylethyl) phenoxy] ethyl}-1-methylpyrrolidine

Cooperated between 448 mg (2R, 4R)-1-etoxycarbonyl-4-hydroxy-2-{2-[4-methoxy-2- (2-phenylethyl) phenoxy]ethyl}pyrrolidine [obtained as described in the above stage (a)], 10 ml of tetrahydrofuran and 120 mg sociallyengaged with subsequent processing as described in stage (b) of example 1. Obtained with the concentrated substance was purified by column chromatography on silica gel using as eluent a mixture of methylene chloride and methanol with a volume ratio of 5:1, and the result was 144 mg (yield 37%) indicated in the title compound as a colourless solid.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques: 1,6-1,8 1IH, multiplet); 1.85 to a 2.0 (2H, multiplet); 2,1-2,3 (1H, multiplet); 2,22 (1H, doublet of doublets, J= 5.1 to 10.2 Hz); 2,39 (3H, singlet); 2,6-2,8 (1H, multiplet); is 2.88 (4H, singlet); of 3.48 (1H, doublet of doublets, J=6,3 and 10.2 Hz); 3,74 (3H, singlet); 3,85-of 4.05 (2H, multiplet); 4,35-4,5 (1H, multiplet); 6,65-6,85 (3H, multiplet); 7,1-to 7.35 (5H, multiplet).

14 (C) (2R, 4R)-4-Hydroxy-2-{2-[4-methoxy-2-(2-phenylethyl) phenoxy]ethyl} -1-methylpyrrolidinone

144 g of (2R, 4R)-4-hydroxy-2-{2-[4-methoxy-2-(2-phenylethyl) phenoxy]ethyl} -1-methylpyrrolidine [obtained as described above stage (b)] was dissolved in 5 ml utilitzar by evaporation under reduced pressure. The obtained oily substance was dissolved in 1 ml of methylene chloride and to the solution was added diethyl ether until turbidity of the solution. Then turbid mixture was allowed to stand at room temperature for about 10 minutes. The crystals deposited precipitates were collected by filtration and dried under vacuum, resulting in 137 mg (yield 86%) indicated in the title compounds as colorless crystals, melting at 63-65oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques: 2,05-2,2 (1H, multiplet); 2,30 (1H, doublet of doublets, J=5,8 and 13.9 Hz); 2,35-to 2.65 (2H, multiplet); 2.8 to 3.0 (1H, multiplet); to 2.85 (3H, singlet); 2,87 (4H, singlet); 3,74 (3H, singlet); 3,7-4,2 (4H, multiplet); 4,55 with 4.65 (1H, multiplet); 6,65 - 6, 85 (2H, multiplet); 6,72 (1H, singlet); 7,1-to 7.35 (5H, multiplet).

EXAMPLE 15

(2R, 4R)-4-Hydroxy-2-{ 2-[5-methoxy-2- (2-phenylethyl) - phenoxy]ethyl}-1-methylpyrrolidinone

15 (a) (2R, 4R)-1-Dimethylcarbamoyl-2-[5-methoxy-2- (2-phenylethyl) phenoxy)ethyl}-1-octyloxybenzophenone

670 mg of 5-methoxy-2-(2-phenylethyl) phenol (obtained as described in obtaining 1) was dissolved in 10 ml of N,N-dimethylacetamide, cooperated resulting solution with 360 mg of tert - butoxide and potassium 1000 mg (2S, 4R-2-(2-chloroethyl) -4 - Dimitri (a) of example 2. The obtained oily substance was purified by column chromatography on silica gel using as eluent a mixture of hexane and ethyl acetate to volume ratio of 1:1 and the received 1500 mg (yield 99%) specified in the title compound as an oily substance.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques: 0,8-0,95 (3H, multiplet); 1,15-of 1.45 (10H, multiplet); 1,5 - 1,75 (2H, multiplet); 1,75-of 2.15 (2H, multiplet); 2,25-2,8 (2H, multiplet); of 2.7-3.0 (4H, multiplet); 2,83 (6N, singlet); of 3.5-3.9 (1H, multiplet); of 3.53 (1H, doublet of doublets, J= 4,3 and 12.6 Hz); of 3.78 (3H, singlet); of 3.9 to 4.3 (5H, multiplet); 5,1-a 5.25 (1H, multiplet); 6,35 to 6.5 (2H, multiplet); 6,98 (1H, doublet, J= 8.1 Hz); 7,1-7,3 (5H, multiplet).

15(b) (2R, 4R)-4-Hydroxy-2-{2-[5-methoxy-2-(2-phenylethyl) phenoxy]ethyl} -1-methylpyrrolidine

Cooperated between 1500 mg of (2R, 4R)-4 - dimethylcarbamoyl-2-{ 2-[5-methoxy-2- (2-phenylethyl) phenoxy] - ethyl}-1-octyloxybenzophenone [obtained as described in the above stage (a)], 25 ml of tetrahydrofuran and 310 mg of sociallyengaged with subsequent processing as described in stage (b) of example 1. Obtained with the concentrated substance was purified by column chromatography on silica gel using as nogo the title compound as a colourless solid.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques is 1.6-1.8 (1H, multiplet); of 1.8-2.0 (2H, multiplet); 2,15-2,3 (1H, multiplet); 2,20 (1H, doublet of doublets, of 5.5 and 10.1 Hz); of 2.38 (3H, singlet); 2,6-of 2.75 (1H, multiplet); 2,84 (4H, singlet); of 3.46 (1H, doublet of doublets, J=6.4 and 10.1 Hz); with 3.79 (3H, singlet); 3,9-4,1 (2H, multiplet); 4,35-4,5 (1H, multiplet); 6,35 to 6.5 (2H, multiplet); 7,00 (1H, doublet, J=8.0 Hz); 7,05-to 7.35 (5H, multiplet).

15 (c) (2R, 4R)-4-Hydroxy-2-{2-[5-methoxy-2-(2 - phenylethyl)phenoxy]ethyl} -1-methylpyrrolidinone

385 g of (2R, 4R)-4-hydroxy-2-{2-[5-methoxy-2-(2-phenylethyl) phenoxy]ethyl} -1-methylpyrrolidine [obtained as described above in stage (b)] was dissolved in 5 ml of dioxane and then to the resulting solution was added with 0.27 ml of 4 n solution of hydrogen chloride in dioxane. Then solvent was removed by evaporation under reduced pressure. The obtained oily substance was dissolved in 10 ml of ethyl acetate and the solution was allowed to stand at room temperature for about 10 minutes. The crystals deposited precipitates were collected by filtration and dried under vacuum, resulting in 385 mg (yield 91%) indicated in the title compounds as colorless crystals, melting at 108-110 C.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques: 1H, doublet, J= 12.3 Hz); 3.75 to a 3.9 (1H, multiplet); with 3.79 (3H, singlet); 3,9-4,2 (3H, multiplet); 4,55 with 4.65 (1H, multiplet); 6,4-6,5 (2H, multiplet); 7,01 (1H, doublet, J=7.9 Hz); 7,1-to 7.35 (5H, multiplet).

EXAMPLE 16

(2R, 4R)-4-Hydroxy-2-{ 2-[6-methoxy-2-(2 - phenylethyl) phenoxy]ethyl}-1-methylpyrrolidinone

16 (a) (2R, 4R)-1-Dimethylcarbamoyl-2-{ 2-[6-methoxy-2- (2-phenylethyl)phenoxy]ethyl}-1-octyloxybenzophenone

670 mg of 6-methoxy-2-(2-phenylethyl) phenol was dissolved in 10 ml of N,N-dimethylacetamide, cooperated resulting solution with 360 mg of tert-butoxide and potassium 1000 mg (2S, 4R)-2-(2 - chloroethyl) -4-dimethylcarbamoyl-1 octyloxybenzophenone and the reaction mixture was extracted as described in stage (a) of example 2. The obtained oily substance was purified by column chromatography on silica gel using as eluent a mixture of hexane and ethyl acetate to volume ratio of 1:1 and the received 1500 mg (yield 99%) specified in the title compound as an oily substance.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl)3memorial plaques: 0,8-0,95 (3H, multiplet); 1,15-of 1.45 (10H, multiplet); 1,5-1,7 (2H, multiplet); 1,75 - 2,05 (1H, multiplet); 2,05-2,2 (1H, multiplet); 2,25-2,6 (2H, multiplet); of 2.75 to 3.0 (4H, multiplet); 2,90 (6H, sin is ipled); 6,7-6,8 (2H, multiplet); of 6.96 (1H, triplet, J=7.9 Hz); 7,1-to 7.35 (5H, multiplet).

16 (b) (2R, 4R)-4-Hydroxy-2-{2-[6-methoxy-2-(2-phenylethyl) phenoxy]ethyl} -1-methylpyrrolidine

Cooperated between 1500 mg of (2R, 4R)-4 - dimethylcarbamoyl-2-{ 2-[6-methoxy-2- (2-phenylethyl) phenoxy]ethyl}-1-octyloxybenzophenone [obtained as described in the above stage (a)], 25 ml of tetrahydrofuran and 300 mg sociallyengaged with subsequent processing as described in stage (b) of example 1. Obtained with the concentrated substance was purified by column chromatography on silica gel using as eluent a mixture of methylene chloride and methanol with a volume ratio of 5:1 and the received 552 mg (yield 59%) indicated in the title compound as a colourless solid.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques: 1,55-1,75 (2H, multiplet); of 1.8-2.0 (2H, multiplet); 2,15-2,4 (1H, multiplet); to 2.18 (1H, doublet of doublets, J=5.4 and 10.1 Hz); is 2.37 (3H, singlet); 2,6-of 2.75 (1H, multiplet); 2.8 to 3.0 (4H, multiplet); of 3.45 (1H, doublet of doublets, J=6.4 and 10.1 Hz); of 3.84 (3H, singlet); 3,85-of 4.05 (2H, multiplet); 4,3-of 4.45 (1H, multiplet); 6,7-6,85 (2H, multiplet); 6,97 (1H, triplet, J=7,8 Hz); 7,1-to 7.35 (5H, multiplet).

16 (c) (2R, 4R)-4-Hydroxy-2-{2-[6-methoxy-2-(2-FeII] ethyl] -1-methylpyrrolidine [received so as described above in stage (b)] was dissolved in 10 ml of ethyl acetate and then to the resulting solution was added to 0.39 ml of 4 n solution of hydrogen chloride in ethyl acetate. Then solvent was removed by evaporation under reduced pressure. The obtained oily substance was dissolved in 10 ml of ethyl acetate and the solution was allowed to stand at room temperature for about 10 minutes. The crystals deposited precipitates were collected by filtration and dried under vacuum, resulting in 424 mg (yield 70%) indicated in the title compounds as colorless crystals, melting at 70-72oC

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques: 2,05-2,2 (1H, multiplet); 2,2-2,6 (2H, multiplet); 2,44 (1H, doublet of doublets, J=5,7 and 13.9 Hz); 2,8-3,1 (1H, multiplet); 2,89 (4H, singlet); of 2.93 (3H, singlet); 3.75 to a 3.9 (1H, multiplet); of 3.84 (3H, singlet); 3,9 - 4,2 (3H, multiplet); 4,55-4, 65 (1H, multiplet); 6,75-6,85 (2H, multiplet); 7,01 (1H, triplet, J=7.9 Hz); 7,1-to 7.35 (5H, multiplet).

EXAMPLE 17

(2R, 4R)-2-{2-[5-Chloro-2- (2-phenylethyl) phenoxy]ethyl}-4 hydroxy-1-methylpyrrolidinone

17 (a) (2R, 4R)-2-{2-[5-Chloro-2-(2 - phenylethyl)phenoxy]ethyl}-4-dimethylcarbamoyl-1 - octyloxybenzophenone

680 mg of 5-chloro-2-(2-phenylethyl)phenol (obtained as described in gaining the sid and potassium 1000 mg (2S, 4R)-2-(2-chloroethyl)-4 - dimethylcarbamoyl-1 octyloxybenzophenone and the reaction mixture was extracted as described in stage (a) of example 2. The obtained oily substance was purified by column chromatography on silica gel using as eluent. a mixture of hexane and ethyl acetate to volume ratio of 1:1 and as a result got to 1.38 g (yield 91%) indicated in the title compound as an oily substance.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques: of 0.8-1.0 (3H, multiplet); 1,15-of 1.45 (10H, multiplet); 1,45 - 1,7 (2H, multiplet); 1,75-of 2.15 (2H, multiplet); 2,25-2,7 (2H, multiplet); of 2.7-3.0 (4H, multiplet); to 2.85 (3H, singlet); 2,87 (3H, singlet); of 3.53 (1H, doublet of doublets, J= 4,1 and 12.6 Hz); 3,6-3,9 (1H, multiplet); of 3.9 to 4.3 (5H, multiplet); 5,1-5,3 (1H, multiplet); 6,7-6,9 (2H, multiplet); 6,97 (1H, doublet, J=7.9 Hz); 7,1-to 7.35 (5H, multiplet).

17(b) (2R, 4R)-2-{2-[5-Chloro-2-(2-phenylethyl)phenoxy]ethyl}-4-hydroxy-1 - methylpyrrolidine

Cooperated between 1380 mg of (2R, 4R)-2-{2- [5-chloro-2- (2-phenylethyl) phenoxy] ethyl}-4 - dimethylcarbamoyl-1 actionstartconversation [obtained as described in the above stage (a)], 20 ml of tetrahydrofuran and 450 mg sociallyengaged with subsequent processing as described in stage (b) primavolta as elution solvent a mixture of methylene chloride and methanol with a volume ratio of 5:1, and the result was 256 mg (yield 30%) specified in the title compound as a colourless solid.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques is 1.6-1.8 (1H, multiplet); 1,8-of 2.05 (2H, multiplet); 2,1-2,3 (1H, multiplet); 2,22 (1H, doublet of doublets, J=5.4 and 10.1 Hz); 2,39 (3H, singlet); 2,6 - of 2.75 (1H, multiplet); 2.8 to 2.95 for (4H, multiplet); of 3.48 (1H, doublet of doublets, J=6.3 and 10.1 Hz); 3,9-4,1 (2H, multiplet); 4,35-4,5 (1H, multiplet); 6,75-6,9 (2H, multiplet); 6,99 (1H, doublet, J=7,8 Hz); 7,1-to 7.35 (5H, multiplet).

17 (c) (2R, 4R)-2-{2-[5-Chloro-2-(2-phenylethyl)phenoxy]ethyl}-4-hydroxy-1-methylpyrrolidinone

256 mg of (2R, 4R)-2-{2-[5-chloro-2-(2 - phenylethyl)phenoxy]ethyl}-4-hydroxy-1-methylpyrrolidine [obtained as described above in stage (b)] was dissolved in 5 ml of ethyl acetate and then to the resulting solution was added to 0.18 ml of 4 n solution of hydrogen chloride in ethyl acetate. Then solvent was removed by evaporation under reduced pressure. The obtained oily substance was dissolved in 10 ml of ethyl acetate and the solution was allowed to stand at room temperature. The crystals deposited precipitates were collected by filtration and dried under vacuum, resulting in 183 mg (yield 65%) indicated in the title compounds as colorless crystals, melting at 99-102oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques: 2,05-of 2.25 (1H, multiplet); 2,31 (1H, DM, multiplet); 4,55 is 4.7 (1H, multiplet); PC 6.82 (1H, doublet, J= 1.9 Hz); 6,85-7,0 (1H, multiplet); 7,02 (1H, doublet, J=8.0 Hz); 7,1-to 7.35 (5H, multiplet).

EXAMPLE 18

(2R, 4R)-2-{ 2-[6-fluoro-2- (2-phenylethyl) phenoxy]ethyl}-4 hydroxy-1-methylpyrrolidinone

18 (a) (2R, 4R)-4-Dimethylcarbamoyl-2-{ 2-[6-fluoro-2 (2-phenylethyl)phenoxy]ethyl}-1-octyloxybenzophenone

520 mg of 6-fluoro-2-(2-phenylethyl) phenol (obtained as described in 10) was dissolved in 10 ml of N, N-dimethylacetamide, cooperated resulting solution with 300 mg of tert-butoxide potassium and 820 mg (2S, 4R)-2-(2-chloroethyl)-4 - dimethylcarbamoyl-1 octyloxybenzophenone and the reaction mixture was extracted as described in stage (a) of example 2. The obtained oily substance was purified by column chromatography on silica gel using as eluent a mixture of hexane and ethyl acetate to volume ratio of 2:1 and as a result got 984 mg (yield 81%) indicated in the title compound as an oily substance.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques: 0,8-0,95 (3H, multiplet); 1,15-of 1.45 (10H, multiplet); 1,55-1,7 (2H, multiplet); 1,7-2,0 (1H, multiplet); a 2.0 to 2.15 (1H, multiplet); 2,25-2,6 (2H, multiplet); of 2.75 to 3.0 (4H, multiplet); 2,89 (6N, singlet); 3,54 (1 is t); 7,1-7,3 (5H, multiplet).

18 (b) (2R, 4R)-2-{2-[6-fluoro-2- (2-phenylethyl)phenoxy]ethyl}-4-hydroxy-1-methylpyrrolidine

Cooperated between 984 mg of (2R, 4R)-4 - dimethylcarbamoyl-2-{ 2-[6-fluoro-2- (2-phenylethyl)phenoxy] ethyl}-1-octyloxybenzophenone [obtained as described in the above stage (a)], 20 ml of tetrahydrofuran and 200 mg sociallyengaged with subsequent processing as described in stage (b) of example 1. Obtained with the concentrated substance was purified by column chromatography on silica gel using as eluent a mixture of methylene chloride and methanol with a volume ratio of 5:1, and the result was 319 mg (yield 53%) indicated in the title compound as an oily substance.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques: 1,55-1,75 (1H, multiplet); of 1.8-2.0 (2H, multiplet); of 2.15 to 2.35 (1H, multiplet); 2,19 (1H, doublet of doublets, J=5.4 and 10.1 Hz); is 2.37 (3H, singlet); 2,6 - of 2.75 (1H, multiplet); 2.8 to 3.0 (4H, multiplet), of 3.45 (1H, doublet of doublets, J=6.3 and 10.1 Hz); 3.95 to to 4.15 (2H, multiplet); 4,35 is 4.45 (1H, multiplet); 6,85-7,0 (3H, multiplet); 7,15-to 7.35 (5H, multiplet).

18 (c) (2R, 4R)-2-{2- [6-fluoro - 2-(2-phenylethyl) phenoxy]ethyl}-4-hydroxy-1-methylpyrrolidinone

319 mg (2R, 4R)-2-{2-[6-fluoro-2-(2 - phenylethyl)pheno is cetate and then to the resulting solution was added to 0.23 ml 4 N. solution of hydrogen chloride in ethylacetate. Then solvent was removed by evaporation under reduced pressure. The obtained oily substance was dissolved in ethyl acetate and the solution was allowed to stand at room temperature. The crystals deposited precipitates were collected by filtration and dried under vacuum, resulting in 320 mg (yield 91%) indicated in the title compounds as colorless crystals, melting at 136-138oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques: to 2.0-2.2 (1H, multiplet); 2,2-2,6 (3H, multiplet); 2,8-3,1 (5H, multiplet); 2,92 (3H, singlet); 3,8-of 4.25 (4H, multiplet); 4,55 is 4.7 (1H, multiplet); 6,85-7,05 (3H, multiplet); and 7.1 to 7.4 (5H, multiplet).

EXAMPLE 19

(2R, 4R) -2- [2-{4-fluoro-2- [2- (4-fluoro-3-methoxyphenyl) ethyl] -phenoxy} ethyl] -4-euroluxe-1-methylpyrrolidinone

19 (a) (2R, 4R)-2-[2-{4-fluoro-2-[2-(4-fluoro-3-methoxyphenyl)- ethyl] -phenoxy}ethyl]-4-euroluxe-1 methylpyrrolidine

513 mg (2R, 4R)-2-[2-{4-fluoro-2-[2-(4-fluoro-3-methoxyphenyl)- ethyl] phenoxy}ethyl] -4-hydroxy-1-methylpyrrolidine [obtained as described in stage (b) of example 4] was dissolved in 10 ml of pyridine and then to the resulting solution was added 652 mg of lauric anhydride and 48 mg of 4-dimethylaminopyridine with stirring at on the 0oC for 1 hour. After this time has added about 100 ml of ethyl acetate and the reaction mixture was washed two times 1 N. chloroethanol acid and then once with a saturated aqueous solution of sodium chloride, in that order. An ethyl acetate layer was dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The obtained oily substance was purified by column chromatography on silica gel using as eluent a mixture of methylene chloride and methanol with a volume ratio of 5: 1 and the received 684 mg (yield 91%) indicated in the title compounds as a colorless oily substance.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques: to 0.88 (3H, triplet, J=6.6 Hz); 1,15-1,4 (16H, multiplet); 1,45-of 1.85 (3H, multiplet); 1.85 to 2.1 a (2H, multiplet); 2,15-2,3 (2H, multiplet); 2,22 (2H, triplet, J= 7,6 Hz); of 2.38 (3H, singlet); 2,55-2,7 (1H, multiplet); of 2.7-3.0 (4H, multiplet); of 3.60 (1H, doublet of doublets, J==6,6 and 10.7 Hz); a 3.83 (3H, singlet); 3,85-of 4.05 (2H, multiplet); of 5.05 was 5.2 (1H, multiplet); 6,6-7,05 (6N, multiplet).

19(b) (2R, 4R)-2-[2-{4-fluoro-2-[2-(4-fluoro-3-methoxyphenyl) ethyl]phenoxy} ethyl]-4-euroluxe-1-methylpyrrolidinone

684 mg of (2R, 4R)-2-[2-{4-fluoro-2-[2-(4-fluoro-3-methoxyphenyl) ethyl]FML dioxane and the resulting solution was added to 0.45 ml of 4 N. solution of hydrogen chloride in dioxane. Then the solution was concentrated by evaporation under reduced pressure. To the residue was added hexane and precipitated precipitated crystals were collected by filtration and dried under vacuum, resulting in 485 mg (yield 67%) indicated in the title compounds as colorless crystals, melting at 49-53oC.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques:

to 0.88 (3H, triplet, J=6.6 Hz); 1.1 to 1.4 (M, multiplet); 1,4-1,7 (2H, multiplet); of 2.21 (2H, triplet, J=7,6 Hz); of 2.3-2.5 (2H, multiplet); 2.5 and 2.7 (2H, multiplet); of 2.75 to 3.0 (5H, multiplet); 2,86 (3H, singlet); 3.45 points to 3.7 (1H, multiplet); a 3.83 (3H, singlet); 3.9 to of 4.05 (1H, multiplet); 4,1-of 4.25 (1H, multiplet); 4.25, as is 4.45 (1H, multiplet); 5,3-5,4 (1H, multiplet); 6,55-7,05 (6N, multiplet).

EXAMPLE 20

(2R, 4R)-2-[2-{ 4-fluoro-2-[2-(3-methoxyphenyl)ethyl] phenoxy}-ethyl]-4-euroluxe-1-methylpyrrolidinone

20 (a) (2R, 4R)-2-[2-{4-fluoro-2-[2-(3-methoxyphenyl)ethyl] phenoxy}ethyl]-4-euroluxe-1 methylpyrrolidine

Cooperated between 1.13 g of (2R, 4R)-2-[2- {4-fluoro-2- [2- (3-methoxyphenyl) ethyl]phenoxy}ethyl]-4-hydroxy - 1-methylpyrrolidine [obtained as described in stage (b) of example 1], 1.50 g of lauric anhydride and 0.11 g of 4-dimethylaminopyridine in 20 ml of pyridine and reactiontime column chromatography on silica gel using as eluent a mixture of methylene chloride and methanol with a volume ratio of 5: 1 and as a result got to 1.34 g (yield 80%) indicated in the title compounds as a colorless oily substance.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques: to 0.88 (3H, triplet, J= 6.6 Hz); 1,15-1,4 (N, multiplet); of 1.45 to 1.8 (3H, multiplet); 1.85 to 2.1 a (2H, multiplet); 2,15-2,3 (2H, multiplet); of 2.21 (2H, triplet, J= 7,6 Hz); 2,39 (3H, singlet); 2,6-of 2.75 (1H, multiplet); of 2.75 to 3.0 (4H, multiplet); 3,62 (1H, doublet of doublets, J=6,6 and 10.8 Hz); of 3.78 (3H, singlet); 3,85 of 4.1 (2H, multiplet); of 5.05 was 5.2 (1H, multiplet); 6,7-6,9 (6N, multiplet); 7,15-of 7.25 (1H, multiplet).

20(b) (2R, 4R)-2-[2-{4-fluoro-2-[2-(3-methoxyphenyl)ethyl] phenoxy}ethyl]-4-euroluxe-1-methylpyrrolidinone

of 1.34 g of (2R, 4R)-2-[2-{4-fluoro-2-[2-(3-methoxyphenyl)ethyl]- phenoxy}ethyl] -4-euroluxe-1 methylpyrrolidine [obtained as described in the above stage (a)] was dissolved in 15 ml of dioxane and the resulting solution was added to 0.90 ml of 4 n solution of hydrogen chloride in dioxane. Then the solution was concentrated by evaporation under reduced pressure. The obtained residue was purified by decantation three times with hexane, and the obtained oily substance was dried under vacuum, resulting in 1.39 g (yield 97%) indicated in the title compounds as a colorless oily substance.

The spectrum of infrared radiation (film)maxcm-1; 1739, 1601, 1584, 1499, 1468, 1456, 1258, 1216, 1156.

Spectrum of nuclear magnetic resonance 5-2,5 (2H, multiplet); at 2.5-2.7 (2H, multiplet); of 2.75 to 3.0 (5H, multiplet); 2,86 (3H, singlet); 3,6-of 3.85 (1H, multiplet); of 3.78 (3H, singlet); 3,85-of 4.05 (1H, multiplet); of 4.1 and 4.3 (1H, multiplet); of 4.35 (1H, doublet of doublets, J= 5,7 and 13.6 Hz); 5,3-5,4 (1H, multiplet); 6,55-7,0 (6N, multiplet); 7,21 (1H, triplet, J=7,8 Hz).

GETTING 1

5-Methoxy-2- (2-phenylethyl)phenol

3.0 g of 2-hydroxy-4-methoxybenzaldehyde was dissolved in 30 ml of acetonitrile and the resulting solution was added 9.2 grams of benzyltriphenylphosphonium. The resulting mixture was stirred at 80oC for 30 minutes and then added 3,53 ml of 1,8-diazabicyclo [5.4.0]-7-undecene (DBU). Then the reaction mixture was heated under reflux for 1 hour. At the end of this time the solvent was removed by evaporation under reduced pressure. To the residue was added ethyl acetate and water. An ethyl acetate layer was separated and concentrated by evaporation under reduced pressure. Then the residue was purified by column chromatography on silica gel using as eluent a mixture of hexane and ethyl acetate to volume ratio of 2:1 and as a result got 4,37 g solids. This solid was dissolved in 50 ml of ethanol and then to the resulting solution was added 0.5 g of 5% (mass/mass) palladium cepo the end of that time was removed by filtration of the catalyst. The filtrate was concentrated by evaporation under reduced pressure and purified by column chromatography on silica gel using as eluent a mixture of hexane and ethyl acetate to volume ratio of 3:1 and as a result got to 1.60 g (yield 36%) indicated in the title compound as a colourless solid.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques: 2,75-2,95 (4H, multiplet); 3,74 (3H, singlet); to 4.87 (1H, singlet); 6,33 (IH, doublet, J= 2.5 Hz); 6.42 per (1H, doublet of doublets, J=2,5 and 8.3 Hz); 6,97 (1H, doublet, J= 8,3 Hz); 7,15-to 7.35 (5H, multiplet).

GETTING 2

4-Bromo-2- (2-phenylethyl) phenol

6.0 g of 2-hydroxy-5-brombenzonitrila was dissolved in 70 ml of acetonitrile and the resulting solution was added to 13.9 g benzyltriphenylphosphonium. The resulting mixture was stirred at 80oC for 15 minutes and then added with 5.3 ml of DBU. Then the reaction mixture was heated under reflux for 1 hour. At the end of this time the solvent was removed by evaporation under reduced pressure. To the residue was added ethyl acetate and water. An ethyl acetate layer was separated and concentrated by evaporation under reduced pressure. Then the residue was purified by column chromatography on silica gel with whether 7,44 g solids. This solid substance was dissolved in 150 ml of ethanol and then to the resulting solution was added 0.8 g of chloride, Tris(triphenylphosphine)rhodium(1). The reaction mixture was stirred under hydrogen at atmospheric pressure and at 50oC for 24 hours. Then to the reaction mixture were added saturated aqueous Hydrosulphite solution of sodium and the mixture was stirred for about 10 minutes. The obtained insoluble substance was filtered using a Celite (trade mark) as an auxiliary filter substance. The filtrate was concentrated by evaporation under reduced pressure and purified by column chromatography on silica gel using as eluent a mixture of hexane and ethyl acetate to volume ratio of 3:1 and he got 7,13 g (yield 86%) indicated in the title compound as an oily substance.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques: a 2.75 to 3.0 (4H, multiplet); 5,13 (1H, singlet); is 6.61 (1H, doublet, J=8.5 Hz); 7,1-to 7.35 (7H, multiplet).

GETTING 3

4-fluoro-2- (2-phenylethyl) phenol

Cooperated 0.91 g of benzaldehyde, of 4.00 g of 5-fluoro-2-ethoxymethylenemalononitrile (obtained as described in obtaining 8) and 1.28 ml of E. using as eluent a mixture of hexane and ethyl acetate with the ratio of 10:1 as well as described in the getting 2 that gave 2,04 g of oily substance. 2,03 g of this oily substance was dissolved in 12 ml of a mixture (1:2 by volume) of benzene and ethanol and to the resulting solution was added to 0.30 g of chloride, Tris(triphenylphosphine) rhodium (1). The resulting mixture was stirred under hydrogen at atmospheric pressure and at 60oC for 8 hours. At the end of this time the reaction solution was filtered through Celite (trademark). The filtrate was concentrated by evaporation under reduced pressure and was purified column chromatography on silica gel using as eluent a mixture of hexane and ethyl acetate with the ratio of 10:1. Then the purified substance was dissolved in 10 ml of ethyl acetate and the resulting solution was added under ice cooling 10 ml of 4 n solution of hydrogen chloride in ethyl acetate. The resulting mixture was allowed to stand at room temperature for 2 hours, after which it was concentrated by evaporation under reduced pressure and purified by column chromatography on silica gel using as eluent a mixture of hexane and ethyl acetate with a ratio of 5:1, resulting in 1.45 g (yield 79%) indicated in the title compound in the form of a solid substance.

Spectrum of nuclear magnetic tx2">

GETTING 4

4-fluoro-2- [2- (3-methoxyphenyl) ethyl]phenol

Cooperated between 312 mg of 2-hydroxy-5 - forventelige, 1110 mg 3-methoxybenzenesulfonamide and 0.37 ml of DBU in 20 ml of acetonitrile, after which the mixture was treated and purified by column chromatography on silica gel using as eluent a mixture of hexane and ethyl acetate to 2:1 as described in the getting 2 that gave 526 mg solids. This solid was dissolved in 12 ml of a mixture (1:2 by volume) of benzene and ethanol and to the resulting solution was added 52 mg of chloride, Tris(triphenylphosphine)rhodium(1). The resulting mixture was stirred under hydrogen at atmospheric pressure and at room temperature for 7 hours. Was added to the reaction mixture, saturated aqueous Hydrosulphite solution of sodium and the mixture is then stirred for about 10 minutes. The obtained insoluble substance was filtered using a Celite (trade mark) as the filter material. The filtrate was concentrated by evaporation under reduced pressure and purified by column chromatography on silica gel using as eluent a mixture of hexane and ethyl acetate to volume ratio of 2: 1 and as a result got a 404 is itogo resonance (270 MHz, CDCl3) memorial plaques: is 2.88 (4H, singlet); of 3.78 (3H, singlet); to 4.52 (1H, singlet); 6,65-6,85 (6N, multiplet); 7,21 (1H, triplet, J=7.5 Hz).

GETTING 5

4-fluoro-2-[2- (4-fluoro-3-methoxyphenyl) ethyl]phenol

5 (a) Simple methoxymethyl { 4-fluoro-2-2-(4-fluoro-3 - methoxyphenyl) ethyl] phenyl}ether

Cooperated between 547 mg of 4-fluoro-3 - methoxybenzaldehyde, 1990 mg of 5-fluoro-2 - ethoxymethylenemalononitrile (obtained as described in obtaining 8) and of 0.58 ml of DBU in 30 ml of acetonitrile, after which the mixture was treated and purified column chromatography on silica gel using as eluent a mixture of hexane and ethyl acetate with the ratio of 4: 1 as described in the getting 2 that gave 948 mg of an oily substance. 936 mg of this oily substance was dissolved in 9 ml of a mixture (1:2 by volume) of benzene and ethanol and to the resulting solution was added 155 mg of chloride, Tris (triphenylphosphine)rhodium(1). The resulting mixture was stirred under hydrogen at atmospheric pressure and at 60oC for 14 hours. Was added to the reaction mixture, saturated aqueous Hydrosulphite solution of sodium and the mixture is then stirred for about 10 minutes. The obtained insoluble substance was filtered using a Celite (trade mark) as filltoy chromatography on silica gel using as eluent a mixture of hexane and ethyl acetate to volume ratio of 4:1 and as a result received 785 mg (yield 73%) indicated in the title compound as an oily substance.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques: a 2.75 to 3.0 (4H, multiplet); 3,47 (3H, singlet); of 3.84 (3H, singlet); 5,12 (2H, singlet); 6,65 to 6.75 (2H, multiplet); 6,75-6,9 (2H, multiplet); 6,9-7,1 (2H, multiplet).

5 (b) 4-fluoro-2-[2- (4-fluoro-3-methoxyphenyl) ethyl]phenol

770 mg methoxymethanol { 4-fluoro-2-[2-(4-fluoro-3-methoxyphenyl) ethyl] phenyl} ether [obtained as described in the above stage (a)] was dissolved in 4 ml of ethyl acetate and then to the resulting solution was added with ice cooling to 4 ml of 4 n solution of hydrogen chloride in ethyl acetate. The resulting mixture was allowed to stand at room temperature for 2 hours. After this time the reaction mixture was concentrated by evaporation under reduced pressure and purified by column chromatography on silica gel using as eluent a mixture of hexane and ethyl acetate to volume ratio of 3: 2, and the result received 631 mg (yield 96%) indicated in the title compound as an oily substance.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques: 2,87 (4H, singlet); a 3.83 (3H, singlet), 4,60 (1H, singlet); 6,6-6,85 (5H, multiplet); 6,98 (1H, doublet of doublets, J=8.5 and 11.3 Hz).

GETTING 6

4-fluoro-2-[2- (4-forfinal)ethyl]phenol

6 (a) Protolanguage, 3860 mg of 5-fluoro-2-ethoxymethylenemalononitrile (obtained as described in obtaining 8) and 1.26 ml of DBU in 60 ml of acetonitrile, after which the mixture was treated and purified by column chromatography on silica gel using as eluent a mixture of hexane and ethyl acetate with the ratio of 9:1 as described in the getting 2 that gave 2030 mg of an oily substance. 198% mg this oily substance was dissolved in 12 ml of a mixture (1:2 by volume) of benzene and ethanol and to the resulting solution was added 155 mg of chloride, Tris(triphenylphosphine)rhodium(1). Then the mixture was stirred under hydrogen at atmospheric pressure and at 60oC for 20 hours. At the end of this time the reaction solution was filtered using diatomaceous earth. The filtrate was concentrated by evaporation under reduced pressure and purified by column chromatography on silica gel using as eluent a mixture of hexane and ethyl acetate to volume ratio of 9:1 and as a result received 1816 mg (yield 87%) indicated in the title compound as an oily substance.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques: a 2.75 to 3.0 (4H, multiplet); 3,47 (3H, singlet); 5,11 (2H, singlet); 6.75 in-6,9 (2H, multiplet); 6,9-7,2 (5H, th is)ethyl] phenyl} ether [received so as in the above stage (a)] was dissolved in 8 ml of ethyl acetate and then to the resulting solution were added under ice cooling 8 ml of 4 n solution of hydrogen chloride in ethyl acetate. The resulting mixture was allowed to stand at room temperature for 2 hours, after which it was concentrated by evaporation under reduced pressure and purified by column chromatography on silica gel using as eluent a mixture of hexane and ethyl acetate to volume ratio of 4:1 and as a result got 1483 mg (yield 99%) specified in the title compound as an oily substance.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques: a 2.75 to 3.0 (4H, multiplet); of 4.57 (1H, singlet); 6,6-6,85 (3H, multiplet); 6,9-7,05 (2H, multiplet); 7,05 to 7.2 (2H, multiplet).

GETTING 7

2-[2-(3,4-Differenl) ethyl]-4-terfenol

Cooperated between 610 mg of 3,4-diferentialglea, 2000 mg of 5-fluoro-2-ethoxymethylenemalononitrile and 0.64 ml of DBU in 20 ml of acetonitrile, after which the mixture was treated and purified by column chromatography on silica gel using as eluent a mixture of hexane and ethyl acetate with the ratio of 15:1 as described in the getting 2 that gave 1230 mg of an oily substance. Analfisting)rhodium (1). Then the resulting mixture was stirred under hydrogen at atmospheric pressure and at 60oC for 14 hours. At the end of this time the reaction solution was filtered using a Celite (trade mark) as the filter material. The filtrate was concentrated by evaporation under reduced pressure, and for some time was allowed him to be adsorbed on a column of silica gel. Then the filtrate was slowly suirable using as eluent a mixture of hexane ethylacetate to volume ratio of 4:1 and as a result got the eluate containing the specified header connection. This eluate was concentrated by evaporation under reduced pressure and dried under vacuum, resulting in 1010 mg (yield 93%) indicated in the title compound in the form of a solid substance.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques: 2,86 (4H, singlet); 4,60 (1H, singlet); 6,6-7,15 (6N, multiplet).

GETTING 8

5-fluoro-2-ethoxymethylenemalononitrile

8 (a) 5 - fluoro-2-hydroxyanisole alcohol

To 50 ml of tetrahydrofuran was added 1.98 g of sociallyengaged and to the resulting solution was added dropwise at room temperature a solution 5,44 g 5-fluoro who begins 1 hour. At the end of this time the mixture was cooled and added to it decahydrate sodium sulfate to decompose excess hydride. Was filtered insoluble substances. The filtrate was concentrated by evaporation under reduced pressure and purified by column chromatography on silica gel using as eluent a mixture of hexane and ethyl acetate to volume ratio of 2:1 and as a result got 4,72 g (yield 95%) specified in the connection header in the form of a solid substance.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques: 1,69 (1H, triplet, J= 3.2 Hz); 4,82 (2H, doublet, J=3.2 Hz); 6,7-7,0 (3H, multiplet); 7,17 (1H, singlet).

8 (b) 5-fluoro-2-methoxyethoxymethyl alcohol

4.71 g of 5-fluoro-2-hydroxybenzoato alcohol [obtained as described in the above stage (a)] was dissolved in 100 ml of N, N - dimethylacetamide and then to the resulting solution were added under ice cooling and 3.72 g of tert-butoxide potassium. The resulting mixture was stirred at the same temperature for 10 minutes and then added at the same temperature to 2.74 ml methoxymethane. Then the mixture was allowed to stand until it returned to room temperature, after which it was stirred for 1 hour. Then to the reaction mixture were added ia, was dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. Concentrated substance was purified by column chromatography on silica gel using as eluent a mixture of hexane and ethyl acetate to volume ratio of 3:2, and the result has been of 4.25 g (yield 69%) indicated in the title compound as an oily substance.

Spectrum of nuclear magnetic resonance (270 MHz,CDCl3) memorial plaques: 2,30 (1H, triplet, J= 6.2 Hz); 3,49 (3H, singlet); of 4.67 (2H, doublet, J=6.2 Hz); 5,19 (2H, singlet); 6,85-7,0 (1H, multiplet); 7,0-to 7.15 (2H, multiplet).

8 (C) 5-fluoro-2-methoxyethoxymethyl

4.15 g of 5-fluoro-2-methoxyethoxymethyl alcohol [obtained as described above in stage (b)] was dissolved in 70 ml of tetrahydrofuran and the resulting solution was added 6,86 g of carbon tetrachloride and 11.69 triphenylphosphine in that order. The resulting mixture was stirred at room temperature for 1 hour and then heated under reflux for 5 hours. At the end of this time was removed by filtration of the insoluble matter. The filtrate was concentrated by evaporation under reduced pressure and purified by column chromatography on silica gel with IP is of 3.27 g (71% yield) specified in the title compound as an oily substance.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques: 3,50 (3H, singlet); to 4.62 (2H, singlet); to 5.21 (2H, singlet); 6,9-7,05 (1H, multiplet); 7,05 to 7.2 (2H, multiplet).

8 (d) 5-fluoro-2-ethoxymethylenemalononitrile

3.25 g of 5-fluoro-2-methoxyethoxymethyl [obtained as described above in stage (C)] was dissolved in 50 ml of toluene and the resulting solution was added 6.25 g of triphenylphosphine. Then the obtained mixture was heated under reflux for 6 hours. At the end of this time the reaction solution was cooled. The obtained crystals were collected by filtration and dried under vacuum to obtain 5,16 g (yield 70%) specified in the connection header. Separately, the filtrate was concentrated by evaporation under reduced pressure and precipitated precipitated crystals were collected by filtration to obtain another 0.75 g (total yield 80%) specified in the connection header.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques: 3,18 (3H, singlet); 4,51 (2H, singlet); the ceiling of 5.60 (2H, doublet, J=14.6 Hz); 6,85-to 6.95 (2H, multiplet); 7,05-to 7.15 (1H, multiplet); 7,55-a 7.85 (15 NM, multiplet).

9

5-Chloro-2- (2-phenylethyl) phenol

Cooperated between 1.10 g of benzaldehyde, of 6.02 g of 4-chloro-2-metatem column chromatography on silica gel using as eluent a mixture of hexane and ethyl acetate with the ratio of 10:1 as well as described in the getting 2 that gave 2.85 g of oily substance. This oily substance was dissolved in 50 ml of ethanol and to the resulting solution was added 0.40 g of chloride, Tris(triphenylphosphine)rhodium(1). The resulting mixture was stirred under hydrogen at atmospheric pressure and at 50oC for 14 hours. At the end of this time the reaction solution was filtered using a Celite (trade mark) as the filter material. The filtrate was concentrated by evaporation under reduced pressure and purified by column chromatography on silica gel using as eluent a mixture of hexane and ethyl acetate to volume ratio of 5:1 and the received intermediate connection. This intermediate compound was dissolved in 10 ml of ethyl acetate and the resulting solution was added under ice cooling 10 ml of 4 n solution of hydrogen chloride in ethyl acetate. Then the reaction mixture was allowed to stand at room temperature for 1 hour. At the end of this time the solvent was removed by evaporation under reduced pressure. The residue was purified by column chromatography on silica gel using as eluent a mixture of hexane and ethyl acetate to volume ratio of 5: 1 and the floor is P CLASS="ptx2">

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques: a 2.75 to 3.0 (4H, multiplet); 6,7-6,9 (2H, multiplet); of 6.96 (1H, doublet, J=8.1 Hz); 7,1-to 7.35 (5H, multiplet).

RECEIVE 10

6-fluoro-2- (2-phenylethyl)phenol

Cooperated between 3.00 g of 3-fluoro-2 - hydroxybenzaldehyde, 9,99 g benzyltriphenylphosphonium and a 3.83 ml of DBU in 30 ml of acetonitrile, after which the mixture was treated and purified column chromatography on silica gel using as eluent a mixture of hexane and ethyl acetate with a ratio of 5:1 as described in the getting 2 that gave 4,58 g colorless solid. This solid was dissolved in 50 ml of ethanol and to the resulting solution was added 0.50 g of chloride, Tris(triphenylphosphine)rhodium(1). The resulting mixture was stirred under hydrogen at atmospheric pressure and at 50oC for 48 hours. At the end of this time the reaction solution was filtered using Celite (trademark) as an auxiliary filter substance. The filtrate was concentrated by evaporation under reduced pressure and was purified column chromatography on silica gel using as eluent a mixture of hexane and ethyl acetate to volume ratio of 5: 1, resulting in a 3.15 g (visning resonance (270 MHz, CDCl3) memorial plaques: 2,8 was 3.05 (4H, multiplet); 6,5-7,0 (3H, multiplet) 7,1-to 7.35 (5H, multiplet).

RECEIPT 11

4-Chloro - 2-ethoxymethylenemalononitrile

11 (a) 4-chloro-2-hydroxybenzoyl alcohol

1,65 g sociallyengaged suspended in 100 ml of tetrahydrofuran and the resulting suspension was added dropwise with stirring and ice cooling to 5.00 g of 4-chlorosalicylic acid in 50 ml of tetrahydrofuran. Then the obtained mixture was heated under reflux for 1 hour. At the end of this time the reaction mixture was cooled on ice and added to it decahydrate sodium sulfate to decompose excess hydride. Was filtered insoluble materials and the filtrate was concentrated by evaporation under reduced pressure. The residue was purified by column chromatography on silica gel using as eluent a mixture of hexane and ethyl acetate to volume ratio of 1:1 and as a result got 4,00 g (yield 87%) indicated in the title compound as a colourless solid.

Spectrum of nuclear magnetic resonance (270 MHz, hexadeuterated dimethyl sulfoxide) 4,43 (2H, singlet); 6.75 in-6,9 (2H, multiplet); 7,28 (1H, doublet, J=8.0 Hz).

11 (b) 4-Chloro-2-methoxyethoxy the(a)] was dissolved in 80 ml of N,N - dimethylacetamide and then to the resulting solution were added under ice cooling 2.83 g of tert-butoxide potassium and the mixture was stirred for 10 minutes. To the reaction mixture were added while cooling with ice is 2.09 ml methoxyethylamine and then the mixture was allowed to stand at room temperature for 1 hour. At the end of this time was added 60 ml of water and 300 ml of ethyl acetate and an ethyl acetate layer was separated and washed with saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. Then it was concentrated by evaporation under reduced pressure. The residue was purified by column chromatography on silica gel using as eluent a mixture of hexane and ethyl acetate to volume ratio of 2:1 and as a result got 4,69 g (yield 92%) indicated in the title compound as an oily substance.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques: 3,48 (3H, singlet); the 4.65 (2H, singlet); 5,20 (2H, singlet); 6,98 (1H, doublet of doublets, J=l,9 and 8.2 Hz); for 7.12 (1H, doublet, J=l,9 Hz); from 7.24 (1H, doublet, J=8,2 Hz).

11 (c) 4-Chloro-2-methoxyethoxymethyl

4,69 g of 4-chloro-2-methoxyethoxymethyl alcohol [obtained as described above in stage (b)] was dissolved in 80 ml of tetrahydrofuran and the resulting solution was added 7,11 g of carbon tetrachloride and 12, 14 triphenylphosphine. The resulting mixture was stirred at room temperature and was removed by filtration of the insoluble matter and the filtrate was concentrated by evaporation under reduced pressure. The residue was purified by column chromatography on silica gel using as eluent a mixture of hexane and ethyl acetate to volume ratio of 10:1 and as a result got to 3.38 g (yield 66%) indicated in the title compound as an oily substance.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques: 3,50 (3H, singlet); br4.61 (2H, singlet);5,24 (2H, singlet); 6,98 (1H, doublet of doublets, J=2.0 and 8.2 Hz); 7,14 (1H, doublet, J=2.0 Hz); 7,26 (1H,doublet, J=8,2 Hz).

11 (d) 4-Chloro-2-ethoxymethylenemalononitrile

to 3.38 g of 4-chloro-2-methoxyethoxymethyl [obtained as described above in stage (C)] was dissolved in 50 ml of toluene and the resulting solution was added of 6.02 g of triphenylphosphine. Then the obtained mixture was heated under reflux in the course of 15.5 hours. At the end of this time the reaction mixture was cooled on ice and precipitated precipitated crystals were collected by filtration and dried under vacuum obtaining of 6.02 g (yield 82%) specified in the connection header.

Spectrum of nuclear magnetic resonance (270 MHz, CDCl3) memorial plaques: 3,19 (3H, singlet); to 4.52 (2H, singlet); to 5.58 (2H, doublet, J=14,3 Hz); 6.8 or 6.9 (1H, multiplet); 9,9-to 6.95 (1H, multiplet); 7,39 (1H, doublet of doublets, J=3.0 and 8.2 Hz); 7,6-7,9 (15 NM, multiplet).


Lactose - 158,7

Corn starch - 70,0

Magnesium stearate - 1,3

Only 250 mg

Powders of the above substances were mixed and the mixed powder was sifted through a sieve with openings 60 mesh (Taylor)

Then the sifted powder was loaded in a 250 mg gelatin capsule No. 3 and received encapsulated dosage form.

EXAMPLE COMPOSITION 2

Tablets

We used the following components:

The compound of example 4 - 20.0 mg

Lactose - 154,0

Corn starch - 25,0

Magnesium stearate - 1,0

Only 200 mg

Powders of the above substances were mixed. The mixed powder was pressed in a tablet machine and got a tablet weight of 200 mg If necessary, the tablets may be coated with sugar.

1. Derivatives of diarylamino containing alicyclic group of the formula (I):

< / BR>
where R1represents a saturated heterocyclic group attached to a link or a group represented by the symbol A, via a ring carbon atom, with the specified saturated heterocyclic group is a 5 ring atoms, of which one is a nitrogen heteroatom and is substituted by at least one carbon atom, at A least one of the substituents defined below;

R2A, R2b, R2Cthe same or different from each other and each represents a hydrogen atom, a methyl group, a methoxy group, a fluorine atom, a chlorine atom, a bromine atom, and at least one of the radicals R2A, R2band R2Crepresents a group or atom other than(th), from hydrogen;

R3A, R3b, R3sand R3dthe same or different from each other and each represents a hydrogen atom, alkoxygroup having from 1 to 6 carbon atoms, or a halogen atom;

And is alkylenes group having from 1 to 6 carbon atoms,

moreover, these substituents selected from hydroxy groups and alkanoyloxy having from 1 to 20 carbon atoms, and the above substituents selected from alkyl groups having from 1 to 6 carbon atoms, and their pharmaceutically acceptable salts and esters.

2. Connection on p. 1, where R1is pyrrolidinyloxy group, which is substituted at a carbon atom, at least one of the substituents1and optionally substituted on the nitrogen atom of at least one of the substituents1where these deputies 1selected from hydroxy groups and alkanoyloxy 1 to 4 carbon atoms.

3. Connection on p. 1, where R1is pyrrolidinyloxy group, which is substituted at a carbon atom by at least one of the substituents3and optionally substituted on the nitrogen atom of at least one of the substituents3where these deputies 3selected from hydroxy - and euroelixir; specified Deputy 3represents a methyl group.

4. Connection on p. 1, where R1is 4-hydroxy-2-pyrrolidinyl, 1-methyl-4-euroluxe-2-pyrrolidinyl or 1-methyl-4-hydroxy-2-pyrrolidinyl group.

5. Connection on p. 1, where R2Aand R2bthe same or different from each other and represent each a hydrogen atom, a methyl group, a methoxy group, a fluorine atom, a chlorine atom, a bromine atom and R2Crepresents a hydrogen atom.

6. Connection on p. 1, where R3A, R3band R3sthe same or different from each other and represent each a hydrogen atom, alkoxygroup having from 1 to 4 carbon atoms or halogen atom, and R3drepresents a hydrogen atom.

7. Connection on p. 1, where R3Aand R3bthe same or different from each other and represent each atom is inania under item 1, where a represents alkylenes group having from 1 to 4 carbon atoms.

9. Connection on p. 1, where a represents ethylene group.

10. Connection on p. 1, where R1such as defined in any of paragraphs. 2,3,4; R2a, R2band R2Csuch as defined in paragraph 5, and R3A, R3b, R3sand R3dsuch as defined in any of paragraphs.6 and 7, and As such, as defined in any of paragraphs.8 and 9.

11. Connection on p. 1, where R1is pyrrolidinyloxy group, which is substituted at a carbon atom by at least one of the substituents1and optionally substituted on the nitrogen atom of at least one of the substituents 1defined below, where these substituents1selected from hydroxy groups, alkanoyloxy having from 1 to 20 carbon atoms, and1selected from alkyl groups having from 1 to 4 carbon atoms; R2Aand R2bthe same or different from each other and represent each a hydrogen atom, a methyl group, a methoxy group, a fluorine atom, a chlorine atom and a bromine atom, and R2Crepresents a hydrogen atom; R3A, R3band R3sthe same or different from each other and represent each an atom of water is a; And is alkylenes group having from 1 to 4 carbon atoms.

12. Connection on p. 1, where R1is pyrrolidino group, which is substituted at a carbon atom by at least one of the substituents3and optionally substituted on the nitrogen atom of at least one of the substituents3defined below, where these substituents3selected from hydroxy - and euroelixir and specified Deputy3represents a methyl group ; R2aand R2bthe same or different from each other and represent each a hydrogen atom, a methyl group, a methoxy group, a fluorine atom, a chlorine atom or bromine atom and R2Crepresents a hydrogen atom; R3A, R3band R3sthe same or different from each other and represent each a hydrogen atom, a methoxy group and a fluorine atom and R3drepresents a hydrogen atom; a represents ethylene group.

13. Connection on p. 1, where R1is pyrrolidinyloxy group, which is substituted at a carbon atom by at least one of the substituents3and optionally substituted on the nitrogen atom of at least one of the substituents3opredelit3represents a methyl group; R2Aand R2bthe same or different from each other and represent each a hydrogen atom, fluorine atom or chlorine atom and R2Crepresents a hydrogen atom; R3A, R3band R3sthe same or different from each other and represent each a hydrogen atom, a methoxy group and a fluorine atom and R3drepresents a hydrogen atom and a represents ethylene group.

14. Connection on p. 1, where R1is 4-hydroxy-2-pyrrolidinyl, 1-methyl-4-hydroxy-2-pyrrolidino or 1-methyl-4-euroluxe-2-pyrrolidinyl group; R2Aand R2bthe same or different from each other and represent each a hydrogen atom, fluorine atom or chlorine atom and R2Crepresents a hydrogen atom; R3Aand R3bthe same or different from each other and represent each a hydrogen atom, a methoxy group and a fluorine atom and R3sand R3dboth represent hydrogen atoms, and a represents ethylene group.

15. Connection on p. 1, where R1is 4-hydroxy-2-pyrrolidinyl, 1-methyl-4-hydroxy-2-pyrrolidinyl, 1-methyl-4-euroluxe-2-pyrrolidinyl group;

R2Arepresents a fluorine atom, and R2b3sand R3dboth represent hydrogen atoms;

A represents ethylene group.

16. Connection on p. 1 representing:

2-{2-[4-fluoro-2-(2-phenylethyl)phenoxy]ethyl}-4-hydroxy-1-methylpyrrolidine;

2-{2-[4-fluoro-2-(2-phenylethyl)phenoxy]ethyl}-4-hydroxypyrrolidine;

2-{ 2-[4-fluoro-2-[2-(3-methoxyphenyl)ethyl] phenoxy] ethyl}-4-hydroxy-1-methylpyrrolidine;

2-[2-{ 4-fluoro-2-[2-(3-methoxyphenyl)ethyl] phenoxy}ethyl]-4-euroluxe-1 methylpyrrolidine;

2-[2-{ 4-fluoro-2-[2-(4-forfinal)ethyl] phenoxy} ethyl]-4-hydroxy-1-methylpyrrolidine;

2-[2-{4-fluoro-2-[2-(4-forfinal)ethyl]phenoxy}ethyl]-4-hydroxypyrrolidine;

2-[2-{ 4-fluoro-2-[2-(4-fluoro-3-methoxyphenyl)ethyl] phenoxy}-ethyl]-4-hydroxy-1-methylpyrrolidine;

2-[2-{ 4-fluoro-2-[2-(4-fluoro-3-methoxyphenyl)ethyl] phenoxy}-ethyl]-4-euroluxe-1 methylpyrrolidine;

2-[2-{ 2-[2-(3,4-differenl)ethyl] -4-fervency}ethyl]-4-hydroxy-1-methylpyrrolidine;

2-[2-{ 2-[2-(3,4-differenl)ethyl] -4-fervency}ethyl]-4-hydroxypyrrolidine, and their pharmaceutically acceptable salts.

17. Composition for the treatment and prevention of cardiovascular diseases that can be prevented or curable compounds exhibiting antagonism against serotoni the formulas I to PP.1 - 16 or its pharmaceutically acceptable salt.

18. Derivatives diarylamino formula I or their pharmaceutically acceptable salts PP.1 - 16 showing antagonism against serotonin-2 receptors and/or inhibitory activity against squalene synthase.

 

Same patents:

The invention relates to ethanol adducts of compounds with formula 1

< / BR>
where R(1) phenyl which may be substituted by 1-2 methyl groups and/or chlorine,

R(2) and R(3) may be the same or different and are H, stands or stands, and

n number 3 and 4

m number 1 and 2, the method of their production and their use as tools for inhalation diseases

The invention relates to polycyclic aminecontaining compounds, to their optically pure enantiomers, the way they are received, to Farmaceutici on their basis, as well as to new intermediate compounds for the synthesis of polycyclic compounds

)6-cyano-3,4-dihydro-2,2 - dimethyl-trans - 4-(2-oxo-1-pyrrolidinyl) -2h-1-benzopyran-3-ol" target="_blank">

The invention relates to organic synthesis and concerns a method for obtaining derived benzopyran representing () -6-cyano-3,4-dihydro-2,2-dimethyl-TRANS-4-(2-oxo-pyrrolidinyl)-2H - 1-benzopyran-3-ol of the formula VI

known as Cromakalim (DRL 34 915)

The invention relates to new cyclic imino-derivatives of General formula

In X And Y E (I) where a 2-pyrrolidinone or pyrrolin-2-it, unsubstituted or substituted residues R1and R2where R1means phenyl, unsubstituted or substituted by carboxyla, methoxycarbonyl, aminocarbonyl, methylaminoethanol, ethylaminoethanol, dimetilaminoflavonola, methanesulfonylaminoethyl or acetaminophe, alkyl with 1-4 carbon atoms, substituted by two phenyl groups, cyclohexyl, naptalam or phenyl, unsubstituted or substituted by fluorine, chlorine, bromine, hydroxyl, alkyl with 1-4 carbon atoms, alkoxyl with 1-4 carbon atoms, phenyl, vinylmation, benzyloxypropionic, methylsulfinyl, methylsulfonyl, trifluoromethyl, two chlorine atoms, two metaxylene groups, alkyl with 1-4 carbon atoms, unsubstituted or substituted by hydroxyl, metaxylem or fenoxaprop, moreover, these substituents are not in the position I, if R1linked to the nitrogen atom of the cycle And; methyl, substituted vinyl, carboxyla, methoxycarbonyl, aminocarbonyl, methylaminoethanol, ethylaminoethanol, dimetilaminoflavonola, benzylaminocarbonyl, pyrrolidinecarbonyl, piperidyl, methylaminopropane, arylaminopoly, AMI - nomation, dimethylaminopropoxy, carboxyla, methoxycarbonyl or dimetilaminoflavonola, if R1not linked to the nitrogen atom of the cycle; or sulfonyl, replaced by stands, dimethylaminopropoxy, phenyl or methoxyphenyl, if R1not linked to the carbon atom adjacent to the nitrogen atom of the cycle A, R2alkyl with 1-4 carbon atoms, unsubstituted or substituted phenyl;

In amino, aminomethyl and amidino, unsubstituted or substituted with one nitrogen atom by a benzyl, hydroxyl, methoxy group, cyano, one or two alkyl groups with 1-4 carbon atoms, alkoxycarbonyl with the total number of carbon atoms 2-5, benzyloxycarbonyl, phenoxycarbonyl or benzoyl, or two atoms of nitrogen amidinopropane linked using ethylene group, cyano, trimethylammonio, guanidino or guanidinate;

Y-E nonbranched alkyl with 2-5 carbon atoms, substituted carboxyla, methoxycarbonyl or stands, substituted vinyl, allyl, 1,2-Diocletian, carboxyla, phosphonopropyl, 0-methylphosphono, 0,0-dimethylphosphoric, oximation, alkoxycarbonyl with the total number of 2-7 carbon atoms, dimethylaminocarbonylmethyl is 1-3 carbon atoms in the CNS group, whereby phenyl may be substituted by one or two metaxylene groups, pyridinedicarboxylate, aminocarbonyl, unsubstituted or substituted by alkyl with 1-4 carbon atoms, biphenyloxy, replaced by carboxyla, carboxymethyl or methoxycarbonylmethyl, and the shortest distance between these substituents and the first nitrogen atom of the residue is at least 10 links;

X group of the formula

-X1X2X3X4X5where X1means a bond, methylene or ethylene, and if methylene not linked to the nitrogen atom of the cycle And then between the methylene and related balance X2may contain oxygen atom or sulfur, sulfonyl imino, -N(COCH3)-, -N(SO2CH3)-, -N(benzyl)-, -СОNH-, -NH-CO - or-NH-SO2- or between methylene and related balance X2can be imino, -N(benzyl) -, or-NH-CO-, and X1associated with the remainder of a, And X5with the rest IN;

X2nonbranched alkylen with 2-4 carbon atoms, albaniles with 2 or 3 carbon atoms and the double bond must not be adjacent to the heteroatom, phenylene, unsubstituted or substituted by fluorine, chlorine, bromine, stands, ethyl, trifluoromethyl, nitro-group, acetaminophe, meansville with 4-7 carbon atoms or bicycloalkyl to 7 carbon atoms;

X3bond, -CO-, -CO-NH -, or-NHCO-, if X3not directly followed by a heteroatom or a triple bond balance, and CO -,- CONH - and-NHCO - may not be adjacent to an aliphatic double bond of residue X2or an oxygen atom, sulfenyl, sulfinil, sulfonyl, oxymethylene, imino or sulfonylamino, if X2no aliphatic double bond at the end and for X3not directly followed by a heteroatom or a saturated carbon atom of the residue IN;

X4communication, the unbranched alkylene with 1-5 carbon atoms, phenylene, unsubstituted or substituted by fluorine, chlorine or stands, cycloalkyl with 4-7 carbon atoms;

X2together with X3and X4forms the unbranched alkylene with 3-6 carbon atoms, phenanthrene and naftilan, which may be fully or partially gidrirovanny, fluorenyl, in which the methylene may be replaced by oxymethylene or carbonyl, indaniel, endangerment or serialkiller from 8 to 11 carbon atoms;

X5link

) 6-cyano-3,4-dihydro-2,2 - dimethyl - trans-4- (2 - hydroxy-1 - pyrrolidinyl) -2h-1 - benzopyran-3 - ol" target="_blank">

The invention relates to organic synthesis and concerns a method for obtaining ()-6-cyano-3,4-dihydro-2,2-dimethyl-TRANS-4-(2-oxo - 1-1-pyrrolidinyl)-2H-1-benzopyran-3-ol formula

(I) known as Cromakalim

The invention relates to the field of production of new derivatives pyrrolidine General formula

Y-Rwhere Y represents - (CH2)n-, whereby n = 0;

X is a hydrogen atom, halogen or lower alkyl group;

R is a phenyl group, phenyl group involved halogen, lower alkyl, hydroxy - or alkoxygroup, trifluoromethyl, naftalina group, thiophene, unsubstituted or substituted lower alkyl, benzothiophen, pyridyl, imidazole, substituted lower alkyl when n = 1;

X is H or halogen,

R is phenyl, unsubstituted or substituted by halogen, hydroxy or alkoxygroup, lower alkyl; thiophene; Y represents S(O)pwhere p = 0 or 2, -O - or-NH; X is hydrogen,

R-phenyl;

having anti-hypertensive activity

The invention relates to new derivatives of camptothecin with enhanced antitumor activity, and intermediate products for their production

The invention relates to physiologically active agents that produce nitric oxide, process for their preparation, containing compositions, and methods of use thereof

The invention relates to improved oral pharmaceutical dosage forms with a high dosage of the active substance
The invention relates to medicine, namely to experimental Oncology, and can be used to reduce toxicity and enhance the antitumor activity of cyclophosphamide
The invention relates to medicine, namely to Oncology, and for the treatment of patients with nodular forms of breast cancer
The invention relates to medicine, namely to cancer and for the treatment of patients with diffuse forms of breast cancer

The invention relates to 2-(4-morpholino)ethyl-S-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4 - methyl-4-hexenoate (hereinafter MM), in particular to MM in the anhydrous crystal form of its salts

The invention relates to medicine, specifically to gynecology
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