Novel compounds as cathepsin inhibitors, pharmaceutical composition based on thereof, their using and method for their preparing

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

SUBSTANCE: invention relates to compounds of the formula (I): wherein both X1 and X2 represent methylene; R3 represents -CR5=CHR6, and R5 and R6 in common with atoms to which R5 and R6 are bound form (C6-C12)-aryl wherein R3 is substituted optionally with 1-5 radicals of the formula: -X4OR9 wherein X4 represents a bond; R9 represents halogen-substituted (C1-C3)-alkyl, and R4 represents -C(O)X5R11 wherein X5 represents a bond, and R11 represents hetero-(C6-C6)-cycloalkyl-(C0-3)-alkyl; X3 represents group of formulae (a) , (b) or (c) wherein n = 0, 1 or 2; R20 represents hydrogen atom (H); R21 is chosen from group consisting of H, -C(O)R26, -S(O)2R26 wherein R23 is chosen from H and (C6-C12)-aryl-(C0-C6)-alkyl; R25 is chosen from H, (C6-C12)-aryl-(C0-C6)-alkyl or -X4S(O)2R26 wherein X4 has above given values; R26 is chosen from group consisting of H, (C6-C12)-aryl-(C0-C6)-alkyl; wherein X3 comprises optionally, except for, one substitute that being in alicyclic or in aromatic ring system represents a radical chosen independently from group consisting of -X6OR17 wherein R17 represents H, (C1-C6)-alkyl, and X represents a bond or (C1-C6)-alkylene; and its N-oxide derivatives, protected derivatives, individual isomers and mixtures of these isomers; and pharmaceutically acceptable salts and solvated of such compounds, its N- oxide derivatives, protected derivatives, individual isomers and mixtures of these isomers. Also, invention describes a pharmaceutical composition possessing inhibitory activity with respect to cathepsin S-proteases based on compounds of the formula (I), and compound of the formula (Ix) given in the invention description. Invention provides preparing novel compounds possessing useful biological properties.

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

16 cl, 3 tbl, 17 ex

 

This application is based on and claims priority on provisional application U.S. S.N. 60/322318, filed September 14, 2001 and is incorporated in this description by reference.

This application relates to compounds and compositions for treatment of diseases associated with the activity cysteinate, in particular, diseases associated with the activity of cathepsin S.

Cysteinate are a class of peptidases, characterized by the presence of a cysteine residue in the catalytic center of the enzyme. Cysteinate associated with normal decomposition and protein processing. However, aberrant activity of cysteinate, for example, increased expression or increased activation may have pathological consequences. In this regard, some cysteinate associated with a number of painful conditions, including arthritis, muscular dystrophy, inflammation, tumor formation, glomerulonephritis, malaria, periodontia disease, the metachromatic leukodystrophy and others. The increased activity of cathepsin S contributes to the pathology and/or symptomology of diseases. Accordingly, molecules that inhibit the activity of cathepsin S protease, are useful as therapeutic agents in the treatment of such diseases.

This application relates to compounds of the formula

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where:

X1and X2both represent methylene or X1is ethylene and X2represents the relationship;

R3represents-CR5=CHR6, -CR5(CR63)2or-CR7=NR8where R5is hydrogen and R6represents hydrogen, or (C1-4)alkyl, or R5and R6together with the atoms to which are attached R5and R6form (C3-12)cycloalkenyl, hetero(C5-12)cycloalkenyl, (C6-12)aryl, hetero(C6-12)aryl, (C9-12)bicycloalkyl or hetero(C8-12)bicycloalkyl, and R7and R8together with the atoms to which are attached R7and R8form a hetero(C5-12)cycloalkenyl, hetero(C6-12)aryl or hetero(C8-12)bicycloalkyl, where R3optionally substituted by 1 to 5 radicals independently selected from the group consisting of (C1-4)alkyl, cyano, halogen, halogen-substituted C1-4)alkyl, nitro, -X4NR9R9, -X4OR9, -X4SR9, -X4C(O)NR9R9, -X4C(O)OR9, -X4S(O)R10, -X4S(O)2R10and-X4C(O)R10where X4represents a bond or (C1-2)alkylene, R9in each case independently represents hydrogen, C1-3)alkyl or halogen-substituted C1-3)alkyl, and R10is (C 1-3)alkyl or halogen-substituted C1-3)alkyl; and

R4represents-C(O)X5R11or-S(O)2X5R11where X5represents a bond, -O - or-NR12-where R12represents hydrogen or (C1-6)alkyl, and R11is

(i) (C1-6)alkyl, optionally substituted-OR13, -SR13, -S(O)R13, -S(O)2R13, -C(O)R13, -C(O)OR13, -C(O)NR13R14, -NR13R14, -NR14C(O)R13, -NR14C(O)OR13, -NR14C(O)NR13R14or-NR14C(NR14)NR13R14where R13is (C3-12)cycloalkyl(C0-3)alkyl, hetero(C5-12)cycloalkyl(C0-3)alkyl, (C6-12)aryl(C0-3)alkyl, hetero(C5-12)aryl(C0-3)alkyl, (C9-12)bicycloalkyl(C0-3)alkyl or hetero(C8-12)bicycloalkyl(C0-3)alkyl, and R14in each case independently represents hydrogen or (C1-6)alkyl, or

(ii) (C3-12)cycloalkyl(C0-3)alkyl, hetero(C5-12)cycloalkyl(C0-3)alkyl, (C6-12)aryl(C0-3)alkyl, hetero(C5-12)aryl(C0-3)alkyl, (C9-12)bicycloalkyl(C0-3)alkyl or hetero(C8-12)bicycloalkyl(C0-3)alkyl, or

(iii) (C3-6)cycloalkyl(C0-3)alkyl,

hetero(C5-6)cycloalkyl(C0-3)alkyl, phenyl(C0-3)alkyl, or

hetero(C5-6)and the sludge(C 0-3)alkyl, substituted-X6OR15, -X6SR15, -X6S(O)R15, -X6S(O)2R15, -X6C(O)R15, -X6C(O)OR15, -X6C(O)NR15R16, -X6NR15R16, -X6NR16C(O)R15, -X6NR16C(O)OR15, -X6NR16C(O)NR15R16, -X6NR16C(O)OR16, -X6NR16(NR16)NR15R16where X6represents a bond or methylene,

R15is (C3-6)cycloalkyl(C0-3)alkyl,

hetero(C5-6)cycloalkyl(C0-3)alkyl, phenyl(C0-3)alkyl, or

hetero(C5-6)aryl(C0-3)alkyl,

and R16represents hydrogen or (C1-6)alkyl; where R4optionally contains, in addition, 1-5 substituents which, while in the alicyclic or aromatic ring system are radicals independently selected from the group consisting of (C1-6)alkyl, (C1-6)alkylidene, cyano, halogen, nitro, halogen-substituted C1-3)alkyl, -X6NR17R17, -X6NR17C(O)OR17, -X6NR17C(O)NR17R17, -X6NR17(NR17)NR17R17, -X6OR17, -X6SR17, -X6C(O)OR17, -X6C(O)NR17R17, -X6S(O)2NR17R17, -X6P(O)(OR18 17, -X6The OP(O)(OR18OR17, -X6NR17C(O)R18, -X6S(O)R18, -X6S(O)2R18and-X6C(O)R18and, being in the aliphatic fragment, are radicals independently selected from the group consisting of cyano, halogen, nitro, -NR17R17, -NR17C(O)OR17, -NR17C(O)NR17R17, -NR17C(NR17)NR17R17, -OR17, -SR17, -C(O)OR17, -C(O)NR17R17, -S(O)2NR17R17, -P(O)(OR17OR17, -OP(O)(OR17OR17, -NR17C(O)R18, -S(O)R18, -S(O)2R18and-C(O)R18where X6represents a bond or (C1-6)alkylene, R17in each case independently represents hydrogen, C1-6)alkyl or halogen-substituted C1-3)alkyl and R18is (C1-6)alkyl or halogen-substituted C1-3)alkyl;

X3represents a group of formula (a), (b), (c), (d), (e), (f), (g) or (h):

== represents a simple bond or double bond;

X7represents aryl, heteroaryl or NR20R25;

n represents 0, 1 or 2;

R20selected from the group consisting of hydrogen, (C1-6)alkyl, (C3-12)cycloalkyl(C0-6)alkyl, hetero(C5-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl and hetero(C5-12)aryl(C 0-6)alkyl;

R21selected from the group consisting of hydrogen, (C1-9)alkyl, (C3-12)cycloalkyl(C0-6)alkyl, hetero(C5-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl, hetero(C5-12)aryl(C0-6)alkyl, (C9-12)bicycloalkyl(C0-3)alkyl, hetero(C8-12)bicycloalkyl(C0-3)alkyl, -C(O)R26, -C(S)R26, -S(O)2R26, -C(O)OR26, -C(O)N(R26R27, -C(S)N(R26R27and-S(O)2N(R27R26;

R23selected from H, (C1-6)alkyl, (C4-6)alkenyl, (C3-12)cycloalkyl(C0-6)alkyl, hetero(C5-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl or hetero(C5-12)aryl(C0-6)alkyl, optionally substituted amino, -NHC(O)R15or-R15where R15has the above values;

R25selected from hydrogen, (C1-6)alkyl, (C3-12)cycloalkyl(C0-6)alkyl, hetero(C5-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl, hetero(C5-13)aryl(C0-6)alkyl, -X4Other15, -X4S(O)2Other26or-X4C(O)R17NR17C(O)R17where R15, R17and X4have the above values;

R26selected from the group consisting of hydrogen, (C1-6)alkyl,

(C3-12)cycloalkyl(C0-6)alkyl, hetero(C5-12)cyclo is lcil(C 0-6)alkyl,

(C6-12)aryl(C0-6)alkyl, hetero(C5-12)aryl(C0-6)alkyl,

(C9-12)bicycloalkyl(C0-3)alkyl and

hetero(C8-12)bicycloalkyl(C0-3)alkyl;

R27represents hydrogen, (C1-6)alkyl, (C3-12)cycloalkyl(C0-6)alkyl, hetero(C5-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl or hetero(C5-12)aryl(C0-6)alkyl;

R28is R20or-O-C(=O)-R29;

R29is (C1-6)alkyl, (C3-12)cycloalkyl(C0-6)alkyl, hetero(C5-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-3)alkyl, hetero(C5-12)aryl(C0-3)alkyl, (C9-12)bicycloalkyl(C0-3)alkyl or hetero(C8-12)bicycloalkyl(C0-3)alkyl;

where X3optionally contains, in addition, 1-5 substituents which, while in the alicyclic or aromatic ring system are radicals independently selected from the group consisting of (C1-6)alkyl, (C1-6)alkylidene, cyano, halogen, nitro, halogen-substituted C1-3)alkyl, -X6NR17R17, -X6NR17C(O)OR17, -X6NR17C(O)NR17R17, -X6NR17(NR17)NR17R17, -X6OR17, -X6C(O)R17, -X6OR15, -X6SR17, -X6C(O)OR7 , -X6C(O)NR17R17, -X6S(O)2NR17R17, -X6P(O)(OR8OR17, -X6The OP(O)(OR8OR17, -X6NR17C(O)R18, -X6S(O)R18, -X6S(O)2R18and-X6C(O)R18and, being in the aliphatic fragment, are radicals independently selected from the group consisting of cyano, halogen, nitro, -NR17R17, -NR17C(O)OR17, -NR17C(O)NR17R17, -NR17C(NR17)NR17R17, -OR17, -SR17, -C(O)OR17, -C(O)NR17R17, -S(O)2NR17R17, -P(O)(OR17OR17, -OP(O)(OR17OR17, -NR17C(O)R18, -S(O)R18, -S(O)2R18and-C(O)R18where R15, R17, R18and X6have the above values.

The second aspect of the present invention is a pharmaceutical composition which contains a compound of formula I or its N-oxide derivative, individual isomers or a mixture of these isomers, or pharmaceutically acceptable salt, in a mixture with one or more of suitable excipients.

The third aspect of the present invention is a method of treating disease in an animal in which inhibition of cathepsin S may prevent, suppress or alleviate the pathology and/or symptoms of the disease, and specified ways which includes an introduction to the animal a therapeutically effective amount of the compounds of formula I or its N-oxide derivative, individual isomer or mixture of these isomers; or their pharmaceutically acceptable salts.

The fourth aspect of the present invention is a method of obtaining the compounds of formula I and its N-oxide derivatives, proletarienne forms of derivatives, protected derivatives, individual isomers and mixtures of these isomers; and their pharmaceutically acceptable salts.

If not indicated otherwise, the following definitions used in the description and the claims presented for the purposes of this application and have the following values.

The term "alicyclic" refers to the fragment, which is characterized by the arrangement of the carbon atoms contained non-aromatic ring structures having properties resembling the properties of aliphatic structures, and may be saturated or partially unsaturated, containing two or more double or triple bonds.

The term "aliphatic" means a fragment that is characterized by unbranched or branched chain structure consisting of carbon atoms and may be saturated or partially unsaturated, containing two or more double or triple bonds.

The term "alkyl" by itself means an unbranched or branched, saturated or unsaturated, aliphatic radical containing the specified number of carbon atoms (e.g the measures (C1-6)alkyl includes methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, vinyl, allyl, 1-propenyl, Isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylallyl, ethinyl, 1-PROPYNYL, 2-PROPYNYL and the like). Alkyl, presents along with other radicals (e.g., as arylalkyl), means an unbranched or branched, saturated or unsaturated aliphatic divalent radical containing the specified number of atoms, or in the absence of atoms means the communication (for example, (C1-6)aryl(C0-3)alkyl includes phenyl, benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl etc).

The term "alkylene", unless otherwise specified, means an unbranched or branched, saturated or unsaturated, divalent aliphatic radical containing the specified number of carbon atoms (for example, (C1-6)alkylene includes methylene(-CH2-), ethylene (-CH2CH2-), trimethylene (-CH2CH2CH2-), tetramethylene (-CH2CH2CH2CH2-), 2-butylen (-CH2CH=CHCH2-), 2-methyltyramine (-CH2CH(CH3)CH2CH2-), pentamethylene (-CH2CH2CH2CH2CH2-and so on).

The term "alkylidene" means an unbranched or branched, saturated or unsaturated, divalent aliphatic radical containing the specified number of carbon atoms (n is an example, (C1-6)alkylidene includes methylene (=CH2), ethylidene (=CHCH3), isopropylidene (=C(CH3)2), propylidene (=CHCH2CH3), allride (=CH-CH=CH2and so on).

The term "amino" means a radical-NH2. If not indicated otherwise, the compounds of the present invention containing Minerageny include their protected derivatives. Suitable protective groups for aminopimelic include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl etc.

The term "animal" includes humans, non-humans mammals (e.g. dogs, cats, rabbits, cattle, horses, sheep, goats, pigs, deer etc) and not mammals (e.g., birds and so on).

The term "aromatic" means a fragment, where its constituent atoms form an unsaturated ring system, and all the atoms in the ring system are in sp2hybridization and the total number of PI electrons is 4n+2.

The term "aryl" means a monocyclic or condensed bicyclic ring system containing a specified total number of ring carbon atoms, where each ring comprises 6 carbon atoms and a is an aromatic or if condensed with the second ring, forms an aromatic ring system. For example, optionally substituted (C6-10)aryl, as used herein, includes, but is only limited by them, biphenyl-2-yl, 2-bromophenyl, 2-bankability, 2-Brompton-5-forfinal, 4-tert-butylphenyl, 4-carbamoylethyl, 4-carboxy-2-nitrophenyl, 2-chlorophenyl, 4-chlorophenyl, 3-chlorocarbonyl, 4-chlorocarbonyl, 2-chloro-4-forfinal, 2-chloro-6-forfinal, 4-chloro-2-nitrophenyl, 6-chloro-2-nitrophenyl, 2,6-dibromophenyl, 2,3-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 2-deformational, 3, 5dimethylphenyl, 2-ethoxycarbonylphenyl, 2-forfinal, 2-iodophenyl, 4-isopropylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-were, 3-were, 4-were, 5-methyl-2-nitrophenyl, 4-methylsulfinylphenyl, naphthas-2-yl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2,3,4,5,6-pentafluorophenyl, phenyl, 2-trifloromethyl, 3-trifloromethyl, 4-trifloromethyl, 2-triptoreline, 3-triptoreline, 4-triptoreline, 2-triftormetilfullerenov, 4-triftormetilfullerenov etc. Optionally substituted C6-10)aryl as used in this description, includes 3-acetylphenyl, 3-tert-butoxycarbonylmethylene, biphenyl-4-yl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-methoxyphenyl, naphthas-2-yl, 3-phenoxyphenyl, phenyl, etc.

The term "bicycloalkyl" means a bicyclic ring system containing a specified number of carbon atoms in the ring, where the rings are linked by a simple relationship or condensed, and at least one of the rings forming the ring system is aromatic is practical, and any carbocyclic ketone, thioketone or aminoketone derived (for example, (C9-10)bicycloalkyl includes cyclohexylphenol, 1,2-dihydronaphtho, 2,4-dioxo-1,2,3,4-tetrahydronaphthyl, indanyl, indenyl, 1,2,3,4-tetrahydronaphthyl etc).

The term "carbarnoyl" means the radical-C(O)NH2-. If not indicated otherwise, the compounds of the present invention containing carbamoyl fragments include their protected derivatives. Suitable protective groups for carbamoyl fragments include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl etc. as unprotected and protected derivatives included in the scope of the present invention.

The term "derived carbocyclic ketone" means derivative containing fragment-C(O)-.

The term "carboxy" means the radical-C(O)OH. If not indicated otherwise, the compounds of the present invention containing carboxyphenyl include their protected derivatives. Suitable protective groups for carboxyterminal include benzyl, tert-butyl, etc.

The term "cycloalkyl" means a saturated or partially unsaturated, monocyclic, condensed bicyclic or bridged polycyclic ring system, containing a specified number of ring carbon atoms, and any carbocyclic ketone, thioketone or aminoketone derived (for example, (Csub> 3-10)cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl, bicyclo[2.2.2]octyl, adamantane-1-yl, decahydronaphthalene, oxocyclohexyl, chlorides, thiacyclohexane, 2-oxobicyclo[2.2.1]hept-1-yl and the like).

The term "cycloalkyl" means a divalent saturated or partially unsaturated monocyclic ring or bridged polycyclic ring system, containing a specified number of ring carbon atoms, and any carbocyclic ketone, thioketone or aminoketone derived. Examples of when R1and R2together with the carbon atom to which are attached both R1and R2form (C3-8)cycloalkyl, includes, but is not limited to, the following:

The term "disease" specifically includes any unhealthy condition of an animal or its agencies and includes a painful condition that can be caused or which is the result of medical or veterinary treatment are taken in respect of the animal, i.e. the "side effects" of such treatment.

The term "halogen" means fluorine, chlorine, bromine or iodine.

The term "halogen-substituted alkyl"as a group or part of a larger group, refers to "alkyl"substituted with one or more atoms of halogen-free", where the availa able scientific C with the as that term is defined in this description. Halogensubstituted alkali include halogenated, dehalogenases, trihalomethyl, perhalogenated and the like (for example, halogen-substituted C1-3)alkyl includes chloromethyl, dichloromethyl, deformity, trifluoromethyl, 2,2,2-triptorelin, perforated, 2,2,2-Cryptor-1,1-dichloroethyl etc).

The term "hetero-atomic fragment" includes-N=, -NR-, -N+(O)=, -O-, -S - or-S(O)2-where R is hydrogen, (C1-6)alkyl or a protective group.

The term "heterocyclochain" means cycloalkyl, as defined herein, provided that one or more of these ring carbon atoms is replaced by a heteroatomic fragment selected from-N=, -NR-, -O-, -S - or-S(O)2-where R is hydrogen or C1-6)alkyl. Examples of when R1and R2together with the carbon atom to which are attached both R1and R2form a hetero(C3-8)cycloalkyl include, but are not limited to, the following:

where R is hydrogen, (C1-6)alkyl or a protective group.

The term "heteroaryl" means aryl, as defined herein, provided that one or more of these ring carbon atoms is replaced by a heteroatomic fragment selected from-N=, -NR-, -N+(O-)=, -O - or-S-, where R is adored, (C1-6)alkyl, a protective group or represents a free valency, which serves as a connection point to the ring nitrogen, and each ring contains 5 or 6 ring atoms. For example, optionally substituted hetero - (C5-13)aryl, in the sense as used herein, includes, but is not limited to, 4-amino-2-hydroxypyrimidine-5-yl, dibenzofuran, benzothiazol-2-yl, 1H-benzoimidazol-2-yl, 2-pampered-5-yl, 5-pampered-2-yl, 4-carbamoylmethyl-2-yl, 3-carboxyphenyl-4-yl, 5-carboxy-2,6-dimethylpyridin-3-yl, 3,5-dimethylisoxazol-4-yl, 5-ethoxy-2,6-dimethylpyridin-3-yl, 5-fluoro-6-hydroxypyrimidine-4-yl, FSD-2-yl, FSD-3-yl, 5-hydroxy-4,6-dimethylpyridin-3-yl, 8-hydroxy-5,7-dimethylindoline-2-yl, 5-hydroxymethylimidazole-3-yl, 3-hydroxy-6-methylpiperid-2-yl, 3-gidroksipinan-2-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, 1H-indol-3-yl, isothiazol-4-yl, isoxazol-4-yl, 2-methylfur-3-yl, 5-methylfur-2-yl, 1-methyl-1H-imidazol-2-yl, 5-methyl-3H-imidazol-4-yl, 5-methylisoxazol-3-yl, 5-methyl-2H-pyrazole-3-yl, 3-methylpiperid-2-yl, 4-methylpiperid-2-yl, 5-methylpiperid-2-yl, 6-methylpiperid-2-yl, 2-methylpiperid-3-yl, 2-methylthiazole-4-yl, 5-nitrapyrin-2-yl, 2H-pyrazole-3-yl, 3H-pyrazole-4-yl, pyridazin-3-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, 5-pyrid-3-yl-2H-[1,2,4]triazole-3-yl, pyrimidine-4-yl, pyrimidine-5-yl, 1H-pyrrol-3-yl, quinoline-2-yl, 1H-tetrazol-5-yl, thiazol-2-yl, thiazol-5-yl, Tien-2-yl, Tien-3-yl, 2H-[1,2,4]-triazole-3-yl, 3H-[1,2,3]Proc. of the azole-4-yl, 5-triptoreline-2-yl and the like, Suitable protective groups include tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, 4-methoxybenzyl, 2-nitrobenzyl etc. Optionally substituted hetero - (C5-10)aryl as defined herein for R4includes benzofur-2-yl, FSD-2-yl, FSD-3-yl, pyrid-3-yl, pyrid-4-yl, China-2-yl, China-3-yl, Tien-2-yl, Tien-3-yl, etc.

The term "heterobinuclear" means bicycloalkyl, as defined herein, provided that one or more of these ring carbon atoms is replaced by a heteroatomic fragment selected from-N=, -NR-, -O - or-S-, where R represents hydrogen, (C1-6)alkyl, a protective group or represents a free valency, which serves as a connection point to the ring nitrogen, and any carbocyclic ketone, thioketone or aminoketone derived. For example, optionally substituted hetero - (C8-10)bicycloalkyl, as used herein, includes, but is not limited to, 2-amino-4-oxo-3,4-dihydropyridin-6-yl, etc. In General, the term heterobinuclear, as used herein, includes, for example, benzo[1,3]dioxol-5-yl,

3,4-dihydro-2H-[1,8]naphthyridines, 3,4-dihydro-2H-chinoline,

2,4-dioxo-3,4-dihydro-2H-hintline,

1,2,3,4,5,6-hexahydro[2,2']bipyridinyl,

3-oxo-2,3-dihydrobenzo[1,4]oxazinyl,

5,6,7,8-tetrahydroquinolin the l etc.

The term "heteroseksualci" means cycloalkyl, as defined herein, provided that one or more of these ring carbon atoms is replaced by a heteroatomic fragment selected from-N=, -NR-, -O - or-S-, where R represents hydrogen, (C1-6)alkyl, a protective group, or represents a free valency, which serves as a connection point to the ring nitrogen, and any carbocyclic ketone, thioketone or aminoketone derived (for example, the term hetero(C5-10)cycloalkyl includes imidazolidinyl, morpholinyl, piperazinil, piperidyl, pyrrolidinyl, pyrrolyl, hinokitiol etc). Suitable protective groups include tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, 4-methoxybenzyl, 2-nitrobenzyl etc. As unprotected and protected derivatives included in the scope of the present invention.

The term "hydroxy" means the radical-OH. If not indicated otherwise, the compounds of the present invention containing hydroxyradicals include its protected derivatives. Suitable protective groups for hydroxy fragments include benzyl, etc.

The term "aminoketone derivative" means a derivative containing fragment-C(NR)-, where R is hydrogen or C1-6)alkyl.

The term "isomer" refers to compounds of formula I, having the same molecular formula, but otlichuy is by nature or sequence of bonding of their atoms, or arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are called stereoisomers". Stereoisomers that are not mirror images of each other are called diastereomers"and stereoisomers that are not imposed by mirror images are called "enantiomers" or sometimes "optical isomers". The carbon atom that is linked to four non-identical substituents, referred to as "chiral center". Compound with one chiral center has two enantiomeric forms of the opposite chirality, and they are called "racemic mixture". A compound that contains more than one chiral center, is 2n-1the enantiomeric pair, where n represents the number of chiral centers. Compounds containing more than one chiral center may exist either as individual diastereomers, or as a mixture of diastereomers, called "diastereomeric mixture". If there is one chiral center, stereoisomer may differ absolute configuration of this chiral center. The absolute configuration refers to the spatial arrangement of the substituents attached to the chiral center. Enantiomers are characterized by the absolute configuration of chiral centers, and describes the rules of R - and S-interleaved mode Kahn, Ingold Etc is log (Cahn, Ingold and Prelog). Rules stereochemical nomenclature, methods for the determination of stereochemistry and the separation of stereoisomers are well-known to specialists in this field (for example, see "Advanced Organic Chemistry", 4th edition, March, Jerry, John Wiley & Sons, New York, 1992). It is clear that the names and illustrations used in this description to define compounds of formula I, imply that they include all possible stereoisomers. For example, assume that the name of [1-(1-benzoyl-4-oxopyrrolidin-3-ylcarbonyl)-2-phenylmethanesulfonyl]amide morpholine-4-carboxylic acid include [S-1-(1-benzoyl-4-oxopyrrolidin-3-ylcarbonyl)-2-phenylmethanesulfonyl]amide morpholine-4-carboxylic acid and [R-1-(1-benzoyl-4-oxopyrrolidin-3-ylcarbonyl)-2-phenylmethanesulfonyl]amide morpholine-4-carboxylic acid and any their mixtures, racemic or not.

The term "derived ketone" means derivative containing fragment-C(O)-. For example, for 2-acetoxyacetyl-3-Il, "derived carbocyclic ketone" should be 2-acetoxy-4-oxoazetidin-3-yl.

The term "nitro" means the radical-NO2.

The term "may" or "optional" means that the described event or circumstances may occur or may not occur, and that the description includes instances where the event or circumstance observed, and cases when they are not viewers who are. For example, the phrase "where R3and R4in any alicyclic or aromatic ring system can be substituted, in addition, 1-5 radicals" means that R3and R4substituted or not, are included in the scope of the present invention.

The term "oxaalkyl" means alkyl as defined above, where one of the specified number of carbon atoms is replaced by a group of oxygen (-O-), for example, oxo(C2-6)alkyl includes methoxymethyl etc.

The term "N-oxide derivatives" means derivatives of compounds of formula I, in which the nitrogen atoms are oxidized state (i.e., O-N) and which possess the desired pharmacological activity.

The term "pathology" of a disease refers to idiopathic natural, induced and developing the disease, but also to structural and functional changes caused by disease.

The term "pharmaceutically acceptable" means that the possibility of use in obtaining pharmaceutical compositions, which are completely safe, non-toxic and is not undesirable neither biological, nor with other points of view, and implies the possibility of application in veterinary medicine, as well as for pharmaceutical applications in medicine.

The term "pharmaceutically acceptable salts" means salts of the compounds of formula I and pharmaceutically p is Jemima, as described above, and which possess the desired pharmacological activity. Such salts include salts accession acids, formed with inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or with organic acids such as acetic acid, propionic acid, hexanoic acid, heptane acid, cyclopentylpropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, ortho(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methansulfonate acid, econsultancy acid, 1,2-ethicality acid, 2-hydroxyethanesulfonic acid, benzolsulfonat acid, parachlorometaxylenol acid, 2-naphthalenesulfonate acid, paratoluenesulfonyl acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]Oct-2-ene-1-carboxylic acid, glucoheptonate acid, 4,4'-Methylenebis(3-hydroxy-2-EN-1-carboxylic acid), 3-phenylpropionate acid, trimethylhexane acid, tert-Butylochka acid, louisanna acid, gluconic acid, Glotova acid, hydroxynaphthoic acid, with the lysiloma acid, stearic acid, Mukanova acid, etc.

Pharmaceutically acceptable salts also include salts of joining bases, which may be formed in the presence of acidic protons, which are capable of reacting with inorganic or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like

The term "prodrug" means a compound that undergoes transformation in vivo as a result of metabolism (e.g., by hydrolysis) to a compound of formula I. for Example, ester compounds of the formula I containing a hydroxy-group, the hydrolysis can be transformed in vivo into a related molecule. Alternative ester compounds of the formula I containing carboxypropyl may develop as a result of hydrolysis in vivo in the preceding molecule. Suitable esters of compounds of formula I containing a hydroxy-group, are for example acetates, citrates, lactates, tartratami, malonate, oxalates, salicylates, propionate, succinate, fumarate, maleate, methylene-bis-b-hydroxynaphthoate, gentisate, isocyanate, departuredate, methansulfonate, atonality is s, benzosulfimide, paratoluenesulfonyl, cyclohexylsulfamate and hinata. Suitable esters of compounds of formula I containing carboxypropyl are, for example, esters described F.J.Leinweber, Drug Metab. Res., 1987, 18, page 379. A particularly useful class of esters of compounds of formula I containing a hydroxy-group, can be formed from acid fragments selected from those described by Bundgaard et al., J. Med. Chem., 1989, 32, page 2503-2507, and include substituted (aminomethyl)benzoate, for example, dialkylaminomethyl, in which the two alkyl groups may be combined together and/or may be interrupted by oxygen atom or optionally substituted nitrogen atom, for example, alkilirovanny a nitrogen atom, more preferably (morpholinomethyl)benzoate, for example, 3 - or 4-(morpholinomethyl)benzoate, and (4-alkylpiperazine-1-yl)benzoate, for example, 3 - or 4-(4-alkylpiperazine-1-yl)benzoate.

The term "protected derivatives" means derivatives of compounds of formula I, in which a reactive site or sites are blocked by protective groups. Protected derivatives of compounds of formula I useful for obtaining the compounds of formula I or they can be active inhibitors of cathepsin S. a Comprehensive list of suitable protective groups can be found in T.W. Greene, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc. 1999.

The term "Ter piticescu effective amount" means such amount, which, being introduced to an animal for treating a disease, is sufficient for the exercise of such treatment.

The term "thioketone derivative" means a derivative containing fragment-C(S).

The term "treatment" or "treating" means any introduction of the compounds of the present invention and includes:

(1) the prevention of the disease in an animal that may be predisposed to this disease, but still does not feel or don't display the pathology or symptomatology of this disease,

(2) inhibiting the disease in an animal that is experiencing or is the pathology or symptoms of such disease (i.e., stop further development of the pathology and/or symptomatic), or

(3) facilitation of the disease in an animal that is experiencing or is the pathology or symptomatology of this disease (i.e., the weakening of the pathology and/or symptomatology).

The compounds of formula I, the intermediate and source materials used for their production, are named in accordance with IUPAC rules of nomenclature, where the characteristic groups have decreasing priority for citation as principal group, in the following order: acids, esters, amides, etc. Alternative, the compounds are named according to AutoNom 4.0 (Beilstein Information Systems, Inc.). For example, the connection form is s I, where R3represents phenyl, R4is morpholine-4-carbonyl and X3is 1-benzoyl-4-oxopyrrolidin-3-ylamino; that is, the compound of the formula:

called [1-(1-benzoyl-4-oxopyrrolidin-3-ylcarbonyl)-2-phenylmethanesulfonyl]amide morpholine-4-carboxylic acid.

Although most broad definitions presented above, some aspects of the present invention is preferable. For example, preferred compounds of formula I, where X1and X2both represent methylene or X1is ethylene, and X2represents a bond; R3represents-CR5=CHR6, -CR5(CR63)2or-CR7=NR8where R5is hydrogen and R6represents hydrogen or (C1-4)alkyl, or R5and R6together with the atoms to which are attached R5and R6form (C3-12)cycloalkenyl, (C6-12)aryl, hetero(C6-12)aryl or (C9-12)bicycloalkyl, and R7and R8together with the atoms to which are attached R7and R8form a hetero(C5-12)cycloalkenyl or hetero(C6-12)aryl, where R3optionally substituted by 1 to 5 radicals independently selected from the group consisting of (C1-4)alkyl, cyano, halogen, halogen-substituted C1-4)alkyl, -X4OR9The-X 4C(O)OR9where X4represents a bond or (C1-2)alkylene, R9in each case independently represents a C1-3)alkyl or halogen-substituted C1-3)alkyl; R4represents-C(O)X5R11or-S(O)2X5R11where X5represents a bond, -O - or-NR12-where R12represents hydrogen or (C1-6)alkyl, and R11is

(i) (C1-6)alkyl, or

(ii) hetero(C5-12)cycloalkyl(C0-3)alkyl, (C6-12)aryl(C0-3)alkyl, hetero(C5-12)aryl(C0-3)alkyl, (C9-12)bicycloalkyl(C0-3)alkyl or hetero(C8-12)bicycloalkyl(C0-3)alkyl, or

(iii) hetero(C5-6)cycloalkyl(C0-3)alkyl, phenyl(C0-3)alkyl, substituted-X6OR15, -X6C(O)R15or-X6NR16C(O)OR16where X6represents a bond or methylene, R15represents phenyl(C0-3)alkyl or hetero(C5-6)aryl(C0-3)alkyl and R16represents hydrogen or (C1-6)alkyl;

where R4optionally contains, in addition, 1-5 substituents which, while in the alicyclic or aromatic ring system are radicals independently selected from the group consisting of (C1-6)alkyl, halogen, -X6NR17R17, -X6OR17, -X6C(O)OR17, -X6NC(O)R16and Xsup> 6C(O)R18; R17in each case independently represents hydrogen, C1-6)alkyl or halogen-substituted C1-3)alkyl and R18is (C1-6)alkyl or halogen-substituted C1-3)alkyl.

In particular, X3represents a group of formula (a), (b) or (c), where n is 0, 1 or 2;

R20selected from the group consisting of hydrogen and (C1-6)alkyl;

R21selected from the group consisting of (C1-9)alkyl, (C6-12)aryl(C0-6)alkyl, -C(O)R26, -S(O)2R26, -C(O)OR26and-C(O)N(R26R27;

R23selected from (C1-6)alkyl, optionally substituted amino, -NHC(O)R15or-R15where R15has the above values;

R25selected from (C1-6)alkyl, (C6-12)aryl(C0-6)alkyl, -X4S(O)2R26or-X4C(O)R17NR17C(O)R17where R17and X4have the above meanings; and

R26selected from the group consisting of (C1-6)alkyl, hetero(C5-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl, hetero(C5-12)aryl(C0-6)alkyl and (C9-12)bicycloalkyl(C0-3)alkyl;

R27is (C1-6)alkyl;

where X3optionally contains, in addition, 1-5 substituents which, while in the alicyclic or aromatic ring system, before which represent radicals, independently selected from the group consisting of (C1-6)alkyl, cyano, halogen, -X6OR17, -X6C(O)R17and-X6OR15.

R3more preferably selected from the group comprising phenyl, pyridin-2-yl, pyridin-3-yl, pyridine-4-yl, vinyl, 2-deformational, 1-oxypyridine-2-yl, 4-methoxyphenyl, 4-were, 2nd were, 4-chlorophenyl, 3, 5dimethylphenyl, 4-triptoreline, 4-trifloromethyl, 2-bromophenyl, naphthalene-2-yl, 3,4-dichlorophenyl, 3-were 3-triptoreline, 3-trifloromethyl, 2,3,4,5,6-pentafluorophenyl, 2-forfinal, 2-chlorophenyl, 2-cyanophenyl, 2-triptoreline, 4-tert-butylphenyl, 3-chlorophenyl, 4-bromophenyl, 2-fluoro-3-chlorophenyl, 2-fluoro-3-were 3-forfinal, 2.5-differenl, 3-bromophenyl, 2,5-dichlorophenyl, 2,6-differenl, 3-cyanophenyl, 4-cyanophenyl, 2-trifloromethyl, 2,3-differenl, biphenyl, 2-bromo-5-forfinal, 4-forfinal, 3,4-differenl, 2,4-differenl, 2,4,6-tryptophanyl, 2,4,5-tryptophanyl, 2,3,4-tryptophanyl, 2-chloro-5-triptoreline, 2,4-bistrifluormethylbenzene, 2,5,6-tryptophanyl, 2-fluoro-3-triptoreline, 2-fluoro-4-triptoreline, 2-fluoro-5-triptoreline, 2,3,5-tryptophanyl, 2-fluoro-5-triptoreline, 5-fluoro-2-triptoreline, 4-fluoro-3-triptoreline, 2-methoxyphenyl, 3,5-bistrifluormethylbenzene, 4-deformational, 3-deformational, 2,6-dichlorophenyl, 4-carboxyphenyl, cyclohexyl, cycloprop is l, the isopropyl thiophene-2-yl, 5-chlorothiophene-2-yl and 3,5-dimethylisoxazol-4-yl.

R4more preferably selected from the group including benzoyl, morpholine-4-carbonyl, acetyl, furan-3-carbonyl, 2-methoxybenzoyl, 3-methoxybenzoyl, naphthalene-2-carbonyl, benzo[1,3]dioxol-5-carbonyl, 3-pyridine-3-ylacrylic, benzofuran-2-carbonyl, furan-2-carbonyl, tert-butoxycarbonyl, biphenyl-4-carbonyl, quinoline-2-carbonyl, quinoline-3-carbonyl, 3-acetylbenzoic, 4-phenoxybenzoyl, 3-hydroxybenzoyl, 4-hydroxybenzoyl, pyridine-3-carbonyl, 3-(tert-butoxycarbonylmethylene), tert-butyl ester 4-carbonyliron-1-carboxylic acid, ethyl ester 4-carbonyliron-1-carboxylic acid, 4-(furan-2-carbonyl)piperazine-1-carbonyl, pyridine-4-carbonyl, 1-oxypyridine-4-carbonyl, 1-oxopyridine-3-carbonyl, thiophene-2-carbonyl, thiophene-3-carbonyl, 4-benzoylbenzoate, 5-methylthiophene-2-carbonyl, 3-chlorothiophene-2-carbonyl, 3-bromothiophene-2-carbonyl, 4-chlorobenzoyl, 3-fluoro-4-methoxybenzoyl, 4-methoxybenzoyl, 4-trifloromethyl, 3,4-differentail, 4-perbenzoic, 3,4-differentail, 3-methylbenzoyl, 4-bromobenzoyl, 4-trifloromethyl, 3-benzoylmethyl, cyclopentanecarbonyl, benzo[b]thiophene-2-carbonyl, 3-chlorobenzo[b]thiophene-2-carbonyl, benzazolyl, naphthalene-2-sulfonyl, 5-methylthiophene-2-sulfonyl, thiophene-2-sulfonyl, foraminotomy ester, 4-methylpentanol, formail subutility ester, formalistically ester, formalizability ester, N,N-dimethylformamid, N-isopropylphenyl, N-pyridine-4-informel, N-pyridine-3-informel, 3-phenylacrylate, 1H-indole-5-carbonyl, pyridine-2-carbonyl, pyrazin-2-carbonyl, 3-hydroxypyridine-2-carbonyl, 2-aminopyridine-3-carbonyl, 2-hydroxypyridine-3-carbonyl, 6-aminopyridine-3-carbonyl, 6-hydroxypyridine-3-carbonyl, pyridazin-4-carbonyl, 3-phenoxybenzoyl and 1-oxo-1,3-dihydroindol-2-carbonyl.

X3more preferably selected from the group comprising benzyl ether of 4-amino-3-oxazepan-1-carboxylic acid,

isobutyl ether 4-amino-3-oxazepan-1-carboxylic acid,

4-amino-1-benzodiazepin-3-one,

4-amino-1-benzosulfimide-3-one,

4-amino-1-(pyridine-2-sulfonyl)azepin-3-one,

4-amino-1-(1-oxypyridine-2-sulfonyl)azepin-3-one,

4-amino-1-(3,4-dichlorobenzenesulfonyl)azepin-3-one,

4-amino-1-(2-permentantly)azepin-3-one,

4-amino-1-(3,4-dimethoxybenzonitrile)azepin-3-one,

4-amino-1-(2-cyanobenzenesulfonyl)azepin-3-one,

4-amino-1-(naphthalene-1-sulfonyl)azepin-3-one,

4-amino-1-(thiophene-2-sulfonyl)azepin-3-one,

4-amino-1-(thiazol-2-sulfonyl)azepin-3-one,

4-amino-1-(pyrrolidin-1-sulfonyl)azepin-3-one,

4-amino-1-methanesulfonate-3-one,

4-amino-1-(pyrrolidin-1-carbonyl)azepin-3-one,

dimethylamide 4-amino-3-oxazepan-1-carbon is acid,

benzylamine 4-amino-3-oxazepan-1-carboxylic acid,

4-amino-1-benzylation-3-one, 4-amino-1-benzylpiperidine-3-one,

4-amino-1-benzylpiperidine-3-one,

4-amino-1-benzylpyrrolidine-3-one,

4-amino-1-benzylpyrrolidine-3-one,

4-amino-1-benzensulphochloramide-3-one,

4-amino-1-(5-etylhexyl)pyrrolidin-3-one,

1-ethyl-2-oxo-3-(toluene-4-sulfonylamino)butylamino,

1-ethyl-2-oxo-3-(4-phenoxybenzenesulfonyl)propylamino,

1-ethyl-2-oxo-3-[4-(pyridine-3-yloxy)benzosulfimide]propylamino,

3-(dibenzofuran-2-sulfonylamino)-1-ethyl-2-oxobutanamide,

1-ethyl-3-[4-methyl-2-(4-methylpentylamino)pentanediamine]-2-oxopropylidene,

5-amino-1-[(4-methoxybenzenesulfonyl)methyl]pentylamine,

5-benzyloxycarbonylamino-1-[(4-methoxybenzenesulfonyl)methyl]pentylamine,

1-[(4-methoxybenzenesulfonyl)methyl]-3-phenylpropylamine,

1-{[4-(1-hydroxyethyl)phenylcarbamoyl]methyl}-3-phenylpropylamine,

1-[(4-acetylphenylalanine)methyl]-3-phenylpropylamine,

1-[(4-hydroxyphenylacetate)methyl]-3-phenylpropylamine and

3-phenyl-1-[(2-phenylenesulfonyl)methyl]propylamino;

and their N-oxide derivatives, proletarienne derivatives, protected derivatives, individual isomers and mixtures of these isomers; and the pharmaceutically acceptable salt and solvate of such compounds and the N-oxide derivatives, Proletarsk the military derivatives, protected derivatives, individual isomers and mixtures of these isomers.

It is understood that the reference to the preferred options presented above include all combinations of particular and preferred groups.

Specific compounds of the present invention can be obtained by joining the carbon atom C* of one of the fragments (A1 to A72), are presented in table 1 to the nitrogen atom (*N) of one of the fragments (B1-B80), are presented in table 2, and by joining methine carbon atom (CH*) of one of the fragments (B1-B80), are presented in table 2, to the acyl carbon atom (C*) of one of the fragments (C1-S), are presented in table 3.

Table 1

Table 2

Table 3

Compounds of the present invention are selective inhibitors of cathepsin S and, as such, are useful in the treatment of sableman the th, when the activity of cathepsin S contributes to the pathology and/or symptomatology of the disease. For example, the compounds of the present invention are useful in the treatment of autoimmune diseases, including, but not limited to, juvenile diabetes, multiple sclerosis, a disease vulgaris, graves ' disease, pseudoparalysis the gravis, lupus erythematosus, rheumatoid arthritis and tiroides Hashimoto, allergic diseases, including, but not limited to, asthma, and allergic immune response, including but not limited to, cases of transplantation of organs or tissue transplantation.

Cathepsin's also involved in diseases involving excessive elastolin, such as chronic obstructive lung disease (e.g. emphysema), bronchiolitis, excessive elastosis of the Airways in asthma and bronchitis, pneumonia and cardiovascular disease, such as separation of plaques and atheroma. Cathepsin S involved in the formation of fibrin, and therefore, inhibition of cathepsin S can be used in the treatment of systemic amyloidosis.

Activity of the compounds of the present invention in relation to the activity of inhibiting cysteinate can be determined by methods known to experts in this field. Known suitable in vitro assays for measuring the activity of protease and its inhibition test joint is mi. Usually, in the analysis measure the degree induced by protease hydrolysis of the substrate on the basis of peptides. The details of the analysis for determining the activity of inhibiting the protease are presented below in examples 14-17.

Typically, the compounds of formula I is administered in therapeutically effective quantities of any of the usual and acceptable methods known in this field, either alone or in combination with one or more therapeutic agents. therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the patient, the effectiveness of the connection you use, and other factors. For example, therapeutically effective amounts of compounds of formula I can vary within the range from about 1 microgram per kilogram of body weight (mcg/kg) per day to about 1 milligram per kilogram of body weight (mg/kg) per day, typically from about 10 μg/kg/day to about 0.1 mg/kg/day. Therefore, a therapeutically effective amount for a patient weighing 80 kg may vary in the range of from about 100 μg/day to about 100 mg/day, typically from about 1 μg/day to about 10 mg/day. In General, the specialist in this field, acting in accordance with their own knowledge and the description of the present invention, will be able to determine a therapeutically effective amount of a compound of the formula is I, necessary for the treatment of specific diseases.

The compounds of formula I can be introduced in the form of pharmaceutical compositions by one of the following ways: oral, systemic (e.g., percutaneous, intranasal, or using suppositories) or parenterally (for example intramuscularly, intravenously or subcutaneously). The composition can be in the form of tablets, pills, capsules, semi-solids, powders, compositions with delayed release of active substances, solutions, suspensions, elixirs, aerosols, and other suitable compositions, which usually consist of the compounds of formula I in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, contribute to the introduction and have no harmful effects on therapeutic effect of the active ingredient. Such excipients may be any solid, liquid, semi-solid or, in the case of aerosol compositions, gaseous excipients that are usually available to professionals in this field.

Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and other Liquid and semi-solid excipients can be selected from water, is canola, glycerin, propylene glycol and various oils, including petroleum, animal, vegetable or synthetic oils (e.g. peanut oil, soybean oil, mineral oil, sesame oil and the like). Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.

The amount of compounds of formula I in the composition can vary widely depending on the type of composition, size, single dose, type of excipients and other factors known to experts in the field of pharmaceutics. In General, the composition of the compounds of formula I for treating a particular disease should include from 0.01 wt.% up to 10 wt.%, preferably, from 0.3 wt.% up to 1 wt.% the active ingredient, and the rest will be excipient or excipients. Preferably the pharmaceutical composition is administered in the form of a single unit dose for continuous treatment or in the form of a single unit dose selection, specifically when you want to achieve attenuation of symptoms. Representative pharmaceutical compositions containing a compound of the formula I, disclosed in example 10 below.

Methods for obtaining compounds of formula I:

Compounds of the present invention can be obtained, set forth in this description or adapted well-known methods, by which I mean the way the, used so far, or the methods described in the literature, for example, described R.C. Larock in Comprehensive Organic Transformations, VCH publishers, 1989.

When carrying out reactions described below, it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxypropyl that must be present in the final product, to avoid their unwanted participation in the reactions. Conventional protective groups can be used in accordance with the usual practice; for example, see T.W. Greene and P. G. M Wuts in "Protective Groups in Organic Chemistry" John Wiley and Sons, 1991.

The compounds of formula I, where X3represents the connection of the formula (a) (as defined above in the description of the present invention), can be obtained in accordance with reaction scheme 1:

The reaction scheme 1

where each of X1X2, R3, R4, R20and R21has the values specified for formula I above.

The compounds of formula I can be obtained by condensing an acid of formula 2 with aminoguanidinium formula (a). The condensation reaction can be carried out using appropriate agent combinations (for example, hexaflurophosphate benzotriazol-1-electroparadise PyBOP®), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), hexaflurophosphate O-benzotriazol-1-yl-N,N,N',N'-tetrameth Urania (HBTU), 1,3-dicyclohexylcarbodiimide (DCC) or the like), it is not necessarily an appropriate catalyst (for example, 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-asobancaria (HOAt), hexaflurophosphate O-(7-asobancaria-1-yl)-1,1,3,3-tetramethyluronium (HATU), or the like) and dinucleophiles base (e.g. triethylamine, N-methylmorpholine, etc. or any suitable combination thereof); at room temperature and within 5-10 hours required for its completion.

Stage of oxidation, if necessary, can be carried out using an oxidizing agent (e.g., Oxone®, metallocarborane acid or the like) in a suitable solvent (such as methanol, water or the like, or any suitable combination) at room temperature for 16-24 hours required for its completion. Detailed description of the synthesis of the compounds of formula I according to the method presented in reaction scheme 1 below in examples 1-11.

The compounds of formula I, where X3represents the connection of the formula (b) (as defined above), can be obtained using the following reaction scheme 2:

The reaction scheme 2

where each of X1X2, R3, R4, R20, R23and R25has the values specified above for formula I.

The compounds of formula I can be obtained by condensing an acid of formula 2 with aminoguanidinium formula (b). Response to what Denali can be done, using the appropriate agent combinations (for example, hexaflurophosphate benzotriazol-1-electroparadise (PyBOP®), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCl), hexaflurophosphate O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium (HBTU), 1,3-dicyclohexylcarbodiimide (DCC) and the like), it is not necessarily an appropriate catalyst (for example, 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-asobancaria(HOAt), hexaflurophosphate O-(7-asobancaria-1-yl)-1,1,3,3-tetramethyluronium (HATU) and the like) and not nucleophilic base (e.g. triethylamine, N-methylmorpholine and the like, or any suitable combination thereof); at room temperature and within 5-10 hours required for its completion.

Stage of oxidation, if necessary, can be carried out using an oxidizing agent (e.g., Oxone®, metallocarborane acid and the like) in a suitable solvent (e.g. methanol, water and the like, or any suitable combination thereof); at room temperature for 16-24 hours required for its completion.

The compounds of formula I, where X3represents the connection of the formula (c) (as defined above), can be obtained by the coupling of compounds of formula 2 with a compound of formula (c) in accordance with the following reaction scheme:

The reaction scheme 3

where each of X1X2, R3, R4, R 20, R23and R25has the values specified above for formula I.

Additional methods of preparing compounds of the formula I:

The compound of the formula I can be obtained in the form of a pharmaceutically acceptable salt accession acid by the interaction of the compounds in free base form with a pharmaceutically acceptable inorganic or organic acid. Alternatively, the pharmaceutically acceptable salt of attaching the base of the compounds of formula I can be obtained by the interaction of the compounds in the form of the free acid with a pharmaceutically acceptable inorganic or organic base. Inorganic and organic acids and bases which are suitable to obtain pharmaceutically acceptable salts of the compounds of formula I above in the definition of terms used in this description. Alternatively, the salt forms of the compounds of formula I can be obtained by using salt source or intermediate compounds.

The form of the free acid or free base of compounds of formula I can be obtained from the corresponding salt form of accession or accession acid. For example, the compound of formula I in salt form accession acid can be converted into the corresponding free base, treating it with a suitable base (e.g. hydroxide solution Ammon is I, sodium hydroxide and the like). The compound of formula I in salt form attachment base can be converted into the corresponding free acid, treating it with a suitable acid (e.g. hydrochloric acid, etc).

N-oxides of compounds of formula I can be obtained by methods known to experts in this field. For example, N-oxides can be obtained by processing the non-oxidized form of the compounds of formula I is an oxidizing agent (for example, cryptocercus acid, permalinki acid, perbenzoic acid, peracetic acid, metallocarboxypeptidase acid or the like) in a suitable inert organic solvent (for example, halogenated hydrocarbon such as dichloromethane) at about 0°C. alternatively, the N-oxides of compounds of formula I can be obtained from N-oxides of the corresponding original substance.

The compounds of formula I in unoxidized form can be obtained from N-oxides of the compounds of formula I, their processing regenerating agent (for example, sulfur, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride, trichloride phosphorus, tribromide phosphorus or the like) in a suitable inert organic solvent (e.g. acetonitrile, ethanol, aqueous dioxane, or the like) at a temperature of from 0 to 80°C.

Proletarienne derivatives of the compounds of formula I can be is the returns in the usual way, well-known experts in this field (for example, for details see Saulnier et al. (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985). For example, appropriate prodrugs can be obtained by the interaction of the previous compounds of formula I with a suitable agent carbamylcholine (for example, 1,1-aryloxyalkanoic, paranitrophenylphosphate or the like).

Protected derivatives of compounds of formula I can be obtained by conventional means, well known to specialists in this field. Detailed description of the techniques used for the introduction of protective groups and their removal can be found in T.W. Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc. 1999. Compounds of the present invention can be conveniently obtained or formed by the method of the present invention in the form of a solvate (e.g. hydrate). Hydrates of the compounds of the present invention can be conveniently obtained by recrystallization from a mixture of water/organic solvent using an organic solvent, such as dioxane, tetrahydrofuran or methanol. The compounds of formula I can be obtained in the form of their individual stereoisomers by the interaction of racemic mixtures of compounds with optically active separating agent with the formation of pairs diastereoisomeric compounds, separation of diastereoisomeric and allocation of optically pure enantiomer the century Although the separation of enantiomers can be carried out using covalent diastereomeric derivatives of the compounds of formula I, the preferred dissociable complexes (e.g., crystalline diastereoisomeric salt). Diastereoisomer have different physical properties (e.g. melting points, boiling points, solubility, reaction ability and so on), and they can be divided easily, taking advantage of their differences. Diastereoisomer can be separated by chromatography or, preferably, methods of detection/separation based on differences in solubility. Then produce optically pure enantiomer with a separating agent, using any practical means, which do not cause racemization. A more detailed description of the methods used for separation of stereoisomeric compounds from their racemic mixtures can be found Jean-Jacues Andre Collet, Samuel H.Wilen, Enantiomers, Racemates and Resolutions, John Wiley & Sons, Inc. (1981).

Thus, the compounds of formula I obtained by the method, which includes:

(A) interactions of the compounds of formula 2:

with the compound of the formula (a):

where X1X2, R3, R4, R20and R21have the meanings indicated above for formula I;

or

(C) the interaction of the compounds of formula 2 with which an Association of the formula (b):

where R20, R23and R25have the meanings indicated above for formula I; or

(C) the interaction of the compounds of formula 2 with the compound of the formula (c):

where R20, R23and R25have the meanings indicated above for formula I; and

(D) optionally converting the compound of formula I in a pharmaceutically acceptable salt;

(E) optionally converting the compound of formula I in salt form in mesolevel form;

(F) optionally converting the non-oxidized form of the compounds of formula I in a pharmaceutically acceptable N-oxide;

(G) optionally converting an N-oxide form of a compound of formula I in its unoxidized form;

(H) optionally separating individual isomers of the compounds of formula I from a mixture of isomers;

(I) optionally converting the original form of the compounds of formula I in the pharmaceutical proletarienne derived; and

(J) optionally transforming proletarienne derivative compounds of formula I in its original form.

Examples:

Further, the present invention is explained, but not limited to the following examples, which illustrate the formation of compounds of formula I (examples) and intermediate compounds (comparative examples) in accordance with the present invention.

Comparative example 1

Tert-butyl is ester 3-amino-4-hydroxypyrrolidine-1-carboxylic acid

Tert-butyl ester 6-oxa-3-azabicyclo[3.1.0]-hexane-3-carboxylic acid (12.1 g, 65.3 mmol) dissolved in a mixture of 8:1 methanol/water (108 ml). Add ammonium chloride (15 g) and sodium azide (21,4 g, 329 mmol) and the mixture is heated at 60°With during the night. After dilution with ether (500 ml) the mixture was washed with saturated aqueous NaHCO3(200 ml) and saturated salt solution (200 ml), dried over MgSO4and evaporated in vacuum. The crude product is dissolved in methanol (200 ml). Add 10% palladium-on-charcoal (1.5 g) and the mixture is stirred at room temperature in a hydrogen atmosphere until such time as according to TLC analysis is not confirmed by the disappearance of the original substance. The mixture is filtered through a layer of celite and evaporated to dryness in a vacuum. The product was then purified flash chromatography on silica gel. Eluent: 5% methanol in ethyl acetate to 20% methanol, 3% triethylamine in ethyl acetate. Yield: 4.3 g tert-butyl ester 3-amino-4-hydroxypyrrolidine-1-carboxylic acid as a yellowish solid.

Comparative example 2

Benzyl ether of 4-amino-3-hydroxyacetone-1-carboxylic acid

Sodium hydride (60% in mineral oil, 10 g, 250 mmol) is suspended in dry DMF. Dropwise at room temperature add benzyl ether allylcarbamate acid (19.1 g, 100 mmol). After stirring for 5 minutes and added dropwise to 5-bromo-1-pins is Yong (25 g, 168 mmol). Stirring is continued at 50°C for 1 hour. The reaction mixture was quenched with water and then partitioned between diethyl ether and water. The ether layer is washed with water and saturated salt solution, dried over MgSO4and evaporated in vacuum. Using flash chromatography (ethyl acetate/hexane 1:9), receive benzyl ether allerpet-4-analkarneval acid (15.5 g).

Benzyl ether allerpet-4-analkarneval acid (15.5 g, to 59.8 mmol) was dissolved in dichloromethane and added dropwise bis(tricyclohexylphosphine)benzylidenemalonate ruthenium(IV) (1 g). The mixture is refluxed in a nitrogen atmosphere until TLC until the data did not indicate the completion of the reaction. The solvent is evaporated in vacuum, the residue is purified with flash chromatography (ethyl acetate/hexane 1:9)to give benzyl ether 2,3,4,7-tetrahydroazepine-1-carboxylic acid (7.8 g).

To a solution of benzyl ether 2,3,4,7-tetrahydroazepine-1-carboxylic acid (4.5 g, 19,45 mmol) in dichloromethane (50 ml) is added metallocarborane acid (60 mmol). The mixture is stirred at room temperature for 16 hours. Add saturated aqueous solution of K2CO3and the mixture is extracted with dichloromethane. The combined organic layers washed with saturated aqueous NaHCO3and saturated salt solution, dried over MgSO4and evaporated in vacuum. Neojidanni the epoxide dissolved in a mixture of 8:1 methanol/water (100 ml). Add ammonium chloride (3.2 g, 60 mmol) and sodium azide (3.9 g, 60 mmol) and the mixture is heated at 60°C for 48 hours. A large part of the solvent is removed in vacuum. The residue is extracted with ethyl acetate. The combined organic layers washed with saturated aqueous NaHCO3(200 ml) and saturated salt solution (200 ml), dried over MgSO4and evaporated in vacuum. In the flash chromatography of the residue (hexane/ethyl acetate 3:1) to obtain benzyl ether of 4-azido-3-hydroxyacetone-1-carboxylic acid (3.3 grams).

To a solution of benzyl ester 4-azido-3-hydroxyacetone-1-carboxylic acid (3.3 g, 11,37 mmol) in methanol (50 ml), add triethylamine (5 ml) and 1,3-propanedithiol (3.42 ml, 35 mmol). The mixture is stirred at room temperature until such time as the results of TLC analysis of the data did not indicate complete consumption of the original substance. A white precipitate is removed by filtration and the filtrate is evaporated to dryness. The residue is triturated with a mixture of 1:1 hexane/diethyl ether to remove excess of dithiol and dried in vacuum, obtaining the benzyl ether of 4-amino-3-hydroxyacetone-1-carboxylic acid.

Comparative example 3

Hydrochloride 2S-amino-N-(4-methoxyphenyl)-4-phenylbutane-1-sulfonamida

The solution containing the crude tert-butyl 1-(4-methoxybenzenesulfonyl)-3-phenylpropylamine (1.92 g, was 4.42 mmol)obtained in comparative example 2, in DCM(10 ml) is treated with 4M solution of hydrogen chloride in dioxane (11 ml). The mixture is stirred for 16 h at room temperature and diluted with diethyl ether. The precipitate is collected by filtration, washed several times with diethyl ether and hexane, and dried with suction and receive hydrochloride 2S-amino-N-4-methoxyphenyl-4-phenylbutane-1-sulfonamida with quantitative yield.

1H NMR (DMSO): 2,05 (2H, m); 2,6-2,7 (2H, m); 3,4 (3H, m*); and 3.72 (3H, s); 6,9 (2H, d, J=Hz); to 7.25 (5H, m); and 7.3 (2H, d, J=Hz); 8,5 (Sirs); and 10.0 (1H, s).

EXAMPLE 1

[1-(1-benzoyl-4-oxopyrrolidin-3-ylcarbonyl)-2-phenylmethanesulfonyl]amide morpholine-4-carboxylic acid

(Compound 1)

Combine 2-[(morpholine-4-carbonyl)amino]-3-phenylmethanesulfonyl acid (1 g, 2.8 mmol), tert-butyl ester 3-amino-4-hydroxypyrrolidine-1-carboxylic acid (700 mg, 3.46 mmol)obtained by the method of comparative example 1, EDC (1.5 g, 7.8 mmol, HOBt (1.5 g, 9.6 mmol). Add dichloromethane (10 ml) and then 4-methylmorpholine (1.5 ml). The mixture is stirred at room temperature for 2 hours. After dilution with ethyl acetate (200 ml) solution was washed with saturated aqueous NaHCO3(100 ml) and saturated salt solution (100 ml), dried over MgSO4and evaporated in vacuum. Tert-butyl ester 3-hydroxy-4-{2-[(morpholine-4-carbonyl)amino]-3-phenylmethanesulfonyl}pyrrolidin-1-carboxylic acid (1,05 g, 1.94 mmol) get in view of the yellow foam was dissolved in dichloromethane (6 ml). Add triperoxonane acid (6 ml), the mixture is stirred at room temperature for 1 hour. As the result of evaporation in a vacuum get the crude [1-(4-hydroxypyrrolidine-3-ylcarbonyl)-2-phenylmethanesulfonyl]amide morpholine-4-carboxylic acid in the form of a salt TFUK, which is used without further purification.

TFUK Sol [1-(4-hydroxypyrrolidine-3-ylcarbonyl)-2-phenylmethanesulfonyl]amide morpholine-4-carboxylic acid (215 mg, 0,39 mmol) dissolved in 1,4-dioxane (20 ml). Add saturated aqueous solution of NaHCO3(10 ml), followed by benzoyl chloride (0.2 ml, 1,72 mmol). The mixture is stirred at room temperature for 1 hour and then extracted with ethyl acetate. The combined organic layers washed with saturated aqueous NaHCO3and saturated salt solution, dried over MgSO4and evaporated in vacuum. The residue is purified flash chromatography on silica gel (eluent: 5% methanol in ethyl acetate to 20% methanol in ethyl acetate)to give [1-(1-benzoyl-4-hydroxypyrrolidine-3-ylcarbonyl)-2-phenylmethanesulfonyl]amide morpholine-4-carboxylic acid (92 mg).

[1-(1-benzoyl-4-hydroxypyrrolidine-3-ylcarbonyl)-2-phenylmethanesulfonyl]amide morpholine-4-carboxylic acid (92 mg, 0,169 mmol) dissolved in DMSO (5 ml). Add triethylamine (0.5 ml) and then the complex SO3/pyridine (150 mg), the mixture is stirred at room Tempe is the atur for 3 hours. After dilution with ethyl acetate (100 ml), the solution washed with water (50 ml) and saturated salt solution, dried over MgSO4and evaporated in vacuum. The residue is purified flash chromatography on silica gel (eluent: 5% methanol in ethyl acetate)to give [1-(1-benzoyl-4-hydroxypyrrolidine-3-ylcarbonyl)-2-phenylmethanesulfonyl]amide morpholine-4-carboxylic acid as a mixture of diastereoisomers (yellowish solid; 38 mg);

1H NMR: (DMSO) 8,50-8,35 (m, 1H), 7,55-7,34 (m, 10H), 7,16-to 6.95 (m, 1H), 4.80 to the 4.65 (m, 1H), 4,54-4,22 (m, 3H), 3,98 is 3.25 (m, 14H); MS: (M+H)+543.

EXAMPLE 2

[1-(1-benzazolyl-4-oxopyrrolidin-3-ylcarbonyl)-2-phenylmethanesulfonyl]amide morpholine-4-carboxylic acid

(Compound 2)

[1-(1-benzoyl-4-hydroxypyrrolidine-3-ylcarbonyl)-2-phenylmethanesulfonyl]amide morpholine-4-carboxylic acid get by the method of example 1, replacing benzoyl chloride with benzosulphochloride.

1H NMR: (DMSO) [8,35 (d, J=7,4 Hz), of 8.28 (d, J=7,Hz), 1H], 7,87 to 7.62 (m, 5H), 7,41-to 7.32 (m, 5H), 7,06-6,98 (m, 1H), 4.72 in-4,60 (m, 1H), of 4.45 (s, 2H), 4,42-to 4.23 (m, 1H), 3,92-with 3.79 (m, 2H), 3,55-3,20 (m, 11H), a 3.06-of 2.97 (m, 1H). MS: (M+H)+579.

EXAMPLE 3

Benzyl ether of 4-{2-[(morpholine-4-carbonyl)amino]-3-phenylmethanesulfonyl}-3-oxazepan-1-carboxylic acid

(Compound 3)

Combine the crude benzyl ether of 4-amino-3-hydroxylase the n-1-carboxylic acid (150 mg, of 0.57 mmol)obtained by the method of comparative example 2, 2-[(morpholine-4-carbonyl)amino]-3-phenylmethanesulfonyl acid (400 mg, 1.12 mmol), EDC (400 mg, 2.1 mmol) and HOBt (400 mg, 2.5 mmol). Add dichloromethane (10 ml), then 4-methylmorpholine (0.5 ml). The mixture is stirred at room temperature for 2 hours. After dilution with ethyl acetate (100 ml) the solution was washed with 1N HCl, saturated aqueous NaHCO3and saturated salt solution, dried over MgSO4and evaporated in vacuum. The residue is purified with flash chromatography (ethyl acetate/methanol 9:1)to give benzyl ester 3-hydroxy-4-{2-[(morpholine-4-carbonyl)amino]-3-phenylmethanesulfonyl}azepin-1-carboxylic acid (320 mg).

Benzyl ester of 3-hydroxy-4-{2-[(morpholine-4-carbonyl)amino]-3-phenylmethanesulfonyl}azepin-1-carboxylic acid (100 mg, 0,167 mmol) dissolved in DMSO (5 ml). Add triethylamine (0.3 ml), then the complex SO3/pyridine (150 mg) and the mixture is stirred at room temperature for 3 hours. After dilution with ethyl acetate (100 ml), the solution washed with water (50 ml) and saturated salt solution, dried over MgSO4and evaporated in vacuum. The residue is purified flash chromatography on silica gel (eluent: 5% methanol in ethyl acetate) and get a benzyl ether of 4-{2-[(morpholine-4-carbonyl)amino]-3-phenylmethanesulfonyl})-3-oxazepan-1-carboxylic sour is s (75 mg);

1H NMR: (DMSO) 8,23-8,08 (m, 1H), 7,40-7,29 (m, 10H), 7,06-6,98 (m, 1H), 5,20-5,09 (m, 2H), 4,79 with 4.65 (m, 1H), to 4.52-or 4.31 (m, 3H), was 4.02-of 3.80 (m, 2H), 3,62 is 3.23 (m, 11H), 3,00-2,78 (m, 1H), 1,88-of 1.55 (m, 4H); MS:(M+H)+601.

EXAMPLE 4

[1-(3-benzosulfimide-2-oxopropylidene)-2-phenylmethanesulfonyl]amide morpholine-4-carboxylic acid

(Compound 4)

TFUK salt of N-(3-amino-2-hydroxypropyl)benzosulfimide get in the way, presents Renee L. DesJarlais et. Al. J. Am. Chem. Soc. 1998, 120, 9114-9115.

Combine 2-[(morpholine-4-carbonyl)amino]-3-phenylmethanesulfonyl acid (50 mg, 0.14 mmol), TFUK salt of N-(3-amino-2-hydroxypropyl)benzosulfimide (60 mg, 0,17 mmol), EDC (100 mg, 0.52 mmol) and HOBt (100 mg, 0.64 mmol). Add DMF (3 ml) and then 4-methylmorpholine (0.3 ml). The mixture is stirred at room temperature for 3 hours. After dilution with ethyl acetate (100 ml) the solution was washed with 1N HCl, saturated aqueous NaHCO3and saturated salt solution, dried over MgSO4and evaporated in vacuum. The residue is dissolved in acetone (5 ml). Added Jones reagent until such time as there is orange in color. The mixture is stirred for 2 hours, quenched with isopropanol and diluted with ethyl acetate (100 ml). The solution is washed with water, saturated aqueous NaHCO3and saturated salt solution, dried over MgSO4and evaporated in vacuum. The crude product is t recrystallized from a mixture of ethyl acetate/diethyl ether, receiving [1-(3-benzosulfimide-2-oxopropylidene)-2-phenylmethanesulfonyl]amide morpholine-4-carboxylic acid as a white solid (19 mg).

1H NMR: (DMSO) 8,17 (t, J=5,GC, 1H), to 7.93 (t, J=5,GC, 1H), 7,76-of 7.48 (m, 5H), was 7.36-7,29 (m, 5H), 7,05 (d, J=8,1 Hz, 1H), 4,68-4,59 (m, 1H), of 4.45 (s, 2H), 3,89 (d, J=5,Hz, 2H), 3,79 of 3.75 (m, 2H), 3,56-up 3.22 (m, 10H); MS: (M+H)+567.

EXAMPLE 5

N-{1S-[1S-(4-methoxybenzenesulfonyl)-3-phenylpropionyl]-2-benzylmalonate}morpholine-4-carboxamide

(Compound 7)

A mixture of 2S-morpholine-4-carbylamine-3-benzyltriphenylphosphonium acid (0,194 g, 0,599 mmol), hydrochloride 2S-amino-N-(4-methoxyphenyl)-4-phenylbutane-1-sulfonamida (0,222 g, 0,599 mmol)obtained by the method of comparative example 3, and HATU (0,228 g, 0,599 mmol) in DMF (5 ml) is treated with 4-methylmorpholine (0,198 g of 1.80 mmol). The mixture is stirred at room temperature for about 12 h and then partitioned between a mixture of 4:1:2:3 (100 ml) ethyl acetate/THF/water/saturated salt solution, respectively. The organic phase is isolated and washed with saturated aqueous sodium bicarbonate (30 ml), saturated salt solution (30 ml), dried over MgSO4), filtered and concentrated. The residue is triturated with a mixture of 5:1 ether/ethyl acetate (100 ml), collected by filtration, washed with ether (30 ml), hexane (30 ml) and dried with suction, the of learn N-{1S-[1S-(4-methoxybenzenesulfonyl)-3-phenylpropionyl]-2-benzylmalonate}morpholine-4-carboxamide.

TLC Rf(ethyl acetate): 0,65;

1H NMR (DMSO): 1,74 (1H, m); of 1.92 (1H, m); 2,39-2,61 (2H, m); 3.1 to the 3.35 (2H, 2 x DD*); to 3.34 (4H, m); 3,42-the 3.65 (6H, m*); and 3.72 (3H, s); 4,24 (1H, m); 4,51 (2H, s); br4.61 (1H, m); to 6.88 (2H, d, J=Hz); 7,1-7,34 (8H, m); to 7.4 (5H, s); to 8.12 (1H, d, J=8,Hz); MS (M+l): 673.

According to the method of example 5 given the following compounds of formula I:

The hydrobromide of N-{1S-[5-amino-1S-(4-methoxybenzenesulfonyl)intercalator}-2-benzisothiazolin-4-carboxamide (Compound 5)1H NMR (DMSO): 1,15-of 1.73 (6H, m*); a 2.71 (2H, m); 3,05-of 3.25 (2H, 2 x DD); 3,37 (4H, m); 3.45 points and 3.6 (6H, m*); and 3.72 (3H, s); is 4.21 (1H, m); of 4.49 (2H, DD); 4,5 (1H, m); 6.89 in (2H, d, J=8,Hz); to 7.09 (1H, m*); to 7.15 (2H, d, J=8,Hz); 7,39 (5H, s); 7,73 (3H, Sirs); 8,03 (1H, d, J=8,Hz); for 9.47 (1H, s); MS (M+l): 640, free base); and

Benzyl 6-(4-methoxybenzenesulfonyl)-5S-(2S-morpholine-4-ylcarbonyl-3-benzyltriphenylphosphonium)hexylcinnamal (Compound 6); TLC Rf(ethyl acetate): 0,3;

1H NMR (DMSO): 1,1-of 1.65 (6H, m); to 2.94 (2H, q, J=Hz); 3,05-up 3.22 (2H, 2 x DD); to 3.34 (4H, m*); 3,35-3,59 (2H, m*); of 3.53 (4H, Sirs); 3,71 (3H, s); 4,19 (1H, m); a 4.53 (2H, DD, J=15Hz); of 4.57 (1H, m); 5,00 (2H, C); 6,89 (2H, d, J=8,4 Hz); 7,05 (1H, d, J=8gts); to 7.15 (2H, d, J=8,4 Hz); from 7.24 (1H, t); 7,3 was 7.45 (10H, 2 x C); to 7.99 (1H, J=8gts); MS (M+): 774.

EXAMPLE 6

[(R)-1-(6-oxocyclohexa-1-anykarbalai)-2-phenylmethanesulfonyl]amide morpholine-4-carboxylic acid

(Compound 8)

A solution of 2-aminocyclohexane-1,3-diol (0.55 g) in dimethylformamide (30 ml) is treated with diisopropylethylamine (1.6 ml, 9.2 mmol. After stirring at room temperature for 5 min the mixture was treated with (R)-2-[(morpholine-4-carbonyl)amino]-3-phenylmethanesulfonyl acid (1.73 g, a 4.86 mmol)and then HATU (1.68 g, was 4.42 mmol). The mixture is stirred at room temperature overnight and then evaporated. The residue is subjected to flash chromatography on silica gel, elwira with ethyl acetate and then a mixture of ethyl acetate and methanol, and receive [(R)-1-(2,6-dihydroxycholecalciferol)-2-phenylmethanesulfonyl]amide morpholine-4-carboxylic acid as a white solid (210 mg). MS: 470 (MH+).

A solution of (R)-1-(2,6-dihydroxycholecalciferol)-2-phenylmethanesulfonyl]amide morpholine-4-carboxylic acid (90 mg, 0,19 mmol) in methylene chloride (6 ml) is treated with periodinane dess-Martin (162 mg, 0.38 mmol). After stirring at room temperature for 2 hours, the reaction mixture was washed with a solution of Na2S2O3in water (0,26M), then saturated aqueous bicarbonate solution, then water, then dried over Na2SO4and then evaporated under reduced pressure. The residue is subjected to flash chromatography on silica gel, elwira a mixture of ethyl acetate and heptane, and receive [(R)-1-(6-oxocyclohexa-1-anykarbalai)-2-phenylmethanesulfonyl]amide morpholine-4-carboxylic acid (8 mg).

1H NMR (CDCl3): 9,00 (s, 1H), 7,82 (t, J=5Hz, 1H), 7,53-,38 (m, 5H), the 6.06 (d, J=Hz, 1H), 5,00 (m, 1H), 4,47-4,27 (m, 2H), 3,85 (m, 1H), of 3.77-3,62 (m, 4H), 3,48-to 3.36 (m, 4H), of 3.27 (m, 1H), 2,58 is 2.46 (m, 4H), 2,08-of 1.97 (m, 2H). MS: 450 (MH+).

EXAMPLE 7

[(R)-2-cyclopropanesulfonyl-1-(6-oxocyclohexa-1-anykarbalai)ethyl]amide morpholine-4-carboxylic acid

(Compound 9)

A mixture of [(R)-3-cyclopropanesulfonyl-2-[(morpholine-4-carbylamine]propionic acid (0,352 g, 1.1 mmol) and N-cyclohexylcarbodiimide N'-metropolitical (1,93 mmol/g of 1.03 g) in DCM (10 ml) is treated with hydroxybenzotriazole (0.27 g, 2 mmol). After stirring at room temperature for 5 min the mixture was treated with 2-aminocyclohexane-1,3-diola (0,0131 g, 1 mmol) and stirring is continued further for 2 days. The reaction mixture is treated with PS trisamine (3.75 mmol/g, 1.3 g), after stirring at room temperature for 2 hours the resin is filtered off and washed with DCM. The combined filtrate and washings evaporated under reduced pressure, obtaining [(R)-2-cyclopropanesulfonyl-1-(2,6-dihydroxycholecalciferol)ethyl]amide morpholine-4-carboxylic acid (0.32 g) as a thick pale yellow oil.

MS: 434(MH+).

To a solution of [(R)-2-cyclopropanesulfonyl-1-(2,6-dihydroxycholecalciferol)ethyl]amide (0.32 g) in DCM (10 ml) add periodinane dess-Martin (0,688 g of 1.62 mmol), the mixture is stirred at room temperature is within 3 hours, then processes related to the resin Na2S2O3(1.5 mmol/g and 1.9 g) and stirred at room temperature for another 24 hours. The reaction mixture was diluted with DCM (2 ml), then filtered. The filtrate is washed with a solution of 0,25M Na2S2O3then with saturated NaHCO3, then dried (MgSO4) and then evaporated under reduced pressure. The residue is subjected to column chromatography, elwira a mixture of ethyl acetate and heptane, and receive [(R)-2-cyclopropanesulfonyl-1-(6-oxocyclohexa-1-anykarbalai)ethyl]amide morpholine-4-carboxylic acid.

1H NMR (CDCl3): 9,00 (s, 1H), 7,78 (t, 1H), 6,18 (d, 1H), 4,9 (m, 1H), 3,85 (m, 1H), of 3.77-3,62 (m, 4H), to 3.58 is-3.45 (DD, 1H), 3,48-to 3.36 (m, 4H), 3.0 (d, 2H), 2,55-to 2.42 (m, 4H), 2,08-of 1.97 (m, 2H), 1,2 (m, 1H), 0,8-0,7 (m, 2H), 0,6-0,4 (m, 2H). MS: 414 (MH+).

EXAMPLE 8

[(R)-1-(3,4-dioxincontaminated)-2-phenylmethanesulfonyl]amide morpholine-4-carboxylic acid

(Compound 10)

A solution of 4-aminocyclopentane-1,2-diol; compound with triperoxonane acid (745 mg, of 3.23 mmol) in DMF (15 ml) is treated with DIPEA (1,12 ml, 6.4 mmol) and the mixture is stirred at room temperature for 5 minutes Then add (R)-2-[(morpholine-4-carbonyl)amino]-3-phenylmethanesulfonyl acid (1,15 g of 3.23 mmol)and then HATU (1,23 g, 3,24 mmol). The mixture is stirred at room temperature overnight and then viparita is so The residue is subjected to flash chromatography on silica gel, elwira with ethyl acetate, then with a mixture of ethyl acetate and methanol, and receive [(R)-1-(3,4-dihydroxycholecalciferol)-2-phenylmethanesulfonyl]amide morpholine-4-carboxylic acid in the form of a brown solid substance (680 mg).

LC/MS: RT=2,64 minutes (215 and 254 nm) MH+=456.

A solution of [(R)-1-(3,4-dihydroxycholecalciferol)-2-phenylmethanesulfonyl]amide morpholine-4-carboxylic acid (670 mg, about 1.47 mmol) in methylene chloride (40 ml) is treated with periodinane dess-Martin (624 mg, about 1.47 mmol) and the reaction mixture was stirred at room temperature overnight. Add periodinane dess-Martin (642 mg and 1.51 mmol) and the reaction mixture was stirred at room temperature for 6 hours and then overnight. The reaction mixture is washed with a solution of Na2S2O3in water (0,26M), then saturated aqueous bicarbonate, then water, then dried over Na2SO4and then evaporated under reduced pressure. The residue is subjected to flash chromatography on silica gel, elwira a mixture of ethyl acetate and heptane, and then with ethyl acetate, and receive [(R)-1-(3,4-dioxincontaminated)-2-phenylmethanesulfonyl]amide morpholine-4-carboxylic acid in the form of not-quite-white solid (45 mg).

1H NMR (CDCl3): 7,50-7,38 (m, 5H), 6,62 (m, 1H), 5,91 (d, J=5Hz, 1H), to 4.81 (m, 1H), 4,58 is 4.35 (m, 3H), to 3.73-3,61 (m, 5H), 3,44-of 3.32 (m, 4H), up 3.22 (m, 1H), 2,72-2,12 (m, 4H). MS: 452(MH+).

EXAMPLE 9

[2-(2-diferentactionsconcretesolver)-1-(2-oxocyclohexyl)ethyl]amide morpholine-4-carboxylic acid

(Compound 11)

Combine 3-(2-diferentactionsconcretesolver)-2-[(morpholine-4-carbonyl)amino]propionic acid (100 mg, 0,237 mmol), 2-aminocyclohexanol (58 mg, 0.5 mmol), EDC (100 mg, 0.52 mmol) and HOBt (100 mg, 0.64 mmol). Add dichloromethane (2 ml) and then 4-methylmorpholine (0.2 ml). The mixture is stirred at room temperature for 2 hours. After dilution with ethyl acetate (100 ml) the solution was washed with 1N aqueous HCl (30 ml), saturated aqueous NaHCO3(30 ml) and saturated salt solution (30 ml), dried over MgSO4and evaporated in vacuum. The crude product is dissolved in dichloromethane (10 ml). Add periodinane dess-Martin (300 mg, 0.71 mmol) and the reaction mixture was stirred at room temperature for 1 hour. After dilution with ethyl acetate (100 ml) the solution was washed with 0,26M Na2S2O3in a saturated aqueous NaHCO3(30 ml), saturated aqueous NaHCO3and saturated salt solution, dried over MgSO4and evaporated in vacuum. As a result of clearing flash chromatography on silica gel (ethyl acetate/hexane) to obtain [2-(2-diferentactionsconcretesolver)-1-(2-oxocyclohexyl)ethyl]amide mo the folin-4-carboxylic acid (78 mg, 0,151 mmol) as a white solid.

A mixture of diastereoisomers:

1H NMR: (DMSO) [8,03 (d, J=7,2 Hz), of 7.96 (d, J=7,2 Hz), 1H], 7,50-7,42 (m, 2H), 7,30-7,21 (m, 2H), 7,10 (t, JH,F=Hz, 1H), 7,03 (d, J=8,4 Hz, 1H), 4,78-4,69 (m, 1H), of 4.54 (s, 2H), to 4.41-to 4.33 (m, 1H), 3,62 is 3.25 (m, 10H), 2,55-of 1.40 (m, 8H). MS: (M+H)+518.

According to the method of example 9, but using 2-aminocyclopentane receive [2-(2-diferentactionsconcretesolver)-1-(2-oxocyclopentanecarboxylate)ethyl]amide morpholine-4-carboxylic acid (Compound 12) in the form of a mixture of diastereoisomers:

1H NMR: (DMSO) [8,19 (d, J=8gts), to 7.15 (d, J=8gts), 1H], 7,49-7,42 (m, 2H), 7,30-7,21 (m, 2H), 7,10 (t, JH,F=Hz, 1H), [7,02 (d, J=8,4 Hz), 7,00 (d, J=8,4 Hz), 1H], 4,77-4,70 (m, 1H), [4,53 (C)to 4.52 (s), 2H], 4,10-3,91 (m, 1H), 3,60 is 3.23 (m, 10H), 2,28 is 1.70 (m, 6H). MS: (M+H)+504.

According to the method of example 9, but using 2-aminocyclohexanol receive [2-(2-diferentactionsconcretesolver)-1-(2-oxacyclobutane)ethyl]amide morpholine-4-carboxylic acid (Compound 13) in the form of a mixture of diastereoisomers:

1H NMR: (DMSO) 8,49 (d, J=7,Hz, 1H), of 7.48-7,42 (m, 2H), 7,30-7,21 (m, 2H), 7,11 (t, JH,F=Hz, 1H), 7,02 (d, J=8,8gts, 1H), 4,88-of 4.67 (m, 2H), 4.53-in (s, 2H), 3,64 is 3.23 (m, 10H), 2,93-2,70 (m, 2H), 2,23 of 1.99 (m, 2H). MS: (M+H)+.

EXAMPLE 10

[1-(2-benzylcarbamoyl-2-oxoethylidene)-2-phenylmethanesulfonyl]amide morpholine-4-carboxylic acid

(Compound 14).

Issurin (3.11 g, 29.6 mmol) dissolved in a mixture of 1,4-dioxane/Hsub> 2O 3:1 (40 ml) and added To the2CO3(0.5 g) and NaHCO3(0.5 g). Add di-tert-butyl dicarbonate (6,45 g, 29.6 mmol) and the mixture is stirred at room temperature overnight. The reaction mixture was extracted with dichloromethane (3 x 100 ml). The combined organic phases are washed with saturated salt solution, dried over MgSO4and evaporated in vacuum. The crude 3-tert-butoxycarbonylamino-2-hydroxypropionic acid (4,76 g, 23.2 mmol) obtained as a colorless oil which solidifies upon standing, and which is used without further purification.

Combine 3-tert-butoxycarbonylamino-2-hydroxypropionic acid (1.5 g, 7,31 mmol), benzylamine (1.1 ml, 10.0 mmol), EDC (2.5 g, 13,1 mmol) and HOBt (2.0 g 12.8 mmol). Add dichloromethane (15 ml) and then 4-methylmorpholine (2 ml). The mixture is stirred at room temperature. After dilution with ethyl acetate (300 ml) the solution was washed with aqueous HCl (100 ml), saturated aqueous NaHCO3(100 ml) and saturated salt solution (100 ml), dried over MgSO4and evaporated in vacuum. Output: 1,83 g, from 6.22 mmol; tert-butyl ether (2-benzylcarbamoyl-2-hydroxyethyl)carbamino acid.

Tert-butyl ether (2-benzylcarbamoyl-2-hydroxyethyl)carbamino acid (0.2 g, of 0.68 mmol) dissolved in dichloromethane (2 ml) and triperoxonane acid (2 ml). After stirring at room temperature for 2 cha is offering the solution is evaporated in vacuum and the residue is dried in high vacuum. To the residue add EDC (200 mg, 1.05 mmol), HOBt (200 mg, 1.28 mmol), 2-[(morpholine-4-carbonyl)amino]-3-phenylmethanesulfonyl acid (200 mg, 0,56 mmol), dichloromethane (5 ml) and 4-methylmorpholine (0.5 ml). The mixture is stirred at room temperature for 2 hours. After dilution with ethyl acetate (100 ml) the solution was washed with 1N. aqueous HCl (30 ml), a saturated solution of NaHCO3(30 ml) and saturated salt solution (30 ml), dried over MgSO4and evaporated in vacuum. The crude product is dissolved in dichloromethane (10 ml). Add periodinane dess-Martin (500 mg, 1.18 mmol) and the reaction mixture was stirred at room temperature for 1 hour. After dilution with ethyl acetate (100 ml) the solution was washed with 0,26M Na2S2O3in a saturated aqueous NaHCO3(30 ml), saturated aqueous NaHCO3and saturated salt solution, dried over MgSO4and evaporated in vacuum. Product ([1-(2-benzylcarbamoyl-2-oxoethylidene)-2-phenylmethanesulfonyl]amide morpholine-4-carboxylic acid) is crystallized from a mixture of ethyl acetate/diethyl ether and receive a white solid (153 mg, 0.29 mmol).

1H NMR: (DMSO) 9,24 (t, J=6,4 Hz, 1H), 8,19 (t, J=5,GC, 1H), 7,39-7,19 (m, 10H), was 7.08 (d, J=8gts, 1H), a 4.83 was 4.76 (m, 1H), 4,49 (s, 2H), 4,48-to 4.33 (m, 2H), or 4.31 (d, J=6,8gts, 2H), 3,68 is 3.25 (m, 10H). MS: (M+H)+531.

EXAMPLE 11

3-{2-[(morpholine-4-carbonyl)amino]-3-phenylmethanesulfonyl}-4-oxoazetidin--silt ether acetic acid

(Compound 15)

3 benzyloxycarbonylamino-4-oxoazetidin-2-silt ether acetic acid get in the way J.C. Arnould et al. Eur. J. Med, Chem 1992, 27, 131-140.

3 benzyloxycarbonylamino-4-oxoazetidin-2-silt ether acetic acid (100 mg, 0.36 mmol) hydronaut in a Parr shaker over 10% palladium-on-coal (100 mg) in ethyl acetate (20 ml) under a pressure of 50 f/CVD for 5 hours. The mixture is filtered through celite and evaporated, getting 3-amino-4-oxoazetidin-2-silt ester of acetic acid with quantitative vychodonemecka 2-[(morpholine-4-carbonyl)amino]-3-phenylmethanesulfonyl acid (100 mg, 0.28 mmol), 3-amino-4-oxoazetidin-2-silt ether acetic acid (52 mg, 0.36 mmol), EDC (100 mg, 0.52 mmol) and HOBt (100 mg, 0.64 mmol). Add dichloromethane (2 ml) and then 4-methylmorpholine (0.2 ml). The mixture is stirred at room temperature for 2 hours. After dilution with ethyl acetate (100 ml) the solution was washed with aqueous HCl (30 ml), saturated aqueous NaHCO3(30 ml) and saturated salt solution (30 ml), dried over MgSO4and evaporated in vacuum. The residue is subjected to flash chromatography on silica gel, elwira with ethyl acetate, and the obtained 3-{2-[(morpholine-4-carbonyl)amino]-3-phenylmethanesulfonyl}-4-oxoazetidin-2-silt ether acetic acid (17 mg, 0.035 mmol).

1H NMR: (DMSO) 9,18 (s, 1H), 8,72 (d, J=6,4 Hz, 1H), 7,41-7,30 (m, 5H), was 7.08 (m, 1H), 5,7 (s, 1H), 4.80 to br4.61 (m, 2H), 4,49 (s, 2H), 3,63-up 3.22 (m, 10H), of 2.08 (s, 3H). MS: (M+H)+483.

EXAMPLE 12

[1-(4-oxitetraciclina-3-ylcarbonyl)-2-phenylmethanesulfonyl]amide morpholine-4-carboxylic acid

(Compound 16)

4-aminotetrahydrofuran-3-ol get in the way Marquis, Robert W. et al. J. Med. Chem 2001, 44, 725-736.

Combine 2-[(morpholine-4-carbonyl)amino]-3-phenylmethanesulfonyl acid (100 mg, 0.28 mmol), 4-aminotetrahydrofuran-3-ol (100 mg, 0.96 mmol), EDC (200 mg, 1.04 mmol) and HOBt (200 mg, 1.28 mmol). Add DMF (2 ml) and then 4-methylmorpholine (0.2 ml). The resulting mixture was stirred at room temperature for 2 hours. After dilution with ethyl acetate (100 ml) the solution was washed with 1N. aqueous HCl (30 ml), saturated aqueous NaHCO3(30 ml) and saturated salt solution (30 ml), dried over MgSO4and evaporated in vacuum. The crude product is dissolved in dichloromethane (10 ml). Add periodinane dess-Martin (300 mg, 0.71 mmol) and the reaction mixture was stirred at room temperature for 1 hour. After dilution with ethyl acetate (100 ml) the solution was washed with 0,26M Na2S2O3in a saturated aqueous NaHCO3(30 ml), saturated aqueous NaHCO3and saturated salt solution, dried over MgSO4and evaporated in vacuum. As a result of clearing flash chromatography on silica gel (ethyl acetate) to obtain [1-(4-oxometry Roferon-3-ylcarbonyl)-2-phenylmethanesulfonyl]amide morpholine-4-carboxylic acid (8.6 mg, at 0.020 mmol) as a colorless glass. A mixture of diastereoisomers:

1H NMR: (DMSO) [8,42 (d, J=6,8gts), to 7.15 (d, J=7,2 Hz), 1H], 7,40-to 7.32 (m, 5H), [7,06 (d, J=8gts), 7,05 (d, J=8gts), 1H], 4,78-and 4.68 (m, 1H), [4,49 (C), 4,48 (s), 2H], 4,32 of 3.75 (m, 5H), 3,60 is 3.23 (m, 10H). MS: (M+H)+440.

EXAMPLE 13

[1-(2-hydroxy-1,1-dimethyl-3-oxo-3-phenylpropionyl)-2-phenylmethanesulfonyl]amide morpholine-4-carboxylic acid

(Compound 17)

Stage 1. In a flask equipped with a membrane and a magnetic stirrer, containing 4.1 g (20 mmol) 2-phenyl-1,3-dithiane (Aldrich) is added in a nitrogen atmosphere dry, distilled THF (20 ml). The solution is cooled to -30°and slowly via syringe type n-utility (1,6M in pentane, to 16.8 mmol, 10.5 ml). The reaction mixture is heated to -20°C and maintained at this temperature for 30 min, and then maintained at -10°C for 15 min, the Yellow solution is cooled to -78°quickly (within 30 seconds) add tert-butyl ether (1,1-dimethyl-2-oxoethyl)carbamino acid (1.5 g, 8 mmol, in 5 ml THF) and after 60 seconds quickly add a solution consisting of 2 ml of acetic acid and 5 ml THF. The cooling bath is removed after 4 min, water is added and the mixture extracted with ethyl acetate. The solvent is removed under reduced pressure and then recrystallized from 10 ml of ethyl acetate. White crystals washed three times with ethyl acetate and dried under reduced is the first pressure, getting tert-butyl ether [2-hydroxy-1,1-dimethyl-2-(2-phenyl[1,3]dition-2-yl)ethyl]carbamino acid (1.6 g, 52%).

Stage 2. To tert-butyl ether [2-hydroxy-1,1-dimethyl-2-(2-phenyl[1,3]dition-2-yl)ethyl]carbamino acid (1 g, 2.6 mmol) in 4.8 ml of dioxane at 10°add hydrochloric acid (4.8 ml, 4M in dioxane). The solution is heated to 23°C. After 2 hours the solution is concentrated to 4 ml and diluted with ether, obtaining a white precipitate, which is collected by filtration. The mother liquor is concentrated to a paste and triturated with ether. The solid part of the combine, getting 726 mg of 2-amino-2-methyl-1-(2-phenyl[1,3]dition-2-yl)propan-1-ol (98% yield).

Stage 3. 2-Amino-2-methyl(2-phenyl[1,3]dition-2-yl)propan-1-ol and 2-[(morpholine-4-carbonyl)amino]-3-phenylmethanesulfonyl acid are combined using standard described above reaction combinations of peptides in standard conditions with {1-[2-hydroxy-1,1-dimethyl-2-(2-phenyl[1,3]dition-2-yl)ethylcarbamate]-2-phenylmethanesulfonyl}amide morpholine-4-carboxylic acid (270 mg, 78%).

Stage 4. To {1-[2-hydroxy-1,1-dimethyl-2-(2-phenyl[1,3]dition-2-yl)ethylcarbamate]-2-phenylmethanesulfonyl}amide morpholine-4-carboxylic acid 200 mg, 0.32 mmol) in a 5.25 ml of a mixture of 4:1 acetonitrile:water at 23°C simultaneously add finely chopped HgCl2(192 mg, 0.7 mmol) and finely ground carbonate ka is ice (80 mg, 0.8 mmol) with stirring. The mixture is stirred for 10 min and then diluted with ethyl acetate. Add methylene chloride and the organic portion washed with water. After separation the organic layer is concentrated to a resin which is cured after the addition of ether. The ether is removed under reduced pressure, obtaining a white solid. The solid is dissolved in a minimum amount of methylene chloride and filtered to remove insoluble substances. The solution is concentrated and receiving [1-(2-hydroxy-1,1-dimethyl-3-oxo-3-phenylpropionyl)-2-phenylmethanesulfonyl]amide morpholine-4-carboxylic acid (165 mg, 100% yield).

Stage 5. [1-(2-hydroxy-1,1-dimethyl-3-oxo-3-phenylpropionyl)-2-phenylmethanesulfonyl]amide oxidized in the usual way, receiving [1-(2-hydroxy-1,1-dimethyl-3-oxo-3-phenylpropionyl)-2-phenylmethanesulfonyl]amide morpholine-4-carboxylic acid.

1H NMR: (CDCl3) [8,0 (d, J=8gts) 1H], and 7.7 to 7.2 (m, 10H), [5,9 (d, J=Hz) 1H], [4,8 (d, J=Hz) 1H], [4,3 (d, J=Hz) 1H], [4,1 (d, J=Hz) 1H], and 3.7 (m, 4H), to 3.36 (m, 4H), [3,3 (d, J=2 Hz) 1H], [3,29 (d, J=2 Hz) 1H], and 1.7 (s, 6H).

LC-MS: elution time=3,71 minutes 527,6(M-1), 529,6(M+1). (MS: API 150EX. LC: HP Agilent 1100 Series. Column: Phenomenex, 5 MK ODS3 100A 100 X 3 mm; flow Rate: 2 ml/min Gradient of two solvents: Solvent A, 99% water, 1% acetonitrile, with 0.1% AcOH. Solvent B, 99% acetonitrile, 1% water, with 0.1% AcOH. The gradient jn 100% A, 0% B to 0% A, 100% B starting from t0 to t=6 minutes Then reverse gradient to 100% A, 0% B, starting from t=7 to t=15 min).

By way of example 13, but using 3-(2-diferentactionsconcretesolver)-2-[(morpholine-4-carbonyl)amino]propionic acid in stage 3 receive [2-(2-diferentactionsconcretesolver)-1-(1,1-dimethyl-2,3-dioxo-3-phenylpropionyl)ethyl]amide morpholine-4-carboxylic acid.

LC-MS: elution time=3,95 minutes 593,4 (M-1), 596,2 (M+1). (MS: API 150EX. LC: HP Agilent 1100 Series. Column: Phenomenex, 5 MK ODS3 100A 100 x 3 mm; flow Rate: 2 ml/min Gradient of two solvents: Solvent A, 99% water, 1% acetonitrile, with 0.1% AcOH. Solvent B, 99% acetonitrile, 1% water, with 0.1% AcOH. A gradient from 100% A, 0% B to 0% A, 100% B from t=0 to t=6 minutes Then reverse gradient to 100% A, 0% B, starting from t=7 to t= 15 min).

EXAMPLE 14

Analysis of cathepsin S

Prepare solutions of test compounds at various concentrations in 10 μl of dimethyl sulfoxide (DMSO) and then diluted analytical buffer (40 μl, contains: MES, 50 mm (pH 6.5); EDTA, 2.5 mm; and NaCl, 100 mm). Cathepsin S man (0,158 pmol 25 ál analytical buffer) are added to the dilutions. The analytical solution is stirred for 5-10 seconds on a flat shaker, cover and incubate for 30 min at room temperature. Z-Val-Val-Arg-AMC (9 nmol 25 ál analytical buffer) are added to the analytical solutions and after hydrolysis analyzed spectrophotometrically (λ 460 nm) for 5 minutes is instanty apparent inhibition (K i) calculated on the basis of the progress curves of the enzyme using standard mathematical models.

EXAMPLE 15

Analysis of cathepsin B

Solutions of test compounds at various concentrations prepared in 10 μl of dimethyl sulfoxide (DMSO) and then diluted analytical buffer (40 μl, contains: N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES), 50 mm (pH 6); polyoxyethylenesorbitan, 0.05% and dithiothreitol (DTT), 2.5 mm). Cathepsin In person (0,025 25 pmol ál analytical buffer) are added to the dilutions. The analytical solution is stirred for 5-10 seconds on a flat shaker, cover and incubate for 30 min at room temperature. Z-FR-AMC (20 nmol in 25 ál analytical buffer) are added to the analytical solutions and after hydrolysis analyzed spectrophotometrically (λ 460 nm) for 5 minutes Constants of the apparent inhibition (Ki) calculated on the basis of the progress curves of the enzyme using standard mathematical models.

EXAMPLE 16

Analysis of cathepsin K

Prepare solutions of test compounds at various concentrations in 10 μl of dimethyl sulfoxide (DMSO) and then diluted analytical buffer (40 μl, comprising: MES, 50 mm (pH 5.5); EDTA, 2.5 mm DTT, 2.5 mm). Catepsin To person (0,0906 pmol 25 ál analytical buffer) are added to the dilutions. The analysis is ski the solution is stirred for 5-10 seconds on a flat shaker, cover and incubate for 30 min at room temperature. Z-Phe-Arg-AMC (4 nmol in 25 ál analytical buffer) are added to the analytical solutions and after hydrolysis analyzed spectrophotometrically (λ 460 nm) for 5 minutes Constants of the apparent inhibition (Ki) calculated on the basis of the progress curves of the enzyme using standard mathematical models.

EXAMPLE 17

Analysis of cathepsin L

Prepare solutions of test compounds at various concentrations in 10 μl of dimethyl sulfoxide (DMSO) and then diluted analytical buffer (40 μl, contains: MES, 50 mm (pH 5.5); EDTA, 2.5 mm DTT, 2.5 mm). Cathepsin L man (0.05 pmol 25 ál analytical buffer) are added to the dilutions. The analytical solution is stirred for 5-10 seconds on a flat shaker, cover and incubate for 30 min at room temperature. Z-Phe-Arg-AMC (1 nmol in 25 ál analytical buffer) are added to the analytical solutions and after hydrolysis analyzed spectrophotometrically (λ 460 nm) for 5 minutes Constants of the apparent inhibition (Ki) calculated on the basis of the progress curves of the enzyme using standard mathematical models.

I found that some of the compounds of the present invention, tested in accordance with the above analysis in respect of inhibition about the EPHA, show selective activity of inhibition of cathepsin S. the Apparent inhibition constants (Kifor compounds of the present invention in relation to cathepsin S are in the range of about from about 10-10M to about 10-7M.

EXAMPLE 18

Representative pharmaceutical compositions containing the compounds of formula I

Compositions for oral administration

The compound of the formula I10-100 mg
Citric acid monohydrate105 mg
Sodium hydroxide18 mg
Flavoring agent
Waterto 100 ml

Compositions for intravenous injection

The compound of the formula I0.1 to 100 mg
Dextrose monohydrateto give isotonicity
Citric acid monohydrate1,05 mg
Sodium hydroxide0.18 mg
Water for injectionto 1.0 ml

Composition for tablets

The compound of the formula I1%
Microcrystalline CE is lulose 73%
Stearic acid25%
Colloidal silicon dioxide1%

1. The compound of the formula I

where X1and X2both represent methylene;

R3represents-CR5=CHR6, R5and R6together with the atoms to which are attached R5and R6form (C6-12)aryl, where R3optionally substituted by 1-5 radicals-X4OR9where X4represents a bond, R9represents a halogen-substituted (C1-3)alkyl, and

R4represents-C(O)X5R11where X5represents a bond, and R11is hetero(C5-6)cycloalkyl(C0-3)alkyl,

X3represents a group of formula (a), (b) or(C)

n represents 0, 1 or 2;

R20represents hydrogen;

R21selected from the group consisting of hydrogen, -C(O)R26, -S(O)2R26, -C(O)OR26;

R23selected from H and (C6-12)aryl(C0-6)alkyl;

R25selected from hydrogen, (C6-12)aryl(C0-6)alkyl or-X4S(O)2R26where X4has the above values

R26selected from the group consisting of hydrogen, (C6-12)aryl(C0-6)alkyl,

where X3optionally contains, in addition, 1 Deputy, who, being in the alicyclic or aromatic ring system, is a radical independently selected from the group consisting of-X6OR17where R17represents hydrogen, (C1-6)alkyl and X6represents a bond or (C1-6)alkylene; and

its N-oxide derivatives, protected derivatives, individual isomers and mixtures of these isomers; and the pharmaceutically acceptable salt and solvate of such compounds, its N-oxide derivatives, protected derivatives, individual isomers and mixtures of these isomers.

2. The compound according to claim 1, where X1and X2both represent methylene, R3represents-CR5=CHR6where R5and R6together with the atoms to which are attached R5and R6form (C6-12)aryl, where R3optionally substituted by 1-5 radicals-X4OR9where X4represents a bond and R9represents a halogen-substituted (C1-3)alkyl, N-oxide derivatives, protected derivatives, individual isomers and mixtures of these isomers; and the pharmaceutically acceptable salt and solvate of such compounds and the N-oxide derivatives, protected production is the breaking, individual isomers and mixtures of these isomers.

3. The compound according to claim 2, where R4represents-C(O)X5R11where X5represents a bond, and R11is hetero(C5-6)cycloalkyl(C0-3)alkyl, and

its N-oxide derivatives, protected derivatives, individual isomers and mixtures of these isomers; and the pharmaceutically acceptable salt and solvate of such compounds, its N-oxide derivatives, protected derivatives, individual isomers and mixtures of these isomers.

4. The compound according to claim 3, where X3represents a group of formula (a), (b) or (C)

n represents 0, 1 or 2;

R20represents hydrogen;

R21represents-C(O)R26, -S(O)2R26, -C(O)OR26;

R25is a (C6-12)aryl(C0-6)alkyl;

R26is a (C6-12)aryl(C0-6)alkyl,

where X3optionally contains, in addition, 1 Deputy, who, being in the alicyclic or aromatic ring system, is a radical independently selected from-X6OR17where X6represents a bond or (C1-6)alkylene and R17represents hydrogen, (C1-6)alkyl,

its N-oxide derivatives, protected derivatives, individual isomers and mixtures of these isomers; and the pharmaceutically acceptable salt and solvate of such compounds, its N-oxide derivatives, protected derivatives, individual isomers and mixtures of these isomers.

5. The compound according to claim 4, where R3selected from the group comprising phenyl, 4-were, 2nd were, 3, 5dimethylphenyl, 4-triptoreline, naphthalene-2-yl, 3-were 3-triptoreline, 2-triptoreline, 4-tert-butylphenyl, 2-fluoro-3-were, biphenyl, 2-chloro-5-triptoreline, 2,4-bistrifluormethylbenzene 2-fluoro-3-triptoreline, 2-fluoro-4-triptoreline, 2-fluoro-5-triptoreline, 2-fluoro-5-triptoreline, 5-fluoro-2-triptoreline, 4-fluoro-3-triptoreline, 3,5-bistrifluormethylbenzene.

6. The compound according to claim 5, where R4is benzoyl, morpholine-4-carbonyl, furan-3-carbonyl, 2-methoxybenzoyl, 3-methoxybenzoyl, benzo[1,3]dioxol-5-carbonyl, 3-pyridine-3-ylacrylic, benzofuran-2-carbonyl, furan-2-carbonyl, biphenyl-4-carbonyl, quinoline-2-carbonyl, quinoline-3-carbonyl, pyridine-3-carbonyl, tert-butyl ester 4-carbonyliron-1-carboxylic acid, ethyl ester 4-carbonyliron-1-carboxylic acid, 4-(furan-2-carbonyl)piperazine-1-carbonyl, pyridine-4-carbonyl, 1-oxypyridine-4-carbonyl, 1-oxopyridine-3-carbonyl, thiophene-2-carbonyl, thiophene-3-carbonyl, methylthiophene-2-carbonyl, 3-chlorothiophene-2-carbonyl, 3-bromothiophene-2-carbonyl, cyclopentanecarbonyl, benzo[b]thiophene-2-carbonyl, 3-chlorobenzo[b]thiophene-2-carbonyl, 5-methylthiophene-2-sulfonyl, thiophene-2-sulfonyl, N-pyridin-4-yl-formamid, N-pyridine-3-informel, 1H-indole-5-carbonyl, pyridine-2-carbonyl, pyrazin-2-carbonyl, 3-hydroxypyridine-2-carbonyl, 2-aminopyridine-3-carbonyl, 2-hydroxypyridine-3-carbonyl, 6-aminopyridine-3-carbonyl, 6-hydroxypyridine-3-carbonyl, pyridazin-4-carbonyl, 1-oxo-1,3-dihydroindol-2-carbonyl.

7. The connection according to claim 6, where X3selected from the group comprising benzyl ether of 4-amino-3-oxazepan-1-carboxylic acid,

isobutyl ether 4-amino-3-oxazepan-1-carboxylic acid,

4-amino-1-benzodiazepin-3-one,

4-amino-1-benzosulfimide-3-one,

4-amino-1-(pyridine-2-sulfonyl)azepin-3-one,

4-amino-1-(1-oxypyridine-2-sulfonyl)azepin-3-one,

4-amino-1-(3,4-dimethoxybenzonitrile)azepin-3-one,

4-amino-1-(naphthalene-1-sulfonyl)azepin-3-one,

4-amino-1-(thiophene-2-sulfonyl)azepin-3-one,

4-amino-1-(pyrrolidin-1-sulfonyl)azepin-3-one,

4-amino-1-methanesulfonate-3-one,

4-amino-1-(pyrrolidin-1-carbonyl)azepin-3-one,

dimethylamide 4-amino-3-oxazepan-1-carboxylic acid,

benzylamine 4-amino-3-oxazepan-1-carboxylic acid,

4-amino-1-benzilate the EN-3-one, 4-amino-1-benzylpiperidine-3-one,

4-amino-1-benzylpiperidine-3-one,

4-amino-1-benzylpyrrolidine-3-one,

4-amino-1-benzylpyrrolidine-3-one,

4-amino-1-benzensulphochloramide-3-one,

4-amino-1-(5-etylhexyl)pyrrolidin-3-one,

3-(dibenzofuran-2-sulfonylamino)-1-ethyl-2-oxobutanamide,

5-amino-1-[(4-methoxybenzenesulfonyl)methyl]pentylamine,

5-benzyloxycarbonylamino-1-[(4-methoxybenzenesulfonyl)methyl]pentylamine.

8. The connection according to claim 7, selected from the group consisting of

(1-{5-amino-1-[(4-methoxybenzenesulfonyl)methyl]intercalator}-2-phenylmethanesulfonyl)amide morpholine-4-carboxylic acid,

benzyl ether (6-(4-methoxybenzenesulfonyl)-5-{2-[(morpholine-4-carbonyl)amino]-3-phenylmethanesulfonyl}hexyl)carbamino acid,

(1-{1-[(4-methoxybenzenesulfonyl)methyl]-3-phenylpropionyl}-2-phenylmethanesulfonyl)amide morpholine-4-carboxylic acid,

[1-(3-benzosulfimide-2-oxopropylidene)-2-phenylmethanesulfonyl] amide morpholine-4-carboxylic acid,

[1-(1-benzoyl-4-oxopyrrolidin-3-ylcarbonyl)-2-phenylmethanesulfonyl] amide morpholine-4-carboxylic acid,

1-(1-benzazolyl-4-oxopyrrolidin-3-ylcarbonyl)-2-phenylmethanesulfonyl] amide morpholine-4-carboxylic acid and

benzyl ester 4-{2-[(morpholine-4-carbonyl)amino]-3-phenylmethanesulfonyl}-3-oxazepan-1-carboxylic acid.

9. Pharmaceutical composition having inhibitory activity against cathepsin S protease, comprising a therapeutically effective amount of a compound according to claim 1 in combination with pharmaceutically acceptable excipients.

10. The use of compounds according to claim 1 for the manufacture of drugs for treating disease in an animal in which the activity of cathepsin S contributes to the pathology and/or symptoms.

11. The method of obtaining the compounds of formula I

where X1and X2both represent methylene;

R3represents-CR5=CHR6, R5and R6together with the atoms to which are attached R5and R6form (C6-12)aryl, where R3optionally substituted by 1-5 radicals-X4OR9where X4represents a bond, R9represents a halogen-substituted (C1-3)alkyl, and

R4represents-C(O)X5R11where X5represents a bond, and R11is hetero(C5-6)cycloalkyl(C0-3)alkyl,

X3represents a group of formula (a), (b) or(C)

n represents 0, 1 or 2;

R20represents hydrogen;

R21selected from the group consisting of hydrogen, -C(O)R26, -S(O)2R26, -C(O)OR26;

R23selected from H and (C6-12)aryl(C0-6)alkyl;

R25selected from hydrogen, (C6-12)aryl(C0-6)alkyl or-X4S(O)2R26where X4has the above values;

R26selected from the group consisting of hydrogen, (C6-12)aryl(C0-6)alkyl,

where X3optionally contains, in addition, 1 Deputy, who, being in the alicyclic or aromatic ring system, is a radical independently selected from the group consisting of-X6OR17where R17represents hydrogen, (C1-6)alkyl and X6represents a bond or (C1-6)alkylene; and the method includes:

(A) interactions of the compounds of formula 2

with the compound of the formula (a)

where X1X2, R3, R4, R20and R21have the meanings indicated above for formula I; or

(C) the interaction of the compound of formula 2 with the compound of the formula (b)

where R20, R23 and R25have the meanings indicated above for formula I; or

(C) the interaction of the compounds of formula 2 with the compound of the formula (C)

where R20, R23and R25have the meanings indicated above for formula I; and

(D) the optional conversion of a compound of formula I in a pharmaceutically acceptable salt;

(E) optional conversion of the compounds of formula I in salt form in mesolevel form;

(F) optional conversion of the non-oxidized form of the compounds of formula I in a pharmaceutically acceptable N-oxide;

(G) optional conversion of the N-oxide forms of the compounds of formula I in its unoxidized form;

(H) optional selection of individual isomers of compounds of formula I from a mixture of isomers.

12. The compound of formula Ix

where X1and X2both represent methylene,

R3represents-CR5=CHR6where R5and R6together with the atoms to which are attached R5and R6form (C3-12)cycloalkenyl or (C6-12)aryl, where R3optional radical substituted 1-X4OR9where X4represents a bond and R9represents a halogen-substituted (C1-3)alkyl;

R4represents-C(O)X5R11, is de X 5represents a bond, and R11is hetero(C5-12)cycloalkyl(C0-3)alkyl;

X3represents a group of formula (a), (b), (C), (d), (e), (f), (g)

or (h)

___ is a simple or a double bond;

X7is (C6-10)aryl or NR20R25;

n represents 0, 1 or 2;

R20represents hydrogen;

R21selected from the group consisting of hydrogen, -C(O)R26, -S(O)2R26, -C(O)OR26;

R23selected from H, (C6-12)aryl(C0-6)alkyl;

R25selected from hydrogen, (C6-12)aryl(C0-6)alkyl, -X4S(O)2R26where X4has the above values;

R26selected from the group consisting of hydrogen, (C6-12)aryl(C0-6)alkyl;

R28represents hydrogen or-O-C(=O)-R29;

R29is (C1-6)alkyl,

where X3optionally contains, in addition, 1 Deputy, who, while in alicyclic or aromatizes the th ring system, is a moiety independently selected from-X6OR17where R17represents hydrogen, (C1-6)alkyl and X6represents a bond or (C1-6)alkylene; and one of its N-oxide derivatives, protected derivatives, individual isomers and mixtures of these isomers; and the pharmaceutically acceptable salts and solvate of such compounds and the N-oxide derivatives, protected derivatives, individual isomers and mixtures of these isomers.

13. The connection section 12, where R23selected from (C6-12)aryl(C0-6)alkyl.

14. The connection 13, selected from the group consisting of

[1-(1-benzoyl-4-oxopyrrolidin-3-ylcarbonyl)-2-phenylmethanesulfonyl]amide morpholine-4-carboxylic acid;

[1-(1-benzazolyl-4-oxopyrrolidin-3-ylcarbonyl)-2-phenylmethanesulfonyl]amide morpholine-4-carboxylic acid;

benzyl ester 4-{2-[(morpholine-4-carbonyl)amino]-3-phenylmethanesulfonyl}-3-oxazepan-1-carboxylic acid;

[1-(3-benzosulfimide-2-oxopropylidene)-2-phenylmethanesulfonyl]amide morpholine-4-carboxylic acid, or

N-{1S-[1S-(4-methoxybenzenesulfonyl)-3-phenylpropionyl]-2-benzylmalonate}morpholine-4-carboxamide.

15. The connection 13, selected from the group consisting of

[(R)-1-(6-oxocyclohexa-1-tilcara who yl)-2-phenylmethanesulfonyl]amide morpholine-4-carboxylic acid;

[(R)-1-(3,4-dioxincontaminated)-2-phenylmethanesulfonyl]amide morpholine-4-carboxylic acid;

[2-(2-diferentactionsconcretesolver)-1-(2-oxocyclohexyl)ethyl]amide morpholine-4-carboxylic acid;

[2-(2-diferentactionsconcretesolver)-1-(2-oxocyclopentanecarboxylate)ethyl]amide morpholine-4-carboxylic acid;

[2-(2-diferentactionsconcretesolver)-1-(2-oxacyclobutane)ethyl]amide morpholine-4-carboxylic acid;

[1-(2-benzylcarbamoyl-2-oxoethylidene)-2-phenylmethanesulfonyl]amide morpholine-4-carboxylic acid;

3-{2-[(morpholine-4-carbonyl)amino-3-phenylmethanesulfonyl}-4-oxoazetidin-2-silt ester of acetic acid;

[1-(2-hydroxy-1,1-dimethyl-3-oxo-3-phenylpropionyl)-2-phenylmethanesulfonyl]amide morpholine-4-carboxylic acid;

[1-(4-oxitetraciclina-3-ylcarbonyl)-2-phenylmethanesulfonyl]amide morpholine-4-carboxylic acid, or

[2-(2-diferentactionsconcretesolver)-1-(1,1-dimethyl-2,3-dioxo-3-phenylpropionyl)ethyl]amide morpholine-4-carboxylic acid.



 

Same patents:

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to lysine or proline L-ascorbic acid derivatives and methods for production thereof. Method for production of lysine L-ascorbic acid derivatives includes treatment of L-ascorbic acid with lysine followed by isolation of said target derivatives, wherein L-ascorbic acid is covalently bonded to lysine in C6-site of L-ascorbic acid. Method for production of proline L-ascorbic acid derivatives includes treatment of L-ascorbic acid with proline covalently bonded to L-ascorbic acid followed by isolation of said target derivatives.

EFFECT: new L-ascorbic acid derivatives useful in medicine as anticancer agents.

14 cl, 16 dwg, 8 ex

The invention relates to the production of carbonyl compounds, which are used as primary intermediates and fine organic synthesis

The invention relates to the production of lactones, which are used as corrosion inhibitors of metals to produce antioxidants for hydrocarbon fuels and lubricants

The invention relates to the derivatives of aminophenylamino formula I

< / BR>
where R is phenyl, substituted C1-C6by alkyl; R1represents hydrogen; X represents -(CH2)3-Y, cyclopropyl or tetrahydro-2-oxo-3-furoyl; Y represents chlorine, bromine or hydroxy,

or their acid additive salts

The invention relates to a method of obtaining new, not previously described in the literature 2,4-dihydroxy-4-carboxy-3-X-butane-4-alidou (X= OH or Cl), are promising for use as biologically active compounds and intermediates of fine organic synthesis

The invention relates to methods for producing lactone 1R, CIS-2,2-dimethyl-3-formultimedia-1-carboxylic acid and halogenated intermediates

The invention relates to the field of organic synthesis of lactones, namely-butyrolactone

The invention relates to new chemical compounds with biological activity, particularly to derivatives of dibenzazepine-6,7-dihydro-5H-dibenz [c, e] azepin-7-it is a General formula

R(I)where R is F, Cl, which have garmentindustry activity against microsomal cytochrome P-450-dependent monooxygenase system, liver, metabolizing foreign compounds - xenobiotics

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new derivatives of sulfonylpyrrolidine of the formula (I): wherein R1 means aryl optionally substituted with halogen atom; R2 means aryl optionally substituted with halogen atom or (lower)-alkyl; R3 means -OR', cyano-group, halogen atom, N-hydroxyamidino-group, -C(O)-OR, -C(O)NR'R'', -N(R')-C(O)-R4, -N(R')-S(O)2-R, -N(R')-C(S)-NR'R, or 5- or 6-membered heteroaryl group comprising from 1 to 4 heteroatoms one of that represents oxygen atom and others represent nitrogen atom, or all heteroatoms represent nitrogen atom only and optionally substituted with (lower)-alkyl or (C3-C7)-cycloalkyl; R4 means (C3-C7)-cycloalkyl, phenyl or (lower)-alkyl that are optionally substituted with halogen atom; R means (lower)-alkyl; R' means hydrogen atom (H), (lower)-alkyl or (C3-C7)-cycloalkyl-(lower)-alkyl being independently of one another if above one R' presents; R'' means H, (lower)-alkyl; n means a whole number from 0 to 5, and to their pharmaceutically acceptable salts under condition that 1-[4-(methylphenyl)sulfonyl]-5-phenylpyrrolidinemethanol is excluded. Compounds of the formula (I) possess affinity to metabotropic glutamate receptors of group I that allows their using as a medicinal agent in treatment, prophylaxis of acute and/or chronic neurological disturbances and states that result to development of glutamate insufficiency taken among the following disorders: damage of spinal cord, head trauma, hypoxia caused by pregnancy, hypoglycemia, Alzheimer's disease, Huntington chorea, amyotrophic lateral sclerosis, disturbance in cognitive ability, memory disturbance and chronic and acute pain, schizophrenia, idiopathic parkinsonism and parkinsonism caused by medicinal agents, convulsions, anxiety (fear) and depressions.

EFFECT: valuable medicinal properties of compounds.

21 cl, 6 sch, 1 tbl, 153 ex

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

The invention relates to substituted cyclic aminoven compounds of formula (I)

< / BR>
where Ar represents thienyl, substituted pyridine, phenyl unsubstituted or substituted with halogen, hydroxy, alkoxy, C1-C4the alkyl, phenyloxy, NO2or phenyl; R1is NHOR2where R2is hydrogen; W is one or more hydrogen atoms; Y is independently one or more members of the group consisting of hydroxy, SR3, alkoxy, NR6R7where R6and R7independently selected from hydrogen, alkyl, pyridylethyl, SO2R8, COR9or R6and R7can be combined with the formation of the ring containing the nitrogen to which they relate, formulas

< / BR>
where Y' is CH2OH , SO2; R3represents hydrogen, alkyl, aryl, benzothiazolyl, pyrazinyl, N-methylimidazole; R8represents C1-C4alkyl, phenyl; R9represents hydrogen, alkyl, phenyl; Z is hydrogen; n = 1, and its optical isomer, diastereoisomer, or enantiomer, or its pharmaceutically acceptable salt

The invention relates to carbamoyloximes General formula I

< / BR>
where R1selected from the group comprising alkyl, substituted alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl and substituted heteroaryl; R2represents alkyl, and R1and R2together with the nitrogen atom associated with R2and SO2the group associated with R1may form a heterocyclic or substituted heterocyclic group; R3represents hydrogen, and when R2does not form a heterocyclic group with R1then R2and R3together with the nitrogen atom associated with R2and the carbon atom bound to R3may form a heterocyclic or substituted heterocyclic group; R5represents -(CH2)x-Ar-R5'where R5'selected from the group comprising-O-Z-NR8R8'and-O-Z-R12where R8and R8'independently selected from the group comprising hydrogen, alkyl, substituted alkyl, heterocyclyl, and where R8and R8'combined with the formation of the heterocycle or substituted heterocycle, R12selected from the group comprising heterocycle substituted heteroaryl, x is an integer from 1 to 4; Q represents-C(X)NR7- where R7represents hydrogen, and X represents oxygen; and its pharmaceutically acceptable salts; the compounds of formula IA, where instead of the hydroxyl group on the C-end - radical R6that represents alkoxy, substituted alkoxy, cycloalkane, or-NH-substituted; two pharmaceutical compositions, having the ability to block or inhibit cell adhesion, containing as active ingredient a compound I or compound IA; method binding VLA-4 in a biological sample, and the method of treating inflammatory conditions in a patient is a mammal

The invention relates to new spirochetes formula I

< / BR>
where Ar is phenyl, substituted phenyl where the substituents are: alkoxy, alkyl, alkoxyalkyl, phenoxy, halogen, pyridyloxy, alkoxyalkane, halogenfree; R1- H; R2- H1-C4alkyl; W represents O or one or more1-C4alkyl fragments; Y is independently one or more members of the group consisting of H2, SR3, alkoxy; R3- H, alkyl; Z is a carbocyclic or heterocyclic Spiro-fragment with a 3-7 member ring system, where the heterocyclic fragment includes 2 oxygen atom or sulfur, or one nitrogen atom and spirits may be unsubstituted or substituted by hydroxy, C1-C4the alkyl, benzyloxy; n=1-3; optical isomers, diastereomers or enantiomers or pharmaceutically acceptable salts

The invention relates to substituted diaminocarbenes acids of the formula I

< / BR>
and/or a stereoisomeric form of the compounds of formula (I), and/or physiologically acceptable salts of the compounds of formula (I), where1- phenyl, phenyl, one - or twofold substituted linear or branched (C1-C7)-alkyl, hydroxyl, group (C1-C6)-alkyl-C(O)-O-group (C1-C6)-alkyl-O-, halogen, CN-group, methylenecyclopropane; group R4- (R5)N-, R2, R4and R5are the same or different and mean a hydrogen atom, (C1-C6)-alkyl; R3and G are the same or different and mean: 1

The invention relates to sulphonilecarbomide acids of the formula

< / BR>
and/or their stereoisomeric forms and/or physiologically acceptable salts, where R1means phenyl, phenyl, one or twice substituted by a group WITH1-C6-alkyl-Oh, halogen, trifluoromethyl, a group WITH1-C6-alkyl-O-C(O)-, methylenedioxy-, R4-(R5)N-; triazole, thiophene, pyridine; R2means H, C1-C6alkyl; R4and R5are adnikowymi or different and denote H, C1-C6-alkyl; R3means H, C1-C10-alkyl, where alkyl unsubstituted and/or one hydrogen atom of the alkyl residue substituted by hydroxyl,2-C10alkenyl, R2-S(O)n-C1-C6-alkyl, where n means 0, 1, 2; R2-S(O)(=NH)-(C1-C6)-alkyl and the other, or R2and R3together form a cycle with a carboxyl group as a substituent cycle of partial formula II:

< / BR>
where r is 0, 1, 2, 3 and/or one of the carbon atoms in the cycle replaced by-O-, and/or the carbon atom in the cycle part of the formula II substituted once by phenyl; a represents a covalent bond, -O-;

The invention relates to derivatives of 5-areolation formula I, where a represents-CH2-, -C(O)- or-S(O)2-; Z denotes a group of formula b or D:

< / BR>
where X is O or S; R6and R7independently from each other selected from the group including hydrogen, C1-C6alkyl, CF3WITH1-C6alkylthio,1-C6alkoxy, halogen, nitro, hydroxy, and-NR9R10where R9and R10independently of one another denote hydrogen or C1-C6alkyl; R1means hydrogen, C1-C6alkyl, C1-C6alkoxy, hydroxy2-C6alkyloxy, hydroxy, halogen, cyano, carboxy, co2SOP(CH3)2, -СОNR9R10, -ОСОNR9R10or ОSO2R11where R9and R10have the meanings indicated above, and R11means1-C6alkyl or CF3; R3means-SO2R12or-SO2NR13R14where R12means1-C6alkyl; R13means hydrogen or C1-C6alkyl, and R14means hydrogen, C1-C6alkyl, C3-C6cycloalkyl,2-C6alkenyl, hydroxy SS1-C6alkyl, benzyl, phenethyl, naphtalate, acyl, morpholino-C1-C6alkyl, pyrrolidino-C1-C6alkyl, pyridyl-C1-C6alkyl, furanyl-C1-C6alkyl, or R13and R14together with the nitrogen atom to which they are attached, optionally form heterocyclization selected from piperidino, morpholino, di-(C1-C6alkyl)morpholino, pyrrolidino, methylpiperazine, phenylpiperazine, forfilipino; and their pharmaceutically acceptable salts or their esters or carbamates, individual isomers and mixtures of isomers and method thereof

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to D-proline derivatives of formula I or IA wherein R1 and R2 are independently lower alcoxy, lower alkenyloxy, hydroxy, -OCH(CH3)OC(O)-lower alkyl or -OCH2C(O)N(R3)N(R4), with the proviso, that only one from R1 and R2 represent hydroxy; R3 and R4 are independently hydrogen, lower alkyl? Lower alkenyl, or cycloalkyl; or R1 and R2 together with carbon atom to which they are attached form linkage group X, wherein X represents -O(CH2)nCH=CH(CH2)nO- or -O(CH2)mO-; n = 1, 2 or 3; m = 4-8.

EFFECT: new prodrugs.

14 cl, 1 tbl, 25(29) ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to new compounds of formula I ,

solvates or pharmaceutically acceptable salts having antiarrhythmic activity, including ventrical fibrillation, as well as pharmaceutical compositions containing the same. Compounds of present invention are useful in treatment or prevention of arrhythmia, modulation of ion channel activity, for topic or local anesthesia, etc. In formula I X is direct bond, -C(R6,R14)-Y- and C(R13)=CH-; Y is direct bond, O, S, and C1-C4-alkylene; R13 is hydrogen, C1-C6-alkyl, C3-C8-cycloalkyl, unsubstituted aryl or benzyl; R1 and R2 are independently C3-C8-alkoxyalkyl, C1-C8-hydroxyalkyl and C7-C12-aralkyl; or R1 and R2 together with nitrogen atom directly attached thereto form ring of formula II ,

wherein said ring is formed by nitrogen and 3-9 ring atoms selected independently from carbon, sulfur, nitrogen and oxygen, etc; R3 and R4 are independently attached to cyclohexane ring in 3-, 4-, 5-, or 6-position and represent independently hydrogen, hydroxyl, C1-C6-alkyl and C1-C6-alkoxy; and when R3 and R4 are bound with the same atom of cyclohexane ring they may form together 5- or 6-membered spiroheterocycle ring containing one or two heteroatoms selected from oxygen and sulfur; A is C5-C12-alkyl, C3-C13-carbocyclic ring, or ring structure as defined herein.

EFFECT: new antiarrhythmic drugs.

30 cl, 12 dwg, 34 ex

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