Derivatives of 2-oxo-1-pyrrolidine, method for their preparing and using

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of 2-oxo-1-pyrrolidine of the formula (I) or their pharmaceutically acceptable salts wherein X means -CA1NR5R6 or -CA1-R8 wherein A1 and A2 mean independently oxygen atom; R1 means hydrogen atom (H), (C1-C20)-alkyl, (C6-C10)-aryl or -CH2-R1a wherein R1a means (C6-C10)-aryl; R3 means H, -NO2, nitrooxy-group, C≡N, azido-group, -COOH, amido-group, (C1-C20)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C6-C10)-aryl, thiazolyl, oxazolyl, furyl, thienyl, pyrrolyl, tetrazolyl, pyrimidinyl, triazolyl, pyridinyl, -COOR11, -COR11 wherein R11 means (C1-C12)-alkyl; R3a means H, (C1-C20)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl or (C6-C10)-aryl; R5 and R6 are similar or different and each means independently H, (C1-C6)-alkyl, and R8 means -OH and wherein each alkyl can be substituted independently with from 1 to 5 substitutes chosen from halogen atom, isothiocyanate, -OH, -NO2, -CN, azido-group, (C3-C6)-cycloalkyl and (C6-C10)-aryl;, and wherein each (C6-C10)-aryl can be substituted independently with from 1 to 5 substitutes chosen from halogen atom, -NH2, -NO2, azido-group, (C1-C6)-alkoxy-group, (C1-C6)-alkyl and (C1-C6)-halogenalkyl, and wherein each alkenyl can be substituted independently with at least one substitute chosen from halogen atom and -OH, and under condition that at least one radical among R and R3a differs from H, and when compound represent a mixture of possible isomers then X means -CONR5R6; A2 means oxygen atom, and R1 means H, -CH3, -C2H5, -C3H7, and when each R1 and R3a means H and A2 means oxygen atom and X means -CONR5R6 then R3 differs from -COOH, -CH, -COOR11, amido-group, naphthyl, phenyl rings substituted with (C1-C6)-alkoxy-group or halogen atom in para-position in naphthyl or phenyl ring. Compounds of the formula (I) can be used in pharmaceutical compositions for treatment of epilepsy, epileptogenesis, convulsions, epileptic seizures, essential tremor and neuropathic pain.

EFFECT: improved method of synthesis, valuable medicinal properties of derivatives and pharmaceutical compositions.

27 cl, 3 tbl, 9 ex

 

The present invention concerns 2-oxo-1-pyrrolidinone derivatives, methods for their preparation, pharmaceutical compositions containing them and their use as pharmaceuticals.

EP 0162036 B1 discloses the compound (S)-α-ethyl-2-oxo-1-pyrrolidineethanol, which has a well-known international non-proprietary name Levetiracetam.

Levetiracetam, levogyrate connection, described as a protective agent for the treatment and prevention of lipoxinol and ischemic disease of the Central nervous system. The specified connection is also effective in the treatment of epilepsy, therapeutic manifestation of which, as has been demonstrated, is lost completely if it programalso enantiomer (R)-α-ethyl-2-oxo-1-pyrrolidineethanol, also known from EP 0165919 B1, (A.J.GOWER etal. Eur. J.Pharmacol., 222. (1992), 193-203).

Racemic α-ethyl-2-oxo-1-pyrrolidineethanol and its analogues are known from Patent GB 1309692. US 3459738 discloses derivatives of 2-oxo-1-pyrrolidineethanol. EP 0645139 B1 discloses anxiolytic activity of Levetiracetam. PCT/EROO/1 1808 discloses the use of Levetiracetam for methodological and/or prophylactic treatment of bipolar disorders, migraine, chronic and neuropathic pain, as well as the combination of Levetiracetam with at least one connection, causes the guide neural inhibition, Mediterranee GABAA receptors.

It has been unexpectedly found that certain analogues of Levetiracetam, especially those that have additional substitution in the pyrolidine ring, demonstrate significantly improved therapeutic properties.

In the first aspect, the invention accordingly provides a compound having formula I or its pharmaceutically acceptable salt,

where X represents-CA1NR5R6or-CA1OR7or-CA1-R8or CN-;

And1and2independently are oxygen, sulfur or-NR9;

R1represents hydrogen, alkyl, aryl or-CH2-R1awhere R1arepresents aryl, heterocycle, halogen, hydroxy, amino, nitro or piano;

R2, R3and R4are the same or different and each independently represents hydrogen, halogen, hydroxy, thiol, amino, nitro, nitroxy, piano, azido, carboxy, amido, sulfonic acid, sulfonamide, alkyl, alkenyl, quinil, ester, simple, ether, aryl, heterocycle or auxiproizvodnykh, diprosone, amine derivative, acylphosphate, sulfanilamide or sulfinpyrazone;

R2a, R3aand R4aare the same or different and each independently represents hydrogen, halogen, alkyl, alkenyl, quinil or aryl;

R5, R6, R7and R9are the same or different and each independently represents hydrogen, hydroxy, alkyl, aryl, heterocycle or auxiproizvodnykh; and

R8represents hydrogen, hydroxy, thiol, halogen, alkyl, aryl, heterocycle or diprosone;

provided that at least one such as R2, R3, R4, R2a, R3aand R4ais other than hydrogen; and that when the compound is a mixture of all possible isomers, X is a CONR5R6And2is oxygen and R1represents hydrogen, methyl, ethyl or propyl, then the substitution on the pyrolidine ring differently from mono-, di - or trimethyl or monoethyl; and that when R1, R2, R4, R2a, R3aand R4aeach is hydrogen, And2is oxygen and X is a CONR5R6then R3different from carboxy, complex, ester, amido, substituted oxopyrrolidin, hydroxy, auxiproizvodnykh, amino, amino derivatives, methyl, naphthyl, phenyl optionally substituted auxiproizvodnykh or in the para position with a halogen atom.

In the definitions below, unless otherwise noted, R11and R12are the same or different and each independent who represents amido, alkyl, alkenyl, quinil, acyl, ester, simple, ether, aryl, aralkyl, heterocycle or auxiproizvodnykh, diprosone, acylphosphate, amino, sulfanilamide or sulfinpyrazone, each optionally substituted with any suitable group, including but not limited to, one or more residues selected from lower alkyl or other groups described below as substituents for alkyl.

The term "auxiproizvodnykh" is defined as including-O-R11group, where R11defined above, with the exception of "auxiproizvodnykh". Non-limiting examples represent alkoxy, alkenylacyl, alkyloxy, acyloxy, oxicology ether, acetamido, alkylsulfonate, alkylsulfonate, arylsulfonate, arylsulfonate, aryloxy, Alcoxy or heterocyclics, such as pentyloxy, allyloxy, methoxy, ethoxy, phenoxy, benzyloxy, 2-naphthyloxy, 2-pyridyloxy, methylendioxy, carbonate.

The term "diprosone" is defined as including-S-R11group, where R11defined above, with the exception of "diprosone". Non-limiting examples are alkylthio, alkanity, alkylthio, aristeo.

The term "aminopropane" is defined as including-other11or other11R12group, where R11and R12defined above. Non-limiting examples of p is establet a mono - or di-alkyl-, alkenyl-, quinil and arylamino or mixed amino.

The term "acylphosphate" represents a radical derived from a carboxylic acid and thus it is defined as including a group of the formula R11-CO-, where R11defined above and may also be hydrogen. Non-limiting examples are formyl, acetyl, PROPYNYL, isobutyryl, valeryl, lauroyl, heptanediol, cyclohexanecarbonyl, crotonyl, fumaroli, acryloyl, benzoyl, Naftoli, furoyl, nicotinoyl, 4-carboxybutyl, oxalyl, ethoxalyl, cysteinyl, oxamyl.

The term "sulfanilamide" is defined as including a group of the formula-SO2-R11where R11defined above, with the exception of "sulfanilamide". Non-limiting examples represent alkylsulfonyl, alkanesulfonyl, alkylsulfonyl and arylsulfonyl.

The term "sulfinpyrazone" is defined as including a group of the formula-SO-R11where R11defined above, with the exception of "sulfinpyrazone". Non-limiting examples are alkylsulfanyl, alkanesulfonyl, alkylsulfonyl and arylsulfonyl.

The term "alkyl" is defined as including saturated, monovalent hydrocarbon radicals having a linear, branched or cyclic residues or their combination it completes containing 1-20 carbon atoms, predpochtitel is but 1-6 carbon atoms for the case of alkyl and 3-6 carbon atoms for cycloalkyl (in these two preferred cases, unless otherwise specified, "lower alkyl"). Alkyl residues may be optionally substituted by 1 to 5 substituents independently selected from the group comprising halogen, hydroxy, thiol, amino, nitro, cyano, thiocyanato, acyl, acyloxy, sulfanilamide, sulfinpyrazone, alkylamino, carboxy, ester, simple ester, amido, azido, cycloalkyl, sulfonic acid, sulfonamide, diprosone, oxicology ether, acetamido, heterocycle, vinyl, C1-5-alkoxy, C6-10-aryloxy and C6-10-aryl.

Preferred alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, ISO or tert-butyl, 2,2,2-trimethylated, each optionally substituted by at least one Deputy, selected from the group comprising halogen, hydroxy, thiol, amino, nitro and cyano, such as trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichlorethyl.

The term "alkenyl" is defined as including both branched and unbranched, unsaturated hydrocarbon radicals having at least one double bond, such as ethynyl (=vinyl), 1-methyl-1-ethynyl, 2,2-dimethyl-1-ethynyl, "1-propenyl, 2-propenyl (=allyl), 1-butenyl, 2-butenyl, 3-butenyl, 4-pentenyl, 1-methyl-4-pentenyl, 3-methyl-1-pentenyl, 1-hexenyl, 2-hexenyl, and the like and which may be optionally substituted by at least one for what estealam, selected from the group comprising halogen, hydroxy, thiol, amino, nitro, piano, aryl and heterocycle, such as mono - and dihalogenide, where halogen represents fluorine, chlorine or bromine,

The term "quinil" is defined as including monovalent branched or unbranched hydrocarbon radical containing at least one carbon-carbon triple bond, such as ethinyl, 2-PROPYNYL (=propargyl), and the like, and which may be optionally substituted by at least one Deputy, selected from the group comprising halogen, hydroxy, thiol, amino, nitro, cyano, aryl and heterocycle, such as halogenation.

If present as bridging groups, alkyl, alkenyl and quinil, they represent a linear or branched chain C1-12, preferably C1-4-alkylene or C2-12-, preferably C2-4-albaniles or alkenylamine residues, respectively.

Group, in which the branched derivatives is usually determined by the prefix, such as "h", "second.", "ISO" and the like (for example, "n-propyl", "Deut.-butyl") are in the protonated form, unless otherwise noted.

The term "aryl" is defined as including an organic radical derived from an aromatic hydrocarbon containing 1-3 rings and containing 6-30 carbon atoms by removal of one hydrogen, such as phenyl and naphthyl, kartinakaterina substituted by 1 to 5 substituents independently selected from halogen, hydroxy, thiol, amino, nitro, cyano, acyl, acyloxy, sulfonyl, sulfinil, alkylamino, carboxy, ether complex, a simple ester, amido, azido, sulfonic acid, sulfonamida, alkylsulfonyl, alkylsulfanyl, alkylthio, exisling ether, acetamido, aryl, C1-6-alkoxy, C6-10-aryloxy, C1-6-alkyl, C1-6-halogenoalkane. Aryl radicals are preferably monocyclic containing 6-10 carbon atoms. Preferred aryl groups are phenyl and naphthyl, each optionally substituted by 1 to 5 substituents independently selected from halogen, nitro, amino, azido, C1-6-alkoxy, C1-6-alkylthio, C1-6-alkyl, C1-6-halogenoalkane and phenyl. The term "halogen" includes an atom of Cl, Br, F, I.

The term "hydroxy" is a group of the formula - HE.

The term "thiol" is a group of the formula - SH.

The term "piano" is a group of the formula - CN.

The term "nitro" is a group of formula-NO2.

The term "Nitrox" represents a group of formula-ONO2-

The term "amino" is a group of formula-NH2-.

The term "azido" represents a group of formula-N3.

The term "carboxy" is a group of formula-COOH.

The term "sulfonic acid" represents a group of the formula-SO3N.

The term "sulfonamide" represents groups of the formula-SO 2NH2-

The term "ester" is defined as including a group of the formula-COO-R11where R11defined above, except auxiproizvodnykh, topouzoglou or amino derivatives.

The term "simple" air " is defined as including a group selected from C1-50 is a linear or branched alkyl, or C2-50 linear or branched alkenyl or etkinlik groups or combinations of the above groups, interruptive one or more oxygen atoms.

The term "amido" is defined as including a group of the formula-CONH2or-CONHR11or-CONR11R12where R11and R12defined above.

The term "heterocycle" is defined as including aromatic or non-aromatic cyclic alkyl, alkanniny, or alkynylaryl the remainder as defined above, having at least one O, S and/or N atom interrupting carbocyclic ring structure and optionally one carbon atom carbocyclic ring structure may be substituted carbonyl. Non-limiting examples of aromatic heterocycles are pyridyl, furyl, pyrrolyl, thienyl, isothiazolin, imidazolyl, benzimidazolyl, tetrazolyl, hintline, hemolysins, naphthyridine, pyridazinyl, pyrimidinyl, pyrazinyl, hinely, ethanolic, isobenzofuranyl, benzothiazyl, pyrazolyl, indolyl, indolizinyl,purinol, isoindolyl, carbazolyl, triazolyl, 1,2,4-thiadiazolyl, thieno(2,3-b)furanyl, touroperador, benzofuranyl, benzocaine, isooxazolyl, oxazolyl, thianthrene, benzothiazolyl or benzoxazolyl, cinnoline, phthalazine, honokalani, phenanthridines, acridines, pyrimidinyl, phenanthrolines, phenothiazinyl, furutani, isopropanol, indolinyl, xantener, hypoxanthine, pteridinyl, 5-azacitidine, 5-azauracil, triazolopyridines, imidazopyridines, pyrrolopyrimidine, and pyrazolopyrimidines optionally substituted by alkyl or as described above for alkyl groups. Non-limiting examples of non-aromatic heterocycles predstavlyaet tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperidinyl, piperazinil, imidazolidinyl, morpholino, morpholinyl, 1 oxaspiro(4.5)Dec-2-yl, pyrrolidinyl, 2-oxopyrrolidin, the remains of a sugar (such as glucose, pentoses, hexose, ribose, fructose, which can also be substituted), or the same groups, which may optionally be substituted with any suitable group, including but not limited to, one or more residues selected from lower alkyl or other groups as described above for alkyl groups. The term "heterocycle" also includes bicyclic, tricyclic and tetracyclic of spirography in which any of the above heterocyclic rings condensed with one the or more rings independently selected from an aryl ring, cyclohexane ring, cyclohexenone ring, cyclopentane ring, cyclopentenone ring, or another monocyclic heterocyclic ring or if monocyclic heterocyclic group linked by a bridge, such as Allenova group, such as hinokitiol, 7-azabicyclo(2.2.1)heptenyl, 7-oxabicyclo(2.2.1)heptanes, 8-azabicyclo(3.2.1)octanol.

It should be clear that in the above definitions, when Deputy, such as R2, R3, R4, R2a, R3a, R4a, R5, R6, R7, R8attached to the rest of the molecule through a heteroatom or a carbonyl, a linear or branched chain With 1 to 12-, preferably C1-4-alkylene or C2-12, preferably C2-4-albaniles or alkynylaryl bridge may optionally be inserted between the heteroatom or a carbonyl and a place of connection to the rest of the molecule.

Preferred examples of X are -- COOR7or-CONR5R6where R5, R6and R7are preferably hydrogen, C1-4-alkyl, phenyl or alkylphenyl.

Preferably X represents a carboxy or - CONR5R6where R5and R6predstavljaet a preferably hydrogen, C1-4-alkyl, phenyl or alkylphenyl, especially CONH2.

Preferably And1and2it is jdy is oxygen.

Preferably R1represent hydrogen, alkyl, especially C1-12 alkyl, particularly lower alkyl or aryl, especially phenyl.

Examples of preferred R1groups are methyl, ethyl, propyl, isopropyl, butyl, ISO - or tert-butyl, 2,2,2-trimethylated, each optionally attached through a methylene bridge, or the same groups substituted by at least one halogen atom, such as trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-three chloroethyl.

R1as ethyl are particularly preferred.

Preferably R2and R2aindependently represent hydrogen, halogen or alkyl, especially lower alkyl.

Examples of preferred R2and R2agroups independently represent hydrogen, halogen or methyl, ethyl, propyl, isopropyl, butyl, ISO or tert-butyl, 2,2,2-trimethylated or the same groups substituted by at least one halogen atom, such as trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichlorethyl.

Especially at least one and most preferably both R2and R2arepresent hydrogen.

Preferably R3a, R4and R4aindependently include hydrogen, alkyl, especially methyl or ethyl, or aryl, especially phenyl, or aralkyl, especially benzyl.

PR is the measure preferred R 3a, R4and R4agroups independently include hydrogen, halogen or methyl, ethyl, propyl, isopropyl, butyl, ISO or tert-butyl, 2,2,2-trimethylated or the same groups substituted by at least one halogen atom, such as trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichlorethyl.

Especially at least one and most preferably both R4and R4arepresent hydrogen.

R3arepresents in particular hydrogen or alkyl, especially lower alkyl and most preferably hydrogen.

Preferably R3represents hydrogen, C1-12-alkyl, especially C1-6-alkyl, each optionally substituted by one or more substituents selected from hydroxy, halogen, cyano, cypionate or alkoxy and attached to the ring either directly or via thio, sulfinyl, sulfonyloxy, carbonyl or oxycarbonyl group and optional, C1-4-Allenby bridge, particularly methylene; C2-6-alkenyl or quinil, especially C2-3-alkenyl or quinil each optionally substituted by one or more Halogens; azido; cyano; amido; carboxy; triazolam, tetrazolium, pyrrolidinium, pyridium, 1-oxidability, thiomorpholine, benzodioxolyl, fullam, oxazolium, pyrimidinium, pirrallo, thiadiazolyl, thiazolyl,tanila or piperazinil each optionally substituted by one or more substituents, selected from halogen, C1-6-alkyl and phenyl, and attached to the ring either directly or via a carbonyl group or a C1-4-Allenby bridge, particularly methylene; naphthyl; or phenyl, phenylalkyl or phenylalkyl, each optionally substituted by one or more substituents selected from halogen, C1-6-alkyl, C1-6 halogenoalkane, C1-6-alkoxy, C1-6-alkylthio, amino, azido, phenyl and nitro and each attached to the ring either directly or through hydroxy, sulfonyloxy, sulfonyloxy, carbonyl or carbonyloxy group and optional additional C1-4-Allenby bridge, particularly methylene.

Also, preferably, R3represents a C1-6-alkyl, optionally substituted by one or more Deputy selected from halogen, thiocyanato, azido, alkoxy, alkylthio, phenylsulfonyl; Nitrox; C2-3-alkenyl or quinil, each optionally substituted by one or more halogen or acetyl; tetrazolyl, pyridyl, furyl, pyrrolyl, thiazolyl or thienyl; or phenyl or phenylalkyl each optionally substituted by one or more substituents selected from halogen, C1-6-alkyl, C1-6 halogenoalkane, C1-6-alkoxy, amino, azido, phenyl and nitro, and each attached to the ring either directly or via sulfonyloxy and optional additional C1-4-Allenby bridge, frequent in the spine methylene.

Other examples of preferred R3groups include hydrogen, halogen or methyl, ethyl, propyl, isopropyl, butyl, ISO or tert-butyl, 2,2,2-trimethylated or the same groups substituted by at least one halogen atom, such as trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichlorethyl.

R3represents a particularly C1-4-alkyl, optionally substituted by one or more substituents selected from halogen, thiocyanato or azido; C2-5-alkenyl or quinil, each optionally substituted by one or more Halogens; thienyl; or phenyl optionally substituted by one or more substituents selected from halogen, C1-6-alkyl, C1-6 halogenoalkane or azido.

Additional examples of preferred R3groups represent C1-6 alkyl and C2-6 halogenoalkanes.

Preferably R5and R6independently represent hydrogen, methyl, ethyl, propyl, isopropyl, butyl, ISO or tert-butyl, 2,2,2-trimethylated, especially hydrogen or methyl. Especially at least one and most preferably both R5and R6represent hydrogen.

Preferably R7represents hydrogen, methyl, ethyl, propyl, isopropyl, butyl, ISO or tert-butyl, 2,2,2-trimethylated, methoxy, ethoxy, phenyl, benzyl or the same groups substituted on graynamore one halogen atom, such as trifluoromethyl, chlorophenyl.

Preferably R7represents hydrogen, methyl or ethyl, especially hydrogen.

Preferably R8represent hydrogen, methyl, ethyl, propyl, isopropyl, butyl, ISO or tert-butyl, 2,2,2-trimethylated, phenyl, benzyl or the same groups substituted by at least one halogen atom, such as trifluoromethyl, chlorbenzyl.

Preferably R8represents hydrogen or methyl.

Combination of one or more of these preferred groups of compounds are particularly preferred.

In particular, the group of compounds of formula I (Compounds 1 (a) contains those in which

A2 represents oxygen;

X is a-CONR5R6or-COOR7or-CO-R8or CN;

R1represents hydrogen or alkyl, aryl, halogen, hydroxy, amino, nitro, cyano;

R2, R3, R4are the same or different and each independently represents hydrogen or halogen, hydroxy, amino, nitro, piano, acyl, acyloxy, sulfanilamide, sulfinpyrazone, amino, carboxy, ester, simple ester, amido, sulfonic acid, sulfonamide, alkoxycarbonyl, diprosone, alkyl, alkoxy, oxicology ether, acetamido, aryl, auxiproizvodnykh, heterocycle, vinyl and R3can additional is about to represent a C2-5 alkenyl, C2-5 quinil or azido, each optionally substituted by one or more halogen, cyano, thiocyano, azido, cyclopropyl, acyl and/or phenyl; or phenylsulfonyl where any phenyl portion may be substituted by one or more halogen, alkyl, halogenation, alkoxy, nitro, amino, and/or phenyl; most preferably methyl, ethyl, propyl, isopropyl, butyl or isobutyl,

R2a, R3aand R4arepresent hydrogen;

R5, R6, R7are the same or different and each independently represents hydrogen, hydroxy, alkyl, aryl, heterocycle or auxiproizvodnykh; and

R8represents hydrogen, hydroxy, thiol, halogen, alkyl, aryl, heterocycle, alkylthio or diprosone.

Among these compounds 1A, R1preferably substitutes a methyl, ethyl, propyl, isopropyl, butyl, or isobutyl; most preferably methyl, ethyl or n-propyl.

R2and R4preferably independently represent hydrogen or halogen or methyl, ethyl, propyl, isopropyl, butyl, isobutyl; and, most preferably, each is hydrogen.

R3represents preferably C1-5 alkyl, C2-5 alkenyl, C2-C5 quinil, cyclopropyl, azido, each optionally substituted by one or more halogen, cyano, thiocyano, azido, alkylthio, C is coprophila, the acyl and/or phenyl; phenyl; phenylsulfonyl; phenylsulfonyl, tetrazole, thiazole, thienyl, furyl, pyrrole, pyridine, where any phenyl portion may be substituted by one or more halogen, alkyl, halogenation, alkoxy, nitro, and amino; and/or phenyl; most preferably methyl, ethyl, propyl, isopropyl, butyl, or isobutyl.

X preferably represents-COOH or-Sooma or-COOEt or -- CONH2; most preferably-CONH2.

In addition, in particular group of compounds of formula I (Compounds IB) include those in which:

X represents-CA1NH2, -CA1NHCH3or-CA1N(CH3)2;

R1represents an alkyl or phenyl;

R3represents alkyl, alkenyl, quinil, cyano, isothiocyanato, ester, carboxyl, amido, aryl, heterocycle; or

R3represents CH2R10where R10represent hydrogen, cycloalkyl, oxicology ether, oxyalkylene, axiallary, aminoalkylsilanes, aminoalcohol, nitroxy, cyano, isothiocyanato, azido, alkylthio, aaltio, alkylsulfanyl, alkylsulfonyl, heterocycle, aryloxy, alkoxy or triptorelin;

R3arepresents hydrogen, alkyl or aryl (especially with the proviso that when R3arepresents hydrogen, R3great for the h from methyl);

or R3R3aform cycloalkyl;

and R2, R2a, R4and R4aeach is hydrogen.

Among the compounds of formula I,

R1preferably represents alkyl, particularly C1-12-, more preferably, C1-6-alkyl and most preferably ethyl;

R2, R2a, R3Aand R4aare preferably hydrogen;

R3preferably Vybrat from hydrogen; C1-12-alkyl, especially C1-6-alkyl, each optionally substituted by one or more substituents selected from hydroxy, halogen, cyano, thiocyanato or alkoxy and attached to the ring either directly or via thio, sulfinyl, sulfonyloxy, carbonyl or oxycarbonyl group and optional additional C1-4-Allenby bridge, particularly methylene; C2-6-alkenyl or quinil, especially C2-3-alkenyl or quinil, each optionally substituted by one or more galogenkami;

azido; cyano; amido; carboxy; triazolam, tetrazolium, pyrrolidinium, pyridium, 1-oxidability, thiomorpholine, benzodioxolyl, fullam, oxazolium, pyrimidinium, pirrallo, thiadiazolyl, thiazolyl, tanila or piperazinil, each optionally substituted by one or more substituents selected from halogen, C1-6-alkyl and phenyl, and attached to the ring is for directly or through a carbonyl group or a C1-4-Allenby bridge, particularly methylene; naphthyl; or phenyl, phenylalkyl or phenylalkyl, each optionally substituted by one or more substituents selected from halogen, C1-6-alkyl, C1-6 halogenoalkane, C1-6-alkoxy, C1-6-alkylthio, amino, azido, phenyl and nitro and each attached to the ring either directly or through hydroxy, sulfanyl, sulfonyloxy, carbonyl or carbonyloxy group and optional additional C1-4-Allenby bridge, in particular methylene;

R3apreferably represents hydrogen or C1-4-alkyl;

R4and R4apreferably, independently represent hydrogen, C1-4-alkyl, phenyl or benzyl.

Another group of compounds of formula I (compounds 1C) include those in racemic form, in which when X is a-CONR5R6and R1represents hydrogen, methyl, ethyl or propyl, then the substitution on the pyrolidine ring differently from mono-, di - or trimethyl or monoethyl.

Another group of compounds of formula I (compounds ID) include those in racemic form, in which when X is a-CONR5R6and R1represents hydrogen or C1-6-alkyl, C2-6-alkenyl or quinil or cycloalkyl, each unsubstituted, then substitution in the ring differs from alkyl, Ala the Nile or quinil, each unsubstituted.

The following specific group of compounds of the formula I (compound IE) contains those in which

X represents-CA1NH2;

R1represents N;

R3is azidomethyl, iodomethyl, ethyl optionally substituted by 1 to 5 halogen atoms, n-propyl, optionally substituted by 1 to 5 halogen atoms, vinyl, optionally substituted with one or two metelli, and/or 1 to 3 halogen atoms, acetylene, optionally substituted C1-4-alkyl, phenyl or halogen;

R3arepresents hydrogen or halogen, preferably fluorine;

and R2, - R2a, R4and R4aeach is hydrogen;

and their racemates or enantiomerically enriched form, preferably pure enantiomers.

Another specific group of compounds of the formula I (compound IF) includes those in which

X represents-CA1NH2;

R1represents N;

R3represents a C1-6-alkyl, C2-6-alkenyl or C2-6-quinil, optionally substituted, azido, axentra, from 1 to 6 halogen atoms;

R3arepresents hydrogen or halogen, preferably fluorine;

and R2, R2a, R4and R4aeach is hydrogen;

and their racemates or enantiomerically enriched form form, preferably Chi is taken enantiomers.

In the above scope of the invention, when the carbon atom to which R1connec is asymmetric, it is preferable that the connection is in "S" - configuration.

"pharmaceutically acceptable salts" according to the invention include therapeutically active non-toxic forms with base and acid compounds of the formula I can form such forms.

Form of acid additive salts of the compounds of formula I, which exists in a free form, in the form of a Foundation, can be obtained by treating the free base with a suitable acid, such as an inorganic acid, for example, hydrohalogenation, such as hydrochloric or gidropony, sulfuric, nitric, phosphoric and the like; or organic acid, such as, for example, acetic, hydroxyestra, propanoic, lactic, pyruvic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methansulfonate, econsultancy, benzolsulfonat, p-toluensulfonate, ciclamino, salicylic, p-aminosalicylic, palemonova and the like.

The compounds of formula I containing acidic protons may be converted into their therapeutically active non-toxic primary additive salt form, for example, salts with a metal or an amine, by treatment with suitable organic and inorganic onewaytoparadise basic salt forms include, for example, ammonium salts, salts of alkaline and alkaline-earth metal, for example, salts of lithium, sodium, potassium, magnesium, calcium and the like, salts with organic bases, for example, salts of N-methyl-D-glucamine, geranamine, and salts with amino acids such as, for example, arginine, lysine and the like.

On the contrary, these salt forms can be converted into a free form by treatment with a suitable base or acid.

The compounds of formula I and their salts may be in the form of MES, which is included in the scope of the present invention. Such solvate include, for example, hydrates, alcoholate and the like.

Many of the compounds of formula I and their intermediate compounds have at least one stereogenic center in their structure. This stereogenic center may be located in the R - or S-configuration, the specified R - and S-notation is used in accordance with the rules described in Pure Appl. Chem., 45 (1976) 11-30.

The invention also relates to all stereoisomeric forms, such as enantiomeric and diastereoisomeric form compounds of the formula I or their mixtures (including all possible mixtures of stereoisomers).

Moreover, certain compounds of formula I, which contain alkeneamine group can exist in the form Z (zusammen) or E (entgegen) isomers. In each case, the invention includes both the mixture and separate the individual isomers.

Compound the substituents pyrrolidinone ring can also be in the cis or trans positions to each other relative to the plane pyrrolidone rings.

Some compounds of formula I may also exist in tautomeric forms. These forms, though not described in detail in the above formula, it is understood that included within the scope of the present invention.

From the point of view of the present invention relative to the compound or compounds should include this compound in all possible isomeric forms and their mixtures, if the individual isomeric form is not specified.

The invention also includes within its scope proletarienne forms of the compounds of formula I and their various sections and sub-groups.

The term "prodrug" as used here includes the forms of the compounds that can easily be transformed in vivo in a related connection according to the invention, for example, hydrolysis in the blood. Prodrugs are compounds that migrate groups which are removed by biotransformation to manifestations of their pharmacological action. Such groups include groups that are easily hatshepsuts in vivo from their connection carrier, and a connection after removal of remains or becomes pharmacologically active. Metabolic otsepleniya groups form a class of groups, well-known specialist in this level the equipment. They include, but are not limited to, groups such as alkanoyl (i.e. acetyl, propionyl, butyryl and the like), unsubstituted and substituted carbocyclic, aroyl (such as benzoyl, substituted benzoyl and 1 - and 2-naphtol), alkoxycarbonyl (such as etoxycarbonyl), trialkylsilyl (such as trimethyl - and triethylsilyl), monetary formed with dicarboxylic acids (such as succinyl), phosphate, sulfate, sulfonate, sulfonyl, sulfinil and the like. Compounds bearing metabolic otsepleniya group, have the advantage that they can be improved biodiscovery as a result of increased solubility and/or rate of absorption given related to the connection due to the presence of metabolic tsepliaeva group. .Higuchi and V.Stella, "Pro-drugs as Novel Delivery System", Vol.14 of the A.C.S. Symposium Series; "Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

The compounds of formula I no invention can be obtained similarly to standard methods known to the expert at this level techniques in synthetic organic chemistry.

The following method describes some ways of synthesis of explanatory way. Other alternative and/or similar methods can be easily understood by a person skilled in this art. As used here is relatively signs Deputy, "=" about who appoints "represents" and "≠ " means "different than".

A. CYCLIZATION of AMINOETHER.

When in formula I And2=O cyclist aminoether formula AA-II in which Q1together with the oxygen to which it is attached, forms a leaving group, especially Q1is an alkyl group, especially, linear or branched alkyl group having from 1 to 4 carbon atoms.

Q1= methyl or ethyl. The reaction is known and is usually performed between room temperature and 150°With, in the presence or absence of a catalyst, such as acetic acid, hydroxybenzotriazole or 2-hydroxypyridine.

Q1≠ methyl or ethyl. The ester of formula AA-II hydrolyzing in acidic or basic conditions, then cyclist under normal conditions of peptide synthesis, using a binding agent, such as dicyclohexylcarbodiimide (Bodanszky, M., Bodanszky, A., "The Practice of Peptide Synthesis", Springer Verlag, 1984).

A.I Synthesis of AA-II connecting derived itaconate.

The compounds of formula AA-N in which R2a=R3a=N and R3=COOQ2in which Q2represents a linear or branched alkyl group, optionally optically active, is obtained by reaction of the compound of formula AA-III derivative itaconate formula AA-IV in accordance with the equation:

This reaction can be about Westley in accordance with the methodology described in: Street, L.J., Baker, R., Book, Etc, Kneen, CO. ManLeod, A.M., Merchant, K.J., Showell, G.A., Saunders, J., Herbert, R.H., Freedman, S.B., Harley, A., J. Med. Chem. (1990), 33, 2690-2697.

A.2 Synthesis of AA-II by reductive amination.

The compound of formula AA-II can be obtained by reductive amination of compounds of formula AA-V with a compound of formula AA-III in accordance with the equation:

This reaction can be carried out using the conditions described in Abdel-Magid, A.F., Harris, B.D., Maryanoff, C.A, Synlett (1994), 81-83. Alternatively, when X is CONR5R6Amin AA-III can be attached through an amide group to a solid substrate (e.g. Rink-resin). The compounds of formula AA-V can be obtained in one of the following ways:

A. The aldehyde of formula AA-VI alkylate alkylhalogenide formula AA-VII in which X1represents a halogen atom, using intermediate enamines, as described in Whitessell, J.K., Whitessell, M.A., Synthesis, (1983), 517-536 or using the hydrazone as described in Cogeo, E.J., Enders, D., Tetrahedron Lett. (1976), 11 - 14, followed by ozonolysis.

A2.2. Nitroethyl formula AA-VIII can be converted into a compound AA-V processing of the primary conjugate with sulfuric acid in methanol and hydrolysis of the intermediate dimethylacetal (Nef reaction as in Urpi, F., Vilarrasa, J., Tetrahedron Lett. (1990), 31, 7499-7500). Nitroethyl formula AA-VIII can be is obtained as described in Homi, A., Hubacek, I., Hesse, M., Helv. Chim. Acta (1994), 77, 579.

A.2.3. Ether AA-X alkylate allergologicum AA-IX (X1=halogen atom) in the presence of a strong base (for example, diisopropylamide lithium), followed by reductive ozonolysis of unsaturated ester as described in Amruta Reggy R., Hsiang B.C.H., Latffi T.N., M.W. Hill, Woodward K.E., S.M. Rothman, Ferrendelli J.A, D.F. Covey, J. Med. Chem. (1996), 39, 1898-1906.

A.3. Synthesis of AA-II alkylation u-halogenerator.

The compound of formula AA-II in which X=CONR^6, COOR7or CN can be obtained by alkylation γ-halogenating AA-XI, where X2represents a halogen atom, with an amine AA-III.

This reaction can be carried out using the conditions described in GB 2225322 A. Synthesis of ether AA-XI described in part C.

A.4. Synthesis of AA-II derivatives by reductive amination of 5 - hydroxylation.

The compound of formula AA-II in which X=CONR5R6, COOR7or CN, Q1=N and R2a=N can be obtained by reductive amination of 5-hydroxylation formula AA-XII with an amine of formula AA-III in accordance with the equation:

5-hydroxylation formula AA-CP can be synthesized as described in B.1.

C. the condensation of the AMINE WITH the DERIVED γ-HALOGENATION.

When in formula I, A2=Q, X=CONR7R8, COOR7or CN and R2a=N, is connected to the e formula AA-XIII is reacted with an amine of formula AA-III in accordance with the equation:

where X3represents a halogen atom, preferably an iodine atom or chlorine, X4represents a halogen atom, preferably a chlorine atom. This reaction can be carried out as described in GB 2225322 A. the compounds of formula AA-XIII can be obtained by opening of the lactone of formula AA-XIV in the presence of a halogenation agent, such as TMSI, SOCl2/ZnCl2(if necessary, with subsequent halogenoalkanes received halogenation (X4=HE)) in accordance with the equation:

Disclosure of lactone AA-XIV can be carried out in accordance with the methodology described in: Mazzini, S., Lebreton, I, Alphand, V., Furstoss, R., Tetrahedron Lett. (1998), 38,1195-1196 and Olah, G.A., Narang, S.C., Gupta, B.G.B., Malhotra, R., J. Org. Chem. (1979), 44,1247-1250. Halogenoalkane (X4=halogen) or etherification (X4=OQ1) received halogenation (X=OH) can be carried out under conditions well-known specialist in this prior art. The lactones of formula AA-XIV can be obtained by one of the following methods:

B.I. Hydrogenation or conjugate adding metalloorganic.

Compound AA-XIV, in which R2a=R4a=N, can be obtained by hydrogenation α,β-unsaturated lactone of formula AA-XV, or conjugate addition of ORGANOMETALLIC derivative of formula R3M, where M presented yet a Li, Na, Mg or Zn, to the connection AA-XV, at the end catalyzed by copper salts (I).

This reaction can be carried out in accordance with the techniques described in: Alexakis, A., Berlan, J., Besace, Y., Tetrahedron Lett. (1986), 27, 1047-1050; Upshutz, B.H., Ellsworth, E.L., Siahaan, T., J. Amer. Chem. Soc. (1989), 111, 1351-1358, or any condition known to the average expert in this technology.

B.2 Restore succinate derived.

When in the formula AA-XIV R2=R2a=N: recovery of carboxylic acids AA-XVI is carried out in the presence of borhydride reagent, preferably LiBH4or CA(BH4)2in an alcohol solvent, in accordance with the equation:

where Q3represents a methyl or ethyl group, G1represents O or S and Q4represents a hydrogen atom or a linear or branched alkyl having from 1 to 4 carbon atoms, provided that when G1=S, Q4= alkyl and when G1=O, Q4=N.

C. ALKYLATION DERIVED LACTAM.

When in formula I And2=O and X=COOR7the compound of formula AA-XVII is reacted with a compound of formula AA-XVIII in accordance with the equation:

where X5represents a halogen atom and M is alkali metal. This reaction can be carried out when used in the Sri methodology, described in GB (case 15-09).

The compounds of formula AA-XVII can be obtained in accordance with the methodology described in Horni, A., Hubacek, I., Hesse, M., Helv. Chim. Acta (1994), 77,579.

D. the TRANSFORMATION of the DERIVED air.

When in formula I And2=O and X=CONR5R6none of the groups R2, R2a, R3, R3a, R4and R4ais not replaced by carboxyla, complex ester or sulfonic acid, the corresponding ester of the formula

where R7represents a hydrogen atom or a linear or branched alkyl group having from 1 to 4 carbon atoms, in turn Amin direct ammonolysis or in ordinary peptide synthesis using amine and a binding agent, such as alkylchloride or dicyclohexylcarbodiimide.

E. RECOVERY α,β-UNSATURATED LACTAM.

When in formula I And2=O and R2a=R3a=R4a=H, the compounds of formula I can be obtained by reduction of unsaturated lactam AA-XIX:

The recovery phase may be carried out in classic conditions, well known to the average expert in this prior art, for example with hydrogen in the presence of Pd/C, or optionally in the presence of an optically active catalyst. When R2, R3or R4sensitive to Gadirov the Oia at low pressure, for example, using Pd/C as catalyst, the double bond of a mixture of olefins can be selectively restored NaBH4in the presence of CoCl2.

Join the AA-XIX can be obtained by one of the following methods:

E.1 Alkylation

The compound of formula AA-III alkylate compound of formula AA-XX, where Q5represents a linear or branched alkyl group having from 1 to 4 carbon atoms, and cyclist. Stage alkylation can be carried out in an inert solvent, such as tetrahydrofuran, dimethylformamide or dichloromethane, between 0 and 50°With, in the presence or absence of tertiary amine. The cyclization reaction may occur spontaneously or may be carried out in accordance with the methodology described in part A.

E.2 Recovery laminirovannom

The compound of formula AA-XXI is reacted with a compound of formula AA-III under conditions of reductive amination. The first stage of this reaction can be carried out in an inert solvent, for example toluene between 0 and 50°With, in the presence of a reductive agent such as NaBH3CN, and in the presence of acid, for example acetic acid. Synthesis of compound AA-XXI described in Bourguignon, J.J., and others, J. Med. Chem. (1988), 31, 893-897.

F. TRANSFORMATION of FUNCTIONAL GROUPS in the SIDE CHAIN.

F.1 Restore esters to alcohols.

With the unification of the formula I, in which And2=Oh, X=CONR5R6or COOR7, R7is a tertiary alkyl group, and one of the groups R2, R2a, R3, R3a, R4and R4arepresents-G2-COOQ6, G2is a bond or alkilinity group and Q6is a linear or branched alkyl group having from 1 to 4 carbon atoms are synthesized key intermediate compounds for the corresponding compounds in which one of the groups R2, R2a, R3, R3a, R4and R4arepresents-G2- CH2HE. These transformations can be carried out in any conditions, well known to the average expert in this technology.

F.2 Activation and oxidation of alcohols.

The compounds of formula I, in which And2=O and one of the groups R2, R2a, R3, R3a, R4andR4arepresents-G2-CH2OH, G2are communication or alkilinity group, are synthesized key intermediate compounds for the corresponding compounds in which one of the groups R2, R2a, R3, R3a, R4and R4arepresents-G2-CH2X6or-G2-CHO, where X6represents a chlorine atom, bromine or iodine, or a group of the formula-O-SO2-Q7or-O-Q8Q 7is an alkyl or aryl group and Q8is an alkyl group. These transformations can be carried out under any conditions, well known to the average expert in this technology.

F.3 Nucleophilic substitution of activated alcohols.

The compounds of formula I, in which And2=O and one of the groups R2, R2a, R3, R3a, R4and R4arepresents-G2-CH2X6, G2is a bond or alkilinity group and X6is a chlorine atom, bromine or iodine, or a group of the formula-O-SO2-O7is the same as described in F.2, are synthesized key intermediate compounds for the corresponding compounds in which one of the groups R2, R2a, R3, R3a, R4and R4arepresents-G2-CH2X7where X7represents azido, halogen, nitro, amino, amino derivatives, diprosone and heterocycles. These transformations can be carried out under any conditions, well known to the average expert in this technology.

F.4 Rafinirovannom aldehyde.

The compounds of formula I, in which And2=Oh, X=CONR5R6, COOR7or CN, and one of the groups R2, R2a, R3, R3a, R4and R4arepresents-G2-CHO, G2is a bond or alkilinity what Ruppel, are synthesized key intermediate compounds for the corresponding compounds in which one of the groups R2, R2a, R3, R3a, R4and R4arepresents-G2-Q9where Q9represents the vinyl group is not substituted, mono - or di - substituted by a halogen atom or alkyl group. These transformations can be carried out under any conditions, well known to the average expert in this technology.

Alternatively, connection-G2CN can be obtained from the corresponding aldehyde by reaction of the oxime with SeO2(as described in Earl, R.A., Vollhardt, K.P.C., J. Org. Chem. (1984), 49, 4786).

F.5 Transformation derived acid in heterocycles.

The compounds of formula I, in which And2=O and one of the groups R2, R2a, R3, R3a, R4andR4arepresents-G2-CN or-G2-COQ10, G2is a bond or alkilinity group and Q10is alkoxy, aryloxy or amino group, a halogen atom or amino, provided that-COQ10different from X, are synthesized key intermediate compounds for the corresponding compounds in which one of the groups R2, R2a, R3, R3a, R4and R4arepresents-G2-Q11where Q11represents whether the o (i) -CO - aryl/a heterocycle, palladium-catalyzed combination of carboxylic acid-G2-COCl and aryl/heterocyclic metalloorganic, for example trimethylpyridine, or (ii) a heterocycle, for example, thiazole (Friedman, B.S., Sparks, M., Adams, R., J. Amer. Chem. Soc. (1933), 55, 2262 or in Iroka, N., Hamada, Y., Shiori, T., Tetrahedron (1992), 48, 7251), eksasol (in Street, LJ., Baker, R., Castro, J.L, Clamber, R.S., Guiblin, A.R., Hobbs, S.C., Metassa, V.G., Reeve, A.J., Beer, M.S., Migglemis, D.N., Noble, A.J., Stanton, T., Scholey, K., Hargreaves, R.J., J. Med. Chem. (1993), 36, 1529), oxidiazol (Ainsworth, S., J. Amer. Chem. Soc. (1955), 77, 1148), tetrazol, starting from the nitrile (Goerlitzer, K., Kogt, R., Arch. Pharm. (1990), 323, 847), or thiadiazole (Lamattina, J. L., Mularski, C. J., J. Org. Chem. (1984). 49,4800).

F.6 Synthesis of ketone derivatives.

The compounds of formula I, in which And2=O and one of the groups R2, R2a, R3, R3aR4and R4arepresents-G2-CH=CQ12Q13or-G2-CQ13=CHQ12, G2is a bond or alkilinity group, Q12and Q13are hydrogen atom or alkyl group, provided that none of the other R1, X, R2, R2a, R3, R3a, R4and R4ais not carrying a functional group sensitive to oxidation, is synthesized key intermediate compounds for the corresponding compounds in which one of the groups R2, R2a, R3, R3a, R4and R4ais a relevant what about the-G 2-CO-CHQ12Q13or-G2-CHQ13-CO-Q12. This transformation can be carried out under any suitable conditions known to the average expert in this prior art, for example, in the presence of O2and PdCl2in an inert solvent, for example dimethylformamide or N-methylpyrrolidine, between 0 and 50° (Bird, Transition Metals Intermediate in Organic Synthesis, Academic Press, NY, (1967), 88-111).

F.7 the Derivatization of ketones.

The compounds of formula I, in which And2=Oh, X=CONR5R6or COOR7and one of the groups R2, R2a, R3, R3a, R4and R4arepresents-G2-CO-Q14where G2is a bond or alkilinity group and Q14represents an alkyl group, are synthesized key intermediate compounds for the synthesis of (i) alcohols-G2-CHOH-Q14recovery hydride reagent (March, J., Advanced Organic Chemistry, Third Edition, John Wiley & Sons, (1985), 809), (ii) fluorinated side chain-G2-CF2-Q14using the conditions described in Lal, G.S., Fez, G.P., Pesaresi, R.J., Prozonic, P.M., Chem. Commun. (1999), 215-216.

F.8 Synthesis etkinlik derivatives.

The compounds of formula I, in which And2=O and one of the groups R2, R2a, R3, R3a, R4andR4arepresents-G2-C=C(X8)2, G2is a bond or alkilinity group and X81, R2, R2a, R3, R3a, R4and R4ais not carrying a functional group sensitive to strong bases are synthesized key intermediate compounds for the corresponding compounds in which one of the groups R2, R2a, R3, R3a, R4and R4arepresents-G2-C=C-Q15where Q15represents hydrogen, halogen, alkyl or aryl. These transformations can be implemented:

- β-elimination caused by a base (for example, 1 equivalent of tert - GFCF at low temperature, as described in Michel, P., Rassat, A., Tetrahedron Lett. (1999), 40, 8579-8581) in halogenations derivative (Q15= halogen) with subsequent substitution catalyzed by metal-halogen ORGANOMETALLIC compound (for example, MeZnCl in the presence CuCN.LiCl, as described in Micouin, L., Knochel, P., Synlett (1997), 327),

- direct conversion into acetylene metal (e.g., 2 EQ. n-utility) and alkylation with alkylhalogenide or carbonyl derivative (as described Corey, E.J., Fuchs, P.L., Tetrahedron Lett. (1972), 36, 3769-3772).

F.9 Synthesis of alkanes.

The compounds of formula I, in which And2=O and one of the groups R2, R2a, R3, R3a, R4and R4arepresents-G2-C=C-Q16Q17, G2is a bond or Ala is lenovos group, Q16and Q17are alkyl or fluorine, are synthesized key intermediate compounds for the corresponding compounds in which one of the groups R2, R2a, R3, R3a, R4and R4arepresents-G2CH-CH-Q16Q17.

The recovery phase may be carried out under standard conditions, well known to the average expert in this prior art, for example with hydrogen in the presence of Pd/C (March, J., Advanced Organic Chemistry, Third Edition", John Wiley & Sons, (1985), HOI-1102).

F.10 Synthesis (halogen)azidoaniline derivatives.

The compounds of formula I, in which And2=Oh, X=CONR5R6or COOR7or CN, and one of the groups R2, R3or R4is a G2-Q18where Q18is nitroil or triazinones,

G2is a bond or alkilinity group, is a key intermediate compounds for the synthesis of the corresponding compounds in which one of the groups R2, R3or R4is a G2-Q19, Q19is asadoorian, optionally substituted by one or more halogen atoms, preferably Br or F atoms. The transformation proceeds through the restoration of the nitro or triazinones group in aniline by any means well known to the average expert at this level the technician is, optional introduction of one or more halogen atoms (as in Xing teng, D., Guo-bin, L., Synth. Commun. (1989), 19, 1261) and the transformation of the amine azide in well known ways.

F.11 Synthesis of heterocycles from amines.

The compounds of formula I, in which And1=Oh, X=CONR5R6, COOR7or CN, and one of the groups R2, R3or R4is a G2-Q20where G2is a bond or alkilinity group and Q20represents COOH, CONH2or CN, are the key intermediate compounds for the synthesis of the corresponding compounds in which one of the groups R2, R3or R4is a G2-NH2or G2-CH2-NH2that leads to obtaining the corresponding compounds in which one of the groups R2, R3or R4is a G2-Het or G2-CH2-Het, where Het represents a heterocycle linked by the nitrogen atom, optionally substituted by one or more halogen atoms.

In the case when X=CONR5R6CN or COOR7with R7other than N, and where R2, R3or R4represent G2-COOH, turning flows through the rearrangement of kurzius (for example, the influence of diphenyltetrazolium and triethylamine and damping in situ benzene alcohol, as described in: Kim, D., Weinreb, S.M., J. Org.Chem. (1978), 43, 125), removing the protection of the amino group by hydrogenolysis or by any conditions, well known to the average expert in this prior art, obtaining R2, R3or R4=G2-NH2with the subsequent synthesis of the ring with getting heterocycle such as pyrrole (as in Jefford, C.W., Tang, Q., Zaslona, A., J. Amer. Chem. Soc. (1991), 113, 3513-3518), and the optional addition of one or more of halogen atoms in the ring (as in Gilow, H.M., Burton, D.E., J. Org. Chem. (1981), 46, 2221-2225).

In the case when X=CONR5R6, COOR7or CN, and one of the groups R2, R3or R4is a G2-CONH2with X non-CONR5R6or G2Is CN, X is different from the CN, the transformation proceeds through a selective reduction of the amide or nitrile in the aminomethyl group in any conditions, well known to the average expert in this art, and synthesis rings with getting heterocycle, such as triazole (as in Miles, R.W., Samano, V., Robins, M.J., J. Amer. Chem. Soc. (1995), 117, 5951-5957).

F.12 Synthesis of triazoles.

The compounds of formula I, in which And2=O and one of the groups R2, R2a, R3, R3a, R4and R4arepresents-G2-CH2N3, G2is a bond or alkilinity group, are synthesized key intermediate compounds for the corresponding compounds in which one of the groups R2, R2 , R3, R3a, R4and R4arepresents-G2- CH2-triazole. These transformations can be carried out by a prolonged heating in the presence of a derivative of 1-(triphenylphosphonio)-ketone (as described in Hammerschmidt, R, Polsterer, J.P., Zbiral, E., Synthesis (1995), 415).

F.13 Conclusion.

When the compounds of formula I contain one or more stereogenic centers and used such asteroceratinae methods of synthesis, separation of the isomers, mixtures of stereoisomers can best be carried out in one or several stages, including General consistent separation of mixtures of diastereoisomers on their components of the racemates, preferably using chromatographic separation on the organization of the achiral or chiral phase reversible or preferably direct way, with the subsequent at least one end-stage splitting each of the racemate on its enantiomers using most preferably a chromatographic separation on chiral phase reversible or preferably direct way. Alternatively, when using partially stereoselective synthesis methods, the final stage may be the separation of the diastereomers using preferably a chromatographic separation on the organization of the achiral or chiral phase reversible or preferably direct way.

Some the intermediate compounds, described above, especially the compounds of formula AA-II, in which the various substituents have the meanings specified above, are novel and also form part of the invention. These new intermediate compounds, in which the leaving group is pharmaceutically acceptable, have the same utility as described compounds of formula I herein.

It was found that the compounds of formula I and their pharmaceutically acceptable salts are useful in a variety of pharmaceutical indications.

For example, the compounds according to the invention are useful for the treatment of epilepsy, epileptogenesis, stroke and convulsions.

These compounds can also be used to treat other neurological disorders including bipolar disorders, mania, depression, anxiety, migraine, trigeminal and other neuralgia, chronic pain, neuropathic pain, cerebral ischemia, cardiac arrhythmia, myotonia, cocaine dependence, paralysis, mioclauniei, essential tremor and other movement disorders, neonatal cerebral palsy, amyotrophy lateral sclerosis, spasticity, Parkinson's disease and other degenerative diseases.

In addition, the compounds according to the invention can be useful for the treatment of bronchial asthma, asthmatic status and allergic bronchitis, asthmatic is one syndrome, bronchial hyperresponsiveness and bronchospastic syndromes as well as allergic and vasomotor rhinitis and rhinoconjunctivitis.

Therefore, the present invention, the following aspect relates to the use of compounds of formula I or its pharmaceutically acceptable salt for a medicinal product for the treatment of neurological and other diseases, such as mentioned above.

In particular, the present invention relates to the use of compounds of formula I or its pharmaceutically acceptable salt for a medicinal product for the treatment of epilepsy, bipolar disorders, chronic pain or neuropathic pain, migraine, bronchial, asthmatic or allergic conditions.

The activity and properties of the active compounds, oral bioavailability and stability in vitro or in vivo may significantly vary among the optical isomers of the described compounds.

In the preferred embodiment the active compound is administered in an enantiomerically enriched form, i.e. mostly in the form of a single isomer.

For example, in the case of the compounds of formula I in which R1represents ethyl, X represents-CONH2And2represents oxygen, when R3represents propyl and all remaining substituents are in dorog, preferred is S (butanamide), R (ring) enantiomer, and when R3represents 2,2-defermined and all remaining substituents represent hydrogen, preferred is S (butanamide), S (ring) enantiomer.

The present invention also relates to a method of treating epilepsy, migraine, bipolar disorders, chronic pain or neuropathic pain, or bronchial, asthmatic or allergic conditions in a mammal in need of such treatment, comprising the introduction of a therapeutic dose of at least one compound of formula I or its pharmaceutically acceptable salt to a patient.

The methods of the invention include administration to a mammal (preferably human)suffering from the above conditions or diseases, the compounds according to the invention in an amount sufficient to alleviate or prevent a disease or condition.

The compound is usually administered in any suitable single dosage form, including, but not limited to it, the content is from 5 to 1000 mg, preferably from 25 to 500 mg of active ingredient per unit dosage form.

The term "treatment", as used here, includes systematic treatment and prophylactic treatment.

Under the "methodical" understand the effectiveness of current treatment symptomatic case of illness the project or condition.

Under "prevention" refers to preventing the occurrence or recurrence of a disease or condition.

The term "epilepsy", as used here, refers to a disorder of brain function characterized by the periodic and unpredictable occurrence of seizures. Seizures can be "epilepsies", when invoked in the normal brain treatment, such as electrical shock or chemical convulsant or "epilepsies"when called without evidentiary reasons.

The term "seizure," as here used, refers to a transient change in behavior caused by disease, synchronous and rhythmic burning populations of brain neurons.

The term "migraine", as used here, refers to a disease characterized by recurrent episodes of headache, which is very wide in intensity, frequency and duration. The attacks are usually unilateral and are usually associated with anorexia, nausea, vomiting, phonophobia and/or photophobia. In some cases they are preceded or accompanied by neurological and psychological disorders. Migrainea headache can last from 4 hours to about 72 hours. International Headache Society (IHS, 1988) classifies migraine with aura (classic migraine) and migraine without aura (common migraine) as the main types of migraine. Migraine with Eurostat of phase headaches with previous visual characteristic, touch, speech, or motor symptoms. In the absence of such symptoms headaches called migraines without aura.

The term "bipolar disease", as used here, refers to diseases that are classified as Mood disease Diagnostic and Statistical Manual of Mental Disorders, 4th edition (Diagnostic and Statistical Manual of Mental Disorders (DSM-IV TM), American Psychiatry Association, Washington, DC, 1994). Bipolar disorder is typically characterized by spontaneously excitable duplicate (i.e. at least two) cases in which hyperactivity, activity and mood of the patient is significantly violated, this violation is in some cases in mood elevation and increased energy and activity (mania or gipomania) and in other cases, worsening of mood and reduce energy and activity (depression). Bipolar disease is divided into four main categories in the DSM-IV bipolar disease I, bipolar disease II, cyclothymia, and bipolar disease not otherwise defined).

The term "case mania", as used here, refers to a specific period during which the increase abnormality and perseverance, open or irritable mood with manifestations of suppression of speech and psychomotor agitation.

The term "hypomania", as used here, refers to less than full-blown mania occasion with decreased the degree of difficulty.

The term "major depressive case", as used here, refers to the period of at least 2 weeks during which happens to be either depressed mood or decreased interest or pleasure in almost all activities with the manifestations of absent-minded concentration and psychomotor slowing.

The term "mixed case", as used here, refers to the period of time (lasting at least 1 week)in which there are indications as for the case of mania, and the main depressive cases almost every day.

The term "chronic pain", as used here, refers to the condition gradually resolves as the underlying disease in contrast to acute pain. Usually defined as pain that continues after the normal time for healing, pain can also be considered chronic when it will become clear that the pain is an integral part of life in predvidyatsya future. It is desirable that the majority of chronic pain syndromes included neuropathic component, which is usually heavier treated than acute somatic pain.

The term "neuropathic pain", as used here, refers to the pain caused by pathological changes of the nerve, which shows the presence of noxious stimuli, when there is no such recognized rasaraj the body, causing incorrect sensitivity pain. In other words, it turns out that the pain system is enabled and cannot be disabled.

The activity of compounds of the formula I or their pharmaceutically acceptable salts as anticonvulsive substances can be determined on audiogenic model fit. The purpose of this test is the measurement of anticonvulsive potential connection through audiogenic seizures caused from zvukousilitelnym mice, a genetic animal model with reflex seizures. In this model, initially produced epilepsy, seizures are caused without electrical or chemical stimulation and types of seizure are at least partially similar in their clinical phenomenology to seizures occurring in humans (Loscher W. & D. Schmidt, Epilepsia Res. (1998), 2, p.145-181; J. R. Buchhalter, Epilepsia (1993), 34, S31-S41). The results obtained with compounds of the formula I, show a strong pharmacological effect.

Other tests that indicate a potential anticonvulsive activity associated with levetiracetam - binding site (LBS), as described below.

The activity of compounds of the formula I or their pharmaceutically acceptable salts are relatively chronic neuropathic pain can be determined in animal models. For example, chronic neuropathic pain can be modeled by a pharmacologist who Cesky caused the diabetes in rats. In these models, animals exhibit progressive hyperalgesia to painful stimuli, the symptom is usually observed in patients with painful peripherally neuropathy (Courteix C, Eschalier, A. and Lavarenne J., Pain, 53, (1993) 81-88). It was shown that this model has a high pharmacological predictability (Courteix C, Bardin, M., Chantelauze S., Lavarenne J, Eschalier, A., Pain, 57 (1994) 153-160).

The activity of compounds of the formula I or their pharmaceutically acceptable salts in bipolar disease can be tested in animal models. For example, bipolar disease and especially mania can be modeled on pharmacologically induced hyperactivity in rats and to evaluate their behavior in Y impasse. In this situation, therapeutic agents effective for the individual, such as lithium and valproate sodium, increase hyperactivity, therefore, giving the predictability of the model (Cao .J. and Peng N; A;, Eur. J. Pharmacol. 237 (1993) 177-181. Vale A.L. and F. Ratcliffe Psychopharmacology, 91 (1987) 352-355).

Potential anti-asthma properties of the compounds of the formula I or their pharmaceutically acceptable salts can be tested in animal models of allergic asthma, in which Guinea pigs are sensitive to ovalbumin injected antigen and investigate changes in pulmonary function and cellular content of the upper respiratory tract (Yamada and others (1992) Development of an animal model of late asthmatic response in guinea pigs and effects of anti-asthmatic drugs. Prostaglndins, 43: 507-521).

The activity of any of the above mentioned indicators can, of course, be determined by conducting appropriate clinical trials by methods well known to the average expert in this prior art, for a particular indicator and/or the development of clinical trials in General.

For the treatment of diseases of the compounds of formula I or their pharmaceutically acceptable salts can be used in effective daily dose to be administered in the form of pharmaceutical compositions.

Therefore, another embodiment of the present invention relates to pharmaceutical compositions containing an effective amount of the compounds of formula I or its pharmaceutically acceptable salt in combination with a pharmaceutically acceptable diluent or carrier.

To prepare the pharmaceutical compositions according to the invention one or more compounds of the formula I or its pharmaceutically acceptable salt is thoroughly mixed with a pharmaceutical diluent or carrier in accordance with the usual methods of pharmaceutical compounds, known to the average expert.

Suitable diluents and carriers can have a wide variety of forms depending on the desired method of administration, e.g. oral, rectal or parenteral.

Pharmaceutical compositions comprising compounds according to the invention, could the t, for example, be administered orally or parenterally, i.e. intravenously, intramuscularly or subcutaneously, intrathecally.

Pharmaceutical compositions suitable for oral administration may be solid or liquid and may, for example, be in the form of tablets, pills, coated tablets, gelatin capsules, solutions, syrups and the like.

Finally, the active ingredient can be mixed with an inert diluent or a nontoxic pharmaceutically acceptable carrier, such as starch or lactose. Optional these pharmaceutical compositions can also include a binder, such as microcrystalline cellulose, a viscous substance or gelatin, a separator such as alginic acid, lubricants such as magnesium stearate, a plasticizer, such as colloidal silicon dioxide, sweetener, such as sucrose or saccharin or dyes, or fragrances, such as peppermint or methyl salicylate.

The invention also relates to compositions, which can release the active ingredient in a controlled manner. pharmaceutical compositions that can be used for parenteral administration, are in standard forms, such as aqueous or oily solutions or suspensions, usually contained in ampoules, disposable syringes, glass or plastic vials or containers for liquids.

In addition to the active ingredient, these solutions or suspensions can optionally also include a sterile diluent such as water for injection, physiological salt solution, oil, glycol, glycerine, propylene glycol or other synthetic solvents, antibacterial agents such as benzyl alcohol, antioxidants such as ascorbic acid or sodium bisulfite, chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and agents to maintain osmolarity, such as sodium chloride or dextrose.

These pharmaceutical forms receive, using techniques that are commonly used by pharmacists.

The amount of active ingredient in the pharmaceutical compositions can vary within a wide range of concentrations and depends on various factors such as gender, age, weight and medical condition, as well as a way of introduction. This amount of compounds of formula I in compositions for oral administration is at least 0.5 weight% and may reach 80% by weight relative to the total weight of the composition.

In accordance with the invention, it is also been found that compounds of the formula I or their pharmaceutically acceptable salts may be administered alone or in combination with other headlight is asepticheski active components. Non-limiting examples of such additional compounds that can be called for use in combination with the compounds according to the invention are anti-virus tools, antisepticise tools (e.g., baclofen), antimimetic, antigenically means, stabilizing mood, analgesics (e.g. aspirin, ibuprofen, paracetamol), narcotic analgesics, local anesthetic, opioid analgesics, lithium salts, antidepressants (e.g., mianserin, fluoxetine, trazodone), tricyclic antidepressants (e.g. imipramine, desipramine), anticonvulsants (for example, valbrona acid, carbamazepine, phenytoin), antipsychotics (e.g., risperidone, haloperidol), neuroleptic, benzodiazepines (eg, diazepam, clonazepam), phenothiazines (eg, chlorpromazine), blockers, calcium channel, amphetamine, clonidine, lidocaine, meksiletin, capsaicin, caffeine, quetiapin antagonists serotonin, β-blockers, antiarrhythmic agent, triptan, ergot derivatives.

Of particular interest in accordance with the present invention cause a combination of at least one compound of formula I or its pharmaceutically acceptable salt or at least one compound that causes neural inhibition mediated by GABAAthe receptors. Connection fo the mules I have shown potential activity in relation to the compounds causing neural inhibition mediated by GABAAreceptors, facilitating, in many cases, effective treatment of conditions and diseases with reduced risk of side effects.

Examples of compounds neural inhibition mediated by GABAAreceptors include the following: benzodiazepines, barbiturates, steroids and anticonvulsants, such as valproate, vigabatrin, tiagabine or their pharmaceutically acceptable salts.

Benzodiazepines include 1, 4 benzodiazepines, such as diazepam and clonazepam and 1, 5-benzodiazepines, such as clobazam. The preferred connection is clonazepam.

Barbiturates include phenobarbital and pentobarbital. The preferred connection is phenobarbital.

Steroids include adrenocorticotropic hormones, such as acetate tetracosactide, etc. Anticonvulsants include hydantoins (phenytoin, ethotoin etc), oxazolidine (trimethadione etc), suktinimida (tosucceed etc), phenacemide (phenacemide, acetylphenyl etc), sulfonamides (Altium, acetazolamide etc), aminobutanoic acid (for example, gammaaminobutyric acid etc), valproate sodium and derivatives, carbamazepine and others.

Preferred compounds include alprenolol acid, valpromide, valproate, valproate sodium, balpreet sodium,divalproex, clonazepam, phenobarbital, vigabatrin, tiagabine.

In a preferred oral compositions, the daily dose ranges from 5 to 1000 milligrams (mg) of compounds of formula I.

In compositions for parenteral administration the amount of the present compounds of formula I is at least 0.5 weight% and may reach 33% by weight relative to the total weight of the composition. In the preferred parenteral compositions, the dose ranges from 5 mg to 1000 mg of the compounds of formula I.

The daily dose varies in a wide range of single doses of the compounds of formula I and usually ranges from 5 to 1000 mg However, it is clear that in special cases may apply specific dose depending on individual requirements, turning to the doctor.

The amount of active ingredient (compound I and the compound that causes neural inhibition mediated by GABAAreceptors) in the pharmaceutical compositions according to the invention is highly dependent on the mammal, which enter the composition, curable disease, other incoming active ingredients, etc. Usually the number of connections that causes neural inhibition mediated by GABAAreceptors, and the amount of compound I for the composition and the dose can be easily determined using standard methods.

The following examples only, with illustrations and in no way are intended and should not be construed as limiting the invention in any way. The average specialist in this prior art, it is clear that can be performed by standard variants and modifications of the following examples without going beyond the region or scope of the invention.

Unless specifically provided in the examples, the characterization of the compounds was performed by the following methods:

NMR spectra were recorded on BRUKER AC 250 Fourier Transform NMR Spectrometer associated with Aspect 3000 computer and 5 mm1H/13Dual probe or BRUKER DRX 400 FT NMR associated with SG Indigo2computer and 5 mm1H/13C/15N triple probe facing geometry. The connection was studied in DMSO-d6(or CDCl3) the solution when the sample temperature 313 K and at a concentration of 20 mg/ml Instrument tuned to a signal of deuterium DMSO-d6(or CDCl3). Chemical shifts are indicated in ppm, behind TMS, taken as internal standard.

Mass-spectrometric measurements LC/MS (liquid chromatography/mass spectrum), the method is carried out in the following way: (high performance liquid chromatography) HPLC conditions

Tests conducted using a WATERS Alliance HPLC system, equipped with INERTSEL ODS 3, DP 5 μm, 250 X 4.6 mm column.

The gradient change from 100% solvent A (acetonitrile, water, TFA (10/90/0 .1, V/V/V)) to 100% solvent B (acetonitrile, water, TFA (90/10/0 .1, V/V/V)) for 7 min at 100% b for 4 minutes is korost flow 2.5 ml/min and the splitting of 1/10 to use the API source. Chromatography was performed at 30°C. MS(mass spectrum) conditions

Samples dissolved in a mixture of acetonitrile/water, 70/30, V/V at a concentration of about 250 (μg/ml API spectra (+ or -) is measured using a FINNIGAN (San Jose, CA, USA) LCQ inorodtsy mass spectrometer. APCI source operates at 450°and the capillary heater at 160°C. ESI source operates at 3.5 kV and the capillary heater at 210°C.

Mass-spectrometric measurements of DIP/EI method is carried out in the following manner: the sample is evaporated by heating the sample from 50°, 250°C for 5 min El (Electron Impact) spectra were recorded using a FINNIGAN (San Jose, CA, USA) TSQ 700 tandem quadrupole mass spectrometer. The source temperature of 150°C.

Specific rotation recorded on Perkin-Elmer MC241 or 341 polarimeter. The angle of rotation of the record at 25°With a 1% solution in Meon. For some molecules, the solvent is CH2Cl2or DMSO, depending on solubility.

The water content is determined with a Metrohm microcoulometric Karl Fischer titrator.

Preparative chromatography is performed on silica gel Merck 60 (particle size 15-40 μm, reference 1.15111.9025, using in place of the modified Jobin Yvon-type axial compression column (80 mm i.d.), flow rate is between 70 and 150 ml/min. and the Amount of silica gel and solvent mixtures described in the specific examples.

Preparation the Yu chiral chromatography performed on a DAICEL Chiralpak AD 20 μ m, 100·500 mm column using in place of the assembled tool with different mixtures of lower alcohols and C5 to C8 linear, branched or cyclic alkanes with ±350 ml/min solvent Mixture described in the specific examples.

The melting point was determined on Büchi 535 Totoli-type melting device and is not correct or if the initial temperature on a Perkin Elmer DSC7.

Measuring the diraction processes X-ray powder is measured at a suitable temperature and atmosphere on a computer-controlled Philips PW 1710 equipment PW3710 mpd control unit, using the monochromator, Cu Kα radiation (tube operating at 40 k1N, 35 mA) and scintillation counter. Data collected in the angular range from 4° to 50° 2θ long scanning method with a scanning speed of 0.02 2θ/s

In the examples the following abbreviations are used:

AcOEtThe ethyl acetate
AsónAcetic acid
BuLin-Utility
n-Bu3PTri-n-butylphosphine
ClCOOEt or ClCO2EtEthylchloride
DCE1,2-Dichloroethane
DICDiisopropylcarbodiimide
DMSODimethyls epoxid
DSCDifferential scanning calorimetry
DMFN,N-Dimethylformamide
Et3NThe triethylamine
Et2ODiethyl ether
EtOHEthanol
FMOCFluorenylmethoxycarbonyl
LDADiisopropylamide lithium
MeCOClAcetylchloride
MeCNAcetonitrile
MeOHMethanol
MTBEMethyl tert-butyl simple ether
NMPN-methylpyrrolidinone
PhMeToluene
PrepLCPreparative liquid chromatography
i-Pr2ODiisopropyl logos ether
i-DIsopropanol
TFATriperoxonane acid
THFTetrahydrofuran
TMOFTriethylorthoformate
TMSC1Chlorotrimethylsilane
TMSIEdotreotide

If not specifically mentioned in the examples, the compounds get in free (not soleve the form.

EXAMPLE 1. Synthesis of 4-substituted 2-oxopyrrolidin by reductive amination of aldehidelor.

1.1. Synthesis of esters of 3-substituted-4-oxobutanoic acid.

1.1.1. Path A: Alkylation of enamines

Synthesis of methyl ester of 5,5-dimethyl-3-formylamino acid 361 as follows:

In a three-neck flask, equipped with a trap Dean-stark in argon atmosphere heated solution diisobutylamine (4.62 ml of Ashes), 4,4 - dimethylpentane 362 (2.5 g, 0.021 mol) in toluene (20 ml) at 130°C for 2 hours and the water is extracted. The yellow solution is cooled to room temperature and add methylbromide (3.7 g, 0.024 mol) at a time. Pink solution was stirred at room temperature over night and 1 hour at 90°C. Add water (10 ml) at the same temperature and after 1 hour, the solution is cooled to room temperature. The organic layer was washed with HCl IN saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and evaporated, giving an oil which is distilled under reduced pressure (1 mm Hg)to obtain methyl ester of 5,5-dimethyl-3-formylamino acid 361 liquid (1.1 g, 0.05 mol, Teb (1 mm Od): 69-71°). Aldehydebase then used at the stage of recovery amination. Alternatively, alkylation of these is bromoacetate can be carried out in the presence of toluene-acetonitrile 1/1 (V/V) as solvent. The final aldehyde can also be distilled under reduced pressure.

1.1.2. Other synthetic path.

Aldehydebase can also be obtained by other methods, including:

(i) Alkylation of hydrazone using the derived bromoacetate. For example, 2,2-dimethylethylene ester 5-(phenyl)-3-formylindole acid get in the interaction of N-(4-phenyl)-propylidene-N,N-dimethylhydrazone with tert-butylbromide and LDA followed by ozonolysis alkylated hydrazone.

(ii) Introduction of nitromethane to α,βunsaturated esters. Ethyl ester of 3-(3-bromo-phenyl)-4-oxobutanoic acid is produced by adding nitromethane to ethyl ether, 3-(3-bromophenyl)-acrylic acid in the presence of 1.8-diazabicyclo[5.4.0]UNDC-7-ene, oxidation of nitro-derivatives in Nef conditions and controlled hydrolysis of metelits using HCl.

(iii) the Ozonolysis of derivatives of 4-pentenol acid. Ethyl ester of 2-benzyl-4-oxobutanoic acid is produced by alkylation using amide diisopropylate ethyl ester 3-phenylbutanoate acid and allylbromide followed by ozonolysis and restore ozonide with PPh3.

1.2. Reductive amination of esters of 3-substituted-4-oxobutanoic acid and cyclization to pyrrolidin-2-it.

1.2.1. Reductive amination

Synthesis of methyl 4-{[((1S)-1-aminocarbonyl)propyl]amino}butane is ATA 363 presents.

In a three-neck flask of 1 l equipped with a partial condenser hot irrigation, in argon atmosphere, heat the suspension of aldehyde 361 (1.7 g, 0.09 mol), (S)-2-aminobutane (1.58 g, 0.15 mol) and molecular sieves (3 Å) in CH3HE at 60°C for 0.5 hours. The suspension is cooled to 0°and added in portions sodium borohydride (0.55 g). After one hour at room temperature, the reaction mixture was diluted with ethyl ether, washed with water, dried over magnesium sulfate, filtered and evaporated, giving a yellow oil. Methyl 4-{[((1S)-1-aminocarbonyl)propyl]amino}of butanoate 363 are used directly in the next stage without further purification.

Alternatively, the reductive amination can be carried out in the same conditions with other regenerating agent such as NaBH3CN or NaBH(OAc)3(using 1.4 mol. equivalent per allegedely).

1.2.2. Cyclization of butane acid (methyl or ethyl) esters.

The synthesis of the two stereoisomers (2S)-2-(4-neopentyl-2-oxo-1-pyrrolidinyl)butanamide 149 and 148 are as follows:

reflux = heated at boiling

In a three-neck flask, equipped with a partial condenser hot irrigation, in argon atmosphere, dissolve oily 363 in a 1/1 mixture of toluene and 1,2-DIH is oratane (25 ml each) in the presence of hydroxybenzotriazole (2.05 g, available from Aldrich) and the solution heated at 90°C for 2 hours and then cooled to room temperature. The organic phase is washed successively with a saturated aqueous solution of sodium bicarbonate, water, dried over magnesium sulfate, filtered and evaporated, giving a brown solid (1.8 g)which is purified by chromatographic column on silica gel (Eluent: CH2Cl2/CH3HE 95/05 (V/V)), which gives (2S)-2-(4-neopentyl-2-oxo-1-pyrrolidinyl)butanamide (0.89 g, 0.0036 mol) in the form of a 1/1 mixture of diastereoisomers. Division 2 isomers is carried out using chromatography on chiral stationary phase (EtOH-hexane 1/1 (V/V)), which gives, after recrystallization in toluene, two stereoisomer (respectively, 0.35 and 0.37 g), physico-chemical properties described in the table. Alternatively, cyclization of aminoether can be made with other reagents, other than hydroxy-benzotriazole, like acetic acid (as a solvent) or 2-hydroxypyridine (1 equivalent). When acetic acid is used as solvent for the cyclization, the reaction mixture is evaporated under vacuum to dryness, diluted with dichloromethane and treated as described above.

1.2.3. Other cyclization.

Alternatively, the cyclization may be carried out in two stages using (i) acid or basic guide is Alisa ether and (ii) cyclization of activated ester in normal conditions, described in peptide synthesis.

1.3. Solid-phase synthesis of pyrrolidones

1.3.1. Join Fmoc protected amino acids on Rink amide resin.

DMF = DMF

4 g of Rink amide resin (0.51 MEK/g, 100-200 mesh) was placed in a glass vessel and stirred in 20% V/V piperidine/DMF (40 ml) for 30 minutes. The resin dry and full unlocks again. The resin was filtered, washed (6 × DMF) and dried. The resin is suspended in DMF (40 ml) and treated with N-Fmoc-2-aminobutyric acid (3.02 g, 9.28 mmol), and then a solution of 1,3-developerirrational (1.4 g, 11.13 mmol) in DMF (20 ml). The reaction mass is stirred for 1 hour at room temperature, then filtered, washed (DMF) and the condensation process is repeated. The resin was filtered, washed (6 × DMF, 6 × CH2Cl2), dried and used in the same state at the next stage.

1.3.2. Reductive amination with added 5-hydroxy-4-profilform-2-one and cyclization.

100 mg of resin with N-Fmoc-2-aminobutyric amidon (0.051 mmol) is inside mitterolang polypropylene syringe. Removal of Fmoc group is accomplished using 20% piperidine in DMF. To the amino add 5-hydroxy-4-profilform-2-he (36.72 mg, 0.25 mmol) in DCE (2 ml). The resin is then treated with acetic acid (15 μl) and what triacetoxyborohydride sodium (54 mg, 0.25 mmol). The reaction mass is stirred for 18 hours at room temperature, then filtered and washed in the following sequence of solvents: N2O/DMF (1:1), DMF, CH2Cl2CH3HE and dried. The resin is suspended in a mixture triperoxonane acid / CH2Cl2(1/1) for 4 hours with vigorous stirring, then filtered, washed (CH2Cl2×2). The filtrate is concentrated and the residue is dissolved in CH2Cl2(2 ml) and concentrated again. The desired connection is cleaned by LC-MS (liquid chromatography/ mass spectrum) (Micromass - Gilson, LCZ - PlatforM, RP-18 column, gradient elution, CH3CN/N2O/F1%).

1.3.3. Reductive amination added aldehydebase and cyclization.

150 mg of resin with N-Fmoc-2-aminobutyric amidon (0.087 mmol) is contained within mitterolang polypropylene syringe. Removal of Fmoc group is accomplished using 20% piperidine in DMF. To the amino add the aldehyde (0.5 mmol) in TMOF (2 ml). The reaction mass is stirred for 18 hours at room temperature, then filtered and washed (CH2Cl2). The resin is saturated with CH2Cl2and then treated with triacetoxyborohydride sodium (22 mg, 0.104 mmol). The reaction mass is stirred for a further 18 hours at room te is the temperature. The resin is then washed in the following sequence of solvents: N2About × 6, CH3HE × 6, CH2Cl2× 6 and dried. The resin is suspended in a mixture triperoxonane acid / water (95/5) for 1 hour with orbital stirring, then filtered, washed (CH2Cl2× 2). The filtrate is concentrated and the residue is dissolved in CH2Cl2(2 ml) and concentrated again. The desired connection is cleaned by LC-MS (Micromass-Gilson, LCZ - PlatforM, RP-18 column, gradient elution, CH3CN/N2O/F1%).

EXAMPLE 2. Synthesis of 4-substituted 2-oxopyrrolidin through disclosure ring substituted γ-Lactones.

2.1. Synthesis of Lactones

2.1.1. Path A: Alkylation of 2,3-furanone

Synthesis of 4-n-butylphthalate 365 is as follows:

In a three-neck flask in an argon atmosphere, add n-utility (1.6 M in hexano, 75 ml, 0.12 mol.) to a suspension of CuI (11.42 g, 0.06 mol) in dry THF (80 ml), cooled at -30°C. After 0.5 hours, the solution is cooled to -78°With dropwise enter TMSC1 (4.75 g, 0.04 mol.), and then 2,3-furanone 364 (from Aldrich, 3.36 g, 0.04 mol.), dissolved in dry THF. The suspension is allowed to warm to room temperature and hydrolyzing a saturated solution of ammonium chloride. The aqueous layer was extracted with AcOEt (3x), washed with water, dried over magnesium sulfate and pariva the t to dryness. The crude lactone clear destileria (1 mm Hg; 73-80° (C)that gives 2.7 g of 4-n-butylphthalate 365.

Alternatively, the cuprate reagent can be obtained by substitution orginality using organomegaly, which can be obtained by interaction between alkylhalides and magnesium shavings in normal conditions for this process. THF can be substituted deethylation ether (For General information see: Lipshutz, B.H.; Sengupta, S. Org. Reactions 1991, 41, 135).

2.1.2. Other ways

Alternatively, the lactones can be obtained:

(i) Recovery succinate esters. 4-(cyclopropyl)methylbutyrate obtained by alkylation of monomethylamine using cyclopropanemethylamine with diisopropylamide lithium, followed by reduction of 2-(cyclopropyl)methyl-succinato (succinic) acid 1-methyl ester using NaBH4and CaCl2.

(ii) Recovery salcinovic acid 1-alkyl ester of 4-alkylthiophene. 4-alivetorrents is obtained from ethyl 4-pontenuovo of tiefer (synthesized from 4-pentenol acid and ethanthiol in the presence of dicyclohexylcarbodiimide). Alkylation of ethyl 4-pentenol acid tiefer ethylbromoacetate with diisopropylamide lithium, allows to obtain 2-allylamino acid 1-methyl ester 4-ethylthioethyl, which is then transferred to 4-alivetorrents by the interaction sequence is correctly with LiBH 4and sulphuric acid.

2.2. Synthesis of pyrrolidones

2.2.1. The acylation/alkylation of butyramide.

The synthesis of the two stereoisomers (2S)-2-(4-allyl-2-oxo-1-pyrrolidinyl)butanamide 228 and 224 as follows:

- Stage 1: Disclosure of lactone

In a three-neck flask in an argon atmosphere, added TMSI (51 ml, Aldrich) to a solution of crude 4-allylmethylamine 366 (see procedure § 2.1.3., 22.9 g, 0.181 mol), cooled to 0°C. the Solution is stirred for 2 hours at room temperature and hydrolyzing IN HCl (300 ml). The aqueous layer was extracted with CH2Cl2and the combined organic phases are washed with brine, dried over magnesium sulfate and concentrated in vacuo, giving crude product 3-(iodine)methyl-5-hexenoic acid 367 (44.5 g).1H NMR (250 MHz, CDCl3): 1.80-2.05 (m, 2H), 2.20 (t, 2H), 2.40-2.60 (t, 2H), 5.10-5.20 (m, 2H), 5.15-5.80 (m, 1H).

- Stage 2: Chlorination of etkileri.

In a three-neck flask, equipped with a partial condenser hot irrigation, in an argon atmosphere a solution of thionyl chloride (25.5 ml) and crude etkileri 367 (44.5 g, 0.175 mol) in benzene (90 ml) is stirred for 24 hours at room temperature. The solvents are evaporated under vacuum, giving the crude acid chloride 3-(iodine)methyl-5-hexenoic acid 368 (47 g), which is used directly in the next stage without further clean the key. 1H NMR (250 MHz, CDCl3): 1.90-2.05 (m, 2H), 2.15 (t, 2H), 2.90-3.10 (m, 2H), 3.25 (DD, 1H), 3.35 (Yes, 1H), 5.10-5.20 (m, 2H), 5.15-5.80 (m, 1H).

- Stage 3: Acylation-alkylation with S-2-aminobutyrate.

In a three-neck flask in an argon atmosphere, the crude acid chloride acid 368 (47 g, 0.172 mol) in CH2Cl2(300 ml) is added dropwise to a mechanically stirred suspension of molecular sieves (29 g), powdered KOH (22.3 g), anhydrous Na2SO4(28.8 g), Tetra-n-butylammonium bromide (2.8 g, 0.0086 mol) and S-2-mode ([α]25D=+19.35°; 26.3 g, 0.26 mol.) in CH2Cl2(470 ml), cooled at 0°C. the Solution is stirred for 5 hours at -5°add powder KOH (6.2 g) and stirring is continued for 3 hours at -5°C. the Reaction mixture is filtered on getlocale and the solvent evaporated in vacuum. The crude reaction mixture was purified sequentially by chromatography on silica gel (AcOEt/i - D: 97/03 (V/V)) and preparative chromatography on a chiral stationary phase (hexane/EtOH), which gives two isomers (2S)-2-(4-allyl-2-oxo-1-pyrrolidinyl)butanamide (6.0 respectively (228) and 5.48 g (224); 16 and 15%). Two small impurities also distinguish the following chiral chromatography, defined as two stereoisomer (2S)-2-[4-(2-improper)-2-oxo-1-pyrrolidinyl]butanamide 225 (0.22 g) and 226 (0.27 g) as white solids after recrystallization.

2.2.2. Alkilirovan the s/acylation butyramide.

The synthesis of the two stereoisomers (2S)-2-(5-nonyl-2-oxo-1-pyrrolidinyl)butanamide as follows:

- Stage 1: Disclosure of lactone

To a solution γ-nonalactone (0.32 ml, 2 mmol) in thionyl chloride (164 μl. 1,2 .25 mmol), added zinc chloride (12 mg, 0.088 mmol) at room temperature and the mixture is stirred for 24 hours. Add an excess of methanol and the reaction mixture is stirred for 10 minutes, and then concentrated under reduced pressure, giving 4-chlorononane acid methyl ester, which is used as such.

- Stage 2: Alkylation

To a solution of methyl ester 4-chlorononane acid (2 mmol) in DM F (2 ml) was successively added 2-aminobutyrate (1 g, 10 mmol), 300 mg of sodium iodide (2 mmol) and 276 mg of potassium carbonate (2 mmol). The mixture is stirred over night at 60°C. the Solids filtered and washed with CH2Cl2(2×2 ml). The filtrate is concentrated under reduced pressure, which gives the derivative of the ether, which is used as such for cyclization.

Stage 3: cyclization: see terms § 1.2.2. and § 1.2.3.

2.3. Synthesis clopyralid-2-ones

Synthesis of (2S)-2-[2-oxo-4-(2-oxopropyl)-1-pyrrolidinyl]butanamide 230 is as follows:

<> In a three-neck flask, propulsive oxygen through a solution of PdCl2(0.68 g, 0.0039 mol.), CuCl2(1.68 g, 0.0098 mol.) in N-methyl-2-pyrrolidinone (NMP, 40 ml) and add dropwise a solution of (2S)-2-[2-oxo-4-(2-oxopropyl)-1-pyrrolidinyl]butanamide 224 (4.13 g, 0.020 mol) in NMP (40 ml) (additional time: 1.2 hours). The solution is stirred at prorokowanie gas within 0.75 hours, filter 3 through celite and evaporated under vacuum (1 mm Od). The crude ketone purify by chromatography on silica gel (CH2Cl2/methyl-t-butyl ether/i-D 9/0.9/0 .1 (V/V)), which gives (2S)-2-[2-oxo-4-(2-oxopropyl)-1-pyrrolidinyl]butanamide 230 in the form of a white solid after recrystallization from AcOEt.

2.4. Deriving ketone 230

2.4.1. Synthesis of alcohols

Synthesis of (2S)-2-[(4S)-4-(2-hydroxypropyl)-2-oxopyrrolidin]butanamide 233 as follows:

- Stage 1: The Restoration.

In a three-neck flask in an argon atmosphere, add portions NaBH4to a solution of 230 (9 g, 0.012 mol) in EtOH (140 ml), cooled at -5°C. the Solution is stirred for 4 hours at the same temperature, zakolerovat a saturated solution of ammonium chloride and evaporated to dryness. The solid is dissolved in CH3HE/CH2Cl2, filtered and concentrated in vacuo, the Residue is purified by chromatography on silica gel (CH3HE/CH2Cl 2: 90/10 (V/V)), which gives epimeno mixture of alcohols 369 (2.2 g, 79%) as oil. The crude mixture was directly acetimidoyl at the next stage.1H NMR (400 MHz, (CD3)2SO): 0.70 (t, 3H), 1.05 (d, 3H), 1.30-1.45 (m, 1H), 1.70-1.80 (m, 1H), 1.80-2.05 (m, 1H), 2.20-2.40 (m, 2H, overlapped with solvent), 3.00-3.20 (m, 1H), 3.30-3.35 (m, 2H, overlapped with solvent), 3.50-3.65 (m, 1H), 4.30 (m, 1H), 4.45 (m,, 1H), 7.10 (singlet (broad), 1H), 7.20 (singlet(broad), 1H).

- Stage 2: Acetylation.

In a three-neck flask in an argon atmosphere, add acetyl chloride (0.91 g, 0.011 mol.) to a solution of 4-N,N-dimethylaminopyridine (0.11 g, 0.001 mol), pyridine (0.86 ml) and alcohol (CH2Cl2(90 ml) at room temperature. The solution is stirred for 5 hours, zakolerovat a saturated solution of ammonium chloride and the aqueous layer was extracted with CH2Cl2(3x), dried over magnesium sulfate and concentrated in vacuo, giving crude acetate, which is purified by column chromatography on chiral phase (hexane/EtOH), which gives two epimeric acetate 370 and 371 (respectively 1.143 and 1.17 g). To a mixture of 1/1 370 and 371 in front of chiral chromatography:1H NMR (400 MHz, CD3SOCD3): 0.90 (t, 3H), 1.21-1.28 (m, 4H), 1.51-1.82 (m, 4H), 1.89-1.98 (m, 1H 1.80-2.05 (m, 1H),), 2.04 (s, 3H), 2.16 (DD, 1H), 2.38 (m, 1H), 2.62 (DD, 1H), 3.11 (DD, 1H); 3.49 (DD, 1H), 4.39-4.49 (m, 1H), 4.89-4.99 (m, 1H), 5.43 (s (broad), 1H), 6.24 (s (broad), 1H).

- Stage 3: The Deacetylation.

In a three-neck flask in an argon atmosphere, a suspension of one enantiomer acetate 371 (1.11 g, 0.0042 mol.) and K2CO3in EtOH is stirred for 20 hours at 0°C, evaporated to dryness and the crude alcohol is purified by chromatography on silica gel (CH3HE/CH2Cl2: 85/15 (V/V)), which gives (2S)-2-[(4S)-4-(2-hydroxypropyl)-2-oxopyrrolidin]butanamide 233 (0.67 g, 72%) as a white solid after recrystallization from acetonitrile.

2.4.2. Fluoridation 230

Fluoridation ketone 230 is used for the synthesis of 2-[(4S)-4-(2,2-deferror)-2-oxopyrrolidin]butanamide 265.

- Stage 1: Fluoridation

In a Teflon flask in an argon atmosphere, add portions (MeOCH2CH2)2NSF3(1.86 g, 0.009 mol) to a solution of 230 (0.389 g, 0.0017 mol) in CH2Cl2and heated 4 hours at 80°C. the Solution is stirred for 4 hours at the same temperature, zakolerovat sodium carbonate, extracted with CH2Cl2, washed with HCL 1N, dried over MgSO4, filtered and concentrated in vacuo, giving tertiary amide 372 (1.2 g). LC/MS: 365 (MH+). The crude mixture was directly used in the next stage.

- Stage 2: Hydrolysis and ammonolysis.

In a three-neck flask in an argon atmosphere heated solution of the crude product 372 (0.28 g) in 6N HCI for 22 hours at 60°C, cooled to the room the temperature and the aqueous solution evaporated to dryness.

The solid is triturated in MeCN, filtered and dried under vacuum, giving the acid (1.2 g) as a white solid.

The crude mixture lidiruyut under standard conditions described in the § 6.3.1. (stage 2), which gives a mixture of (2S) and (2R)-2-[(4S)-4-(2,2-deferror)-2-oxopyrrolidin]butanamide (respectively 87%and 13%).

2.5. Synthesis of (2S)-2-(2-oxo-4-propyl-1-pyrrolidinyl)butanamide 158 and 159

2.5.1. Stage 1: Reductive amination

In a three-neck flask in an argon atmosphere, 4-n-propylhydroxybenzoate 373 (35.5 g, 0.25 mol, synthesized by Bourguignon JJ et al; J.Med. Chem, 1988, 31, 893-897), added to a solution of S-2-mode (28.1 g, 0.275 mol.) in PhMe (355 ml) at 18°C. the Solution is stirred for 0.5 hour at the same temperature and precipitate appears. The reaction mixture is stirred for 2 hours and added dropwise 4N NaOH (37.5 ml) to the suspension, and then an aqueous solution of NaBH4(6.2 g, 0.16 mol) in water (62 ml). After 1 hour the reaction mixture is carefully zakolerovat Asón (30 ml), heated to 50°C for 3 h and cooled to room temperature over night. Added (20 ml) NaOH 50% V/V and the aqueous phase extracted with PhMe (2). The combined organic phases washed with brine and concentrated in vacuo, giving crude unsaturated pyrrolidone 374 (43.4 g) as an orange oil, which is used in the following studies is without further purification. It can be recrystallized in a white solid (DSC, the beginning; TPL = 72.9°).

2.5.2. Stage 2: the Hydrogenolysis

In a three-neck flask in an argon atmosphere, add portions of an aqueous solution of NH4COOH (8 g, 0.126 mol) to a suspension of the crude product 374 (22 g, 0.105 mol) and 10% Pd/C (1.1 g) in water (220 ml) and heated to 50°C. the Suspension is stirred for 3 hours at 50°C, cooled to room temperature and stirred over night. After 18 h, the suspension is heated to 50°and add portions of an aqueous solution of NH4COOH (8 g, 0.126 mol). After 1.5 hours, add the third portion of the aqueous solution NH4COOH (8 g, 0.126 mol.). The suspension is stirred for 0.5 hour at 50°and add 10% Pd/C (1.1 g). The suspension is stirred for 5 hours at the same temperature and left overnight without stirring at room temperature. The reaction mixture was filtered through celite, washed with water (30 ml) and the aqueous layer was extracted with AcOEt (3x). The combined organic phases are washed with brine and concentrated in vacuo, giving crude pyrrolidone in the form of white crystals (18.1 g). Two diastereoisomers separated using preparative HPLC (high performance liquid chromatography (HPLC) on a chiral phase (EtOH/heptane: 1/1), which gives, after recrystallization from iPr2Oh, two pyrrolidone 158 (9.5 g) and 159 (7.2 g) as white solids.

Two forms of terdag the substances 159 see, calling them form a and form C. Form And usually characterizes peaks diaphragms 8.8, 9.8, 14.9, 15.0, 17.0, 17.1, 21.2, 21.4, 24.8 (26°). The form usually characterizes peaks diaphragms 6.50, 11.25, 19.22, 23.44, 28.47, 29.94 (29°).

2.5.3. Synthesis of 5-hydroxy-4-profilform-2-it

5-Hydroxy-4-propyl-5H-furan-2-he 373 (15 g, 0.1 mol), ethyl acetate (260 ml) and Pd/C 5% is placed in a Parr apparatus. The mixture Tegaserod and hydrogen is injected at a pressure of 35 psi. This mixture is then vigorously stirred at 25°C for 2 hours. After filtration on celite, the solvent is removed under reduced pressure at 50°that gives 5-hydroxy-4-profilform-2-it is in the form of a crude product (100% yield). LC/MS: 145 (MH+).

EXAMPLE 3. Synthesis of 4-substituted 2-oxopyrrolidin by alkylation of 2-oxopyrrolidin ethyl 2-bromobutane.

3.1. Synthesis of 4-substituted 2-oxopyrrolidin

A. Obtain ethyl 3-(3-chlorophenyl)-2-propenoate 375:

A 2-liter three-neck flask, equipped with a mechanical stirrer and a separating funnel, in an inert atmosphere, dissolve 106,6 g (755 moles, 1 EQ.) 3-chlorobenzaldehyde in 1 l of THF and cooled to 0°C. Then add 341.9 g (980 mmol, 1.3 EQ), ethyl(triphenylphosphonium) acetate with vigorous stirring, the temperature was raised to 10°C. the Mixture continued to stir for one hour at 0°and then overnight at room temperature. The mixture is concentrated to dryness, the residue suspended in diethyl ether, the triphenylphosphine oxide is filtered off and the filtrate concentrated to dryness. The residue is purified using preparative liquid chromatography (1 kg SiO2, petroleum ether/EtOAc, 75:35), which gives 191.8 g of pure 375, 92% yield.1H NMR (250 MHz, (CD3)2SO): 1.30 (t, 3H), 4.25 (q, 2H), 6.70 (d, 1H), 7.40 (m, 2H), 7.50-7.70 (m, 2H), 7.85 (s(broad), 1H).

A. Other ways:

Alternatively, derivatives of cinnamate also synthesized using catalyzed by palladium carbometalation acrylic derivatives.

For example, ethyl (2E)-3-(5-pyrimidinyl)-2-propenoate 376 produced by interaction between the acrylate and 5-bromopyrimidine in the presence of palladium acetate.

3.1.1-b. Obtain ethyl 3-(3-chlorophenyl)-4-nitrobutane 377:

In a three-neck flask with a volume of 500 ml, equipped with a partial condenser hot irrigation, magnetic stirrer and dropping funnel under inert atmosphere, dissolve 100 g (447 mmol, 1 EQ) of ethyl 3-(3-chlorophenyl)-2-propenoate 375 127 ml (2.37 mol, 5 EQ) of nitromethane. Then added dropwise 70.9 ml (447 mmol, 1 EQ) of diazabicyclo with vigorous stirring, keeping the temperature below 25°With (bath ice/water). The dark red mixture is stirred over night in to matnog temperature. The mixture is diluted with diethyl ether, washed with 1N HCl, the aqueous phase is again extracted twice with ethyl ether. The combined organic phases are dried over magnesium sulfate, filtered and concentrated to dryness, giving 128.5 g of crude product 377, 99% yield, which is used as such in the next stage.1H NMR (250 MHz, (CD3)2SO): 1.10 (t, 3H), 2.70 (DD, 1H), 2.75 (DD, 1H). 3.95 (q, 2H), 4.95 (m, 2H), 7.20-7.45 (m, 4H).

3.1.1.c. Obtain ethyl 4-amino-3-(3-chlorophenyl)butanoate 378:

A 2-liter autoclave in an inert atmosphere, dissolve 196 g (733 mmol) ethyl 3-(3-chlorophenyl)-4-nitrobutane 377 200 ml of ethanol.

A suspension of 200 g of pre-dried (3 x, ethanol) of Raney Nickel added to 700 ml of ethanol and the mixture hydronaut in a Parr apparatus at maximum pressure of H220 psi (STRONGLY EXOTHERMIC REACTION, cooling is required, the ice/water). The mixture Tegaserod, filtered on Celite/Noritoshi cushion and the filtrate was concentrated in vacuo, giving 136.7 g of crude product 378, 78% yield, which is used as such in the next stage.

3.1.1.d. Getting 4-(3-chlorophenyl)-2-pyrrolidinone 379:

In the flask, 500 ml, equipped with a partial condenser hot irrigation and a magnetic stir bar, dissolve 135.7 g (561 mmol) ethyl 4-amino-3-(3-chlorophenyl)butanoate 378 200 ml of toluene and the ect is refluxed for 30 minutes The solution is concentrated to dryness and the residue purified using preparative liquid chromatography (1 kg SiO2CH2Cl2/EtOH, 98:2- > 95:5), which gives 54.4 g of pure 379 (49.2%). GC/MS: 197/197 M+

3.1.1.f. Obtain ethyl 2-[4-(3-chlorophenyl)-2-oxo-1-pyrrolidinyl]butanoate 380

A 2-liter three-neck flask, equipped with a partial condenser hot irrigation, magnetic stirrer and dropping funnel under inert atmosphere, dissolve 54.4 g (278 mmol, 1 EQ) of 4-(3-chlorophenyl)-2-pyrrolidinone 379 in 1.4 ml of acetonitrile. Add 64 ml (100.7 g, 556 mmol, 2 EQ) of methyl 2-bromobutyrate and the temperature raised to 50°C. Then add portions 22.24 g (556 mmol, 2 EQ) of sodium hydride, the temperature was raised to 65°C. the Mixture is stirred for about one hour at 50°C. the Mixture is concentrated to dryness, the residue suspended in ethyl acetate, washed with water, the aqueous phase is again extracted with ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and concentrated to dryness. The residue is purified using preparative liquid chromatography (1 kg SiO2, petroleum ether/EtOAc, 70:30), which gives 56.7 g of pure 380, 69%.1H NMR (250 MHz, (CD)3)2SO): 0.80-1.00 (m, 3H), 1.60-1.90 (2H, m), 2.35-2.55 (m, 1H: partially overlapped with solvent), 2.60-2.90 (m, 1H: partially overlapped with solvent), 3.70 (s, 3H), 3.50-3.80 (m 3 is), 4.50 (m, 1H), 7.20-7.50 (m, 4H).

3.1.1.g. Getting 2-[4-(3-chlorophenyl)-2-oxo-1-pyrrolidinyl]butanamide 381:

In a three-neck flask with a volume of 1 l equipped with a partial condenser hot irrigation, magnetic stir bar, dissolve 56.7 g (192 mmol) of ethyl 2-[4-(3-chlorophenyl)-2-oxo-1-pyrrolidinyl] butanoate 380 600 ml of methanol. Gaseous ammonia propulsive through the solution and a saturated solution incubated at room temperature for 5 days, during which time ammonia evaporates. After completion of the reaction, the solution is concentrated to dryness. The residue is purified using preparative liquid chromatography (1 kg SiO2CH2Cl2/EtOH, 97:3), which gives 50 g of pure 381, 97.8%. 82.2 g of a Mixture of diastereoisomers separated using chiral preparative liquid chromatography (Chiralpak AD, benzene/EtOH, 50:50) and each pair of enantiomers again separated using chiral preparative liquid chromatography (Chiralpak AD, benzene/EtOH, 50:50).

Four compounds crystallized from toluene, giving 16.79 g, 13.9 g, 15.84 g, and 14.84 g 202, 203, 204 and 205, respectively, 72% of the total output.

EXAMPLE 4. Synthesis of 4-substituted 2-oxopyrrolidin alkylation/cyclization of esters of 4-bromo-3-substituted-but-2-ene acid with 2-aminopolyamide.

4.1. Synthesis of ester 4-bromo-3-substituted-but-2-ene acid, alkylated the e & restore

4.1.1 Bromination of ethyl ester of 3-substituted crotonic acid

Synthesis of ethyl ester of 4-bromo-3-(2-thiophenyl)-but-2-ene acid 382 as follows:

A 2-liter three-neck flask equipped with a mechanical stirrer, is refluxed in an argon atmosphere for 6 hours degassed solution of ethyl ester of 2-thiophene-3-yl-but-2-ene-acid 383 (32.88 g, 0.211 mol), N-bromosuccinimide (37.56 g, 0.211 mol) and 2,2'-Aza-bis-isobutyronitrile (3.46 g, 0.021 mol) in CCl4(600 ml), then cooled to room temperature and stirred for 20 hours. The suspension is filtered and concentrated in vacuo, giving crude bromide, which is purified by chromatography on silica gel (Hexane/CH2Cl2: 65/35 (V/V)), which gives the ethyl ester of 4-bromo-3-(2-thiophenyl)-but-2-ene acid 382 (36.72 g, 78%).1H NMR (250 MHz (CDCl3): 3.80 (s, 3H), 4.95 (s, 2H), 6.25 (s, 1H), 7.10 (DD, 1H), 7.35 (d, 1H), 7.45 (d, 1H).

4.1.2. Alkylation of 2-aminobutane.

Synthesis of 2-[2-oxo-4-(2-thienyl)-1-pyrrolidinyl]butanamide 71 as follows:

4.1.2.1. Step 1: Alkylation-cyclization

In a three-neck flask with a volume of 1 l in an argon atmosphere a solution of methyl ester 4-bromo-2-thiophene-3-yl-but-2-ene-acid 382 (36.72 g, 0.134 mol), (S)-2-aminobutyrate ([α]25D: 19.09°; 31.6 g, .270 mol) in THF (350 ml) is stirred for 20 hours at room temperature. The suspension is filtered and concentrated in vacuo, giving crude unsaturated pyrrolidone 384 and 385 (43.47 g), which is used in the next stage without further purification. Crude pyrrolidone can be selected and usually is a mixture of isomers of the double bond (olefin 3.4 and 4.5, the first of which is the main).1H NMR (250 MHz, (CD3)2SO): 0.80 (t, 3H), 1.30-1.90 (m, 2H), and 4.40 (d, 1H), 4.45 (m, 1H), 4.70 (d, 1H), 6.30 (s, 2H), 7.0 (s (broad), 1H), 7.15 (DD, 1H), 7.40 (s (broad), 1H), 7.50 (d, 1H), 7.85 (d, 1H).

4.1.2.2. Stage 2: Restoration

In a three-neck flask with a volume of 0.5 l in argon atmosphere, add portions NaBH4(1.75 g, 0.044 mol.) to a solution of crude unsaturated pyrrolidone 384/385 (14 g, 0.044 mol.), CoCCl2(0.062 g, 0.0005 mol) in EtOH (100 ml) - diethylene glycol dimethyl ether (65 ml), cooled at 0°C. Over 0.75 hour, the reaction mixture is heated at the boil under reflux for 48 hours and during this time successively with three portions added NaBH4(1.75 g, 0.045 mol) and CoCl2(0.062 g, 0.0005 mol) every 10 hours until there is no longer the original substance. The reaction mixture is cooled to room temperature, hydrolyzing a saturated solution of ammonium chloride, extracted with AcOEt, dried over magnesium sulfate and concentrated in vacuo, giving crude pyrrolidone, which is purified by column chromatography on silica gel (sub> 2Cl2/CH3OH: 97/03 (V/V)), which gives 4.15 g of 2-[2-oxo-4-(2-thienyl)-1-pyrrolidinyl] butanamide (38%). The mixture of stereoisomers purified by column chromatography on chiral phase (hexane/EtOH), which gives two diastereoisomers (2S)-2-[2-oxo-4-(2-thienyl)-1-pyrrolidinyl] butanamide 71 (paracrystal-lizovyvatj from AcOEt) and 72 (recrystallized from AcOEt). In the specified case, two small impurities which two diastereoisomers (2R)-2-[2-oxo-4-(2-thienyl)-1-pyrrolidinyl]butanamide 84 (0.25 g, is recrystallized from AcOEt) and 85 (0.44 g, is recrystallized from AcOEt) e also receive during treatment.

4.2. Synthesis of azidoanilide

The synthesis of a single enantiomer (2S)-2-[4-(3-azidophenyl)-2-oxo-1-pyrrolidinyl]butanamide 86 as follows:

4.2.1. Synthesis of anilines.

4.2.1.1. Step 1: Alkylation of (S)-2-mode methyl ether 4-bromo-3-(3-nitrophenyl)-but-2-ene-acid 386

Synthesis 386 carried out as described in § 4.1.1.1H NMR (250 MHz, (CD3)2SO): 1.30 (t, 3H), 4.20 (q, 2H), 5.15 (s, 2H), 6.45 (s, 1H), 7.75 (DD, 1H), 8.10 (DD, 1H), 8.25 (DD, 1H), 8.45 (d, 1H).

The alkylation is carried out, following ekperimentalni the procedure described in § 4.1.2.1. (59%).LC/MS: 290 (MH+).

4.2.1.2. Stage 2: Restoration

In an autoclave with a volume of 2.5 liters, in an inert atmosphere, dissolve 7.22 g (0.025 mol) 387 and Pd on coal (10% V/V, g) in EtOH (11) and the mixture hydronaut in a Parr apparatus at maximum pressure of H 220 psi. After one hour the mixture Tegaserod, filtered on Celite/Noritoshi cushion and the filtrate was concentrated in vacuo, giving crude pyrrolidone, which is purified by chromatographic column on silica gel (CH2Cl2/CH3OH: 93/07 (V/V)), which gives a mixture of diastereoisomers, which is cleaned by column chromatography on chiral phase (hexane/EtOH), giving, after reaction with HCl in EtOH (for the synthesis of hydrochloride) two diastereoisomers (2S)-2-[4-(3-AMINOPHENYL)-2-oxo-1-pyrrolidinyl] butanamide 90 (0.800 g, recrystallized from EtOH) and 91 (1.21 g, recrystallized from EtOH) in the form hydrochloric salt.

4.2.2. Synthesis of penilised 86.

In a three-neck flask in an argon atmosphere, is added dropwise NaNO2(0.232 g, 0.0037 mol) in water (1.5 ml) to a solution of free base (2S)-2-[4-(3-AMINOPHENYL)-2-oxo-1-pyrrolidinyl] butanamide 90 (0.8 g, 0.0031 mol) in 10 M HCl (6.5 ml), cooled to 0°C. After 0.5 hours at room temperature, add NaN3(0.220 g, 0.0037 mol) in water (2 ml) and the resulting solution was stirred for 0.5 hour at 0°C. the Reaction mixture zakolerovat NaOH (33% V/V) and diluted with EtOAc. The aqueous phase is acidified to pH 5-6 and extracted with EtOAc. The combined organic phases are dried over magnesium sulfate and concentrated in vacuo, giving crude pyrrolidone, which is purified by chromatographic column on forces is the Kagel (CH 2Cl2/CH3HE: 97/03 (V/V)), which gives, after recrystallization MeCN, 0.42 g of a single enantiomer (2S)-2-[2-oxo-4-(3-azidophenyl)-1-pyrrolidinyl]butanamide 86 (48%).

4.3. Synthesis of (2S)-2-[4-(3-amino-2,4,6-tribromophenyl)-2-oxo-1-pyrrolidinyl]butanamide 107

In a three-neck flask in an argon atmosphere was stirred solution of Ph3RSN2PhBr3(2.870 g, 0.048 mol) and 90 (0.420 g, 0.0016 mol) in CH2Cl2(10 ml) and CHCHE (5 ml) with NaHCO3(0.407 g, 0.048 mol) for 4 h at room temperature (orange solution). The reaction mixture was filtered and concentrated in vacuo, giving crude aniline, which is purified by chromatographic column on silica gel (AcOEt/ethanol 98/02 (V/V)), which gives 0.38 g of the expected aniline 107 (47%, recrystallization from Et2O).

4.4. Synthesis of (2S)-2-[4-methyl-2-oxo-1-pyrrolidinyl]butanamide 35 and 36

35 and 36 were obtained by chiral purification of the racemate 389 on chiral stationary phase using EtOH and hexane as solvents, 35 receive in the form of white crystals after recrystallization from i-Pr2OEt, 36 receive in the form of white crystals after recrystallization in Et2O,

EXAMPLE 5. Synthesis of 4-substituted 2-oxopyrrolidin by derivatization to methyl 1-[1-(aminocarbonyl)propyl]-5-oxo-3-pyrrolidinecarboxylic 11.

5.1. Synthesis of methyl 1-[1-(aminocarbonyl) propyl]-5-oxo-3-pyrrolidinecarboxylic 11/12

The specified transformation is also described in the § 7.0.1 for two esters 11 and 12.

5.2. Synthesis of 1-[2S-1-(aminocarbonyl)propyl]-5-oxo-3-pyrrolidinecarboxylic acid 48

In a three-neck flask in an argon atmosphere add a solution of 1N NaOH (126 ml) to a solution of enantiomerically pure ester 11 (22.62 g, 0.1 mol) in CH3HE cooled at 0°C. After 1.5 hours at the same temperature, the reaction mass is acidified with HCl (In (109 ml), the solvents evaporated in vacuo. The residue is extracted with i-D, filtered and the filtrate concentrated in vacuo to obtain the crude acid (17.82 g)which is recrystallized from MeCN to get enantiomer pure 1-[2S-1-(aminocarbonyl)propyl]-5-oxo-3-pyrrolidinecarbonyl acid 48.

5.3. Synthesis of (2S)-2-{4-(1,3,4-oxadiazol-2-yl)-2-oxo-1-pyrrolidinyl]butanamide 50

Stage 1; the Reaction with hydrazine

In a three-neck flask in an argon atmosphere was stirred solution of ester 11 (3 g, 0.013 mol) and hydrazine hydrate is added (0.7 ml) in EtOH (3 ml) for 24 hours. Then the yellow solution is concentrated, giving the crude hydrazide 391, which crystallized upon standing (2.37 g, 79%). GC/MS: 228 (M+).

Stage 2: Synthesis of oxadiazole

In a three-neck number is e, in an argon atmosphere a solution of crude hydrazide 391 (this patent, 3 g, 0.013 mol), triethyl of orthoformate (2 ml) and p-toluensulfonate acid (0.010 g) is heated at 110°C for 24 hours. The reaction mixture is cooled to room temperature, concentrated under vacuum giving the crude oxadiazole, which is cleaned by chromatography on silica gel (CH2Cl2/CH3HE: 95/05 (V/V)), which gives (2S)-2-[4-(1,3,4-oxadiazol-2-yl)-2-oxo-1-pyrrolidinyl]butanamide 50 (0.312 g) in the form of oil.

5.4. The synthesis of derivatives of 1,3,4-oxadiazole

Alternatively, derivatives of 1,3,4-oxadiazole can be obtained from hydrazine 391. For example, 2-[2-oxo-4-(5-effect-free remedy 1,3,4-oxadiazol-2-yl)-1-pyrrolidinyl]butanamide 51 get in the interaction of hydrazine with CS 3912and KOH in EtOH.

5.5. Synthesis of 4-aminopyrrolidine-2-it 392

5.5.1. Stage 1: Synthesis of carbamate 393

In a three-neck flask in an argon atmosphere a solution of enantiomerically pure 1-[2S-1-(aminocarbonyl)propyl]-5-oxo-3-pyrrolidinecarboxylic acid 48 (19.06 g, 0.089 mol.), diphenylphosphinite (26.9 g, 0.097 mol.) and Et3N (13.5 ml) in MeCN (225 ml) is heated at 55°with the formation of N2. Temperature withstand at 55°C for 0.5 hour at 70°C for 2 hours and cooled to room temperature. Add benzyl alcohol (9.25 ml) and the solution refluxed is for 4 h, cooled to room temperature and concentrated in vacuo. The crude carbamate purify by chromatography on silica gel (AcOEt/CH3HE/NH4OH: 95/04/01 (V/V)), which gives two diastereoisomeric carbamate 394 (2.64 g, 9.3%) and 393 (11.9 g, 42%). For 393:1H NMR (250 MHz, CDCl3): 0.90 (t, 3H), 1.30-1.90 (m, 2H), 2.35 (DD, 1H), 2.75 (m, 1H), 3.30 (m, 1H), 3.75 (m, 1H), 4.30-4.50 (m, 2H), 5.10 (s, 2H), 5.35 (s (broad), 1H), 5.55 (s (broad), 1H), 6.40 (s (broad), 1H), 7.30-7.45 (m, 5H).

5.5.2. Stage 2: Synthesis of 4-aminopyrrolidine-2-it 392

In an autoclave with a volume of 0.25 l, in an inert atmosphere, dissolve 11.9 g (0.037 mmol) 393 and Pd on coal (10% V/V, 0.2 g) in EtOH (300 ml) and the mixture hydronaut in a Parr apparatus at maximum pressure of H220 psi. After 20 hours, the mixture Tegaserod, filtered on Celite/Noritoshi cushion and the filtrate was concentrated in vacuo, giving crude amine, which is recrystallized from PhMe, giving 2-[4-amino-2-oxo-1-pyrrolidinyl]butanamide 392 (6.99 g, quantitative).

5.6. Synthesis of 4-pyramidality-2-it 223

In a three-neck flask in an argon atmosphere, a suspension of 2-[4-amino-2-oxo-1-pyrrolidinyl]butanamide 393 (6.99 g, 0.037 mol), dimethoxytetrahydrofuran (5.53 g, 0.041 mol), pyridine (50.6 ml) and Asón (36 ml) is heated to 70°and the dissolution occurs. After 2 h at this temperature the reaction mass is then cooled to room temperature, concentrated in vacuo the crude product is purified by chromatography on silica gel (CH 2Cl2/CH3HE: 95/05 (V/V)), which gives 223 in the form of oil (2.67 g, 30.1%).

5.7. Bromination of 4-pyrrolidinone-2-it 223

In a three-neck flask with a volume of 0.25 l with a magnetic stirrer in an atmosphere of argon, degassed solution of 2S-4-pyramidality-2-it 223 in the form of a single enantiomer (1.18 g, 0.0049 mol) in THF (35 ml) cooled to -78°and portions add N-bromosuccinimide (NBS) (0.877 g, 0.005 mol).

The reaction mixture is stirred for 0.5 hour and add Na2S2O3(0.9 g) for damping NBS. The reaction mixture is heated to room temperature, concentrated in vacuo and purified by chromatography on silica gel (EtOH/CH2Cl2: 05/95 (V/V)), which gives, after recrystallization in MeCN, (2S)-2-[4-(2-bromo-1M-pyrrol-1-yl)-2-oxo-1-pyrrolidinyl]butanamide 234 (1.05 g, 67%) as a white solid.

Alternatively, using the same experimentalnoy methodology and 2 EQ. N-Bromo-succinimide, can be obtained depomedrol 237.

5.8. Synthesis of derivatives tetrazolyl

Alternative to § 5.6, the reaction of 2-[4-amino-2-oxo-1-pyrrolidinyl]butanamide with triethylorthoformate, NaN3and Asón get 2-[2-oxo-4-(1N-tetrazol-1-yl)-1-pyrrolidinyl]butanamide 67.

5.9. Synthesis of (4H-1,2,4-triazole-4-yl) derivatives

Alternative to § 5.6, the reaction of 2-[4-amino-2-oxo-1-pyrrolidinyl]butanamide with pyridine and 12-bis((dimethylamino)methylene)hydrazine get 2-[2-oxo-4-(4H-1,2,4-triazole-4-yl)-1-pyrrolidinyl]butanamide 65 and 66.

EXAMPLE 6. Synthesis of 4-substituted 2-oxo-pyrrolidinecarboxamido refinaria 1-[1-(tert-butoxycarbonyl)propyl]-5-oxo-3-pyrrolidinecarboxylic 396.

6.1. Synthesis of 1-[1-(tert-butoxycarbonyl)propyl]-5-oxo-3-pyrrolidinecarboxylic 396

Stage 1: condensation of 2-aminobutyrate with metalitalia.com

In a three-neck flask, 1 liter, in an argon atmosphere refluxed solution of 2,2-dimethylethyl (S)-2-aminobutanoic (commercially available, 46.6 g, 0.268 mol) and dimethylcarbonate (83 ml, 0.59 mol) in CH3HE (400 ml) for 20 hours. The mixture is stirred at room temperature for 20 h, concentrated in vacuo and the residue purified by chromatography on silica gel (CH2Cl2/CH3HE: 97/3 (V/V)), which gives methyl 1-[(1S)-1-(tert-butoxycarbonyl)propyl]-5-oxo-3-pyrrolidinecarboxylic 397 (81.6 g, quantitative). Analysis of 1/1 mixture of methyl 1-[(1S)-1-(tert-butoxycarbonyl)propyl]-5-oxo-3-pyrrolidinecarboxylic 397:1H NMR (250 MHz, (CD3)2SO): 1.05 (t, 3H), 1.44 (s,N), 1.60-1.65 (m, 1H), 1.65-1.90 (m, 1H), 2.40-2.65 (m, 2H partially overlaps with the signal of solvent), 3.30-3.65 (m, 3H), 3.70 (s, 3H), 4.40 (DD, 1H). Alternatively, the reaction can also be carried out with racemic 2,2-dimethylethyl-2-aminobutanoic that gives the racemic butanamide with the same output.

Stage 2: Synthesis of aldehyde 396.

Recovery ester 397 to alcohol 398

This is carried out using the procedure described in § 7.0.2., using 397 or in the form of a single enantiomer, a mixture of two diastereoisomers or 1/1/1/1 mixture of 4 stereoisomers. For diastereoisomers 1:1-mixture of tert-butyl (2S)-2-[4-(hydroxymethyl)-2-oxo-1-pyrrolidinyl]butanoate 398: GC/MS:257 M+'

Oxidation of the aldehyde 396

In a three-neck flask in an argon atmosphere add a solution of tert - butyl (2S)-2-[4-(hydroxymethyl)-2-oxo-1-pyrrolidinyl]butanoate 398 (4.0 g, 0.016 mol.) in CH2Cl2(8 ml) to a suspension CrO3(6.2 g, 0.062 mol) in pyridine (11.3 ml/CH2Cl2(80 ml), stir at room temperature. The temperature was raised to 30°and the suspension is stirred for 0.2 hour. The suspension is filtered through celite and the filtrate washed sequentially with HCl 1N, brine, dried over magnesium sulfate and concentrated in vacuo, giving crude aldehyde, which was purified by chromatographic column on silica gel (hexane/acetone 70/30 (V/V)), which gives 2.03 g of 1-[(1S)-1-(tert-butoxycarbonyl)propyl]-5-oxo-3-pyrrolidinecarboxylic 396 (41%). Alternatively, the reaction could also be carried out with racemic ether, which gives racemic aldehyde with a similar output. Analysis of the mixture 1/1 1-[(1S)-1-(tert-butoxycarbonyl)propyl]-5-oxo-3-pyrrolidinecarboxylic 396:1H NMR (250 MHz (CDCl3): 0.91 t, 3H), 1.44 (s, N), 1.55-1.77 (m, 1H), 1.90-2.15 (m, 1H), 2.63-2.82 (m, 2H), 3.47-3.61 (m, 1H), 3.65-3.79 (m, 1H), 3.83-3.94 (m, 1H, one of diastereoisomers), 4.48-4.62 (m, 1H), 9.74 (s (broad), 1H).

6.2. Refinace 1-[(1S)-1-(tert-butoxycarbonyl)propyl]-5-oxo-3-pyrrolidinecarboxylic 396

6.2.1. Synthesis of ethylene derivatives.

Alternative to § 6.2.3., ethylene derivatives can be obtained by refinaria by Wittig 1-[(1S)-1-(tert-butoxycarbonyl)propyl]-5-oxo-3-pyrrolidinecarboxylic 396 and phosphonium salts of the presence of a strong base. For example, (2S)-2-(2-oxo-4-vinyl-1-pyrrolidinyl)butane acid 2,2-(dimethyl)ethyl ester, obtained by the interaction of the aldehyde 396 with Ph3RSN3Br and n-BuLi in THF.

6.2.2. Refinace with Ph3R/CBr4

Alternative to § 6.2.3., derivatives halogeniniu can be obtained by refinaria by Wittig 1-[(1S)-1-(tert-butoxycarbonyl)propyl]-5-oxo-3-pyrrolidinecarboxylic 396 in the presence of phosphine and halogenoalkane. For example, (2S)-2-(2-oxo-4-(2,2-dibromovinyl)-1-pyrrolidinyl)butane acid 2,2-(dimethyl)ethyl ester obtained from aldehyde 396 and CBr4in the presence of triphenylphosphine.

6.2.3. Refinace with (Me2N)3P/CF2Br2

Presents a synthesis of two diastereoisomers (2S)-2-(2-oxo-4-(2,2-defermined)-1-pyrrolidinyl)butane acid 2,2-(dimethyl)ethyl ester 399. In Trigg rloi flask, in argon atmosphere, add (Me2N)3P (89.8 g, 0.55 mol.) to a solution of CF2Br2(58 g, 0.25 mol.) in THF (280 ml) at -78°With (appears white precipitate) and warmed to room temperature. To the resulting phosphonium salts of added dropwise a solution of aldehyde 396 in the form of a 1/1 mixture of diastereoisomers (35.2 g, 0.138 mol) in THF. After 1 hour the reaction mixture was filtered through celite and concentrated in vacuo, the Reaction mixture was diluted with hexane, washed with brine, dried over magnesium sulfate and concentrated in vacuo, giving crude olefin, which is purified by chromatographic column on silica gel (CH2Cl2/CH3HE 99/01 (V/V)), which gives 34.6, 1/1 mixture of diastereoisomers (2S)-2-(2-oxo-4-(2,2-defermined)-1-pyrrolidinyl)butane acid 2.2-(dimethyl)ethyl ester 399 (87%).:1H NMR (250 MHz, (CD3)2SO): 0.81-0.91 (m, 3H), 1.44 (s, N), 1.50-1.75 (m, 1H), 1.80-1.95 (m, 1H), 2.30-2.40 (m, 2H, partially overlapped with solvent), 3.00-3.35 (m, 2H), 3.45-3.55 (m, 1H), 4.20-4.40 (m, 1H), 4.60 (DDD, 1H for one diastereoisomer), 4.75 (DDD, 1H for another diastereoisomer).

6.2.4. Olivencia with (nBu)3P/CCl3F

Alternative to § 6.2.3., derivatives halogeniniu can be obtained by refinaria by Wittig 1-[(1S)-1-(tert-butoxycarbonyl)propyl]-5-oxo-3-pyrrolidinecarboxylic 396 in the presence of phosphine and halogenmethyl. For example, 2-(2-oxo-4-2-(Z)-Porvenir)-1-pyrrolidinyl) butane acid 2,2-(dimethyl) ethyl ester obtained from the aldehyde of 396 consecutive reaction with CFCl 3and n-Bu3R, then dephosphorylating intermediate vinyl phosphonium using NaOH.

6.2.5. Synthesis of 4-cyanopyrrolidine

Alternatively, 4-cyanopyrrolidine derivatives, get in the interaction of 1-[(1S)-1-(tert-butoxycarbonyl)propyl]-5-oxo-3-pyrrolidinyl-localdevice 396 with hydroxyl, and then SeO2.

6.3. Amination of 2.2-dimethylammonio ether

6.3.1. Remove protection using triperoxonane acid and aminals

The synthesis of two diastereoisomers (2S)-2-(2-oxo-4-(2,2-defermined)-1-pyrrolidinyl)butanamide 213 and 222 as follows:

Stage 1: removing protection from a 2.2-(dimethyl)ethyl ester

In a three-neck flask in an argon atmosphere, a solution of a 1/1 mixture of diastereoisomers (2S)-2-(2-oxo-4-(2,2-defermined)-1-pyrrolidinyl)butane acid 2.2-(dimethyl) ethyl ester 399 (31.8 g, 0.110 mol.) in triperoxonane acid (170 ml) and CH2Cl2(500 ml) is stirred for 20 hours at room temperature. The reaction mixture is evaporated to dryness. The residue is dissolved in toluene and again evaporated to dryness, to exclude the presence triperoxonane acid, giving 32 g of crude acid, which is used in the next stage without further purification. LC/MS: 234 (MH+)

Stage 2: Activation and ammonolysis

In a three-neck flask in an argon atmosphere, equipped with a mechanical what esilkoy, CICOOEt (23 ml, 0.24 mol) are added to a solution of the mixture of acids (25.6 g, 0.11 mol) in CH2Cl2(250 ml) and triethylamine (33.7 ml)cooled at -15°C. the Reaction mixture is stirred for 1.5 hours at -10°With, then passed through a solution of gaseous NH3, while the temperature of the support below 0°C. the Suspension is stirred for 1 hour at 0°C, warmed to room temperature, filtered and the filtrate evaporated under vacuum, the Crude amides purified by chromatographic column on silica gel (CH2Cl2/EtOH 99/01 (V/V)), which provides 23 g of a 1/1 mixture of diastereoisomers (2S)-2-(2-oxo-4-(2,2-defermined)-1-pyrrolidinyl)butane acid 2.2-(dimethyl) ethyl ester, which is purified by column chromatography on chiral phase (hexane/EtOH), which gives two diastereoisomers 213 (10.1 g, is recrystallized from i-Pr2O) and 222 (11.2 g, is recrystallized from i-Pr2O).

6.3.2. Alternatively, removing the protection can be carried out with the help of bromethalin.

4 diastereoisomer 2-(2-oxo-4-(2,2-dimethylvinyl)-1-pyrrolidinyl)butanamide 163 receive when interacting 1/1/ 1/1 mixture of diastereoisomeric 2-(2-oxo-4-(2,2-dimethylvinyl)-1-pyrrolidinyl)butane acid 2,2-(dimethyl) ethyl ester with bromoethanol that gives the acid and then aminating the conditions described in the § 6.3.1 (stage 2).

6.4. Synthesis of acetylene derivatives

6.4.1. Synthesis of 2-(4-ethinyl-2-oxo-1-pyrrolidinyl)butanamide 206/207

In a three-neck flask in an argon atmosphere, add n-utility (1.6 M in hexano, 116 ml) to a solution of a 1/1 mixture of two diastereoisomeric 2-[4-(2,2-dibromovinyl)-2-oxo-1-pyrrolidinyl]butanamide (unspecified stereochemistry, 10.95 g, 0.031 mol) in THF, cooled at -78°C. the White suspension is stirred for 1.5 hours at the same temperature, zakolerovat CH3HE (120 ml), warmed to room temperature and concentrated in vacuo. Crude alkyne was dissolved in EtOH/CH2Cl2(10/90 V/V)), filtered through celite, concentrated in vacuo and the resulting solid is purified sequentially by using chromatography on silica gel (EtOH/CH2Cl2: 10/90 (V/V)) and using chromatography on chiral phase (EtOH/hexane), giving two diastereoisomer 2-(4-ethinyl-2-oxo-1-pyrrolidinyl) butanamide 206 (0.84 g, is recrystallized from PhMe) and 207 (0.44 g, is recrystallized from PhMe).

Alternatively, 2-(4-bromo-ethinyl-2-oxo-1-pyrrolidinyl)butanamide 267 get in the interaction of 2-[4-(2,2 - dibromovinyl)-2-oxo-1-pyrrolidinyl] butanamide 47 with two equivalents of tert.-the butyl potassium in THF at low temperature (-50°0°).

6.4.2. Synthesis of 2-(4-propyne-1-yl-2-oxo-1-pyrrolidinyl)butanamide 280

In a three-neck flask in an argon atmosphere a solution of methyl chloride zinc (obtained from metallyte (1.5 M in ethyl ether, 6.14 ml) and ZnCl2(1.25 g) in THF (15 ml)) is added to a solution of CuCN (0.82 g) and LiCl (0.78 g) in THF (10 ml) at -10°C. In another three-neck flask in an argon atmosphere, added NaH (80% in oil, 0.097 g) to a solution of 2-(4-bromo-ethinyl-2-oxo-1-pyrrolidinyl)butanamide (1 g, 0.0036 mol.) in THF (20 ml) at -10°and then ZnCl2(0.50 g). The specified amide solution is then added dropwise in organocopper, cooled at -78°C. the Reaction mixture is stirred for 3 hours at the same temperature and allowed to warm to room temperature over night. After hydrolysis with a saturated aqueous solution of NH4Cl, the aqueous layer was extracted with CH2Cl2, dried over MgSO4, filtered and concentrated in vacuo, giving crude alkyne, which is purified by chromatography on chiral phase (EtOH/hexane), giving 2-(4-propyne-1-yl-2-oxo-1-pyrrolidinyl)butanamide 280.

6.5. Hydrogenation of olefinic pyrrolidones

Synthesis 1/1/ 1/1 mixture of 4 diastereoisomers 2-[4-(2,2-dottorati)-2-oxo-1-pyrrolidinyl]butanamide 157 as follows:

In an autoclave with a volume of 0.25 l, in an inert atmosphere, dissolve 1 g (0.0043 mmol) and Pd 156 coal (10% V/V, 0.2 g) in EtOH (50 ml) and the mixture hydronaut in the Parr apparatus. After 20 the speakers the mixture Tegaserod, filtered on Celite/Noritoshi cushion and the filtrate was concentrated in vacuo, giving crude floralcy, which is recrystallized from PhMe, which gives 1/1/ 1/1 mixture of 4 diastereoisomers 2-[4-(2,2-dottorati)-2-oxo-1-pyrrolidinyl]butanamide in the form of a white solid (0.75 g).

6.6. Synthesis of 2-[4-(5-methyl-1,3-oxazol-2-yl)-2-oxo-1-pyrrolidinyl]butanamide 62 and 63

Stage 1: Hydrolysis of ester

In a three-neck flask in an argon atmosphere, add 1N NaOH (39 ml) to a solution of methyl 1-[1-(tert-butoxycarbonyl)propyl]-5-oxo-3-pyrrolidinecarboxylic 397 in the form 1/1/ 1/1 mixture of 4 stereoisomers (10 g, 0.035 mol) in CH3HE (100 ml) at 20°C. the Solution is stirred for 0.5 hour, evaporated to dryness and acidified to pH 1 using 1N HCl. The aqueous layer was extracted with AcOEt, dried over MgSO4, filtered and concentrated in vacuo, giving crude acid 400 (8.45 g) in the form of a white solid which is used without further purification in the next stage.1H NMR (250 MHz, (CD3)2SO): 0.80 (t, 3H), 1.44 (s, N), 1.55-1.60 (m, 1H), 1.70-1.95 (m, 1H), 2.40-2.55 (m, 2H, partially overlapped with solvent), 3.10-3.55 (m, 1H, partially overlapped with solvent), 4.45 (DD, 1H).

Stage 2: Synthesis of amide 401

In a three-neck flask in an argon atmosphere, add CICOOEt (0.50 ml, 0.005 mol) to a solution of acid 400 (0.678 g, 0.0025 mol) in CH2Cl2(10 m is) and triethylamine (0.77 ml), chilled at -20°C. the Reaction mixture is stirred for 1.5 hours at -10°With, then add propargylamine (0.36 ml) to the solution, at the same time maintaining the temperature below 0°C. the Suspension is stirred for 1 hour at 0°C, warmed to room temperature, filtered and the filtrate evaporated under vacuum. The crude amide purified by chromatographic column on silica gel (CH2Cl2/CH3OH 98/02 (V/V)), giving 0.8 g of propargylamine 401 in the form 1/1/ 1/1 mixture of four diastereoisomers.1H NMR (250 MHz, (CD3)2SO): 0.80 (t, 3H), 1.44 (s, N), 1.55-1.65 (m, 1H), 1.70-1.95 (m, 1H), 2.40-2.55 (m, 4H, partially overlapped with solvent), 3.0-3.70 (m, 3H, partially overlapped with solvent), 3.70-3.90 (m, 2H), 4.45 (m, 1H), 8.45 (m, 1H).

Stage 3: Synthesis of oxazole 402

In a three-neck flask in an argon atmosphere a solution of amide 402 (0.77 g, 0.0025 mol) in Asón (40 ml) and Hg(SLA)2(0.048 g, 0.00015 mol) is heated under reflux for 1 hour, the reaction mass is then cooled to room temperature, concentrated under vacuum and hydrolyzing a saturated solution of Na2CO3. The aqueous layer was extracted with CH2Cl2and the organic phase is washed with brine, dried over MgSO4, filtered and concentrated in vacuo, giving crude compound, which was purified by chromatography on silica gel (Hexane/AcOEt: 50/50 (V/V)), which gives the net about Sasol 402 (0.15 g, 20%). GC/MS: 308 (M-K), which can be turned into 62 and 63 by ammonolysis similar to 6.3.1.

6.7. Synthesis of tetrazoles.

6.7.1. Synthesis of unsubstituted tetrazole

In a three-neck flask in an argon atmosphere a solution of racemic nitrile 403 (2.66 g, 0.011 mol), NaN3(4.8 g, 0.073 mol) and Et3N - hydrochloride (10.12 g) is heated at 110°in DMF (60 ml) for 2 h, then cooled to room temperature and evaporated under vacuum. The crude product is purified by chromatography on silica gel (CH2Cl2/ CH3OH / Asón: 90/08/02 (V/V)), which gives the racemic ester tetrazole 404 (3.42 g, 0.010 mol) in the form 1/1/ 1/1 mixture of diastereoisomers. LC/MS: 295 (MH+).

6.7.2. Alkylation of tetrazoles

In a three-neck flask in an argon atmosphere, a stirred suspension of racemic tetrazole 404 (5.6 g, 0.019 mol), K2CO3(2.88 g) and Mel (1.3 ml) in DMF (60 ml) at room temperature for 29 hours and evaporated under vacuum. The crude mixture is purified by chromatography on silica gel (MTBE/Hexane: 50/50 (V/V)), which gives two regioisomer of tetrazole 405 (1.98 g, 34%) and 406 (1.03 g, 17%) as oil. LC/MS: 309 (MH+).

6.8. Synthesis of thiazolo.

6.8.1. Synthesis thioamides.

6.8.1.1. The ammonolysis 397

In a three-neck flask with a volume of 0.5 liters, equipped with a partial condenser hot irrigation, magnetic IU the Alcoy, and an additional tube for supplying a gas into the solution, dissolve 10 g (0.035 mmol) 397 100 ml of methanol. Then miss gaseous ammonia through the solution and a saturated solution incubated at room temperature for 1 day, while the ammonia gradually evaporates. After completion of the reaction, the solution was concentrated in vacuo, giving crude amide 407 (9.6 g, 100%).1H NMR (250 MHz, (CD3)2SO): 0.85 (t, 3H), 1.44 (s, N), 1.55-1.60 (m, 1H), 1.70-1.95 (m, 1H), 2.40-2.60 (m, 2H, partially overlapped with solvent), 3.00-3.70 (m, 1H, partially overlapped with solvent), 4.35-4.45 (m, 1H), 6.95 (s (broad), 1H), 7.40 (s (broad), 1H).

6.8.1.2. Synthesis thioamide 408

In a three-neck flask in an argon atmosphere, a solution of crude amide 407 (6 g, 0.022 mol), (4.93 g, 0.011 mol) and NaHCO3(3.73 g) in MeCN (100 ml) stirred at 5°C for 6 hours. The reaction mixture was filtered, concentrated in vacuo and the crude thioamide purify by chromatography on silica gel (AcOEt / hexane: 50/50 (V/V)), which gives, after recrystallization from AcOEt tioned 408 (3.7 g, 60%). GC/MS: 286 (M+).

6.8.2. Synthesis of substituted thiazolo

In a three-neck flask in an argon atmosphere a solution of thioamide 408 in the form 1/1/ 1/1 mixture of 4 diastereoisomers (in this patent, 1.5 g, 0.005 mol.), Al2About3(12 g) and 1-bromo-2-dimethoxypropane-2-ene (0.85 ml) in PhMe (100 ml) is refluxed for 3 hours. The reaction mixture is cooled to room temperature, f is trout and concentrated in vacuo, that gives the crude product thiazole 409 (0.5 g, 30%) which is used in the following stage without further purification. GC/MS: 324 (M+')-

6.8.3. Synthesis of unsubstituted thiazolo

Alternative unsubstituted thiazole can be obtained by the reaction thioamides 408 with Al2O3and bromoacetaldehyde (obtained in situ from bromo-2,2-dimethoxyethane in acidic conditions).

6.8.4. Synthesis of 1,2,4-Guadiana-5-yl-derivatives

Alternatively, a 1,2,4-thiadiazole-5-yl-derivatives can be obtained by the reaction thioamide 408 sequentially with N,N-dimethylethylenediamine, and then followed by cyclization in the presence of pyridine.

6.9. Synthesis of 2-[2-oxo-4-(3-pyridylcarbonyl)-1-pyrrolidinyl]butane acid 2.2-dimethylammonio ether 410

In a three-neck flask in an argon atmosphere, add SOCl2(0.56 ml) to a solution of acid 400 (1.90 g, 0.007 mol) in PhMe (20 ml) at room temperature. The reaction mixture is refluxed 1.5 hours, after which it becomes yellow. After cooling to room temperature, add one portion PdCl2(PPh3)2(0.25 g, 0.00035 mol) and 3-trimethylindolenine (1.7 g, 0.007 mol), the reaction mixture is refluxed for 0.5 hour, cooled to room temperature, zakolerovat water. The aqueous layer was extracted with dichloromethane and the combined organic phases are washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo (3.2 g). The crude ketone purified by chromatographic column on silica gel (CH2Cl2/CH3HE 97/03 (V/V)), giving 1.3 g of the ketone 410 in the form 1/1/ 1/1 mixture of four diastereoisomers. LC/MS: 333 (MH+).

EXAMPLE 7. Synthesis of 2-(4-substituted-2-oxopyrrolidin)-butanamide substitution of activated 2-(4-hydroxymethyl-2-oxopyrrolidin)-butanamide

7.0. The synthesis of the original startof

7.0.1. Synthesis apyramid

A. Synthesis of methyl 1-[(1S)-1-(aminocarbonyl)propyl]-5-oxo-3-pyrrolidinecarboxylic 11/12.

In a three-neck flask with a volume of 10 l, equipped with a mechanical stirrer and a partial condenser hot irrigation, in an inert atmosphere, 1226 g (12 moles, 1 EQ) of (2S)-2-aminobutanoic and 1912 ml (2150 g, 13.2 moles, 1.1 EQ) of dimethyl itaconate dissolved in 6.13 l CH3HE. The mixture was kept at boiling under reflux for 10 hours and slowly cooled to 20°C for more than 4 hours. Then it is filtered, the precipitate washed with CH3HE and the combined organic phases are concentrated to dryness, giving 3.283 g of crude intermediate product 74%.

In a three-neck flask with a volume of 20 liters, equipped with a mechanical stirrer, a column of Rusinga and distiller, in an inert atmosphere, the crude intermediate product and 84.7 g (891 mmol, 0.1 EQ.) 2-g is toxipedia dissolved in 11.6 l of toluene. The mixture is kept at boiling under reflux and the resulting methanol is distilled off within 8 hours, until you collect 480 ml. Temperature in the boiler reaches 112°C. the Mixture is cooled and concentrated to dryness, giving 2,187 g crude amidoamine in the form of a mixture of diastereoisomers in the ratio of 57.5/42.5. 2 diastereoisomers separated using Preparative Liquid Chromatography on chiral phase (Chiralpak AD 100x500 mm, EtOH/H2About 99.9:0.1), eluate concentrated to dryness, giving 968 g of crude product 12 (first elateroidea) and 1,052 g crude product 11 (second elateroidea). The crude product 12 is not crystalline, it is dissolved in 1.5 l of EtOH and stored as such for future use.

The crude product 11 is recrystallized from 2 l of EtOAc, giving 676 g of pure 11.

Alternatively, methyl 1-[(1S)-2-amino-1-methyl-2-oxoethyl]-5-oxo-3-pyrrolidinecarboxylic, methyl 1-[(15)-1-(aminocarbonyl)butyl]-5-oxo-3-pyrrolidinecarboxylic, methyl 1-{(1S)-1-[(methylamino)carbonyl]propyl}-5-oxo-3-pyrrolidinecarboxylic receive similar ways.

7.0.2. Synthesis spirtuality

A. Synthesis of (2S)-2-[4-(hydroxymethyl)-2-oxo-1-pyrrolidinyl]butanamide 6.

In a three-neck flask with a volume of 2 l, equipped with a mechanical stirrer and a partial condenser hot irrigation, in an inert atmosphere a solution of 133 g (583 mmol, 1 EQ) of (2S)-2-(4-methoxy shall arbonyl-2-oxo-1-pyrrolidinyl)butanamide 11 in 200 ml of EtOH is added to 300 ml of EtOH and the mixture is cooled to 0° C. Then add portions of 66.2 g (1.74 moles, 12 EQ) solid NaBH4for more than 1.5 hours, all the while maintaining the temperature between 2 and 4°C. After 2 hours, the temperature was raised to 12°C for 1 hour, and again lowered to 2-4°C. is Added dropwise 240 ml of a saturated solution of NH4Cl for more than 1 hour, and then 120 ml of acetone, and the mixture is left overnight at room temperature. The mixture is filtered, the precipitate washed 3×70 ml EtOH and the combined organic fractions concentrated to dryness, giving 148 g of crude product 6. It is suspended in 300 ml of CH2Cl2and stirred for 30 min, filtered, washed 2×100 ml of CH2Cl2and dried, giving 114 g of pure 6, 98%.

Alternatively, (2S)-2-[4-(hydroxymethyl)-2-oxo-1-pyrrolidinyl]propanamide, (2S)-2-[4-(hydroxymethyl)-2-oxo-1-pyrrolidinyl]pentanone, (2S)-2-[4-(hydroxymethyl)-2-oxo-1-pyrrolidinyl]-N-methylbutanoic receive similar paths.

7.1. The synthesis of the direct conversion of the alcohol using PPh3

7.1.1. Synthesis of (2S)-2-[4-(iodomethyl)-2-oxo-1-pyrrolidinyl]butanamide 10

In a three-neck vessel with a volume of 10 l, equipped with a mechanical stirrer and a partial condenser hot irrigation in an inert atmosphere, dissolve 400 g (2 moles, 1 EQ) of (2S)-2-[4-(hydroxymethyl)-2-oxo-1-pyrrolidinyl]butanamide 6 3 is acetonitrile. Add 629 g (2.4 moles, 1.2 EQ) of triphenylphosphine, and then 608 g (2.4 moles, 1.2 EQ) of iodine is added in three portions over 5 minutes the Mixture is heated to 60°With 30 min and stirred at this temperature for 5 hours. After cooling, the mixture is concentrated to dryness, the residue suspended in a solution of 750 g of Na2S2About3in 10 l of water and stirred at 50°C for 4 hours. The precipitate is filtered and washed 3×1 l of water. The combined aqueous phase is treated with 1 kg of NaCl and extracted with 6×1 l CH2Cl2. The combined organic phases are dried over MgSO4filter and concentrate to dryness, giving 482 g of crude product 10. It crystallized from toluene. Multiple downloads recrystallized with ethyl ether from ethyl acetate, giving 425 g of pure is 10.68%.

Alternatively, (2S)-2-[4-(iodomethyl)-2-oxo-1-pyrrolidinyl]-N-methylbutanoic 146, (2S)-2-[4-(iodomethyl)-2-oxo-1-pyrrolidinyl]propanamide 110, (2S)-2-[4-(iodomethyl)-2-oxopyrrolidin-1-yl]pentanone 105, (2S)-2-[4-(methyl bromide)-2-oxo-1-pyrrolidinyl]butanamide 8, (2S)-2-[4-(chloromethyl)-2-oxo-1-pyrrolidinyl]butanamide 30 receive similar paths.

7.1.2. Synthesis of (2S)-2-[2-oxo-4-(phenoxymethyl)-1-pyrrolidinyl]butanamide 18

In a three-neck flask with a volume of 50 ml, equipped with a magnetic stirrer and dropping funnel under inert atmosphere, dissolve 1 g (5 mmol,1 EQ) of (2S)-2-[4-(hydroxymethyl)-2-oxo-1-pyrrolidinyl]butanamide 6 in 20 ml of THF and cooled to 0° C. Successively added 517 mg of phenol, 0.87 ml (960 mg) of diethylazodicarboxylate and 1.44 g of triphenylphosphine (5.5 mmol, 1.1 EQ) and the mixture is stirred for 2 hours. The mixture is concentrated to dryness and purified using preparative LC (500 kg SiO2CH2Cl2/EtOH, 97.5:2.5), which gives 1.1 g of pure 18, 80%, crystallized from ethyl acetate.

7.2. Synthesis by substitution of nelfinavir

7.2.1. Synthesis of {1-[(18)-1-(aminocarbonyl)propyl]-5-oxo-3-pyrrolidinyl} methyl methansulfonate 37

In a three-neck flask with a volume of 4 l, equipped with a mechanical stirrer, addition funnel, and a partial condenser hot irrigation in an inert atmosphere, dissolve 114 g (569 mmol, 1 EQ) of (2S)-2-[4-(hydroxymethyl)-2-oxo-1-pyrrolidinyl]butanamide 6 in 2 l of CH2Cl2and cooled to 0°C. Add one portion 158.5 ml (115 g, 2 EQ) of dry triethylamine, and then add dropwise a solution of 66.3 ml (96.2 g, 1.5 EQ) of methane sulphonylchloride in 190 ml of CH2Cl2for more than 1 hour, all the while maintaining the temperature below 4°C. After 4 hours, add 7.5 ml methanesulfonyl chloride and 15 ml of triethylamine and the mixture was incubated over night in the fridge. The mixture is filtered, the residue washed with CH2Cl2and the combined organic phases are concentrated to dryness, giving 216 g of crude product 37. It is cleaned by ven the dispensing of liquid chromatography in several volumes (1 kg SiO 2CH2Cl2/EtOH, 100:0 -> 96:4), which gives 109 g of pure 37, 69%. Alternatively, {1-[(1S)-1-(aminocarbonyl)propyl]-5-oxo-3-pyrrolidinyl}methyl 4-methylbenzenesulfonate 31, receive a similar way.

7.2.2. Synthesis of (2S)-2-[4-(azidomethyl)-2-oxo-1-pyrrolidinyl]butanamide 32

In a three-neck flask with a volume of 3 l equipped with a mechanical stirrer and a partial condenser hot irrigation, in an inert atmosphere, dissolve 89.7 g (322 mmol, 1 EQ) {1-[(1S)-1-(aminocarbonyl)propyl]-5-oxo-3-pyrrolidinyl}methyl methansulfonate 37 in 300 ml of acetonitrile. Add one portion of 27.3 g (419 mmol, 1.3 EQ) of sodium azide in 150 ml of acetonitrile. The mixture of support at boiling for 20 min and stirred over night. Added 3.1 g (48 mmol, 0.2 EQ) of sodium azide and continue boiling for another 44 hours. After cooling to 10°C, the mixture is filtered, the precipitate washed 3×50 ml of acetonitrile and the combined organic fractions concentrated to dryness, giving 77.3 g of crude product 32. It crystallized from 150 ml of ethyl acetate at 10°that gives 60 g of pure 32, 82%.

Alternatively, (2S)-2-[4-(permitil)-2-oxo-1-pyrrolidinyl]butanamide 44, (2S)-2-[2-oxo-4-(1N-tetrazol-1-ylmethyl)-1-pyrrolidinyl]butanamide 39, (2S)-2-[2-oxo-4-(1N-tetrazol-1-ylmethyl)-1-pyrrolidinyl]butanamide 40, (2S)-2-[2-oxo-4-(1N-1,2,4-triazole-1-ylmethyl)-1-pyrrolidinyl]butanamide 55, 2-[2-oxo-4-(1N-1,2,-triazole-1-ylmethyl)-1-pyrrolidinyl]butanamide 56, (2S)-2-{4-[(isopropylphenyl)methyl]-2-oxo-1-pyrrolidinyl}butanamide 24, (2S)-2-[2-oxo-4-(1-pyrrolidinyl)-1-pyrrolidinyl]butanamide 15, (2S)-2-[2-oxo-4-(4-thiomorpholine)-1-pyrrolidinyl]butanamide 17, receive the same ways, from the activated derivative of the alcohol, such as mesylates, tozilaty or halides.

7.3. Other syntheses

7.3.1. Synthesis of {1-[(1S)-1-(aminocarbonyl)propyl]-5-oxo-3-pyrrolidinyl}methyl nitrate 38

In a three-neck flask with a volume of 500 ml, equipped with a mechanical stirrer and a partial condenser hot irrigation in an inert atmosphere, dissolve 8.10 g (26 mmol, 1 EQ) of (2S)-2-[4-(iodomethyl)-2-oxo-1-pyrrolidinyl]butanamide 10 in 250 ml of acetonitrile. Add 4.86 g (28.6 mmol, 1.1 EQ) of silver nitrate and the mixture brought to a boil. After two hours, add 440 mg (2.8 mmol, 0.1 EQ) of silver nitrate and continue boiling for another full 4 hours. After cooling, the mixture is concentrated to dryness and purified using preparative liquid chromatography (200 g of SiO2CH2Cl2/CH3HE/NH4OH, 96:5.4:0.6), giving 5.7 g of crude product 38. It is crystallized from 50 ml of ethyl acetate, giving 4.13 g of pure 38, 65%.

7.3.2. Synthesis of 2-{4-[(benzyloxy)methyl]-2-oxo-1-pyrrolidinyl}butanamide 153/154

A. Synthesis of tert-butyl (2S)-2-{4-[(benzyloxy)methyl]-2-oxo-1-arrayline]is ethanoate

In a three-neck flask with a volume of 100 ml, equipped with a magnetic stirrer and a partial condenser hot irrigation in an inert atmosphere, suspended 1.1 g (60%, 27.5 mmol, 1.1 EQ) of sodium hydride in 60 ml of DMF and the mixture cooled to 0°C. Carefully add 6.37 g (24.8 mmol, 1 EQ) of tert-butyl (25)-2-[4-(hydroxymethyl)-2-oxo-1-pyrrolidinyl]butanoate 398 in 10 ml of DMF. After 10 minutes, add 3.3 ml (4.75 g, 27.8 mmol, 1 EQ) of benzylbromide in 10 ml of DMF and stirring is continued for 30 minutes at 0°and then another 3 hours at room temperature. The mixture is concentrated to dryness, the residue suspended in brine/CH2Cl2will decandrum and extracted with CH2Cl2. The combined organic phases are dried over MgSO4concentrate to dryness and the residue purified using preparative liquid chromatography (1 kg SiO2, hexane/MTBE, 40:60 -> 0:100), giving 3.2 g of a mixture of tert-Bu and benzyl ether in two fractions, 37% of the total output. It is used as such for the next stage 7.3.1.b.1H NMR (250 MHz (CDCl3): 0.85 (t, 3H), 1.44 (s, N), 1.55-1.95 (m, 2H), 2.10 (DD, 1H), 2.45 (Yes., 1H), 2.55-2.70 (m, 1H), 3.45-3.55 (m, 1H), 4.40 (DD., 1H), 4.55 (s, 2H), 7.20-7.40 (m, 5H).

7.3.2.b. Synthesis of 2-{4-{(benzyloxy)methyl]-2-oxo-1-pyrrolidinyl}butanamide 153

In a three-neck flask with a volume of 50 ml, equipped with a magnetic stirrer and a partial condenser hot irrigation in an inert atmosphere, RA is tworay 1.75 g of benzyl ester enriched fraction in 20 ml of CH 3HE.

Then bubbled through a solution of ammonia gas and a saturated solution, incubated at room temperature for 24 hours, during which time ammonia evaporates. After completion of the reaction, the solution is concentrated to dryness and purified using preparative liquid chromatography (1 kg SiO2CH2Cl2/CH3HE, 98:2 -> 90:10), which gives two diastereoisomer.

In a three-neck flask with a volume of 25 ml, equipped with a magnetic stirrer and a partial condenser hot irrigation in an inert atmosphere, dissolve 1.24 g of tert-Bu ester enriched fraction in 16 ml of a mixture 1:1 of CH2Cl2/TPA and maintained at 0-5°C for 24 hours. The solution is concentrated to dryness and the residue is dissolved in 10 ml of CH2Cl2. Add 1.2 ml (2.2 EQ of theory) of triethylamine and the mixture cooled to -20°C. is Added dropwise 780 ál ethylchloride and the mixture is left to slowly warm to -10°for more than 1.5 hours. Then pass ammonia gas through the solution for 0.5 hour and the mixture was incubated over night at room temperature. It is filtered, the precipitate washed with CH2Cl2combined organic fractions concentrated to dryness and purified using preparative liquid chromatography (1 kg SiO2CH2Cl2/CH3OH, 98:2 -> 90:10), which gives two diastereomer the RA. The first and second eluruume diastereoisomer of the two streams are combined and crystallized from toluene, giving, respectively, 305 mg of pure 153 and 480 mg of pure 154, 11% of the total output.

7.3.3. Synthesis of (2S)-2-{4.[(5-methyl-1N-1,2,3-triazole, 1-yl)methyl]-2-oxo-1-pyrrolidinyl]butanamide 52

In a three-neck flask with a volume of 50 ml, equipped with a magnetic stirrer and a partial condenser hot irrigation in an inert atmosphere, suspended 1 g (4.44 mmol, 1 EQ) of (2S)-2-(4-(azidomethyl)-2-oxo-1-pyrrolidinyl]butanamide 32 in 20 ml of toluene. Added 1.55 g (4.88 mmol, 1.1 EQ), 1-(triphenylphosphonio) of acetone and the mixture is heated to 80°C for 24 hours. After cooling, the mixture is concentrated to dryness and purified using preparative liquid chromatography (1 kg SiO2CH2Cl2/CH3HE/NH4OH, 94.5:5:0.5). It is suspended in 15 ml of water and lyophilized that provides 240 mg of pure 52 in the form of a clear oil 42%.

7.3.4. Synthesis of (2S)-2-[4-(isothiocyanates)-2-oxo-1-pyrrolidinyl]butanamide 49

In an autoclave with a volume of 500 ml, in an inert atmosphere, suspended 900 mg of 10% Pd adsorbed on coal in 100 ml of ethanol. Add a solution of 8.7 g (38 mmol) of (2S)-2-[4-(azidomethyl)-2-oxo-1-pyrrolidinyl]butanamide 32 in 150 ml of ethanol and the mixture hydronaut in a Parr apparatus at maximum pressure H2in PE within 2 hours. The mixture Tegaserod, filtered on Celite/Noritoshi cushion, the residue is washed 2×100 ml of EtOH and the combined filtrates concentrated to dryness, giving 7.93 g of crude product 412, 100% output, which is used as such in the next stage. GC/MS: 199 (M+).

A. Synthesis of (2S)-2-{4-(isothiocyanates)-2-oxo-1-pyrrolidinyl]butanamide 49

In a three-neck flask with a volume of 100 ml, equipped with a magnetic stirrer and a partial condenser hot irrigation in an inert atmosphere, dissolve 4.5 g (22.7 mmol, 1 EQ) of thiocarbonyldiimidazole in 25 ml of DMF and the mixture cooled to 0°C. is Added dropwise 4.53 g (22.7 mmol, 1 EQ) of (2S)-2-[4-(aminomethyl)-2-oxo-1-pyrrolidinyl]butanamide 412 in 25 ml of DMF over 30 min, the mixture is stirred for 3 hours at room temperature and stored in throughout the night. The mixture is concentrated to dryness, the residue was dissolved in 20 ml of toluene, and concentrated again to dryness and the residue purified using preparative liquid chromatography (350 g SiO2CH2Cl2/CH3HE/NH4OH, 93.4:6:0.6), which gives 3.1 g of crude product 49. His triturated in 20 ml of ethyl ether, filtered and the residue (1.9 g) is crystallized from 15 ml of acetonitrile, giving 1.2 g of pure 49 (22%).

The compounds of formula I are presented in the following Table can be obtained analogously or as described here.

In the table, information regarding the stereochemistry is derzhitsja in two columns titled "configuration data". The second column indicates whether the compound has the stereogenic center (ACHIRAL), the pure enantiomer (PURE), the racemate (RAC) or a mixture of two or more stereoisomers, perhaps not in equal proportions (MIXT). The first column contains the stereochemical asigment for each of the detected center, IUPAC recommendations, used in the next column. One number shows the existence of both configurations at this center. And then the icons "R" or "S" indicate the known absolute configuration at this center. The number followed by "§" indicates the existence of one, but unknown absolute configuration at this center. Letters (a, b, C, D) are ahead of the pointer of the various enantiomers or racemates one structure.

In the table, the melting point is in most cases determined by using a DSC curve. When visual (visionamerica) the melting point is given, its value is given in parentheses.

In the table, the number in the column of "synthesis" refers to the synthesis according to which are most important compounds. Slight variations will be required to obtain similar compounds. Such modifications are known to the expert in the field of organic synthesis.

EXAMPLE 8: the Test binding LBS

[LBS notation for Levetiracetam-binding saiga, M. Noyer and others, Eur. J. Pharmacol., 286 (1995) 137-146.]

The inhibition constant (Ki) compounds was determined in competition experiments binding by measuring the binding of a single concentration of radioactive ligand at equilibrium with different concentrations of unlabeled test substance. The concentration of the test substance, inhibiting 50% of specific binding of radioligand marked IC 50. The equilibrium dissociation constant Ki is proportional to IC50and is calculated by the equation of Cheng and Prusoff (Cheng Y., And others, Biochem, Pharmacol. 1972, 22, 3099-3108).

Area concentrations usually consisted of 6 log units with different steps (from 0.3 to 0.5 log). The tests were carried out once or twice every definition of KIwas conducted on two different samples of the test substance.

Cerebral cortex from 200 to 250 g male Sprague - Dawley rats was homogenized using a Potter S homogenizer (10 strokes at 1,000 rpm; Braun, Germany) in 20 mmol/l Tris-HCl (pH 7.4), 250 mmol/l sucrose (buffer A); all operations are performed at 4°C. the Homogenate was centrifuged at 30,000 g for 15 min Obtained pellets crude membrane re-suspended in 50 mmol/l Tris-HCl (pH 7.4) (buffer A) and incubated 15 min at 37°C, centrifuged at 30,000 × g for 15 min and washed twice in the same buffer. The final pellet re-suspended in the buffer And when the concentration of protein in the range of 15 to 25 mg/ml and stored in liquid nitrogen.

Membrane (150-200 μg of protein per test) incubated at 4°C for 120 min in 0.5 ml of 50 mmol/l Tris-HCl-buffer (pH 7.4)containing 2 mmol/l MgCl2from 1 to 2 10-9mol/l [3H]-2-[4-(3-azidophenyl)-2-oxo-l-pyrrolidinyl]butanamide and increasing concentrations of the test substance. Nonspecific binding (NSB) was determined as the East is internal linking, observed in the presence of concentrations of the substances (for example, 10-3mol/l of levetiracetam), which is associated with virtually all receptors. Membrane-bound and free radio is separated by rapid filtration through glass fiber filters (equivalent to Whatman GF/C or GF/B; VEL, Belgium), pre-soaked in 0.1% polyethylenimine and 10-3mol/l levetiracetam to reduce nonspecific binding. Samples and filters are washed at least 6 ml of 50 mmol/l Tris - HCl (pH 7.4) buffer. All the filter does not exceed 10 seconds per sample. The radioactivity remaining on the filters, calculate liquid scintillation β-meter (Tri-Carb 1900 or TopCount 9206, Camberra Packard, Belgium, or any other equivalent meter). Data analysis is conducted computer nonlinear method suitable curve using a series of equations that describe some models of binding, given the population of independent non-interacting receptors, which are governed by the law of the masses.

Compounds according to the invention showed a pKi value of 6.0 or more. Special affinity shown by compounds 8, 9, 10, 22, 23, 27, 30, 31, 32, 33, 38, 40, 41, 43, 46, 47, 49, 64, 71, 72, 73, 75, 81, 83, 86, 87, 88, 92, 93, 95, 96, 98, 100, 103, 105, 110, 119, 127, 142, 146, 149, 151, 152, 156, 157, 158, 159, 162, 163, 164, 165, 166, 169, 170, 171, 173, 174, 175, 176, 180, 181, 185, 187, 188, 195, 196, 197, 198, 200, 201, 204, 205, 207, 209, 211, 212, 213, 214, 215, 219, 221, 222, 223, 24, 225, 226, 228, 229, 234, 250, 251, 252, 264, 265, 267, 304, 306, 350 and 351.

EXAMPLE 9: an Animal model mice, sound-sensitive

The purpose of this test is the measurement of anticonvulsive the ability of the compound on mice that are sensitive to sound, a genetic animal model of reflex seizures. In this model, primary produced epilepsy, seizures cause no electrical or chemical stimulation and types of attack are, at least partially, similar in their clinical phenomenology seizures occurring in humans (Loscher W. & D. Schmidt, Epilepsy Rec, (1998), 2, 145-181; J. R. Buchhalter, Epilepsia (1993), 34, S31-S41).

Use of genetically zvukousilitelnym mice male or female (14-28 g; N=10)produced from DBA breed, bred Dr. Lehmann in the Laboratory of Acoustic discrimination (Paris) and grown at UCB Pharma Sector husbandry unit from 1978. The pilot project consisted of several groups, one group was administered a control substance, and other groups of different doses of the test compounds. Compounds administered intraperitoneally administered 60 minutes prior to the call audiogenic seizures. The area of the injected dose had a logarithmic progression, usually between 1.0×10-5mol/kg and 1.0×10-3mol/kg, but if necessary, tested, lower or higher doses.

To test animals are placed in small cages, one mouse in the tile is in, in zvukopronitsaemost the camera. After a period of orientation within 30 seconds transmit acoustic stimulus (90 dB, 10-20 kHz) for 30 seconds through loudspeakers located above each cell. During this time the mice see and identify the presence of 3 phases seizure activity, namely wild throwing, muscle contraction and tonic convulsions. Calculate the proportion of mice protected from wild tossing, muscle contraction and tonic convulsions, respectively.

For active compounds calculate the ED50 value, i.e. the dose which produces 50% protection relative to the control group, with 95% confidence intervals, using Probit Analysis (SAS/STAT® Software version 6.09, PROBIT procedure) correlations protected mice for each of the 3 phases of seizure activity.

Compounds according to the invention showed ED50 values 10-4(mol/kg) or less. Especially promising activity showed a connection 8, 9, 10, 22, 23, 27, 30, 31, 32, 33, 38, 40, 41, 46, 47, 64, 71, 72, 81, 86, 87, 88, 92, 93, 95, 96, 100, 105, 110, 146, 151, 152, 156, 158, 159, 162, 163, 164, 165, 166, 180, 181, 187, 188, 195, 196, 197, 198, 200, 201, 204, 205, 207, 209, 211, 212, 213, 214, 215, 219, 221, 222, 223, 224, 226, 228, 229, 234, 250, 251, 252, 264, 265, 267 AA 1, AA 2, AA 3, 4 AA and AA 5.

Below are the results of the tests of the claimed compounds.

Under the tested compounds ucb 34714 (brivaracetam) and ucb 44212 (seletracetam) are the compounds of formula 1 where R3 and R3a mean sootvetstvenno is C1-20 alkyl and C2-6 alkenyl.

Test 1.1. The opposite effect ucb 34714 and drugs against essential tremor the tremor caused by harmaline, compared with spontaneous tremor and sedation in rats.

Objective: to Compare ucb 34714, a new derivative of pyrrolidone with high affinity to the binding site of levetiracetam, with the medicinal substances prescribed for essential tremor, caused by antagonistic harmaline (HARM) the tremor in rats.

Base: HARM - induced tremor is used as a model of essential tremor. However, causes HARM as sedation and tremor. Thus, in this model, the medicinal substance can reduce tremor only by increasing sedation. Behavioral (behavioral) methodology allows us to try to measure independent of sedatives antitremor effect, to find drugs that more effectively confront essential tremor without causing side effects.

Methods: the Tested compounds injected I.P. (IPR) for 30 minutes prior to I.P. introduction of 20 mg/kg HARM that causes tremor for 3 hours. The test was performed at 15, 30 and 60 minutes after HARM and behavioral effects were estimated as: (1) the index set (identified) tremor (ET) (motion tests during the ascent, at a given pose, the ri tilt); (2) the index of spontaneous tremor (ST) (tremor when relaxed position of the head/body); and (3) sedative index (SED) (fixed support head/limbs, locomotion, ptosis).

Results: ucb 34714 depending on the dose decreases as ET and ST (the maximum effect - 53 and 43%, respectively) in doses (21-70 mg/kg), which slightly change the SED. At the dose of 120 mg/kg, which reduces spontaneous locomotion, decreased ET (-56%) and ST (-68%) was associated with an increased SED (57%). Propranolol (2.5-20 mg/kg) reduced ET (max - 49%), but stronger reduced ST (max - 63%), and increased SED (28-37%), and at a dose of 20 mg/kg caused postural hypotension. Primidone (160 - 320 mg/kg) had no effect on ET, but also reduced ST (-30 ÷ -37%) and increased SED (Max. 46%). Clonazepam (0.3-3 mg/kg), which caused sedation and ataxia, decreased ET (max - 49%), but was also more effective against ST (max - 77%) and was significantly increased SED (63-132%).

Conclusions: In General, when the medicinal substance reduces ST more than NO, it is correlated with increased SED that does the index set tremor optional for measurement independent of sedatives antitremor effect. Of all the subjects of drugs ucb 34714 showed significant efficacy against EM in doses that do not increase induced HARM SED and who had no side effects. This suggests that the future is positive therapeutic opportunities ucb 34714 with essential tremor.

Test 1.2

Compared the ability of ucb 34714 to withstand the tremor caused by harmaline in rats, with some drugs against tremor and anti-epileptic. The tremor triggered by harmaline, was evaluated using a 3 behavioral (behavioral) tests (rise, set, pose, angle), which gives the index set (identified) tremor (ET). We used a dose of 20 mg/kg of harmaline I.P., which caused a tremor for 3 hours. Test compounds were administered I.P. for 30 minutes prior to the introduction of harmaline. Tests tremor carried out after 15, 30 and 60 minutes after administration of harmaline. Levetiracetam (54-540 mg/kg) caused a small change EM (3-25%) compared with the control group, which took the media. On the contrary, ucb 34714, in doses that caused only reduced exploratio, reduced ET 25, 53, and 66% after the introduction of 38, 70 and 120 mg/kg I.P. respectively. Propranolol (2.5-20 mg/kg) and clonazepam (0.3 - 3 mg/kg) were less active than ucb 34714, and caused a marked postural hypotension. Primidone (160 - 320 mg/kg) is very slightly reduced ET (10%). Carbamazepine (5-40 mg/kg), depending on the dose reduced EM on the 17-55%;

then as phenytoin (50-200 mg/kg) and valproate (inlet 150 up to 450 mg/kg) were active only in a narrow range of doses. Gabapentin (30-120 mg/kg) gave a moderate effect (29-42%). These antiepileptic medicinal substances were effective only in doses, call the living noticeable behavioral side effects.

Conclusions: compared with other medicinal substances ucb 34714 showed higher efficiency and caused fewer side effects, suggesting promising therapeutic opportunities ucb 34714 with essential tremor

Test 1.3.

Tested ucb 38714 on rats with induced harmaline tremor, comparing the compound's potency and side effects with activity and side effects of recognized drugs against tremor and AED. In order to avoid or minimize the impact of sedatives, we evaluated the processed harmaline rats during the intentionally induced behavioral activity, getting 'index set tremor' (ET).

The results:

Levetiracetam (50, 170, 340 and 540 mg/kg I.P.) caused a small, statistically insignificant decrease in ET (3-25%).

On the contrary, ucb 38714 (10, 21, 38, 70 and 120 mg/kg, I.P.) was significantly reduced ET at doses 38-120 mg/kg At a dose of 10 mg/kg ucb 38714 was similar to the media. At a dose of 38 mg/kg average value of ET was decreased relative to its control (medium), 33, 26 and 15% after 15, 30 and 60 min after injection of harmaline, respectively, whereas at the dose of 70 mg/kg, the average decrease was reached 64, 58 and 38%, respectively. At the dose of 120 mg/kg, the decrease amounted to 86, 73 and 40%, respectively. During the total observation time of one hour (AUC) dose 38, 70 and 120 mg/kg ub 38714 depending on the dose (dose effect) reduced ET 25, 53 and 66%, respectively. Propranolol (2.5, 5, 10 and 20 mg/kg I.P.) statistically significantly reduced the ET from 5 mg/kg and above. The reduction of NO in a dose of 20 mg/kg was 64, 51 and 32% after 15, 30 and 60 min after injection of harmaline, respectively. During the total observation time of one hour (AUC) propranolol caused a dose-dependent decrease in ET 12, 29, and 49% at doses of 2.5, 10 and 20 mg/kg, respectively.

In the case of primidone (160 and 320 mg/kg, I.P.) failed clearly to reduce the set tremor, despite the high doses. The maximum mean reduction of EM was 10% at the dose of 320 mg/kg

Clonazepam (0.3, 1 and 3 mg/kg, I.P.) caused a dose-dependent decrease in ET. Average dose-dependent decrease in ET (AUC) for doses of 0.3, 1 and 3 mg/kg was 1, 24, and 48%, respectively.

Carbamazepine (5, 10, 20 and 40 mg/kg) at doses of 10, 20 and 40 mg/kg, significantly reduced ET 17, 33, and 55%, respectively.

Phenytoin (50, 100, 150 and 200 mg/kg, I.P. in doses of 100, 150 and 200 mg/kg significantly reduced EM 29, 42, and 49%, respectively.

Valproate (150, 300 and 450 mg/kg, I.P.) was cut EM in a very narrow range of doses. Significant decrease of 22 and 49% receive at doses of 300 and 450 mg/kg, respectively.

Gabapentin (30, 60 and 120 mg/kg, I.P.) caused only moderate, independent of dose reduction set tremor (30-40%).

SIDE EFFECTS: ucb 38714 more effectively reduced in rats caused by harmaline have been fitted the th tremor, than modern standard drugs for the treatment of essential tremor and AED, while the effectiveness of drugs is evident, apparently, only in doses that cause serious side effects such as postural hypotension (flaccid posture, muscle weakness and gait disturbance (staggering gait, ataxia). This is not observed in the case of ucb 34714 or levetiracetam.

CONCLUSIONS: Resistance induced harmaline tremor in rats to pharmacological treatment, apparently, is a partial reflection of the effectiveness of existing pharmacological agents for the treatment of essential tremor.

Test 2. Seletracetam (ucb 44212) inhibits causing epilepsy reactions in hippocampal slices in vitro.

Objective: to Seletracetam (ucb 44212) is a new derivative of pyrrolidone, related in structure to levetiracetam (LEV, Keppra), which exhibits a higher affinity than LEV, to the binding site LEV (synaptic - vesicle protein 2A - Lynch et al., PNAS, 101, 9861, 2004). This study focuses on assessing the activity of seletracetam in two in vitro models of epilepsy.

Methods. Effect on epileptic reaction induced by perfusion fluid with high K+, low Ca2+ (HKLCF) or by adding to the normal perfusion (ACSF) 5 μm bicuculline under the conditions (BMI), was estimated using charts the guide of the field potential in the field SA slices of hippocampus in rats. The field potentials were caused by stimulation fibrillose Department regular pulses, revealing a single peak population (PS) in ACSF.

Results. HKLCF and BMI induce causing the epilepsy field potentials in the field SO with increasing amplitude of the PS and the production of multiple PS in response to single stimuli. HKLCF, but not BMI, regularly induced spontaneous impulses. Seletracetam, 1-10 μm, significantly reduced induced using HKLCF increasing amplitude PS (?PS) and amplitudes and the number of multiple PS with a maximum effect at 3.2 microns. LEV showed previously shown a similar, but less activity is maximal at 32 μm (Margineanu & Klitgaard, Pharmacol. Res. 42, 281, 2000). Seletracetam did not reduce the rate of spontaneous impulses, similar to LEV (Margineanu et al., Epilepsia 44, Suppl. 9, 261, 2003). Seletracetam inhibited induced BMI PS with significant value at 10 μm. Seletracetam, 1-10 μm reduced the number of induced multiple PS. It was reported that LEV inhibits these markers occurrence of epilepsy with a maximum effect at 32 microns.

Conclusion. Seletracetam inhibited causing epilepsy reactions in sections biocamp in rats with higher activity and efficiency than LEV, in two in vitro models of epilepsy.

Test 3. Seletracetam (ucb 44212) prevents seizures in animal models of chronic epilepsy in vivo.

This study is dedicated to the do study the possible ability of seletracetam to prevent attacks on in vivo models of epilepsy.

Methods. Activity for the prevention of attacks is evaluated on the male NMRI mice with corneal excitation (25-35 g; n=10), male rats Sprague Dawley with an excited hippocampus (350-45 g; n=8), predisposed to audiogram attacks the male mice (20-25 g; n=10) and rats with genetic epilepsy absenses type from Strasbourg (GAERS), as well as at maximal electroshock and seizures induced by pentylenetetrazole male NMRI mice (22-28 g; n=10). For the quantitative determination of side effects CNS used rotarod.

Results. Seletracetam warned motor seizures secondarily generalized epilepsy in mice with corneal excitation (ED50=0.31 mg/kg, I.P.) and rats with excitation of the hippocampus (the minimum active dose = 0.23 mg/kg, P.O.). Similarly, seletracetam suppressed clonic convulsions in mice prone to audiogram seizures (ED50=0.17 mg/kg, I.P.) and peak wave discharges in rats GAERS (ED50=0.15 mg/kg I.P.). This is contrary to the lack of protection in the tests with maximum shock and seizures caused by pentylenetetrazole (ED50>232 mg/kg I.P.). TD50 values (rotarod) seletracetam in mice with excited cornea (corneal excited) and GAERS rats were 325 and 449 mg/kg I.P. respectively. Compared with the protective ED50 values obtained on the same animal, this results in a high the th border security (safety) 1048 and 3075, respectively.

Conclusion: This study showed reliable protection from attacks and high CNS tolerability of seletracetam in various in vivo models of epilepsy.

Test 4. Anticonvulsive action of seletracetam (ucb 44212) in animal models of epileptic status

In this study, we study the possible protective properties of seletracetam against attacks from in vivo models of self-sustaining epileptic status (SSSE).

Methods. SSSE cause with a 30-minute periodic stimulation perforating path (PPS) using permanently implanted electrodes in freely moving adult male Wistar rats. Seletracetam (100-300 mg/kg), medium or levetiracetam (500 mg/kg) were intravenously injected with 10 minutes after the induction of SSSE (early treatment of established SSSE). Electrophotographic and behavioral (behavioral) symptoms SSSE analyzed offline.

Results. Seletracetam, injected centuries during the early stages of the installed SSSE (10 min after PPS), reduced the duration of seizures with effect dose (depending on dose). The total residence time in a state of seizure after levetiracetam was 32+5 min (500 mg/kg), total time spent in a state of seizure after the introduction of seletracetam was 3.5+0.7 min (300 mg/kg), 11+1.7 min (200 mg/kg) and 25± 3.4 min (100 mg/kg), whereas the control animals stay in a state of attack (the attack) was 32.5+5.1 minutes Protection from seizures with centuries of conducting seletracetam (300 mg/kg) was significantly more effective than the previously described protection through I.V injection of diazepam (10 mg/kg) or V.V. introduction of levetiracetam (300 mg/kg), and comparable to the protection under centuries the introduction of phenytoin (50 mg/kg). However, this effect was observed at doses of seletracetam significantly higher (100-300 mg/kg I.V)than doses causing protection in animal models of partial or generalized epilepsy (0.1-0.3 mg/kg I.P.).

The conclusions. Seletracetam showed a significant protective effect against seizures in these animal models SSSE.

Test 5. Ucb 34714 effective in models of neuropathic pain in rats: comparison with gabapentin.

The aim of this study was to compare the actions ucb 34714 action gabapentin in two models of neuropathic pain in rats.

The effect of ucb 34714 on the reaction of acute pain was studied using the test "hot plate" in rats. Ucb 34714 (21-210 mg/kg) and gabapentin (50-200 mg/kg) administered intraperitoneally injected (I.P.) for 30 min before testing (=study 3).

Action ucb 34714 on hyperalgesia was studied on rats with mononeuropathy (model Bennett, ligation of the sciatic nerve = study 1) and with diabetes (streptozocin, 75 mg/kg, p = study 2). Induced hyperalgesia determine pushing the paw. 2 weeks after induction of mononeuropathy or 3 weeks after induction of diabetes rats ipoda ucb 34714 (2.1-68 mg/kg) or gabapentin (30,60 mg/kg). Intervals after injection to determine the threshold vocalizations.

The results showed that ucb 34714 does not change the reaction time in the test of the "hot plate". In contrast, gabapentin significantly increases the reaction time at 200 mg/kg to 66%. As in rats with diabetes and in rats with mononeuropathy ucb 34714 significantly increases the threshold vocalizations and completely cancels (reverses) hyperalgesia in a dose of 21 mg/kg Gabapentin causes significant antihyperalgesic effect at a dose of 30 mg/kg in rats with diabetes, but only at a dose of 60 mg/kg in rats mononeuropathies.

Ucb 34714 had no analgesic action in acute pain reflexes. However, as in rats with diabetes and in rats with mononeuropathy, ucb 34714 caused antihyperalgesic effect, which is comparable with the action gabapentin. These data suggest therapeutic potential of ucb 34714 in patients suffering from neuropathic pain.

Test 6. Ucb 34714 - comparison with levetiracetam in animal models of chronic epilepsy in vivo.

This study compares protivogrippoznaya and antiepileptogenic activity ucb 34714 and levetiracetam (Lev) namnoga in vivo models of epilepsy.

Study 1: the Excitation of the cortex (corneal) in mice: Totally excited to male NMRI mice (20-25 g; N=10 per group) pre-morning give saline solution, and then stimulate and see convulsions. Similarly morning after pre-treatment given saline, ucb 34714 (0.6-2.4 mg/kg I.P.) or Lev (1.8-10.0 mg/kg I.P.).

The ED50 value: 1.2 mg/kg iPods ucb 34714 and 7.3 mg/kg I.P. for Lev.

Study 2: the Excitation of the hippocampus in rats: Fully excited male rats Sprague-Dawley (250 - 350 g; N=8 per group) once stimulated after oral administration of water. Two days later, this Protocol is repeated with the same animals after oral administration of either water or ucb 34714 or Lev.

The minimum active dose, i.e. the dose that causes a noticeable reduction index (in points) the severity of seizures compared with the value before administration of the drug: 0.21 mg/kg P.O. for ucb 34714 and 54 mg/kg P.O. for Lev.

Study 3: the Arousal of the amygdala in rats: Fully excited male rats Sprague-Daw-ley (250 - 350 g; N=8 per group) once stimulated after injection of saline.

After 2 days and treated similarly after pretreatment with saline, ucb 34714 (6.8, 21.2, 67.9 and 212.3 mg/kg I.P.) or Lev (17, 54, 170, 540 and 1700 mg/kg I.P.).

Ucb 34714 caused a marked suppression of gravity of the motor-Prip the exploration of the state at the dose of 21.2 mg/kg, while Lev caused a similar effect at a dose of 170 mg/kg Ucb 34714 also ADD significantly reduced in a dose 212.3 mg/kg, while Lev was inactive for this indicator up to a dose of 1700 mg/kg

Study 4: Audiogone seizures in mice: Clonic convulsions caused in mice genetically susceptible to sound (165-28 g; N=10 per group). Mice pre-injected with either saline or ucb 34714 (1.4-4.0 mg/kg I.P.)or Lev (24-48 mg/kg I.P.).

From the appearance of the Kli (?)technical convulsing mice were protected ucb 34714 with ED50 value of 2.4 mg/kg and Lev at 30 mg/kg

Study 5: Spontaneous pulse-wave discharges (SWD) in rats with genetic epilepsy absenses type from Strasbourg (GAERS):

Each male rats GAERS implanted 4 platinum electrode in the left and right cortical region. After 20 minutes, the period of habituation, rats injected ipib saline or ucb 34714 (2,1, 6.8 and 67.9 mg/kg)or Lev (5.4, 17.0 and 170 mg/kg), and continuously recorded EEG sequentially through 20-minute intervals up to 120 minutes.

Ucb 34714 significantly suppressed spontaneous SWD in GAERS rats at a dose of 2.1 mg/kg with complete inhibition observed at 67.9 mg/kg on the other hand, Lev caused a marked suppression of SWD at a dose of 5.4 mg/kg, but never caused a complete inhibition even at a dose of 170 mg/kg

Studies 6 and 7: Rotarod (rotational) test initiated mice, the rats: Fully corneal excited mice (N=10 per group) or rats with the excitation of the amygdala (N=8 per group) pre-teach and leave only those animals, who are able to remain on a rotating surface, at least 60 seconds in 3 consecutive trials. The next day, administered either saline or ucb 34174, or Lev and record the number of animals, not able to stay on a rotating surface (rod)for at least 60 seconds.

Previous studies have given a greater ratio of TD50/ED50 for Lev (148) compared with those relations to other classic or newer AED (2-21), which shows an unusually high interval between doses of Lev, which cause a significant deterioration in rotarod - test, and doses that cause warning motor seizures in corneal excited mice. The ratio of the TD50/ED50 for ucb 34714 was 46. In a similar assessment in rats by stimulation of the amygdala relations for ucb 34714 and Lev was 4 and 2, respectively.

Research 8: Development of corneal excitation in mice: Stimulation evoked carried out twice a day stimulation in groups of 20 male NMRI mice (20-25 g)which had previously given either saline or ucb 34714 (0.21, 0.68, 2.1 and 6.8 mg/kg I.P.)or Lev (1.7, 5.4, 17 and 54 mg/kg I.P.) before each stimulation. 19 days, during which time twice a day stimulation, the introduction of the drug was stopped, and within 2 days spent washing without trims the population. After washing animals restimulative twice a day for 5 days without administration of a drug. The advent of generalized seizures was used as an endpoint for evaluating the development of corneal stimulation.

The preliminary introduction of ucb 34714 during corneal excitation mice resulted in a significant decrease in the frequency of generalized motor seizures. A similar decrease in the frequency of generalized motor seizures in the case of Lev observed at higher doses. Continuous corneal stimulation with subsequent cessation of treatment showed a steady decrease in the frequency of generalized motor seizures in the group who had a higher dose of ucb 34704. A similar effect was not observed in any of the groups, which were formerly Lev.

Conclusions: Protivogrippoznaya activity detected at ucb 34714 in animal models, which are believed to mimic incomplete (excited animals) and generalized (mice, susceptible to audiogram seizures, and mouse GAERS) epilepsy in people, the stronger and more effective than protivogrippoznoj activity Lev.

Assessment of excited animals suggests that the boundary (limit) security ucb 34714 similar boundary (limit) security Lev.

The preliminary introduction of ucb 34714 in p is acesse corneal excitation in mice shows a strong and sustainable ability to inhibit the development of excitation, higher than this ability in Lev.

The present study shows that ucb 34714 has a higher activity and efficiency than Lev, as protivogrippoznogo and antiepileptogenic agent in various in vivo models of epilepsy.

1. The derived 2-oxo-1-pyrrolidine formula I or its pharmaceutically acceptable salt,

where X represents-CA1NR5R6or-CA1-R8;

And1and2independently represent oxygen;

R1represents hydrogen, C1-20 alkyl, C6-10 aryl, or-CH2-R1awhere R1arepresents a C6-10 aryl;

R3represents hydrogen, nitro, nitroxy, cyano, azido, carboxy, amido, C1-20 alkyl, C2-6 alkenyl, C2-6 quinil, C6-10 aryl, thiazolyl, oxazolyl, furyl, thienyl, pyrrolyl, tetrazolyl, pyrimidinyl, triazolyl, pyridinyl, -COOR11, COR11 where R11 is a C1-12 alkyl;

R3arepresents hydrogen, C1-20 alkyl, C2-6 alkenyl, C2-6 quinil or C6-10 aryl;

R5and R6are the same or different and each independently represents hydrogen, C1-6 alkyl;

R8represents hydroxy;

each alkyl can independently be substituted by 1 to 5 substituents selected from the of alogena, isothiocyanate, hydroxy, nitro, cyano, azido, C3-6 cycloalkyl and C6-10 aryl,

each C6-10 aryl may independently be substituted by 1 to 5 substituents selected from halogen, amino, nitro, azido, C1-6 alkoxy, C1-6 alkyl, C1-6 haloalkyl;

each of alkenyl can independently be substituted by at least one Deputy, selected from halogen and hydroxy;

provided that at least one of R3and R3adifferent from hydrogen, and that when the compound is a mixture of all possible isomers,

X is a-CONR5R6And2represents oxygen and R1represents hydrogen, methyl, ethyl or propyl, and that, when R1and R3aeach are hydrogen, And2represents oxygen, and X is a-CONR5R6then R3different from carboxy, methyl, -COOR11, amido, naphthyl, phenyl, substituted C1-6 alkoxy or halogen atom at the para-position of the naphthyl, phenyl.

2. The derived 2-oxo-1-pyrrolidine according to claim 1, where X represents a group-Deputy selected from the

a) -CONR5R6;

b) -CONR5R6where R5and R6represent hydrogen or C1-4 alkyl;

c) -CONR5R6where R5and R6independently represent hydrogen, methyl, ethyl, propyl, shall sapropel, butyl, ISO or tert-butyl;

d) -CONR5R6where R5and R6independently represent hydrogen or methyl;

e) -CONR5R6where at least one of R5and R6or both represent hydrogen; or

f) -CONH2.

3. The derived 2-oxo-1-pyrrolidine according to claim 1, where R1represents a group-Deputy selected from the

a) hydrogen, C1-20 alkyl or C6-10 aryl;

b) hydrogen, C1-12 alkyl or C6-10 aryl;

c) hydrogen, lower alkyl or phenyl;

d) methyl, ethyl, propyl, isopropyl, butyl, ISO - or tert-butyl, 2,2,2-trimethylamino, or the same groups substituted by from one to five halogen atoms; or (e) of ethyl.

4. The derived 2-oxo-1-pyrrolidine according to claim 1, where

R3arepresents a group-Deputy selected from the

a) hydrogen, C1-20 alkyl, C6-10 aryl;

b) hydrogen, methyl, ethyl, phenyl or benzyl;

c) hydrogen or methyl, ethyl, propyl, isopropyl, butyl, ISO - or tert-butyl, 2,2,2-trimethylamino, or the same groups substituted by from one to five halogen atoms.

5. The derived 2-oxo-1-pyrrolidine according to claim 4, where R3arepresents a group-Deputy selected from a) hydrogen or C1-20 alkyl; (b) hydrogen or lower alkyl; (c) hydrogen.

6. The derived 2-oxo-1-pyrrolidine according to claim 1, in which the PR R 3is a Deputy selected from such groups as:

a) hydrogen, C1-alkyl, each optionally substituted by 1-5 substituents selected from hydroxy, halogen; C2-6 alkenyl possibly substituted by at least one Deputy, selected from hydroxy, halogen; C2-6 quinil; C1-6 alkyl and phenyl, naphthyl, each optionally substituted by 1-5 substituents selected from halogen, C1-6 alkyl, C1-6 halogenoalkane, C1-6 alkoxy, amino, azido and nitro;

b) as a), except that the alkyl is a C1-6 alkyl;

c) C1-6 alkyl, possibly substituted by 1-5 substituents selected from halogen, azido; C2-3 alkenyl, possibly substituted by at least one halogen; C2-3 quinil; tetrazolyl, pyridyl, furyl, pyrrolyl, thiazolyl or thienyl; phenyl, possibly substituted by 1-5 substituents selected from halogen, C1-6 alkyl, C1-6 halogenoalkane, C1-6 alkoxy, amino, azido, and nitro;

d) hydrogen or methyl, ethyl, propyl, isopropyl, butyl, isobutyl, trebuil, 2,2,2-trimethylated, possibly substituted by 1-5 halogen atoms;

e) C1-4 alkyl, possibly substituted by 1-5 substituents selected from a halogen or azido; C2-5 alkenyl, possibly substituted by at least one halogen atom; C2-5 quinil; thienyl; or phenyl, possibly substituted by 1-5 substituents selected from halogen, C1-6 alkyl, C1-6 Gal which of ganancia or azido; or

f) C1-6 alkyl With 1-6 halogenated.

7. The derived 2-oxo-1-pyrrolidine of claim 1, wherein A2represents oxygen; X is a-CONR5R6or-CO-R8; R1represents hydrogen or C1-20 alkyl, C6-10 aryl; R3represents hydrogen, nitro, cyano, amido, C1-20 alkyl, C6-10 aryl, thiazolyl, oxazolyl, furyl, thienyl, pyrrolyl, tetrazolyl, pyrimidinyl, triazolyl, pyridinyl, COOR11, -COR11 where R11 is a C1-12 alkyl, R3may additionally represent C2-5 alkenyl, possibly substituted by at least one halogen; C2-5 quinil or azido; R3arepresents hydrogen, provided that then R3is not hydrogen; R5and R6are the same or different and each independently represents hydrogen, C1-6 alkyl; R8represents hydroxy.

8. The derived 2-oxo-1-pyrrolidine according to claim 1, in which R1represents methyl, ethyl, propyl, isopropyl, butyl or isobutyl; R3represents a C1-5 alkyl, possibly substituted by 1-5 substituents selected from halogen, cyano, azido, cyclopropyl and phenyl; C2-5 alkenyl, possibly substituted by at least one halogen; C2-C5 quinil, azido; tetrazolyl; thiazolyl; thienyl; furyl; pyrrolyl, pyridinyl, which phenyl may be substituted by 1-5 substituents, selected the data from halogen, C1-6 alkyl, C1-6 halogenoalkane, C1-6 alkoxy, nitro, amino, most preferably, methyl, ethyl, propyl, isopropyl, butyl or isobutyl; X represents-COOH or-CONH2.

9. The derived 2-oxo-1-pyrrolidine according to claim 1, in which R1represents methyl, ethyl or n-propyl and X represents-CONH2.

10. The derived 2-oxo-1-pyrrolidine according to claim 1, where X represents a-CA1NH2, -CA1NHCH3or-CA1N(CH3)2; R1represents a C1-20 alkyl or phenyl; R3represents a C1-20 alkyl, C2-6 alkenyl, C2-6 quinil, cyano, COR11 where R11 is a C1-12 alkyl; C6-10 aryl; thiazolyl; oxazolyl; furyl; thienyl; pyrrolyl; tetrazolyl; pyrimidinyl; triazolyl; pyridinyl; or R3represents CH2R10where R10represents hydrogen; R3arepresents hydrogen, C1-20 alkyl or C6-10 aryl.

11. The derived 2-oxo-1-pyrrolidine according to claim 1, in which R1represents a C1-20 alkyl; R3arepresents hydrogen; R3represents hydrogen; C1-12 alkyl, possibly substituted by 1-5 substituents selected from hydroxy, halogen, cyano; C2-6 alkenyl possibly substituted by at least one halogen; C2-6 quinil; azido; cyano; amido; triazolyl; tetrazolyl; pyridinyl; furyl; oxazolyl; pyrimidinyl; pyrrolyl; thiazolyl; ITIL; naphthyl or phenyl, each possibly substituted by 1-5 substituents selected from halogen, C1-6 alkyl, C1-6 halogenoalkane, C1-6 alkoxy, amino, azido and nitro.

12. The derived 2-oxo-1-pyrrolidine according to claim 11, in which R1is a group of Deputy selected from (a) C1-12 alkyl; (b) C1-6 alkyl; or (c) ethyl.

13. The derived 2-oxo-1-pyrrolidine according to claim 1, which is racemates form and in which, when X is a-CONR5R6and R1represents hydrogen, methyl, ethyl or propyl, then the substitution on the pyrolidine ring differently from mono-, dimethyl or monoethyl.

14. The derived 2-oxo-1-pyrrolidine according to claim 1, which is racemates form and in which, when X is a-CONR5R6and R1represents hydrogen or unsubstituted C1-6 alkyl, then substitution in the ring is different from C1-6 alkyl or C2-6 alkenyl, each unsubstituted.

15. The derived 2-oxo-1-pyrrolidine according to claim 1, in which X represents-CA1NH2; R1represents hydrogen; R3is azidomethyl, iodomethyl, optionally substituted from 1 to 4 halogen atoms or vinyl, optionally substituted with one or two metelli, or from 1 to 3 halogen atoms or acetylene; R3arepresents hydrogen; and its racemates or enantiomerically enriched F. the PMA, preferably pure enantiomer.

16. The derived 2-oxo-1-pyrrolidine according to claim 1, in which X represents-CA1NH2;

R1represents hydrogen; R3represents a C1-6 alkyl, C2-6 alkenyl or C2-6 quinil, each optionally substituted, azido, 1-5 halogen atoms; and R3arepresents hydrogen; and its racemates or enantiomerically enriched form, preferably pure enantiomer.

17. The derived 2-oxo-1-pyrrolidine of claim 1, wherein A2represents oxygen; R1represents ethyl; X represents-CONH2; R3represents n-propyl or 2,2-defermined; R3arepresents hydrogen.

18. The derived 2-oxo-1-pyrrolidine according to any preceding paragraph, in the form of a pure enantiomer.

19. The derived 2-oxo-1-pyrrolidine according to any preceding paragraph, which, when the carbon atom to which R1attached is asymmetric, is in S-configuration.

20. The derived 2-oxo-1-pyrrolidine selected from the

(2S)-2-[4-(methyl bromide)-2-oxo-1-pyrrolidinyl]butanamide

(2S)-2-[(4R)-4-(iodomethyl)-2-oxopyrrolidin]butanamide

(2S)-2-(2-oxo-4-phenyl-1-pyrrolidinyl)butanamide

2S)-2-[4-(iodomethyl)-2-oxo-1-pyrrolidinyl]butanamide

(2S)-2-[4-(chloromethyl)-2-oxo-1-pyrrolidinyl]butane is and

(2S)-2-[(4R)-4-(azidomethyl)-2-oxopyrrolidin]butanamide

2-[4-(2,2-dibromovinyl)-2-oxo-1-pyrrolidinyl]butanamide

1-[(1S)-1-(aminocarbonyl)propyl]-5-oxo-3-pyrrolidinyl}methyl nitrate

(2S)-2-[2-oxo-4-(1N-tetrazol-1-ylmethyl)-1-pyrrolidinyl]butanamide

2-(2-oxo-4-vinyl-1-pyrrolidinyl)butanamide

(2S)-2-[(4R)-4-(2,2-dibromovinyl)-2-oxopyrrolidin]butanamide

2S)-2-[(4S)-4-(2,2-dibromovinyl)-2-oxopyrrolidin]butanamide

2S)-2-[4-(isothiocyanates)-2-oxo-1-pyrrolidinyl]butanamide

2-[2-oxo-4-(1,3-thiazol-2-yl)-1-pyrrolidinyl]butanamide

(2S)-2-[2-oxo-4-(2-thienyl)-1-pyrrolidinyl]butanamide

(2S)-2-[4-(2-methoxyphenyl)-2-oxo-1-pyrrolidinyl]butanamide

2S)-2-[4-(3-methoxyphenyl)-2-oxo-1-pyrrolidinyl]butanamide

(2S)-2-[4-(4-azidophenyl)-2-oxo-1-pyrrolidinyl]butanamide

[(2S)-2-[2-oxo-4-(3-thienyl)-1-pyrrolidinyl]butanamide

(2S)-2-[4-(3-azidophenyl)-2-oxo-1-pyrrolidinyl]butanamide

(2S)-2-[2-oxo-4-(3-thienyl)-1-pyrrolidinyl]butanamide

(2S)-2-[(4S)-2-oxo-4-vinylpyrrolidone]butanamide

(2S)-2-[(4R)-2-oxo-4-vinylpyrrolidone]butanamide

2-[4-(2-bromophenyl)-2-oxo-1-pyrrolidinyl]butanamide

2-[2-oxo-4-(3-pyridinyl)-1-pyrrolidinyl]butanamide

2-[2-oxo-4-(3-pyridinyl)-1-pyrrolidinyl]butanamide

2-[4-(iodomethyl)-2-oxo-1-pyrrolidin the Il]butanamide

(2S)-2-((4R)-4-(iodomethyl)-2-oxo-1-pyrrolidinyl]pentanolide

(2S)-2-[(4R)-4-(iodomethyl)-2-oxopyrrolidin]propanamide

2-(2-oxo-4-propyl-1-pyrrolidinyl)propanamide

2-(2-oxo-4-propyl-1-pyrrolidinyl)butanamide

2-(2-oxo-4-pentyl-1-pyrrolidinyl)butanamide

(2S)-2-[(4R)-4-(iodomethyl)-2-oxopyrrolidin]-N-methylmethanamine

(2S)-2-(4-neopentyl-2-oxo-1-pyrrolidinyl)butanamide

(2S)-2-(4-ethyl-2-oxo-1-pyrrolidinyl)butanamide

2-[4-(2,2-defermined)-2-oxo-1-pyrrolidinyl]butanamide

2-[4-(2,2-dottorati)-2-oxo-1-pyrrolidinyl]butanamide

2-{4-[(2)-2-toretail]-2-oxo-1-pyrrolidinyl)butanamide

2-[4-(2-methyl-1-propenyl)-2-oxo-1-pyrrolidinyl]butanamide

2-(4-butyl-2-oxo-1-pyrrolidinyl)butanamide

2-[4-(cyclopropylmethyl)-2-oxo-1-pyrrolidinyl]butanamide

2-(4-isobutyl-2-oxo-1-pyrrolidinyl)butanamide

2-[4-(4-chlorophenyl)-2-oxo-1-pyrrolidinyl]butanamide

2-[4-(3-chlorophenyl)-2-oxo-1-pyrrolidinyl]butanamide

2-[2-oxo-4-[2-(trifluoromethyl)phenyl]-1-pyrrolidinyl)butanamide

2-[4-(2-forfinal)-2-oxo-1-pyrrolidinyl]butanamide

2-[4-(3-were)-2-oxo-1-pyrrolidinyl]butanamide

(2S)-2-[2-oxo-4-(2-phenylethyl)-1-pyrrolidinyl]butanamide

(2S)-2-[4-(3-bromophenyl)-2-oxo-1-pyrrolidinyl]butanamide

2-{4-[3,5-bis(trif ormetal)phenyl]-2-oxo-1-pyrrolidinyl}butanamide

2-[4-(3,4-dichlorophenyl)-2-oxo-1-pyrrolidinyl]butanamide

2-[4-(2,4-dichlorophenyl)-2-oxo-1-pyrrolidinyl]butanamide

(2S)-2-[2-oxo-4-(3-phenylpropyl)-1-pyrrolidinyl]butanamide

(2S)-2-[4-(3,5-dibromophenyl)-2-oxo-1-pyrrolidinyl]butanamide

2-[4-(3,4-dichlorophenyl)-2-oxo-1-pyrrolidinyl]butanamide

2-(2-oxo-4-propyl-1-pyrrolidinyl)butanamide

2-[4-(3-chlorophenyl)-2-oxo-1-pyrrolidinyl]butanamide

2-(4-ethinyl-2-oxo-1-pyrrolidinyl)butanamide

2-[4-(2-forfinal)-2-oxo-1-pyrrolidinyl]butanamide

(2S)-2-[4-(cyclopropylmethyl)-2-oxo-1-pyrrolidinyl]butanamide

2S)-2-[2-oxo-4-(3,3,3-cryptochromes)-1-pyrrolidinyl]butanamide

2-[4-(3-were)-2-oxo-1-pyrrolidinyl]butanamide

(2S)-2-[4-(cyclopropylmethyl)-2-oxo-1-pyrrolidinyl]butanamide

(2S)-2-[(4R)-4-(2,2-defermined)-2-oxopyrrolidin]butanamide

(2S)-2-[2-oxo-4-(1H-pyrrol-1-yl)-1-pyrrolidinyl]butanamide

(2S)-2-(4-allyl-2-oxo-1-pyrrolidinyl)butanamide

2S)-2-[4-(2-iodopropane)-2-oxo-1-pyrrolidinyl]butanamide

(2S)-2-(4-allyl-2-oxo-1-pyrrolidinyl)butanamide

(2S)-2-[2-oxo-4-(2-oxopropyl)-1-pyrrolidinyl]butanamide

(2S)-2-[4-(2-bromo-1H-pyrrol-1-yl)-2-oxo-1-pyrrolidinyl]butanamide

(2S)-2-(4-methyl-2-oxo-4-propyl-1-pyrrolidinyl)butanamide

(2R)-2-[4-(2,2-dichlorovinyl)-2-oxo-1-Pirro is idini]butanamide

2-[4-(bromamines)-2-oxo-1-pyrrolidinyl]butanamide

2-[(4S)-4-(2,2-deferror)-2-oxopyrrolidin]butanamide

(2S)-2-(4-(bromamines)-2-oxo-1-pyrrolidinyl]butanamide

2-(2-oxo-4-propyl-1-pyrrolidinyl)pentanolide

2-(2-oxo-4-propyl-1-pyrrolidinyl)-3-(1,3-thiazol-4-yl)propanamide

2-(2-oxo-4-propyl-1-pyrrolidinyl)-4-pentanolide including all isomeric forms and their mixtures, or a pharmaceutically acceptable salt.

21. (2S)-2-[4-(2,2-defermined)-2-oxopyrrolidin-1-yl]butane acid.

22. (4R) diastereoisomer connection item 21.

23. (4S) diastereoisomer connection item 21.

24. Pharmaceutical composition for the treatment of epilepsy, epileptogenesis, convulsions, epileptic seizures, essential tremor and neuropathic pain, containing an effective amount of a compound according to any preceding paragraph in combination with a pharmaceutically acceptable diluent or carrier.

25. Pharmaceutical composition for the treatment of epilepsy, epileptogenesis, convulsions, epileptic seizures, essential tremor and neuropathic pain, containing an effective amount of at least one of the compounds of formula I according to claim 1, or its pharmaceutically acceptable salt, where the individual substituents defined in claim 1, provided that at least one of R3and R3adifferent from in Dorada and when the connection is a mixture of all possible isomers, X is a-CONR5R6And2represents oxygen and R1represents hydrogen, methyl, ethyl or propyl, in combination with a pharmaceutically acceptable diluent or carrier.

26. The pharmaceutical composition according A.25, in which the compound of formula I is a compound according to any one of PP-23.

27. A method of treating epilepsy, epileptogenesis, convulsions, epileptic seizures, essential tremor and neuropathic pain, which consists in introducing a therapeutic amount of at least one compound according to any one of claims 1 to 23.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (1):

and their salts wherein ring A comprises optionally heteroatom oxygen (O); dotted lines represent the optional unsaturation; R1 represents (C1-C4)-alkoxy-group; R2 and R3 represent independently hydrogen atom (H), optionally halogenated (C1-C4)-alkyl, optionally substituted aromatic group, or R2 and R3 in common can form substituted or unsubstituted 5-7-membered ring condensed with ring E; k = 0-4; L1 represents a covalent bond or (C1-C6)-alkyl optionally comprising nitrogen atom (N); X represents unsubstituted or substituted carbon © atom or N, or represents O or sulfur (S) atom; Ar represents phenylene; each n = 0-2 independently; each R represents independently H or (C1-C6)-alkyl; Y represents optionally substituted aromatic or heteroaromatic group or 5-11-membered heterocyclic group comprising 1-4 heteroatoms cgosen from N, O and S that are bound with chemokine receptors comprising CXCR4 and CCR5, and elicit the protective affect against damage of host-cells by human immunodeficiency virus (HIV).

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds 2,6-di-tert.-butyl-4-{2-[2-(methylamino)ethyl]-1,3-thiazole-4-yl}phenol, 2,6-di-tert.-butyl-4-[4-(hydroxymethyl)-1,3-oxazole-2-yl]phenol, 4-methylphenyl-2-[4-(1,1-biphenyl-4-yl)-1H-imidazole-2-yl]ethylcarbamate and others or their pharmaceutically acceptable salts. Also, invention relates to using these compounds for preparing a medicinal agent possessing one of the following three activities: inhibition of monoamine oxidases activity, inhibition of lipids peroxidation and modulating activity with respect to sodium channels. Proposed derivatives of thiazole, oxazole or imidazole possess one of the following species of pharmacological activity: inhibition of monoamine oxidases activity, inhibition of lipids peroxidation and modulation of sodium channels.

EFFECT: valuable biochemical and biological properties of derivatives.

34 cl, 119 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new benzofuran derivatives of formula 1 , wherein X represents group of formula -N= or -CH=; Y represents optionally substituted amino group, optionally substituted cycloalkyl group, or optionally substituted saturated heterocycle; A represents direct bond, carbon chain optionally containing double bond in molecular or in the end(s) thereof, or oxygen atom; R1 represents hydrogen, halogen, lower alkoxy, cyano, or amino optionally substituted with lower alkyl B represents optionally substituted benzene ring of formula ; and R2 represents hydrogen or lower alkyl; or pharmaceutically acceptable salt thereof. Invention also relates to pharmaceutical composition containing abovementioned compounds, uses thereof and method for thrombosis treatment.

EFFECT: new compounds for thrombosis treatment.

27 cl, 2 tbl, 429 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I)

or their pharmaceutically acceptable salts or esters hydrolyzing in vivo and possessing activity inhibiting the cellular cycle and selective with respect to CDK-2, CDK-4 and CDK-6. Compounds can be used in cancer treatment. In the formula (I) R1 represents halogen atom, amino-group, (C1-C)-alkyl, (C1-C6)-alkoxy-group; p = 0-4 wherein values R1 can be similar or different; R2 represents sulfamoyl or group Ra-Rb-; q = 0-2 wherein values R2 can be similar or different and wherein p + q = 0-5; R3 represents halogen atom or cyano-group; n = 0-2 wherein values R3 can be similar or different; R4 represents hydrogen atom, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, phenyl or heterocyclic group bound with carbon atom wherein R4 can be optionally substituted at carbon atom with one or some groups Rd; R5 and R6 are chosen independently from hydrogen, halogen atom, (C1-C)-alkyl, (C2-C6)-alkenyl or (C3-C8)-cycloalkyl wherein R5 and R6 can be substituted at carbon atom independently of one another with one or some groups Re; Ra is chosen from (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkyl, phenyl, heterocyclic group, phenyl-(C1-C)-alkyl or (heterocyclic group)-(C1-C6)-alkyl wherein Ra can be substituted optionally at carbon atom with one or some groups Rg and wherein if indicated heterocyclic group comprises residue -NH- then its nitrogen atom can be optionally substituted with group chosen from the group Rh; Rb represents -N(Rm)C(O)-, -C(O)N(Rm)-, -S(O)r-, -OC(O)N(Rm)SO2-, -SO2N(Rm)- or -N(Rm)SO2- wherein Rm represents hydrogen atom or (C1-C6)-alkyl, and r = 1-2. Also, invention relates to methods for synthesis of these compounds, a pharmaceutical composition, method for inhibition and using these compounds.

EFFECT: improved preparing method, valuable medicinal properties of compounds and pharmaceutical compositions.

24 cl, 3 sch, 166 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new 2-arylimino-2,3-dihydrothiazole derivatives of formula described in claims having affinity and selectivity to somatostatin receptors and useful as drugs for treatment of pathological conditions or diseases mediated by one or more somatostatin receptors, such as acromegalia, chromophone adenoma, endocrine pancreatic tumor, argentaffinoma syndrome, gastrointestinal hemorrhage, etc.

EFFECT: new agent for treatment of pathological conditions or diseases mediated by somatostatin receptors.

6 cl, 2836 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new compounds of the general formula (I) in racemic form, enantiomer form or in any combinations of these forms possessing affinity to somatostatin receptors. In the general formula (I): R1 means phenyl; R2 means hydrogen atom (H) or -(CH2)p-Z3 or one of the following radicals: and Z3 means (C3-C8)-cycloalkyl, possibly substituted carbocyclic or heterocyclic aryl wherein carbocyclic aryl is chosen from phenyl, naphthyl and fluorenyl being it can be substituted, and heterocyclic aryl is chosen from indolyl, thienyl, thiazolyl, carbazolyl, or radicals of the formulae and and it can be substituted with one or some substitutes, or also radical of the formula: R4 means -(CH2)p-Z4 or wherein Z4 means amino-group, (C1-C12)-alkyl, (C3-C8)-cycloalkyl substituted with -CH2-NH-C(O)O-(C1-C6)-alkyl, radical (C1-C6)-alkylamino-, N,N-di-(C1-C12)-alkylamino-, amino-(C3-C6)-cycloalkyl, amino-(C1-C6)-alkyl-(C3-C6)-cycloalkyl-(C1-C6)-alkyl, (C1-C12)-alkoxy-, (C1-C12)-alkenyl, -NH-C(O)O-(C1-C6)-alkyl, possibly substituted carbocyclic or heterocyclic aryl; p = 0 or a whole number from 1 to 6 if it presents; q = a whole number from 1 to 5 if it presents; X means oxygen (O) or sulfur (S) atom n = 0 or 1. Also, invention relates to methods for preparing compounds of the general formula (I), intermediate compounds and a pharmaceutical composition. Proposed compounds can be used in treatment of pathological states or diseases, for example, acromegaly, hypophysis adenomas, Cushing's syndrome and others.

EFFECT: improved preparing method, valuable medicinal properties of compounds and composition.

11 cl, 2 tbl

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention describes derivatives of substituted triazoldiamine of the formula (I): wherein R1 represents (C1-C4)-alkyl, phenyl possibly substituted with halogen atom, amino-group substituted with -SO2-(C1-C4)-alkyl, imidazolyl, 1,2,4-triazolyl, imidazolidinone, dioxidoisothiazolidinyl, (C1-C4)-alkylpiperazinyl, residue -SO2- substituted with amino-group, (C1-C4)-alkylamino-group, (C1-C4)-dialkylamino-group, pyridinylamino-group, piperidinyl, hydroxyl or (C1-C4)-dialkylamino-(C1-C3)-alkylamino-group; R2 represents hydrogen atom (H); or R1 represents H and R2 means phenyl possibly substituted with halogen atom or -SO2-NH2; X represents -C(O)-, -C(S)- or -SO2-;R3 represents phenyl optionally substituted with 1-3 substitutes comprising halogen atom and nitro-group or 1-2 substitutes comprising (C1-C4)-alkoxy-group, hydroxy-(C1-C4)-alkyl, amino-group or (C1-C4)-alkyl possibly substituted with 1-3 halogen atoms by terminal carbon atom; (C3-C7)-cycloalkyl possibly substituted with 1-2 groups of (C1-C4)-alkyl; thienyl possibly substituted with halogen atom, (C1-C4)-alkyl that is substituted possibly with -CO2-(C1-C4)-alkyl, (C2-C4)-alkenyl that is substituted possibly with -CO2-(C1-C4)-alkyl, (C1-C4)-alkoxy-group, pyrrolyl, pyridinyl or amino-group substituted with -C(O)-C1-C4)-alkyl; (C1-C4)-alkyl substituted with thienyl or phenyl substituted with halogen atom; (C2-C8)-alkynyl substituted with phenyl; amino-group substituted with halogen-substituted phenyl; furyl, isoxazolyl, pyridinyl, dehydrobenzothienyl, thiazolyl or thiadiazolyl wherein thiazolyl and thiadiazolyl are substituted possibly with (C1-C4)-alkyl; to their pharmaceutically acceptable salts, a pharmaceutical composition based on thereof and a method for its preparing. New compounds possess selective inhibitory effect on activity of cyclin-dependent kinases and can be used in treatment of tumor diseases.

EFFECT: improved preparing method, valuable medicinal and biochemical properties of compounds and composition.

16 cl, 3 tbl, 26 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel biologically active compounds that act as agonists of arginine-vasopressin V2-receptors. Invention describes a derivative of 4,4-difluoro-1,2,3,4-tetrahydro-5H-benzazepine represented by the general formula (I): or its pharmaceutically acceptable salt wherein symbols have the following values: R1 represents -OH, -O-lower alkyl or optionally substituted amino-group; R2 represents lower alkyl that can be substituted with one or more halogen atoms, or halogen atom; among R3 and R4 one of them represents -H, lower alkyl or halogen atom, and another represents optionally substituted nonaromatic cyclic amino-group, or optionally substituted aromatic cyclic amino-group; R5 represents -H, lower alkyl or halogen atom. Also, invention describes a pharmaceutical composition representing agonist of arginine-vasopressin V2-receptors. Invention provides preparing new compounds possessing with useful biological properties.

EFFECT: valuable medicinal properties of compound and composition.

9 cl, 18 tbl, 13 ex

FIELD: organic chemistry, medicine, virology.

SUBSTANCE: invention relates to new derivatives of piperidine of the general formula (II): or their pharmaceutically acceptable salts wherein Xa means -C(R13)2-, -C(R13)(R19)-, -C(O)-, and others; Ra means R6a-phenyl or phenyl substituted with methylsulfonyl; R1 means hydrogen atom or (C1-C6)-alkyl; R2 means R7-, R8-, R9-phenyl wherein R7-, R8 and R9 mean substituted 6-membered heteroaryl and others; R3 means R10-phenyl, pyridyl and others; R4 means hydrogen atom, (C1-C6)-alkyl, fluoro-(C1-C6)-alkyl; R6a means from 1 to 3 substitutes taken among the group involving hydrogen, halogen atom, -CF3 and CF3O-; R7 and R8 mean (C1-C6)-alkyl and others; R9 means R7, hydrogen atom, phenyl and others; R10 means (C1-C6)-alkyl, -NH2 or R12-phenyl wherein R12 means hydrogen atom, (C1-C6)-alkyl and others; R13, R14, R15 and R16 mean hydrogen atom or (C1-C6)-alkyl; R17 and R18 in common with carbon atom to which they are bound form spirane ring comprising from 3 to 6 carbon atoms; R19 means R6-phenyl wherein R6 means R6a or methylsulfonyl; R20, R21 and R22 mean hydrogen atom or (C1-C6)-alkyl; R23 means (C1-C6)-alkyl under condition that if Ra means phenyl substituted with methylsulfonyl then Xa can mean the group only. Compounds of the formula (II) possess properties of CCR5-antagonist and can be used in medicine in treatment of HIV-infection.

EFFECT: improved method for treatment, valuable medicinal properties of compounds and composition.

15 cl, 1 dwg, 12 tbl, 15 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new nitrogen-containing aromatic derivatives of the general formula:

wherein Ag represents (1) group of the formula:

; (2) group represented by the formula:

or ; (3) group represented by the formula:

; Xg represents -O-, -S-, C1-6-alkylene group or -N(Rg3)- (wherein Rg3 represents hydrogen atom); Yg represents optionally substituted C6-14-aryl group, optionally substituted 5-14-membered heterocyclic group including at least one heteroatom, such as nitrogen atom or sulfur atom, optionally substituted C1-8-alkyl group; Tg1 means (1) group represented by the following general formula:

; (2) group represented by the following general formula: . Other radical values are given in cl. 1 of the invention claim. Also, invention relates to a medicinal agent, pharmaceutical composition, angiogenesis inhibitor, method for treatment based on these compounds and to using these compounds. Invention provides preparing new compounds and medicinal agents based on thereof in aims for prophylaxis or treatment of diseases wherein inhibition of angiogenesis is effective.

EFFECT: improved treatment method, valuable medicinal properties of compounds and agents.

40 cl, 51 tbl, 741 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to novel coumarone derivatives of the general formula (1): wherein two OH-substitutes in phenyl moiety are in ortho-position with respect to one to another; R1 is in ortho-position with respect to one hydroxyl group; X means oxygen atom (O); R1 represents -NO2; R2 represents hydrogen atom or (C1-C6)-alkyl; R3 means -(Y)n-(B)m-COOH or -(Y)n-(B)m-R8 wherein m = 0 or 1; n = 0; Y represents -CO-; B represents (C1-C6)-alkylene; R8 represents phenyl or 5- or 6-membered heterocycle with one-four heteroatoms chosen from nitrogen atom (N) wherein indicated phenyl is substituted optionally with one substitute chosen from halogen atom, -NO2 or (C1-C6)-alkyl; or R2 and R3 form in common -(CH2)r- wherein r = 3, 4 or 5; R4 and R5 form in common -O; R6 means hydrogen atom (H), or to their pharmaceutically acceptable salts or pharmaceutically acceptable esters that are inhibitors of enzyme - catechol O-methyltransferase (COMT). Invention provides preparing novel coumarone derivatives possessing the valuable biologically active effect.

EFFECT: valuable biochemical property of derivatives.

9 cl, 1 tbl, 13 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing 3,4-diaryl(hetaryl)maleimides of the formula (I): wherein R means (C1-C4)-alkyl or benzyl, or phenyl; R1 means bromine atom (Br) or aryl, such as phenyl or naphthyl substituted with alkyl, alkoxy-group or halogen atom; unsubstituted hetaryl or substituted, such as thienyl-, benzothienyl-, furyl-, benzofuryl-, pyrrolyl or indolyl- wherein substitutes represent alkyl, alkoxy-, alkylthio-group, halogen atom or trifluoromethyl group; Ar means aryl, such as phenyl or naphthyl substituted with alkyl, alkoxy-group or halogen atom; unsubstituted hetaryl or substituted, such as thienyl-, benzothienyl-, furyl-, benzofuryl-, pyrrolyl or indolyl- wherein substitutes represent alkyl, alkoxy-, alkylthio-group, halogen atom or trifluoromethyl group with exception for 3,4-di-(2,5-dimethyl-3-thienyl)-1-butylmaleimide. Method involves interaction of aryl(hetaryl)boronic acid of the formula: ArB(OH)2 wherein Ar has abovementioned values with N-substituted 3,4-dibromomaleimide of the formula (III): or N-substituted 3-bromo-4-aryl(hetaryl)maleimide of the formula (IV) wherein R and Ar have abovementioned values and with using palladium catalyst in the presence of base in organic solvent medium. Also, invention to some new derivatives of 3,4-diaryl(hetaryl)maleimides that show photochrome properties.

EFFECT: improved preparing method.

7 cl, 2 dwg, 14 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes phenylpyridazine compounds represented by the following formula (I): wherein R1 represents unsubstituted or substituted phenyl wherein substitutes are taken among the group comprising halogen atom, lower alkyl, lower alkoxy-group and phenylthio-group, or pyridyl; R2 represents lower alkoxy-group, lower alkylthio-group, lower alkylsulfinyl or lower alkylsolfonyl; R3 represents hydrogen atom or lower alkoxy-group; or R2 and R3 can be condensed in common forming lower alkylenedioxy-group; R4 represents cyano-group, carboxyl, unsubstituted or substituted lower alkyl wherein substitutes are taken among the group comprising hydroxyl, carboxyl and N-hydroxy-N-lower alkylaminocarbonyl; lower alkenyl; lower alkylthio-group; lower alkylsulfinyl; lower alkylsulfonyl; lower alkylsulfonyloxy; unsubstituted or substituted phenoxy-group wherein substitutes are taken among the group comprising halogen atom, lower alkoxy-, nitro-, cyano-group; unsubstituted phenylthio-group or phenylthio-group substituted with halogen atom; pyridyloxy-; morpholino-group; morpholinylcarbonyl; 1-piperazinylcarbonyl substituted with lower alkyl; unsubstituted or substituted amino-group wherein substitutes are taken among the group comprising lower alkyl, benzyl, phenyl that can be substituted with halogen atoms or lower alkoxy-groups, and n = 0, or their salts. Proposed compounds possess the excellent inhibitory activity against biosynthesis of interleukin-1β and can be used in preparing a medicinal agent inhibiting biosynthesis of interleukin-1β, in particular, in treatment and prophylaxis of such diseases as diseases of immune system, inflammatory diseases and ischemic diseases. Also, invention proposes intermediate compounds for preparing compounds of the formula (I). Except for, invention proposes a medicinal agent and pharmaceutical composition that inhibit biosynthesis of interleukin-1β and inhibitor of biosynthesis of interleukin-1β.

EFFECT: valuable medicinal properties of compounds and composition.

7 cl, 1 tbl, 66 ex

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention relates to a method for preparing 5-(1-piperazinyl)-benzofuran-2-carboxamide. Method involves reaction of bromosalicylic aldehyde with compound of the formula (I): L-CH2-COOR1 (I) wherein L represents Cl, Br or J atoms, or reactive esterified group -OH; R1 means (C1-C6)-alkyl or benzyl followed by reaction with formamide to yield 5-L-benzofuran-2-carboxamide (II) and the following its amination with R2-piperazine wherein R2 represents hydrogen atom (H) or amino-protecting group in the presence of a catalyst based on transient metals; in case if R2 is not H then R2 is removed, and/or prepared 5-(1-piperazinyl)-benzofuran-2-carboxamide is converted to one of its salts by treatment with acid. Except for, the invention proposes two additional methods for preparing 5-(1-piperazinyl)-benzofuran-2-carboxamide and intermediate compounds of the formula (V): wherein R2 represents H or amino-protected group; R3 means H or -CH2R6; R4 and R5 in common represent carbonyl; R6 means -CN, -COOH, -COOR7 or -CONH2; R7 means (C1-C6)-alkyl, and also their salts and solvates. Invention provides a new method for preparing the valuable intermediate compound used in preparing pharmaceutical preparations and increase of the yield of the end compound.

EFFECT: improved preparing methods.

6 cl, 10 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of urea of the formula (I): wherein A means heteroaryl that is taken among the group that comprises: and wherein radicals B, R1 and R2 have values given in description. These compound possess capacity to inhibit activity of enzyme RAF kinase and to inhibit growth of tumor cells. Also, invention relates to a method for inhibition of activity of RAF kinase in mammal body and to pharmaceutical compositions based on compounds of the formula (I). Invention provides preparing new derivatives of urea possessing valuable pharmaceutical properties.

EFFECT: improved method for inhibition, valuable properties of compounds and composition.

25 cl, 6 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of pyrazine of the general formula (I):

wherein R1 means hydrogen (H) or halogen atom; R2, R3 and R5 mean hydrogen atom (H); R4 and R6 mean hydroxy-group optionally protected with acetyl or benzoyl group; A means oxygen atom (O); n = 0; Y means oxygen atom (O), or their salts. Compounds show the excellent anti-viral activity and useful as a therapeutic agent in treatment of viral infections. Also, invention describes a pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds and composition.

7 cl, 2 tbl, 15 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to new stable crystalline forms of derivative of pyrimidine nucleoside of the formula (I) eliciting the excellent anti-tumor activity. Also, invention relates to pharmaceutical composition eliciting an anti-tumor effect, applying crystalline form for preparing medicinal agent and to a method for prophylaxis or treatment of tumor diseases.

EFFECT: improved method for prophylaxis and treatment, valuable medicinal properties of derivative.

10 cl, 2 tbl, 4 dwg, 9 ex

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: 5-aryl-1H-1,2,4-triazole derivatives of general formula I

, pharmaceutically acceptable salts thereof or pharmaceutical composition containing the same are described. In formula R1 is C1-C6-alkyl, C1-C6-haloalkyl or phenyl; R2 is C3-C8-cycloalkyl; phenyl optionally substituted with one or more substituents selected from C1-C4-alkyl; halogen, hydroxyl, C1-C4-alkoxy, nitro, di-(C1-C4)-alkylamino, C1-C4-alkylsulphonyl, C1-C4- alkylsulphonylamino, and methylenedioxy; phenyl-(C1-C4)-alkyl, wherein phenyl is substituted with C1-C4-alkoxy; or pyridil. New compounds are effective and selective cyclooxygenase-2 (COX-2) inhibitors and useful in treatment of inflammations.

EFFECT: new compounds for inflammation treatment.

10 cl, 36 ex, 1 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of 1-arenesulfonyl-2-arylpyrrolidine and piperidine of the formula (I):

wherein R1 means hydrogen atom (H), (C1-C7)-alkyl; R2 means furyl, thienyl, pyridyl or phenyl optionally substituted with 1-3 substitutes taken among (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom, cyano-group, CF3 or -N(R4)2; R3 means naphthyl or phenyl optionally substituted with 1-3 substitutes taken among (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom, acetyl, cyano-group, hydroxy-(C1-C7)-alkyl, -CH2-morpholine-4-yl, (C1-C7)-alkyloxy-(C1-C7)-alkyl, (C1-C7)-alkyl-N(R4)2 or CF3; R4 means independently of one another hydrogen atom (H), (C1-C7)-alkyl with exception for (RS)-2-phenyl-1-(toluene-4-sulfonyl)pyrrolidine, (RS)-1-(toluene-4-sulfonyl)-2-p-tolylpyrrolidine, N-tosyl-cis-3-methyl-2-phenylpyrrolidine, 3-[1-(toluene-4-sulfonyl)pyrrolidine-2-yl]pyridine and N-tosyl-2-(3,4-dimethoxyphenyl)pyrrolidine, and their pharmaceutically acceptable salts also. Compounds of the formula (I) elicit the effect of agonists or antagonists of metabotropic glutamate receptors that allows their using in pharmaceutical agent useful for treatment or prophylaxis of acute and/or chronic neurological disturbances.

EFFECT: valuable medicinal properties of compounds.

9 cl, 1 tbl, 3 sch, 94 ex

FIELD: color-forming compositions and recording material.

SUBSTANCE: claimed composition includes developer containing urea-urethane compound and colorless or light colored leuco dye. Recording material based on this composition also is proposed.

EFFECT: color-forming compositions with improved image conservation ability and increased image intensity.

21 cl, 14 tbl, 153 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention describes a novel method for synthesis of functionally substituted fullerenes of the general formula (I): Method involves interaction of fullerene[60] with 1H-1,2,3-benzotriazol-1-N,N-dimethylmethaneamine in the presence of Cp2TiCl2 as a catalyst in argon atmosphere, in toluene medium, at temperature 140-160°C for 2-4 h. The yield of the end product is 68-89%. Proposed compounds can be used as chelate compounds, sorbents, biologically active compounds and in the development of material with required electronic, magnetic and optical properties.

EFFECT: improved method of synthesis, valuable properties of compounds.

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