Derivatives of 4-mercaptopyridine as inhibitors farnesyltransferase

 

(57) Abstract:

The invention relates to derivatives of 4-mercaptopyridine formulae of the following classes of i), ii) and iii), represented by the following formula:

< / BR>
where X1means N; C1-6alkoxyl1-6alkyl; C1-6alkoxyl1-6alkylsulphonyl; And means phenyl, naphthyl; X2means H, phenyl, phenyl WITH1-6alkyl; X3means N; C1-6alkyl; X4means1-6alkylsulfanyl, carbarnoyl;

< / BR>
where X5means-C(O)-C1-4alkyl-Phenyl; -C(O)-C1-6alkyl; -C(O)-C1-4alkylpyridine, and Ph and pyridyl optionally substituted C1-4the alkyl, C1-4alkoxy, C1-4alkalosis1-4by alkyl; a represents naphthyl; R3selected from the group comprising H; HE; NO2; -(CH2)nCOOR8where n is 0 to 3 and R8represents H, C1-4alkyl, C2-4alkenyl; -CONR9R10where R9and R10independently represent H, C1-4alkyl, C2-4alkenyl, -CON(R11OR12where R11and R12independently represent H, C1-4alkyl and C2-4alkenyl; a group of formula II: -CONR13-CHR14-COOR17where R13represents N or C1-4alkyl; R17presented which may be the same or different;

< / BR>
where X6has any value defined above for X5in ii); X7is Ph, optionally substituted by substituent (substituents), selected from the group comprising FROM1-4alkoxy; a represents Ph or naphthyl; R3and R such as defined above, or its N-oxide, MES, ester, pharmaceutically acceptable salt. 3 S. and 3 C.p. f-crystals, 47 schemes.

The present invention relates to compounds that inhibit farnesiana products of mutant ras genes by inhibiting the enzyme farnesyltransferase (FPT-Aza). The invention relates also to methods of making the compounds, pharmaceutical compositions and methods for treating diseases, especially cancer, which mediasource by farnesiana ras.

I believe that cancer include a change in expression or function of genes regulating growth and differentiation of cells. Not pretending to theoretical considerations, the following text is a scientific basis for the role of ras in cancer tumors. The genes of the ras in tumors frequently mutate. Genes encode ras-binding GTP-independent (GTP) proteins, which are believed to be involved in signal transduction, proliferation and malignant transformation. Genes N, Katsia protein ras is required for biological activity. I believe that farnesiana ras catalyzed FPT-Azoy, is an integral stage in the processing of the ras. It proceeds by transferring farnesenes group farnesylpyrophosphate (FPP) to the cysteine at the C-terminal tetrapeptide ras in structural motif called block SAAH. After further pokeronline modifications, including proteolytic cleavage at cysteine residue block SAAH and methylation of carboxyl cysteine, ras is able to communicate with the cellular membrane to transmit growth signals into the internal portion of the cell. I believe that in normal cells activated ras acts together with growth factors to stimulate cell growth. I believe that in tumor cells mutations in ras causes it to stimulate cell division even in the absence of growth factors (Travis J. Science 1993, 260, 1877-1878), possibly due to the fact that he is constantly present in the GTP-activated form, is not converted to cycle back into GDP-Deaktivierung form. Inhibition of farnesiana products of mutant ras gene will stop or reduce activation.

One class of known inhibitors farnesyltransferase based on analogues of farnesylpyrophosphate (see , for example, the application for the European patent EP 53454 tetrapeptide, such as CVIM (Cys-Val-Ile-Met). James (1993) Science 260, 1937-1942, described based on the benzodiazepines coworkers peptide compounds. After the earliest priority date of the present invention Lerner (1995) J. Biol. Chem., 270, 26802, and Eisai in the application for international patent WO 95/25086 described the following coworkers peptide compounds, based on s as the first residue. In addition, after the earliest priority date of the present invention Bristol-Myers Squibb in the application for the European patent EP 696593 first described inhibitors farnesyltransferase with the remainder of the 4-sulfanilamide in the first position.

According to one aspect of the present invention proposed a pharmaceutical composition comprising an inhibitor of farnesiana ras formula I

< / BR>
where R1selected from the group comprising H; -C1-4alkyl; -C1-3alkylen-PH, optionally mono - or disubstituted in the Ph substituents selected from the group comprising FROM1-4alkyl, halogen, HE1-4alkoxy, C1-4alkanoyl,1-4alkanoyloxy, amino, C1-4alkylamino, di(C1-4alkyl) amino, C1-4alkanolamine, nitro, cyano, carboxy, carbarnoyl, C1-4alkoxycarbonyl, thiol, C1-4alkylsulfanyl,1-4alkylsulfonyl, C1-4)nPH, optionally substituted in the Ph, as defined above for substitution in Ph for R1= -C1-3alkylen-RH, and n is 0-4; -C1-4alkylen-CONR4R5where R4and R5independently selected from H and C1-4of alkyl; and-C1-4alkylen-R6where R6selected from H, C1-4of alkyl;

R2selected from the group comprising H; -C1-4alkyl; -C1-3alkylen-PH, optionally substituted in the Ph, as defined above for substitution in Ph in R1= -C1-3alkylen-PH; -SOS1-4alkyl and-SOOS1-4of alkyl;

R3selected from the group comprising H; HE; CN; CF3; NO2; -C1-4of alkyl; -C1-4alkylen-R7where R7selected from phenyl, naphthyl, a 5-10 membered monocyclic or bicyclic heteroaryl ring containing up to 5 heteroatoms selected from O, N and S, and any aryl ring in R7optionally substituted as defined above for substitution in the Ph-group in R1= -C1-3alkylen-Ph; R7;2-4alkenyl; halogen; -(CH2)nCOOR8where a = 0-3 and R8represents H, C2-4alkyl or C2-4alkenyl; -CONR9R10where R9and R10independently represent H, C1-4alkyl, C2-4alkenyl, O-C1-41;

-CON(R11OR12where R11and R12independently represent H, C1-4alkyl and C2-4alkenyl;

a group of the formula II: -CONR13-CHR14-COOR17where R13represents N or C1-4alkyl, R17represents N or C1-6alkyl, R14selected from the group comprising a side chain lipophilic amino acids, carbamoyl1-4alkyl, N-(mono1-4alkyl)carbarnoyl1-4alkyl and N-(dis1-4alkyl)carbamoyl1-4alkyl, and the group of formula II is L - or D-configuration at the chiral alpha carbon in the corresponding free amino acid; lactone of the formula

< / BR>
monosubstituted WITH1-4the alkyl has carbon C =N-OH;

a group of the formula-X-R15where X is selected from O, CO, CH2, S, SO, SO2and R15selected from C1-6of alkyl, phenyl, naphthyl, a 5-10 membered monocyclic or bicyclic heteroaryl ring containing up to 5 heteroatoms selected from O, N and S, and any aryl ring in R15optionally substituted as defined for group Ph for R1= C1-3alkylen-PH;

p is 0-3, and R3may be the same or different;

L represents a linking group selected from the following is 1-4
alkylen-Z

-CO-C1-4alkylen-Z, -CO-C1-6of alkyl, -COZ, Z, and Z is selected from

-O-C1-4of alkyl, phenyl, naphthyl, a 5-10 membered monocyclic or bicyclic heteroaryl ring containing up to 5 heteroatoms selected from O, N and S, and any aryl ring in R16optionally substituted as defined for group Ph for R1= C1-3alkylen-PH; -CH2-NR18- where R18has any value defined for R16; -CH2S-; -CH2O-; -CH2-CHR19where R19has any value defined for R16; -CH=CR20- where R20has any value defined for R16; -CH2NR21-T-, where R21has any value defined for R16T represents -(CH2)n-, where n is 1-4 and T is optionally monogamist R22where R22has any value for R16but H; -CH2NR23-SO2- where R23has any value defined for R16; -CH2-NR24-CO-T-, where R24has any value defined for R16T represents -(CH2)n-, where n is 0-4 and T is optional monogamist R29where R29has any value for R16but H; -CO-NR25-T, where the T optional monogamist R26where R26has any value for R16but H; -CH2S-T, where T represents -(CH2)n-, where n is 1-4 and T is optionally monogamist R27where R27has any value for R16but H; -CH2O-T-, where T represents -(CH2)n-, where n is 1-4 and T is optionally monogamist R28where R28has any value for R16but H;

A is selected from phenyl, naphthyl, a 5-10 membered monocyclic or bicyclic heteroaryl ring containing up to 5 heteroatoms, where the heteroatoms independently selected from O, N and S;

or-S-S-dimer, when R2= N, or N-oxide;or an enantiomer, diastereoisomer, pharmaceutically acceptable salt, prodrug or MES together with a pharmaceutically acceptable diluent or carrier.

R1preferably selected from H; -CO-O-(CH2)nPh, optionally substituted in the Ph, as defined for R1= -C1-3alkylen-PH, where n=0-4; -CO-O-C1-4alkenyl; -CO-C1-4alkyl; -C1-4alkylen-CONR4R5where R4and R5independently selected from H, C1-4the alkyl.

R2preferably selected from H and-CO-C1-4alkyl.

L predpochtitel, pyridyl and tanila.

The combination of R3and R is preferably selected from the following combinations:

i) R3selected from the group of formula II; -C1-4alkyl-R7; -O-R7and R7; p is 1-3, provided that one of the values of R3is a group of formula II;

ii) p = 0, provided that a represents naphthyl and L is-CH2NR21-T;

iii) p = 1, provided that R3= a group of formula II and a is naphthyl.

In another implementation of the invention, preferably, when R1selected from the group comprising H; -C1-4alkyl; -C1-4alkylen-PH, optionally mono - or disubstituted in the Ph substituents selected from the group comprising FROM1-4alkyl, halogen, HE1-4alkoxy, C1-4alkanoyl,1-4alkanoyloxy, amino, C1-4alkylamino, di(C1-4alkyl) amino, C1-4alkanolamine, thiol,1-4alkylthio, nitro, cyano, carboxy, carbarnoyl,1-4alkoxycarbonyl,1-4alkylsulfonyl, (C1-4alkylsulfonyl, sulfonamide; -CO-C1-4alkyl; -CO-O-C1-4alkyl; -CO-O-C2-4alkenyl; -CO-O-CH2-Ph, optionally mono - or disubstituted in the phenyl substituents selected from the group comprising FROM1-4alkyl, halogen, Ol)amino, WITH1-4alkanolamine, thiol,1-4alkylthio, nitro, cyano, carboxy, carbarnoyl,1-4alkoxycarbonyl,1-4alkylthio,1-4alkylsulfonyl, sulfonamide; -C1-4alkylen-CONR4R5where R4and R5independently selected from H, C1-4of alkyl; -C1-4alkylen-R6where R6selected from H, C1-4of alkyl;

R2selected from the group comprising H; -C1-4alkyl; -C1-3alkylen-PH; -SOS1-4alkyl; -SOOS1-4alkyl;

R3selected from the group comprising H; HE; CN; CF3; NO2; -C1-4alkyl, -C1-4alkylen-R7where R7selected from phenyl, naphthyl, a 5-10 membered monocyclic or bicyclic heteroaryl ring containing up to 3 heteroatoms selected from O, N and S; WITH2-4alkenyl; halogen; - (CH2)nCOOR8where n= 0-3 and R8represents H, C1-4alkyl, C1-4alkenyl; -CONR9R10where R9and R10independently represent H, C1-4alkyl, C2-4alkenyl, -O-C1-4alkyl, -O-C2-4alkenyl;

-CON(R11OR12where R11and R12independently represent H, C1-4alkyl and C2-4alkenyl; a group of formula II, -CONR13-CHR14-COOR17where R1-4
alkyl, monosubstituted at carbon C =N-OH; -SO1-4alkyl; -SO2-C1-4alkyl;

a group of the formula-X-R15where X is selected from CO, CH2, S, SO, SO2and R15selected from C1-6of alkyl, phenyl, naphthyl, a 5-10 membered monocyclic or bicyclic heteroaryl ring containing up to 3 heteroatoms selected from O, N and S;

p is 0-3, and R3may be the same or different.

L represents a linking group selected from the following groups, written in the formula from left to right:

-CO-NR16- where R16selected from H, C1-4of alkyl, C1-4alkylen-Z and Z is selected from the group comprising-O-C1-4alkyl, phenyl, naphthyl, a 5-10 membered monocyclic or bicyclic heteroaryl ring containing up to 3 heteroatoms selected from O, N and S; CH2-NR18- where R18has any value defined for R16; -CH2S-; -CH2O-; -CH2-CHR19- where R19has any value defined for R16; -CH-CR20- where R20has any value defined for R16; -CH2NR21-T-, where R21has any value defined for R16T represents -(CH2)n21and R22represents H; -CH2NR23-SO2- where R23has any value defined for R16; -CH2-NR24-CO-T-, where R24has any value defined for R16T represents -(CH2)n-, where n is 0-4 and T is optional monogamist R29where R29has any value for R16but H, provided that at least one of R24and R25represents H; -CO-NR25-T-, where R23has any value defined for R16T represents -(CH2)n-, where n is 1-4 and T is optionally monogamist R26where R26has any value for R16but H, provided that at least one of R24and R25represents H; -CH2S-T-, where T represents -(CH2)n-, where n is 1-4 and T is optionally monogamist R27where R27has any value for R16but H; -SNO-T-, where T represents -(CH2)n-, where n is 1-4 and T is optionally monogamist R28where R28has any value for R16but H;

A is selected from phenyl; naphthyl; a 5-10 membered monocyclic or bicyclic heteroaryl rings, soderjasimi independently selected from Oh, N and S, or-S-S-dimer, when R2=N.

The preferred pharmaceutical composition is in the form of tablets.

Accordingly, another aspect of the invention proposed compound of formula I, III, IV or V for use as a medicine.

Accordingly, another aspect of the invention proposed compound of formula I, III, IV or V for use in obtaining a medicinal product for the treatment of disease, mediawindow through farnesiana ras.

Many of the compounds of formula I are the distinguishing feature of this invention, and, accordingly, another aspect of the invention is particularly proposed connection of any of the following classes of i), ii) or iii):

< / BR>
where X1selected from the group comprising H; C1-6alkyl; hydraxis1-6alkyl; C1-6alkoxyl1-6alkyl, C1-6alkylsulphonyl; hydroxy1-6alkylsulphonyl; C1-6alkoxyl1-6alkylsulphonyl;

And selected from the group comprising phenyl, naphthyl, and a 5-10 membered heteroaryl ring containing up to 5 heteroatoms selected from O, N and S;

X2selected from the group consisting of H; phenyl; phenyls1-6alkyl; 5-6-membered heteroaryl ring containing in the nutrient substituted at any ring, as defined for phenyl in R1= -C1-3alkylen-RH in paragraph 1;

X3selected from H; C1-6of alkyl;

X4selected from the group comprising C1-6alkylsulfanyl; C1-6alkylsulfanyl; C1-6alkylsulfonyl; carbarnoyl; N-(C1-6alkyl)carbarnoyl; N-(dis1-6alkyl)carbarnoyl; hydroxy or C1-4alkilany ether;

< / BR>
where X5selected from the group comprising-WITH-C1-4alkyl-PH; -CO-C1-6alkyl; -CO-C1-4alkylglycerol where heteroaryl represents a 5-10 membered heteroaryl ring containing up to 5 heteroatoms selected from O, N and S, and Ph or heteroaryl optionally substituted as defined for Ph in R1= -C1-3alkylen-Ph; C1-4alkalosis1-4alkyl;

A represents naphthyl or 10-membered heterocyclic ring having up to 5 heteroatoms selected from O, N and S;

R3and R such as defined in paragraph 1;

< / BR>
where X6has any value defined above for X5in ii);

X7is Ph, optionally substituted as defined for Ph in R1= -C1-3alkylen-PH;

And is Ph or naphthyl or a 5-10 membered heterocyclic ring having up to 5 heteroatoms selected from O, N and S;

Preferred values for compounds of class (i) include:

X1selected from H and C1-6alkoxyl1-6of alkyl;

X2selected from H; phenyl or panels1-6of alkyl;

X4represents C1-6alkylsulfanyl;

A is selected from phenyl or naphthyl.

Other preferred values for X4are-OMe and lactone, which can be generated when X4is HE and X3is N.

Preferred values for compounds of class ii) include p, 0.

Preferred values for compounds of class (iii) include:

X7is Ph;

And is Ph;

p is 0.

In another implementation of the invention proposed compound of formula I, where R1selected from N or C1-4of alkyl; R2selected from the group including H, C1-4alkyl, -SOS1-4alkyl; -C1-4h, L is selected from the following values, as defined here: CONR16CH2S, CH2O, CH2CHR19CH=CHR20CH2NR24COT, CONR25T, CH2ST, and CH2OT and values for A, R3and R such as defined here, provided that excluded 2-(benzylcarbamoyl)-4-sulfanilamide and 4(and the tick products for the synthesis of beta-lactam antibiotics in the patent application of Japan 60233076 (Sumitomo Chemical).

Accordingly, another aspect of the present invention proposed any one of the following individual compounds or their pharmaceutically acceptable salts:

methyl ester (2S)-2-{ 2-benzyl-5-[([2S,4S]-4-sulfanilamide-2-ylmethyl)amino]benzoylamine}-4-methylsulfonylmethane acid;

(2S)-2-{ 2-benzyl-5-[([2S, 4S] -4-sulfanilamide-2-ylmethyl)amino] benzoylamine}-4-methylsulfonylmethane acid;

methyl ester (2S)-2-({ 2-phenyl-5-[([2S,4S]-4-sulfanilamide-2-ylmethyl)amino]phenylcarbamoyl}amino)-4-methylsulfonylmethane acid;

(2S)-2-({2-phenyl-5-[([2S,4S]-4-sulfanilamide-2-ylmethyl)amino]phenylcarbamoyl}amino)-4-methylsulfonylmethane acid;

methyl ester (2S)-2-({ 3-[([2S, 4S] -4-sulfanilamide-2-ylmethyl)amino]naphthalene-1-carbonyl}amino)-4-metralha-lalmalani acid;

(2S)-2-({ 3-[([2S,4S]-4-sulfanilamide-2-ylmethyl)amino]naphthalene-1-carbonyl}amino)-4-methylsulfonylmethane acid;

methyl ester (2S)-2-({ 3-phenyl-5-[([2S,4S]-4-sulfanilamide-2-ylmethyl)amino]phenylcarbamoyl}amino)-4-methylsulfonylmethane acid;

(2S)-2-({3-phenyl-5-[([2S,4S]-4-sulfanilamide-2-ylmethyl)amino]phenylcarbamoyl}amino)-4-methylsulfonylmethane acid;

(2S, 4S)-2-[{ N-(4-methoxybenzyl)-N-(naphthalene-1-or the

N-(naphthalene-1-ylmethyl)-n-([2S, 4S] -4-sulfanilamide-2-ylmethyl)-2-(pyridin-3-yl)ndimethylacetamide;

N-((2S, 4S)-4-sulfanilamide-2-ylmethyl)-3-methyl-N-(2-naphthalene-1-retil)butyramide;

N-([2S, 4S]-4-sulfanilamide-2-ylmethyl)-N-(2-naphthalene-1-retil)-2-pyridin-3-ylacetamide;

(2S, 4S)-2-[{(3-methoxypropyl)-(2-naphthalene-1-retil)amino]methyl}pyrrolidin-4-thiol;

N-([2S, 4S] -4-sulfanilamide-2-ylmethyl)-2-(4-methoxide-nil)-N-(2-naphthalene-1-retil)ndimethylacetamide;

(2S, 4S)-2-{ [(2-(4-methoxyphenyl)ethyl)-(2-naphthalene-1-retil)amino]methyl} pyrrolidin-4-thiol;

N-(2,2-diphenylether)-N-([2S, 4S] -4-sulfanilamide-2-ylmethyl)-3-methylbutyrate;

N-([2S, 4S]-4-sulfanilamide-2-ylmethyl)-3,3-dimethyl-N-(2-naphthalene-2-retil)butyramide;

N-(2,2-diphenylether)-N-([2S, 4S] -4-sulfanilamide-2-ilma-Tyl)-3,3-dimethylbutyramide;

(2S)-2-{ 3-[([2S, 4S] -4-sulfanilamide-2-ylmethyl)-(3-methoxypropyl)amino]benzoylamine}-4-methylsulfonylmethane acid;

N-([2S, 4S]-4-sulfanilamide-2-ylmethyl)-3,3-dimethyl-N-(2-naphthalene-1-retil)butyramide;

(2S)-4-carbarnoyl-2-({ 2-phenyl-5-[([2S, 4S]-4-sulfanilamide-2-ylmethyl)amino]phenylcarbamoyl}amino)butyric acid;

methyl ester (2S)-4-carbarnoyl-2-({2-phenyl-5-[([2S,4S]-4-sulfanilamide-2-ylmethyl)amino]phenylcarbamoyl}amino)by weight of the Oia, containing the compound as defined in any one of formulas III, IV or V, or above the individual connection together with a pharmaceutically acceptable diluent or carrier.

Accordingly, another aspect of the invention, a method for producing compounds of classes (i), (ii) or (iii) as defined above, which is to remove the protective group from compounds of formula VI

< / BR>
where X8is the right part of the connection class i), ii) or iii), as defined above,

WG1represents H or aminosidine group; WG2represents H or thosewithout group and any functional group X8optional protected, provided that there is at least one protective group and optionally, if necessary, converting the thus obtained product in its pharmaceutically acceptable salt.

In the example embodiment of the invention:

examples of values for R1include methyl; -CH2-Ph; -CH2-Ph, substituted in Ph nitro, especially 4-nitro; acetyl; VOS; allyloxycarbonyl; -CO-O-CH2-Ph, substituted in Ph nitro, especially 4-nitro; -CH2CONH2;

examples of values for R2include-Soma-and-COO-tert-butyl;

when the>
)n-COOR8suitable value for n is 0;

examples of lipophilic amino acids, which provide their side chain (denoted R14within the definition of values for R3include methionine, phenylglycine, phenylalanine, serine, leucine, isoleucine or valine. In the corresponding free amino acid preferred L-configuration. Examples of amino acid side chains are presented below. The preferred value for R14is-CH2-CH2-S-CH3. Other preferred values for R14are-CH2-OMe, and-CH2-CH2-OMe.

When R17is N, i.e., in the formula II is a group COOH, and R14represents-CH2-CH2-OH, you can form a lactone, where R17and R14together form part of dihydrofuran-2-about heterocyclic ring. The same lactone can be formed from compounds of formula III, where X4is HE and X3is N.

The amino acid Side chain

Methionine - CH2-CH2-S-CH3< / BR>
Phenylglycine - Ph

Phenylalanine - CH2-Ph

Serine - CH2HE or his1-4alkilany (preferably methyl) ether

Latino methyl) ether

A preferred value for R equal to 2.

When L represents-CH2NR21-T-, a suitable value for n is 1. When L represents-CH2-NR24-CO-T-, a suitable value for n is 1. When L represents-CH2-NR25-T-, a suitable value for n is 1. When L represents-CH2-S-T-a suitable value for n is 1. When L represents-CH2-O-T-, a suitable value for n is 1. L in particular represents-CONH-, -CH2-NH-, -CH2NHSO2-, -CH2NHCO-. Examples of values for A, when a is heteroaryl are thienyl, pyridyl, chinosol and honokalani. More preferred values are presented below.

For R1: 4-nitrobenzenesulfonyl; allyloxycarbonyl; carbamoylmethyl; acetyl; phenoxycarbonyl; N.

For R2: acetylmethadol; N.

For R3: methoxycarbonyl, N-methyl-N-methoxycarbonyl; nitro; allyloxycarbonyl; N methylaminoethanol; etoxycarbonyl; 3,4-dichloraniline; hydroxy; carboxy; methyl ester (2S)-4-methylsulfonylmethane acid-2-ylcarbonyl; (2S)-4-methylsulfonylmethane acid-2-ylcarbonyl; phenoxy.

For R: 1-2, especially 2, the following preferred is(O)-NH-.

For A: phenyl; pyridyl; thienyl; naphthyl.

For R16and R18-26: H, C1-4alkyl, especially N.

In another example embodiment of the invention the preferred values listed below.

In compounds of formula III: X1represents H or metaxis1-4alkyl (especially N); X2represents H, phenyl or benzyl (especially benzyl); X3represents N or C1-4alkyl (especially N); X4represents C1-4alkylsulfanyl (especially methylsulfanyl) and a is phenyl. When a represents a 6-membered aryl or heteroaryl ring, then the group-NX1and Deputy containing X4preferably located in the meta-position relative to each other; X2if present, preferably is in the para-position relative to the-NX1-. Chiral carbon to which is attached-COOH3preferably has the S-configuration. Chiral carbons at positions 2 and 4 rings pyrrolidine preferably have the S-configuration.

In the compounds of formula IV: X5represents-CO-C1-4alkyl (especially-CO-CH2-CHMe2or-CH2-PH-O-C1-4alkyl (especially-CH2-PH - represents-O-C1-4alkyl (especially methoxy) and a represents naphthyl. Chiral carbons at positions 2 and 4 rings pyrrolidine preferably have the S-configuration. The place of connection And with respect to -(CH2)1-2preferably located in position 1 of naphthalene and the equivalent provision in the heterocyclic values for A (regardless of the numberings of the rings, the usual heterocycles). The preferred value for (CH2)1-2is -(CH2)2-.

In the compounds of formula V: X6represents-CO-C1-5alkyl (more preferably-CO-CH2-Snme2or-CO-CH2tert-butyl, especially-CO-CH2-Snme2or-CH2-PH-O-C1-4alkyl (especially-CH2-Ph-OMe); heteroaryl preferably represents pyridyl and preferred Deputy aryl represents-O-C1-4alkyl (especially methoxy) and a represents phenyl or naphthyl, especially phenyl). Chiral carbons at positions 2 and 4 rings pyrrolidine preferably have the S-configuration. The preferred value for -(CH2)1-2is -(CH2)1-.

A suitable pair of values for R3when p=2, is-Sooma, -CON(Me)OMe; NO2, -CON(Me)OMe; -Sooma, allele, CON-methyl ester of methionine; Ph-CON-methionine; benzyl, -CON-methyl ester of methionine; benzyl, -CON-methionine; benzyl, -CON-isopropyl ester of methionine; Ph-CON-methyl ether-glutamine; Ph-N--glutamine.

Appropriate values for L=CHNR21't include CH2N(COCH2CHMe2)CH2CH2; CH2N (CH2CH2CH2OMe)CH2CH2; CH2N(CH2-p-PhOMe)CH2CH2; CH2N(PINES2Snme2)CH2; CH2N (PINES2CH2CH2IU)CH2; CH2N(PINES2Snresn2IU)CH2; CH2N (PINES2CH2OMe)CH2; CH2N(PINES2pyridine-3-yl CH2; CH2N(4-methoxybenzyl)CH2; CH2N(PINES2Snme2)CH2CH2CH(Ph); CH2N(PINES3)CH2CH2CH(Ph); CH2N(PINES2Snme2)CH2;

CH2N(PINES3)CH2; CH2N(PINES2Snme2)CH2CH (Ph); CH2N(COCH2CMe3)CH2CH(Ph);

CH2N(PINES2pyridine-3-yl)CH2CH( Ph); CH2N(CO-1-hydroxy-6-methoxypyridine-3-yl)CH2CH (Ph); CH2N(PINES2Snme2)CH2CH2; CH2N(PINES2CME3)CH2CH2;

CH22NR18include CH2NH; CH2NMe; CH2N(PINES2Snme2and CH2N(PINES2CH2OMe).

Various forms of prodrugs are well known in this field. Examples of such proletarienne derivatives, see the following links:

a) Design of Prodrugs, edited by H. Bundgaard (Elsevier. 1985); Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder et al. (Academic Press, 1985);

b) A Texbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Prodrugs" by H. Bundgaard, p. 113-191 (1991);

C) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);

d) H. Bundgaard, et al. Journal of Pharmaceutical Sciences, 77, 285 (1988) and

e) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984).

Examples of prodrugs include hydrolyzable in vivo esters of compounds of formula I. Hydrolyzable in vivo, the ester compounds of formula (I) containing carboxypropyl is, for example, pharmaceutically acceptable ester which is hydrolysed in the body of a human or animal with the formation of the original acid. Suitable pharmaceutically acceptable esters for carboxy include C1-6alkoxymethyl esters, for example methoxymethyl ether, C1-6alkanoyloxy esters, for example, pivaloyloxymethyl ether, telegrafie esters, WITH3-8cycloalkylcarbonyl1-6alkalemia esters, for example 1-methyl ester, and C1-6alkoxycarbonylmethyl esters, for example 1-methoxycarbonylmethylene ether, they can form at any carboxypropyl in the compounds of this invention.

Special deputies And 6-membered rings are in the meta - or para-position.

Some compounds within the scope of formula I are known as intermediates in the synthesis of the side chain of carbapenems, but I believe that they have not previously been described in forms suitable as pharmaceutical compositions, and had no pharmaceutical activity associated directly with them. The reader in this regard, and also in connection with the synthetic details of obtaining compounds refer to the following publications: Matsumura, Heterocycles (1995), 41, 147-59; the application for the European patent EP 590885 (Zeneca; Betts et al); the application for the European patent EP 592167 (Zeneca; Siret); the application for the European patent EP 562855 (Zeneca; Jung et al); the application for international patent WO 92/17480 (Jmperial Chemical Industries; Betts et al); the application for the European patent EP 508682 (Jmperial Chemical Industries; Betts et al); the application for the European patent EP 280771 (Fujisawa Pharmaceutical, Murata et al) and the application for international patent WO 92/17479 (Jmperial Chemical Industries; Betts et al).

In this description, the generic term "alkyl" includes alkyl, such as "propyl" are specific only for option unbranched chain and references to individual alkyl groups branched chain, such as "isopropyl", are specific only for option branched chain. A similar Convention applies to other generic terms.

It should be clear that because some of the compounds of formula I defined above may exist in optically active or racemic forms as a result of one or more asymmetric carbon atoms, the invention includes in its definition any such optically active or racemic form which possesses the property of inhibiting F. Synthesis of optically active forms can be performed by standard methods of organic chemistry well known in this field, for example by synthesis from optically active starting products or splitting of racemic form of optical antipodes. Similarly, inhibiting properties against F can be assessed using standard laboratory methods listed below.

The term "halogen" refers to fluorine, chlorine, bromine and iodine. The term "carbarnoyl" refers to-C(O)NH2. The term "BOC" refers to tert-blnie rings belong to the cyclic systems, in which both of the bicyclic ring system is aromatic.

Examples of C1-6of alkyl include methyl, ethyl, propyl, isopropyl, sec-butyl, tert-butyl and pentyl; examples1-4of alkyl include methyl, ethyl, propyl, isopropyl, sec-butyl and tert-butyl; examples of C1-3of alkyl include methyl, ethyl, propyl and isopropyl; examples of-C1-3h include benzyl, phenylethyl, phenylpropyl; examples1-4alkoxy (called here also-O-C1-4alkyl) include methoxy, ethoxy and propoxy; examples1-4alkanoyl include formyl, acetyl and propionyl; examples1-4alkanoyloxy include the atomic charges and propionyloxy; examples1-4alkylamino include methylamino, ethylamino, propylamino, isopropylamino, sec-butylamino and tert-butylamino; examples of di(C1-4alkyl)amino include dimethylamino, diethylamino and N-ethyl-N-methylamino; examples1-4alkanolamine include acetamido, propionamido; examples1-4alkoxycarbonyl include methoxycarbonyl, etoxycarbonyl and propoxycarbonyl; examples1-4alkylsulfanyl include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylphenyl, second-butylsulfonyl and tert-butylsulfonyl; examples1-4alcalali the pet-butylsulfonyl; examples1-4alkylsulfonyl include methylsulphonyl, ethylsulfonyl, propylsulfonyl, isopropylphenyl, second-butylsulfonyl and tert-butylsulfonyl; examples-WITH-C1-4alkyl include formyl, acetyl, propionyl, butyryl and valeryl; examples-CO-O-C1-4alkyl include ethoxycarbonyl, propylenecarbonate and tert-butyloxycarbonyl (VOS); examples-CO-O-C2-4alkenyl include allyloxycarbonyl and vinyloxycarbonyl; examples-CO-O-(CH2)nPh, where n=0-4, include vinyloxycarbonyl, benzyloxycarbonyl, generatelockkey and phenylpropanolamine; examples of-C1-4alkylen-R4R5include carbamoylmethyl, carbamoylethyl, N-methylcarbamoylmethyl, N-methyl-N-ethylcarbamate; examples of-C1-4alkylen-R6include carboxymethyl, carboxyethyl, carboxypropyl, methyl ester propionic acid, ethyl ester acetic acid; examples2-4alkenyl include allyl and vinyl; examples of --O-C2-4alkenyl include allyloxy, vinyloxy; examples of lipophilic amino acids include valine, leucine, isoleucine, methionine, phenylalanine, series, threonine and tyrosine; examples carbamoyl1-4of alkyl include carbamoylmethyl, carbamoylethyl and carbamoylethyl; examples of N-(mon is1-4alkyl)carbamoyl1-4the alkyl includes N, N-dimethylcarbamoyl and N-methyl-N-ethylcarbamate; examples1-4of alkyl, monosubstituted at carbon C =N-OH, includes oxime Butyraldehyde and the reaction of propionic aldehyde; examples hydraxis1-6of alkyl include hydroxymethyl, hydroxyethyl, hydroxypropyl, 2-hydroxypropyl, 2-(hydroxymethyl)propyl and hydroxyphenyl; examples1-6alkoxyl1-6of alkyl include methoxyethyl, ethoxyethyl and methoxybutyl; examples of C1-6alkylcarboxylic include methylcarbamyl, ethylcarboxyl, propylmalonic, isopropylcarbonate, second-butylcarbamoyl, tert-butylcarbamoyl and internabonal;

examples hydraxis1-6alkylcarboxylic include hydroxyacetic, hydroxypropionic, hydroxybutyl, 3-hydroxybutyryl and hydroxypentanal; examples1-6alkoxyl1-6alkylcarboxylic include methoxyacetyl, methoxypropanol, ethoxymethyl and butoxyethyl; examples finals1-6of alkyl include benzyl, phenylethyl and phenylpropyl; examples-WITH-C1-4alkyl-PH include phenylacetyl and phenylpropionyl; examples-WITH-C1-4alkylglycerol include 2-(3-pyridyl)acetyl, and 2-(3-thienyl)acetyl; examples of N-(C1-6alkyl)carbamoyl include N-methylcarbamoyl and N-IS CLASS="ptx2">

Examples 5-10-membered monocyclic or bicyclic heteroaryl ring containing up to 5 heteroatoms selected from O, N and S, include the following. Examples of 5 - or 6-membered heteroaryl cyclic systems include imidazole, triazole, pyrazin, pyrimidine, pyridazine, pyridine, isoxazol, oxazol, isothiazol, thiazole and thiophene. 9 - or 10-membered bicyclic heteroaryl cyclic system is a bicyclic aromatic system containing a 6-membered ring condensed with either a 5-membered ring or another 6-membered ring. Examples of bicyclic systems 5/6 and 6/6 include benzofuran, benzimidazole, benzothiophen, benzthiazole, benzisothiazole, benzoxazole, benzisoxazole, predominate, pyrimidinemethanol, quinoline, isoquinoline, cinoxacin, hinzelin, phthalazine, cinnoline and naphthiridine.

Monocyclic heteroaryl rings preferably contain up to 3 heteroatoms and bicyclic heteroaryl rings preferably contain up to 5 heteroatoms. Preferred heteroatoms are N and S, especially n Usually heterocyclic rings are connected with other groups through carbon atoms. Suitable values of heterocycles containing only N in ka is pteridine.

Any chiral carbon atoms in positions 2 and 4 rings pyrrolidine in formulas I and III-V preferably have the S-configuration.

The compounds of formula I and III-V can form salts which are, within the scope of the invention. Preferred pharmaceutically acceptable salts, although there may be other useful salts, for example, for isolation and purification of compounds.

When the compound contains a basic part (a group of basic character), it can form pharmaceutically acceptable salts with various inorganic or organic acids, for example hydrochloric, Hydrobromic, sulfuric, phosphoric, triperoxonane, citric or maleic acid. A suitable pharmaceutically acceptable salt of the invention, when the compound contains an acid part is a salt of an alkali metal such as sodium salt or potassium salt, alkaline earth metal, for example a salt of calcium or magnesium, ammonium salt or a salt with an organic base, which forms a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or Tris-(2-hydroxyethyl)amine.

A solvate, for example hydrates, are also the WMD aspect of the present invention proposed a compound of formula I for use as pharmaceuticals.

Accordingly, another aspect of the present invention proposed a compound of formula I to obtain a medicinal product for the treatment of mediasound ras diseases, especially cancer.

Accordingly, another aspect of the present invention, a method of treatment mediasound ras diseases, especially cancer, the introduction of an effective amount of the compounds of formula I to a mammal in need of such treatment.

According to other features of the present invention proposed a compound of formula I or its pharmaceutically acceptable salt for use in the method of treatment of a human or animal therapy.

The invention also includes a method of treating a disease or medical condition, MediaLounge fully or partially farnesiani ras, which is administered to a mammal in need of such treatment, an effective amount of the active ingredient, as defined above. The invention also provides the use of such active ingredient to obtain a new drug for use in the treatment of mediawindow farnesiani ras illness or medical condition.

Specific, representing docnoj ulcer, kidney, liver, lung, ovary, pancreas, stomach, neck, thyroid and skin;

hematopoietic tumors of lymphoid origin, including acute lymphocytic leukemia, b-cell lymphoma and Burkitt's lymphoma;

hematopoietic tumors of myeloid origin, including acute and chronic myelogenous leukemias and promyelocytic leukemia;

- tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma, and

- other tumors, including melanoma, seminoma, teratocarcinoma, neuroblastoma and glioma.

The compounds of formula I are particularly useful in the treatment of tumors having a high frequency of ras mutations, such as tumors of the colon, lung and pancreas. By introducing a composition having one (or combination) of the compounds of this invention, reduces the development of tumors in a mammalian host.

The compounds of formula I may also be useful in the treatment of diseases other than cancer that may be associated with signal transduction pathways operating through ras, such as neurofibromatosis.

The compounds of formula I may also be useful for treatment of diseases associated with SAH-containing proteins, jugmental farnesyltransferase.

Compositions of the invention can be in a form suitable for oral use (for example, in the form of tablets, pellets, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example, in the form of creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example, in the form of finely ground powder or a liquid aerosol), for administration by insufflating (for example, in the form of finely ground powder) or for parenteral administration (for example, in the form of a sterile aqueous or oily solution for intravenous, subcutaneous or intramuscular dosage injection or as a suppository for rectal dosing).

Compositions of the invention can be obtained by conventional means using conventional pharmaceutical excipients, well known in this field. Thus, compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavouring and/or preservative agents.

Suitable pharmaceutically acceptable excipients ready for the rija, calcium phosphate or calcium carbonate, granulating and dezintegriruetsja agents such as corn starch or alginic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl - or propyl-p-hydroxybenzoate, and antioxidants, such as ascorbic acid. Preformed ready preparative forms may be uncovered or covered, or for

modification of their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, and in any case, the use of conventional agents to produce coatings and methods, well known in this field.

Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or oil, such as peanut oil, liquid paraffin or olive oil.

Aqueous suspensions generally contain their agents, such as sodium carboxymethyl cellulose, methylcellulose, hypromellose, sodium alginate, polyvinylpyrrolidone, tragacanth gum or Arabian gum; dispersing or wetting agents such as lecithin or condensation products of accelerated with fatty acids (for example, polyoxyethylenated), or condensation products of ethylene oxide with aliphatic alcohols with long chain, such as heptadecafluorooctane, or condensation products of ethylene oxide with partial esters derived from fatty acids and exit, such as monooleate of polyoxyethylenesorbitan, or condensation products of ethylene oxide with aliphatic alcohols with long chain, such as heptadecafluorooctane, or condensation products of ethylene oxide with partial esters, derived from fatty acids and exit, such as monooleate of polyoxyethylenesorbitan, or condensation products of ethylene oxide with partial esters derived from fatty acids and anhydrides of hexitol, such as monooleate of polyoxyethylenesorbitan. Aqueous suspensions can also contain one or more preservatives (such as ethyl - or propyl-p-hydroxybenzoate), antioxidants (such as ascorbin or aspartame).

Oil suspensions can be made by suspendirovanie active ingredient in a vegetable oil (such as peanut butter, olive oil, sesame oil or coconut oil) or mineral oil such as liquid paraffin). Oily suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. To obtain a palatable oral preparation can be added sweetening agents, such as the above, and flavoring agents. These compositions may be preserved by the addition of antioxidants, such as ascorbic acid.

Dispersible powders and granules suitable for receiving the aqueous suspension by the addition of water, usually contain the active ingredient together with a dispersing or wetting agent, suspenders agent and one or more preservatives. Examples of suitable dispersing or wetting agents and suspendida agents are the agents mentioned above. Can also be additional fillers such as sweetening, flavoring and coloring agents.

The pharmaceutical compositions of the invention may also be in the form of emulsion t, what does mineral oil, such as, for example, liquid paraffin, or a mixture of any of them. Suitable emulsifying agents may be, for example, exist in nature gums, such as Arabian gum or tragacanth gum, existing in nature phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and anhydrides of hexitol (for example, monooleate sorbitan) and condensation products of these partial esters with ethylene oxide, such as monooleate of polyoxyethylenesorbitan. The emulsions may also contain sweetening, flavouring and preservative agents.

Syrups and elixirs can be made with the use of sweetening agents, such as glycerin, propylene glycol, sorbitol, aspartame or sucrose, they may contain means for reducing irritation, preservative, flavoring and/or coloring agent.

Pharmaceutical compositions may also be in the form of a sterile injectable aqueous or oily suspensions, which can be manufactured in accordance with known methods using one or more suitable dispersing or wetting agents and suspendida agents such as those mentioned above. ranks parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol.

The finished formulation in the form of suppositories can be obtained by mixing the active ingredient with a suitable not irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Suitable fillers include, for example, cocoa butter and polyethylene glycols.

Local ready preparative forms, such as creams, ointments, gels, and aqueous or oil solutions or suspensions, can usually be obtained by combining the active ingredient with ordinary, tapicerki acceptable excipient or diluent using conventional manner well known in this field.

Compositions for administration by insufflating can be in the form of finely ground powder containing particles with an average diameter of, for example, 30 microns or much less, and the powder contains either only active ingredient or that ingredient, diluted with one or more physiologically acceptable carriers such as lactose. Powder for insufflation then usually remain in the capsule containing, for example, 1-50 mg Akti known agent, sodium cromoglycate.

Compositions for administration by inhalation may be in the form of a conventional pressurized aerosol adapted to the filing of the active ingredient or in the form of an aerosol containing finely ground solid particles, or liquid droplets. You can use normal propellant for aerosols, such as volatile fluorinated hydrocarbon or hydrocarbons, or aerosol device is generally adapted to supply a measured amount of the active ingredient.

For more information on ready preparative form the reader refer to Chapter 25.2 in Volume 5 of Comprehensive Medicinal Chemistry (corwin Hansch; Chairman of Editorial Board), Pergamon Press, 1990.

The amount of active ingredient that is mixed with one or more fillers to obtain a dosage form with a single dose will necessarily vary depending on the host, which is treated and the particular route of administration. For example, ready preparative form intended for oral administration to humans will generally contain from 0.5 mg to 2 g of active agent mixed with an appropriate and suitable amount of excipients which may vary from about 5 to about 98 wt. % of mA what about the ingredient. For more information on routes of administration and schemes of medicine reader refer to Chapter 25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press, 1990.

The magnitude of the doses of the compounds of formula I for therapeutic or prophylactic purposes will naturally vary according to the nature and severity of the condition, age and sex of the animal or patient and routes of administration, according to well known principles of medicine. As mentioned above, the compounds of formula I useful in the treatment of diseases or medical conditions that are caused entirely or partially by the impact of farnesiana ras.

When using the compounds of formula I for therapeutic or prophylactic purposes it will generally enter to accept the daily dose in the range, for example, from 0.5 mg to 75 mg per 1 kg of body weight, if required, given in divided doses. When used parenteral route of administration, usually give smaller doses. For example, for intravenous administration will typically use a dose in the range, for example, from 0.5 mg to 30 mg per 1 kg of body weight. Similarly to the introduction of therapy will be to use a dose in the range, for example, from 0,retene can be used in combination with known anti-cancer and cytotoxic agents. If these combined products are made with a fixed dose, use of the compounds of this invention within described here range of doses and the other pharmaceutically active agent within its approved dosage range. When the combination of the finished formulation is impractical, it is assumed their consistent application.

Although the compounds of formula I are valuable mainly as therapeutic agents for use for warm-blooded animals (including man), they are also useful whenever it is required for inhibition of the action of the activation of ras by farnesiana. Thus, they are useful as pharmacological standards for use in the development of new biological tests and in search of new pharmaceuticals.

Accordingly, another aspect of the present invention proposed individual compounds obtained as the final products of the examples below and their salts.

The compound of the invention or its salt can be obtained by any method which is known to be suitable for obtaining such compounds or structurally related compounds. Such methods illusen for formula I, if not otherwise stated. Functional groups can be protected and be freed from the protective groups, using conventional methods. Examples of protective groups, such as amino - and carboxyamide group (as well as resources for education and possible removal of the protective groups), see T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Second Edition, John Wiley and Sons, New York, 1991. Used abbreviations are listed immediately prior to the following examples.

The protective group may be removed by any conventional method described in the literature or known to the chemist, a specialist in this field, as appropriate to uninstall the protective group, and such methods chosen to carry out the removal of the protective group with minimal disruption of groups present in the molecule somewhere in another place.

For convenience, the following are specific examples of protective groups in which the term "lower" means that the group to which it is applied, preferably has 1-4 carbon atoms. It should be clear that these examples are not exhaustive. The following are specific examples of methods for removing protective groups, they are also not exhaustive. The use of protective groups and methods udaleniya">

Carboxyamide group may be the residue afrobrazil aliphatic or analiticheskogo alcohol or afrobrazil of silanol (alcohol or silanol combined with caffeine preferably contains 1-20 carbon atoms).

Examples carboxyamide groups include (1-12C)alkyl groups with unbranched or branched chain (for example, isopropyl, tert-butyl); lower (lower alkoxy)alkyl groups (for example, methoxymethyl, ethoxymethyl, isobutoxide); low (lowest of aliphatic, acyloxy)alkyl groups (for example, acetoxymethyl, propionylacetate, butyraldoxime, pivaloyloxymethyl); low (lowest of alkoxycarbonyl)alkyl groups (for example, 1-methoxycarbonylethyl, 1-ethoxycarbonylethyl); lower (aryl)alkyl groups (for example, p-methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, benzhydryl and phthalidyl); three(lower alkyl)silyl groups (for example trimethylsilyl and tert-butyldimethylsilyl); three(lower alkyl)siciliane lower alkyl groups (for example, trimethylsilylmethyl) and (2-6C)alkeneamine group (for example, allyl and vinylaryl).

The methods are particularly suitable for removal carboxyamide groups include, for example, hydrolysis, acid catalyzed, metallome); lower alcoholnye groups (for example acetyl); lower alkoxycarbonyl group (e.g. tert-butoxycarbonyl); lower altneratively group (for example, allyloxycarbonyl); lower (aryl)alkoxycarbonyl group (for example, benzyloxycarbonyl, p-methoxybenzenesulfonyl, o-nitrobenzenesulfonyl, p-nitrobenzenesulfonyl); three(lower alkyl/aryl)silyl groups (for example trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl); lower (aryl)alkyl group (e.g. benzyl group) and lower (Triaryl)alkyl groups (for example, triphenylmethyl).

Examples aminosidine groups include formyl, kalkilya groups (e.g. benzyl and substituted benzyl such as p-methoxybenzyl, nitrobenzyl and 2,4-dimethoxybenzyl and triphenylmethyl); di-p-untilmately and furylmethyl group; a lower alkoxycarbonyl (for example, tert-butoxycarbonyl); lower alkenylbenzenes (for example, allyloxycarbonyl); lower (aryl)alkoxycarbonyl group (for example, benzyloxycarbonyl, p-methoxybenzenesulfonyl, o-nitrobenzenesulfonyl, p-nitrobenzenesulfonyl); trialkylsilyl (for example trimethylsilyl and tert-butyldimethylsilyl); alkylidene (for example, methylidene); benzilan groups, include, for example, hydrolysis catalyzed by acid, base, metal or enzyme, or photolytic methods for groups such as o-nitrobenzyl-oxycarbonyl, or processing of fluoride ions for silyl groups.

Examples of protective groups for amide groups include Alcoceber (for example, benzyloxyethyl and substituted benzyloxyethyl); alkoxymethyl (for example, methoxymethyl and trimethylsilylethynyl); three(alkyl/aryl)silyl (e.g., trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl); three(alkyl/aryl)similarilty (for example, tert-butyldimethylsilyloxy, tert-butyldiphenylchlorosilane); 4-alkoxyphenyl (e.g., a 4-methoxyphenyl); 2,4-di(alkoxy)phenyl (e.g., 2,4-acid); 4-alkoxybenzyl (for example, 4-methoxybenzyl); 2,4-di(alkoxy)benzyl (e.g., 2,4-di(methoxy)benzyl) and ALK-1-enyl (for example, allyl, but-1-enyl and substituted vinyl, for example 2-phenylphenyl).

Arelaxation group you can enter in the amide group by reaction of the latter group with a suitable oralmaxillofacial and remove catalytic hydrogenation. Alkoxymethyl, three(alkyl/aryl)silyl and triallylisocyanurate group, you can enter the reaction of the amide with a suitable chloride and silnee group is conveniently introduced by AllYouNeed or by alkylation with a suitable halide and removing the oxidation of mixed cerium nitrate (IV) and ammonium. And finally, ALK-1-aniline group, you can enter the reaction of the amide with a suitable aldehyde and remove the acid.

The compounds of formula I where L is-CO-NR16-, can be obtained by the formation of amide linkages between connections 1 and 2, as depicted in scheme 23. The compounds of formula I where L is-CO-NR23-T-, can be obtained in a similar way. Suitable conditions for the combination include the following:

i) Using EEDQ at room temperature in an organic solvent (e.g. dichloromethane, methanol).

ii) Use of oxalicacid in an organic solvent (such as DMF, CH2Cl2in the presence of an organic base (for example, NMM, triethylamine, DMAP) at a temperature of from 0oWith up to room temperature for 0.5-16 hours

iii) Using the EDC/HOBT in an organic solvent (such as DMF, CH2Cl2).

iv) using the DCCI/HOBT in an organic solvent (such as DMF, CH2Cl2in the presence of an organic base (e.g. triethylamine).

v) using the reactions of mixed anhydrides in standard conditions, such as isopropylcarbamate in an organic solvent (such as DMF), DMA of ester under standard conditions, for example pentafluorophenyl ester in an organic solvent (such as dichloromethane) in the presence of an organic base (e.g. triethylamine).

vii) By carboxylic acid under standard conditions, for example using thionyl chloride and heating for about 150 min followed by treatment with an organic base (e.g. triethylamine) in the presence of an organic solvent (e.g. acetonitrile).

The compounds of formula I where L is-CH2NR18-, -CH2O - or-CH2S, can be obtained as depicted in scheme 24. LG represents a leaving group (for example, mesilate, tosyloxy, halogen and X represents S, O or NR18. Suitable conditions for the combination include the following:

i) Use of inorganic bases (for example, NaHCO3, NaH, K2CO3utility) in an organic solvent (such as THF, DMF, DMSO) and temperature range from about 70 to 150oC.

ii) the Use of organic bases (e.g. triethylamine, DNAP) in an organic solvent (such as THF, dichloromethane, DMA, DMF) at a temperature range from room temperature to 150oC.

iii) Using nargileh (for example, dichloromethane) in the two-phase system, optionally in the presence of a catalyst transfer phases (for example, tetrabutylammonium bromide).

The compounds of formula I where L is-CH=CR20- can be obtained by using the Wittig reaction as depicted in scheme 25. Suitable reaction conditions include the following conditions.

i) using a base (e.g. potassium carbonate, metal hydride, metal alkoxide in the presence of an organic solvent (such as THF, toluene, DMSO), optionally in the presence of an aqueous solvent two-phase system), and optionally in the presence of forming a complex with the catalyst agent, which dissolves the alkali metal ions in non-polar solvents, such as 1,4,7,10,13-pentachlorobenzene (also known as 15-crown-5) or 1,4,7, 10,13,16-hexaoxacyclooctadecane (also known as 18-crown-6).

The compounds of formula I where L is-CH2-NR18-, can be obtained as depicted in scheme 26, the combination of the aldehyde (2) with compound 4. Suitable conditions for the combination include the following:

i) Using a reducing agent (for example, NaCNBH3, NR3, hydrogen plus catalyst, LiHBEt3, Diisobutyl ethanol and acetic acid.

The aldehyde (2) can be obtained by oxidation of the corresponding alcohol (1) in suitable conditions, such as the use of an oxidant (for example, TRAR, NMM-O) in the presence of an organic solvent (e.g. acetonitrile, dichloromethane) at room temperature. Other suitable oxidizing agents include chromium oxide, chlorproma pyridinium, pyridinium dichromate, sodium dichromate and sodium hypochlorite.

The aldehyde (2) can also be obtained by appropriate recovery of ester (1) under standard conditions using, for example, diisobutylaluminium.

The compounds of formula I where L is-CH2NR21-T-, -CH2-O-T - or-CH2-S-T-, can be obtained as depicted in scheme 27, in which LG represents a leaving group (for example, mesilate, tosyloxy, halogen and X represents O, S or NR21. A suitable combination of conditions described above for scheme 24. The provisions of the LG and HN in compounds 1 and 2 in scheme 27 optional, you can pay to obtain the same final product.

The compounds of formula I where L is-CH2NR23-SO2-, can be obtained as depicted in scheme 28. Compounds 1 and 2 can be combined in standard conditions, such as the following.

oC.

ii) the Use of inorganic bases (e.g. potassium carbonate) in the presence of an organic solvent (such as DMF) at temperatures from 0 to 150oC.

Compounds of the formula where L is-CH2-NR24-CO-T-, can be obtained as depicted in scheme 29. Compounds 1 and 2 can be combined in standard conditions, such as described above for L=-CO-NR16-.

The compounds of formula I where L is-CH2-CHR19-, can be obtained, for example, the recovery of compounds of the type specified as compound 3 in scheme 25, but with the substitution of R19instead of R20. The restoration carried out in standard conditions standard reagents, for example, using a hydrogenation catalyst such as palladium on charcoal, at room temperature.

The biological activity was tested as follows. Farnesyltransferase (FPT) was partially purified from human placenta by fractionation with ammonium sulfate followed a single anion-exchange chromatography on Q-sepharose(Pharmacia. Jnc), essentially as described by Ray and Lopez-Belmonte (Ray K. R. and Lopez-Belmonde (1992), J. Biochemica the Anta c-Ki-ras-2 4B person was obtained from the plasmid pSW11-1 (ATSS). It was then subcloned into polylinker a suitable expression vector, for example RS. Kras was obtained after expression in E. Coli strain BL21. Expression and purification of c-KI-ras-2 and 4B v112-variant in E. Coli is described also Lowe et al (Lowe, P. N. et al. J. Biol. Chem. (1991), 266, 1672-1678).

Incubation was performed containing enzyme with 300 nm of tritium-labeled farnesylpyrophosphate (DuPont/New England Nuclear), 120 nm ras-CVIM, 50 mm Tris-model HC1 to pH 8.0, 5 mm MgCl2, 10 μm ZnCl2, 5 mm dithiothreitol, and compounds were added at appropriate concentrations in DMSO (final concentration of 3% in the test and control experiment with filler). Incubation was carried out for 20 minutes at 37oWith and stopped by acid ethanol as described Pompliano et al. (Pompiiano D. L. et al (1992), 31, 3800-3807). Precipitated protein is then collected on the filters glass fiber (C) using the collector cells Tomtecand the label of tritium was measured in a scintillation counter Betaplate 1204 Wallac.

Although the pharmacological properties of the compounds of formula I, as expected, change in accordance with structural change, in General the compounds of formula I have the IC50in the above test in the range of, for example, from 0.01 to 200 microns. So as an example, the connection allyl ester 5-{[(2S, 4S)-and the acid (see example 7) has the IC50approximately 0.5 μm. For proven effective doses of the compounds of the present invention were not observed physiologically unacceptable toxicity.

The invention will now be illustrated by the following not limiting examples in which, unless otherwise stated:

(i) the evaporation was carried out on a rotary evaporator under vacuum and the processing operation is carried out after removal of residual solid product by filtration;

(ii) operations were carried out at room temperature, which is in the range 18-25oWith, and in the atmosphere of inert gas, such as argon;

(iii) column chromatography (flash method) and liquid chromatography with an average pressure (MPLC) were performed on silica Merck Kieselgel (art. 9385) or silicon dioxide with reversed phase Merck Lichroprep RP-18 (art. 9303) obtained from E. Merck, Darmstadt, Germany;

(iv) the outputs are given for illustration only and are not necessarily the maximum attainable;

(v) final products of formula I have satisfactory results microanalysis, their structures were confirmed by means of nuclear magnetic resonance (NMR) and mass spectroscopy; the magnitude of the chemical shifts were measured on the Delta scale; espressomachine products usually are not fully characterized, and their purity was determined by thin-layer chromatography, infrared (IR) spectroscopy or NMR;

(vii) are unadjusted melting points were determined using an automatic device for determining the melting point Mettler SP62 or device with an oil bath; the melting point for the end products of the formula I were determined after crystallisation from a conventional organic solvent, such as ethanol, methanol, acetone, simple ether or hexane, in pure form or as mixtures thereof and

(viii) used the following abbreviations:

Bare - tert-butoxycarbonyl

DCCI - 1,3-dicyclohexylcarbodiimide

DMA N,N-dimethylacetamide

DMAP - 4-dimethylaminopyridine

DMF - N,N-dimethylformamide

DMSO - dimethyl sulfoxide

EDS - 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide

EEDQ - 2-ethoxy-1-etoxycarbonyl-1,2-dihydroquinoline

NAVT - 1-hydroxybenzotriazole

NMM is N-methylmorpholine

NMM-Q - 4-methylmorpholin-N-oxide

TFU - triperoxonane acid

THF - tetrahydrofuran

TMSI - trimethylsilylmethyl

TRAR - perruthenate of tetrapropylammonium

Note that in the diagrams are only those hydrogen atoms which are believed will help to clarify the scheme (i.e., given not all hydrogen atoms).

email)phenylcarbamoyl]pyrrolidine-1-carboxylic acid.

A mixture of 1-(4-nitrobenzyl) ether 4-acetylsulfapyridine-1,2-dicarboxylic acid (1(s)) (0.2 g) and 3-amino-N-methoxy-N-methyl-5-nitrobenzamide (1b)) (0,122 g) and EEDQ (0,201 g) in dichloromethane (20 ml) was stirred at room temperature for 16 hours. The solution is then stirred with 0.3 M hydrochloric acid (20 ml) for ten minutes. The organic phase is separated, dried over magnesium sulfate and evaporated under reduced pressure, collecting the resin. Its clear by chromatography using 1) a mixture of ethyl acetate/hexane (50: 50) and 2) a mixture of ethyl acetate/hexane (75:25) to give the target product (1) in the form of a colourless resin (0,132 g).

The NMR spectrum (CDCl3): 2,35 (s, 3H), 2,62 (m, 2H), 3,4 (s, 3H), 3,44 (m, 1H), 3,6 (s, 3H), 4,1 (m, 2H), 4,59 (t, 1H), 5,3 (m, 2H), 7,55 (d, 2H), 8,09 (m, 1H), 8,25 (d, 2H), 8,3 (m, 1H), and 8.6 (m, 1H), of 9.55 (Shir. s, 1H).

The original product (1(C)) are synthesized as described in reference example 1-4 in the European patent No 126587 (Sumit).

The original product (1(b)) was obtained as follows. A mixture of 3-amino-5-nitrobenzoic acid (10 g), pentafluorophenol (10 g) and DCCI (11.3 g) was stirred at room temperature for 24 hours. The reaction mixture is filtered and the filtrate was poured on the chromatographic column, which is then elute with a mixture of ethyl acetate/hexane (10:90), peg).

The NMR spectrum (CDCl3): 4,3 (Shir. s, 2H), 7,7 (Tr, 1H), 7,8 (Tr, 1H), at 8.36 (Tr, 1H).

A mixture of (1(a)) (1.0 g) salt with Hcl N,O-dimethylhydroxylamine (0.84 g) and triethylamine (1,82 ml) in dichloromethane (50 ml) was stirred at room temperature for 48 hours. Add water (50 ml) and the mixture is stirred for an additional 5 minutes. The organic phase is separated, dried over magnesium sulfate and evaporated under reduced pressure, collecting the resin. Its clear by chromatography using 1) a mixture of ethyl acetate/hexane (10:90) and 2) a mixture of ethyl acetate/hexane (50: 50) as eluent, getting the original product, 3-amino-N-methoxy-N-methyl-5-nitrobenzamide, (1b)) in the form of a yellow solid product (0.55 g).

The NMR spectrum (CDCl3): to 3.36 (s, 3H) to 3.58 (s, 3H), 7,26 (Tr, 1H), 7,56 (Tr, 1H), of 7.90 (Tr, 1H).

Example 2 (see diagram 2).

Allyl ester of (2S,4S)-4-acetylmethadol-2-[3-(N-methoxy-N-methylcarbamoyl)-5-nitrophenylamino]pyrrolidin-1-carboxylic acid.

A mixture of 1-allyl ester (2S,4S)-4-acetylsulfapyridine-1,2-dicarboxylic acid (1(d)) (0.2 g), 1(b) (0,165 g) and EEDQ (0,271 g) in dichloromethane (20 ml) was stirred at room temperature for 16 hours. The solution is then stirred with 0.3 M hydrochloric acid for an additional 10 minutes. The organic is purified column chromatography using a mixture of ethyl acetate/hexane (50:50) as eluent, receiving target product (2) in the form of a colourless resin (0.152 g).

NMR-spectrum (Dl3): of 2.33 (s, 3H) 2,62 (m, 2H), 3,38 (m, 1H), 3,4 (s, 3H), 3,6 (s, 3H), of 4.05 (m, 2H), 4,59 (Tr, 1H), 4,69 (d, 2H), 5,3 (m, 2H), 5,95 (m, 1H), 8,14 (t, 1H), 8,28 (Tr, 1H), 8,6 (Tr, 1H), 9,7 (Shir. s, 1H).

The synthesis of the original product (1(d)) as "compound (A)" described on page 31 of the application for international patent application No WO 92/17479 (Imperial Chemical Industries). The synthesis of the original product (1(b)) described in example 1.

Example 3 (see diagram 3).

1-Allyl ether-3-methyl ester-5-{[(2S,4S)-4-acetylmethadol-1-(4-nitrobenzenesulfonyl)pyrrolidin-2-carbonyl]amino}isophthalic acid.

DMF (0,07 ml) is added to a mixed solution of oxalicacid (0,078 ml) in dichloromethane (20 ml), cooled to -20oC in argon atmosphere. After 15 minutes, add a solution of (1 ()) (0.3 g; see example 1) in dichloromethane, and then a solution of N-methylmorpholine (0,099 ml) in dichloromethane (2 ml). After an additional 15 minutes, add a solution of methyl ester 5-aminoisophthalic acid (3(b)) (0,192 g) in dichloromethane (5 ml) and then a solution of N-methylmorpholine (0,099 ml) in dichloromethane (2 ml). Mixture is allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was poured into a column for flash chromocult (3) in the form of a colourless resin (0.24 g).

NMR-spectrum (Dl3): of 2.33 (s, 3H), 2,62 (m, 2H) to 3.45 (m, 1H), 3,95 (s, 3H), a 4.03 (m, 1H), 4,17 (m, 1H), 4,57 (Tr, 1H), 4,85 (m, 2H), 5,32 (m, 2H), are 5.36 (m, 2H), equal to 6.05 (m, 1H), 7,51 (m, 2H), to 8.20 (m, 2H), 8,32 (m, 2H), a 8.34 (s, 1H), 9,2 (Shir. s, 1H).

The original product (3(b)) are synthesized as follows. The mixture monomethyl-5-nitroisophthalate (13.8 g), allylbromide (of 7.96 g), potassium carbonate (13,94 g) and DMF (160 ml) was stirred at room temperature for 4.5 hours. The hard part is separated by filtration and the DMF is evaporated from the filtrate under reduced pressure. The residue is dissolved in diethyl ether (300 ml) and water (100 ml) and stirred for five minutes. The organic layer is separated and washed with saturated sodium bicarbonate solution (220 ml), brine (200 ml), dried over magnesium sulfate and evaporated under reduced pressure, obtaining allyl ether-methyl ester 5-nitroisophthalic acid (3(a)) as a yellow oil (14,74 g).

NMR-spectrum (Dl3): 4,0 (s, 3H), 4,9 (m, 2H), 5,4 (m, 2H), 6,1 (m, 1H), 9,0 (m, 3H).

A mixture of (3(a)) (15,46 g), dihydrate chloride tin (II) (65,78 g) and methanol (200 ml) is stirred while boiling under reflux for 4 hours. The methanol is evaporated under reduced pressure and the residue is again dissolved in ethyl acetate (400 ml). Added dropwise a solution adca. The hard part is separated by filtration and the filtrate washed with water (100 ml), brine (100 ml), dried over magnesium sulfate and evaporated under reduced pressure, getting the original product 3(b) in the form of a yellow solid product (of 13.56 g).

NMR-spectrum (Dl3): 3,91 (s, 3H), of 3.94 (s, 2H), 4,82 (m, 2H), 5,35 (m, 2H), equal to 6.05 (m, 1H), 7,52 (m, 2H), 8,08 (m, 1H).

Example 4 (see diagram 4).

1-Allyl ether-3-methyl ester 5-{ [(2S, 4S)-4-acetylmethadol-1-(carbamoylmethyl)pyrrolidin-2-carbonyl]amino}isophthalic acid.

A mixture of salts of 1-allyl ether-3-methyl ester 5-{[(2S,4S)-4-acetylsulfapyridine-2-carbonyl] amino}isophthalic acid with TFU (4(e)) (0.12 g), iodated (of 0.085 g), sodium bicarbonate (0,058 g) and DMF (3.0 ml) was stirred at room temperature for 16 hours DMF is evaporated under reduced pressure and the residue purified by chromatography using 1) a mixture of ethyl acetate/hexane (60:40), 2) ethyl acetate and 3) methanol/ethyl acetate (5:95) as eluents, obtaining the target product 4 as a yellow solid product (by 0.055 g).

NMR spectrum: 2,19 (2 Tr, 1H), to 2.29 (s, 3H), 2,82 (m, 1H), up 3.22 (m, 2H), 3,48 (K, 2N), and 3.6 (m, 1H), 3,94 (s, 3H), of 4.05 (m, 1H), 4,85 (m, 2H), 5,35 (m, 2H), 6,04 (m, 1H), 6,1 (Shir. s, 1H), 6.30-in (lat. s, 1H), 8,43 (m, 1H), 8,55 (m, 1H), 10,46 (Shir. s, 1H).

NMR spectrum (DMSO-d6): of 1.34 (2s, N), of 1.97 (m, 1H), 2,15 (m, 1H), 3,30 (m, 1H), 3.46 in (m, 1H), 3,9 (s, 3H), 4,32 (m, 2H), 4,84 (d, 2H), is 5.06 (d, 1H), 5,35 (m, 2H), 6,07 (m, 1H), 8,18 (m, 1H), 8,54 (m, 2H).

A mixture of (4(a)) (0.8 g), methanesulfonamide (0,152 ml), triethylamine (0,256 ml) and dichloromethane (20 ml) stirred at 5oC in an atmosphere of argon for 10 minutes and then at room temperature for 2 hours Then add water (20 ml) and the mixture is stirred for another 5 minutes. The organic phase is separated, dried over magnesium sulfate and evaporated under reduced pressure. The product was then purified by chromatography using mixtures 1) ethyl acetate/hexane (30: 70) and (2) ethyl acetate/hexane (80:20) as eluents, getting 1-allyl ether-3-methyl ester 5-{[(2S,4S)-4-methanesulfonate-1-(tert-butoxycarbonyl)pyrrolidin-2-carbonyl] amino} isophthalic acid (4(b)) in light of 4.66 (m, 1H), 4,85 (m, 2H), 5,27 (m, 1H), are 5.36 (m, 2H), equal to 6.05 (m, 1H), of 8.37 (m, 3H), for 9.64 (Shir. s, 1H).

A mixture of 4(b) (0.74 g), thioacetate potassium (0.32 g) and acetone (25 ml) is refluxed for 18 hours. The mixture was then cooled to room temperature and the acetone is evaporated under reduced pressure. The residue is dissolved in a mixture of ethyl acetate (50 ml), 1.5 M hydrochloric acid (25 ml) and ice (25 ml). The organic phase is separated, dried over magnesium sulfate and evaporated under reduced pressure, obtaining a red resin. It cleans chromatography using a mixture of 1) ethyl acetate/hexane (30:70) and (2) ethyl acetate/hexane (70: 30) to give 1-allyl ether-3-methyl ester 5-{[(2S,4S)-4-acetylmethadol-1-(tert-butoxycarbonyl)pyrrolidin-2-carbonyl] amino} isophthalic acid (4(C)) as an orange resin (0,48 g).

NMR-spectrum (Dl3): 1,5 (, N), 2,32 (s, 3H), of 2.56 (m, 2H), 3.33 and (m, 1H), 3,93 (s, 3H), Android 4.04 (m, 2H), to 4.52 (Tr, 1H), 4,85 (m, 2H), 5,35 (m, 2H), equal to 6.05 (m, 1H), scored 8.38 (m, 3H), 9,63 (Shir. s, 1H).

A mixture of (4 ()) (3.6 g) and TFU (80 ml) was stirred at room temperature for 10 minutes. TFU is evaporated under reduced pressure and the residue is dissolved in ethyl acetate (200 ml) and saturated sodium bicarbonate solution (100 ml). The solution is then stirred for 10 minutes, the organic phase is separated, washed with AI and the residue purified by chromatography using mixtures 1) ethyl acetate/hexane (30:70) and (2) ethyl acetate/hexane (80: 20) as eluents, getting 4(f) (free base, which is used in example 6) as a brown oil (2.3 g).

NMR-spectrum (Dl3): 2,05 (m, 1H), 2,30 (s, 3H), 2,42 (Shir. s, 1H), 2,78 (m, 2H), to 3.58 (m, 1H), 3,85 (m, 1H), 3,94 (s, 3H), 3,99 (m, 1H), 4,84 (m, 2H), 5,35 (m, 2H), equal to 6.05 (m, 1H), of 8.47 (m, 3H), 9,83 (Shir. s, 1H).

A mixture of (4 (C)) (0.45 g) and TFU (10 ml) was stirred at room temperature for 10 minutes. TFU is evaporated under reduced pressure and the residue purified column chromatography using 1) a mixture of ethyl acetate/hexane (30:70), 2) a mixture of ethyl acetate/hexane (60:40), 3) ethyl acetate and (4) a mixture of methanol/ethyl acetate (10:90) as eluents, receiving targeted of the original product (4(e)) in the form of a brown resin (0,46 g).

NMR-spectrum (Dl3): of 2.15 (m, 1H), 2,33 (s, 3H), of 2.97 (m, 1H), 3,44 (m, 1H), 3,91 (s, 3H), of 3.97 (m, 1H), 4,08 (m, 1H), 4,82 (d, 2H), 4,98 (Tr, 1H), 5,35 (m, 2H), 6,03 (m, 1H), 8,12 (m, 2H), compared to 8.26 (m, 1H).

Example 5 (see diagram 5).

1-Allyl ether-3-methyl ester 5-{[(2S,4S)-4-acetylmethadol-1-acetylpyrrolidine-2-carbonyl]amino}isophthalic acid.

A mixture of (4(e)) (0.08 g; see example 4), triethylamine (,083 ml), acetic anhydride (0,056 ml) and dichloromethane (5 ml) is refluxed for 16 hours. The mixture is cooled, evaporated under reduced pressure and purified by chromatography with s product 5 as a colourless resin (0,048 g).

NMR-spectrum (Dl3): to 2.18 (s, 3H), of 2.35 (s, 3H), 2,48 (m, 1H), 2,77 (m, 1H), 3,42 (m, 1H), 3,95 (s, 3H), 4,1 (m, 2H), around 4.85 (m, 3H), to 5.35 (m, 2H), the 6.06 (m, 1H), 8,40 (m, 3H), 9,88 (Shir. s, 1H).

The original product 4(e) are obtained as described in example 4.

Example 6 (see diagram 6).

1-Allyl ether-3-methyl ester 5-{[(2S,4S)-4-acetylmethadol-1-phenoxycarbonylamino-2-carbonyl]amino}isophthalic acid.

A mixture of (4(f)) (0.07 g), phenylcarbamate (0,026 ml), triethylamine (0,07 ml) and dichloroethane (3 ml) was stirred at room temperature for 16 hours. The mixture was then evaporated under reduced pressure, obtaining a resin, which is purified by chromatography using 1) dichloromethane, 2) a mixture of ethyl acetate/hexane (30:70) and (3) a mixture of ethyl acetate/hexane (60:40) to give the target product as a colorless resin (0,048 g).

NMR spectrum (DMSO-d6): 1,93-of 2.24 (m, 1H), 2,38 (C, H), 2,70 (m, 1H), 3,63 (m, 1H), 3,91 (d, 3H), 4,18 (m, 2H), 4,60 (m, 1H), 4,87 (Tr, 2H), 5,38 (m, 1H), between 6.08 (m, 1H), 6,70-of 7.69 (m, 5H), 8,20 are 8.53 (m, 3H), 10,61 (d, 1H).

The original product (4(f)) are obtained as described in example 4.

Example 7 (see diagram 7).

Allyl ester 5-{ [(2S,4S)-4-acetylmethadol-1-(4-nitrobenzenesulfonyl)pyrrolidin-2-carbonyl] amino} -3-(N-metrotextual)benzoic acid.

Compounds g) and dichloromethane (20 ml) is stirred for 16 h at room temperature. The mixture was then washed with 0.3 M hydrochloric acid (30 ml), the organic phase is separated, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue is purified column chromatography using a mixture of ethyl acetate/hexane (75: 25) as eluent, obtaining the desired product 7 as a yellow solid product (0,053 g).

NMR-spectrum (Dl3): of 2.33 (s, 3H), 2,60 (m, 2H), 3,38 (s, 3H), 3,42 (m, 1H), 3,60 (s, 3H), Android 4.04 (m, 1H), 4,15 (m, 1H), 4,55 (m, 1H), a 4.83 (m, 2H), and 5.30 (m, 2H), 5,35 (m, 2H), 6,04 (m, 1H), 7,52 (m, 2H), 8,10 (m, 3H), 8,18 (m, 2H), 9,12 (Shir. s, 1H).

The original product (1(C)) are obtained as described in example 1. The original product 7(d) are obtained as follows. A mixture of potassium carbonate (17,00 g), 5-nitroisophthalic acid (52,00 g), allylbromide and dimethylacetamide (400 ml) was stirred at 90oC for 4 h Dimethylacetamide is evaporated under reduced pressure and the residue is dissolved in ethyl acetate, washed with water (2300 ml) and then extracted with aqueous saturated sodium bicarbonate solution (3300 ml). The extracts are combined acidified to pH 4 with concentrated hydrochloric acid and again extracted with ethyl acetate (2300 ml). The extracts are combined, washed with water (300 ml), dried over magnesium sulfate and evaporated under reduced pressure, obtaining 3-UB>3/DMSO-d6): 4,90 (m, 2H), 5,42 (m, 2H), between 6.08 (m, 1H), 9,00 (m, 3H).

Solution 7(a) (10,00 g), N-hydroxysuccinimide (5,04 g) and DCCI (9,03 g) in dichloromethane (400 ml) was stirred at room temperature for 3.5 hours the Formed white precipitate was separated by filtration and the filtrate is evaporated under reduced pressure, obtaining a yellow oil. Its clean flash chromatography with elution with a mixture of ethyl acetate/hexane (75:25) to give 5-(2,5-dioxopiperidin-1-silt) ether-3-allyl ester 5-nitroisophthalic acid (7(b)) in the form of a yellow solid product (7,58 g).

NMR-spectrum (Dl3): 2,95 (s, 4H), to 4.92 (m, 2H), 5,43 (m, 2H), 6,07 (m, 1H), 9,12 (m, 3H).

A mixture of (7(b)) (2.00 g), hydrochloride of N,O-dimethylhydroxylamine (0,62 g), triethylamine (0,86 ml) and dichloro-methane (60 ml) was stirred at 5oC for 30 min and then allowed to warm to room temperature and stirred for additional 16 h the Mixture was poured into a column for flash chromatography and elute with a mixture of ethyl acetate/hexane (40:60) to give allyl ester 3-(N-metrotextual)-5-nitrobenzoic acid (7) as a yellow oil.

NMR-spectrum (Dl3): of 3.43 (s, 3H), to 3.58 (s, 3H), of 4.90 (m, 2H), of 5.40 (m, 2H), 6,07 (m, 1H), 8,71 (m, 1H), 8,76 (m, 1H), 8,95 (m, 1H).

A mixture of 7(C)) (1,11 g), dihydrate chloride the mixture is cooled and the methanol is evaporated under reduced pressure.

The residue is again dissolved in ethyl acetate (100 ml) and added dropwise a solution of ammonia (specific gravity 0,880) to achieve pH 8. The residue that is formed is separated by filtration and washed with ethyl acetate (2100 ml). The combined filtrate and wash liquid is evaporated at reduced pressure, obtaining the target source product, allyl ester 3-amino-5-(N-metrotextual)benzoic acid, (7(d)) in the form of a white solid product (0,610 g).

NMR-spectrum (Dl3): at 3.35 (s, 3H) and 3.59 (s, 3H), 3,90 (Shir. s, 2H), 4,82 (m, 2H), 5,35 (m, 2H), 6,04 (m, 1H), 7,15 (m, 1H), 7,45 (m, 1), 7,72 (m, 1H).

Example 8 (see diagram 8).

Allyl ester 5-{[(2S,4S)-4-acetylmethadol-1-(4-nitro-benzyloxycarbonyl)pyrrolidin-2-carbonyl] amino} -3-(N-me-telelocator)benzoic acid.

A mixture of (1 ()) (0,293 g; see example 1), allyl ester 3-amino-5-(N-methylaminoethanol)benzoic acid (8(C)), (0,210 g), EEDQ (0,268 g) and dichloromethane (20 ml) is stirred for 16 h at room temperature. The mixture was then washed with 0.3 M hydrochloric acid (30 ml), dried over magnesium sulfate and immediately placed in a column for flash chromatography, elwira a mixture of ethyl acetate/hexane (75:25). The resulting product is placed in a column for flash chromatography and elute see the Dl3): of 2.33 (s, 3H), 2,61 (m, 2H), 3,40 (s, 3H), 3,42 (m, 1H), Android 4.04 (m, 1H), 4,15 (m, 1H), 4.26 deaths (d, 2H), 4,55 (m, 1H), a 4.83 (m, 3H), and 5.30 (m, 6N), of 5.75 (m, 1H), 6,04 (m, 1H), 7,53 (m, 2H), 8,12 (m, 2H), 8,21 (m, 3H), 9,12 (Shir. s, 1H).

The original product (8) was obtained as follows. A mixture of 7(b) (2.00 g; see example 7), the hydrochloride of N-methylhydroxylamine (1.06 g), triethylamine (1,72 ml) and dichloromethane (60 ml) was stirred at 5oC for 30 minutes. The mixture then allowed to warm to room temperature and stirred for additional 16 hours. The reaction mixture was then immediately poured into a column for flash chromatography and elute with a mixture of ethyl acetate/hexane (50:50) to give allyl ester 3-(N-methylhydroxylamine)-5-nitrobenzoic acid (8(a)) in the form of a cream solid product (1,43 g).

NMR spectrum: (Dl3) of 3.48 (s, 3H), of 4.90 (m, 2H), 5,42 (m, 2H), equal to 6.05 (m, 1H), 8,28 (Shir. s, 1H), 8,55 (m, 1H), 8,63 (m, 1H), 8,96 (m, 1H).

A mixture of 8(a)), allylbromide (0.28 g), potassium carbonate (0,59 g) and DMF (20 ml) is stirred for 3 hours at room temperature in argon atmosphere. Then the dimethylformamide is evaporated under reduced pressure and the residue is dissolved in ethyl acetate (50 ml) and water (50 ml). The organic phase is separated, washed with brine (50 ml), dried over magnesium sulfate and evaporated under reduced pressure oil (0,571 g).

NMR spectrum: 3,47 (s, 3H), 4,25 (m, 2H), 4,90 (m, 2H), 5,35 (m, 4H), 5,65 (m, 1H), the 6.06 (m, 1H), 8,73 (m, 1H), 8,78 (m, 1H), 8,95 (m, 1H).

A mixture of 8(b)) (0,523 g), dihydrate chloride tin (II) (1.84 g) and ethyl acetate (50 ml) heated to boiling under reflux for 6 hours. The mixture is allowed to cool to room temperature and added dropwise a solution of ammonia (specific gravity 0,880) until the solution pH 8. A white precipitate which forms is separated by filtration, washed with ethyl acetate (250 ml) and the combined washing liquid and the filtrate is evaporated to dryness, receiving targeted of the original product (8) as a yellow oil (0,472 g).

NMR spectrum: (Dl3) to 3.38 (s, 3H), 3,88 (m, 2H), 4.25 in (d, 2H), 4,80 (m, 2H), 5,32 (m, 4H), of 5.75 (m, 1H), 6,03 (m, 1H), 7,15 (m, 1H), 7,45 (m, 1H), to 7.75 (m, 1H).

Example 9 (see diagram 9).

Allyl ester 5-{ [(2S, 4S)-1-(allyloxycarbonyl)-4-sulfanilamide-2-carbonyl]amino}-3-(N-methylaminoethanol)benzoic acid.

An aqueous solution of 0.1 M sodium hydroxide (to 4.41 ml) was added to a solution of allyl ester 5-{[(2S,4S)-4-acetylmethadol-1-(allyloxycarbonyl)pyrrolidin-2-carbonyl] -amino} -3-(N-methylaminoethanol)benzoic acid (9(a)) in allyl alcohol (15 ml) and the mixture is then stirred at room temperature for 1 cha the leaders introduce pressure. The residue is dissolved in ethyl acetate (40 ml) and washed with water (240 ml). The organic phase is separated, dried over magnesium sulfate and evaporated to dryness, obtaining a yellow foam. It cleans chromatography using a mixture of ethyl acetate/hexane to 75:25) as eluent, obtaining the target product 9 as a yellow resin (0,148 g).

NMR spectrum: (Dl3) a 1.88 (d, 2H), 2,62 (m, 2H), 3,37 (s, 3H), of 3.45 (m, 2H), 3,60 (s, 3H), 4,08 (m, 1H), to 4.52 (Tr, 1H) and 4.65 (m, 2H), a 4.83 (m, 2H), 5,35 (m, 4H), 6,00 (m, 2H), 8,10 (m, 1H), 8,15 (m, 1H), 8,21 (m, 1H), 9,15 (Shir. s, 1H).

The original product 9(a) was prepared as follows. A mixture of 7(d) (0,568 g; see example 7), 1(d) (to 0.645 g; see example 20), EEDQ (0,585 g) and dichloromethane (50 ml) was stirred at room temperature for 16 hours. The mixture was then washed with 0.3 M hydrochloric acid (50 ml), dried over magnesium sulfate and injected into the column for flash chromatography, elwira a mixture of ethyl acetate/hexane (75: 25). The product is further purified by a second column with elution with a mixture of ethyl acetate/hexane (50: 50), receiving targeted of the original product (9) is in the form of a colourless resin (0,401 g).

NMR-spectrum (Dl3): of 2.33 (s, 3H), 2,60 (m, 2H), 3,37 (s, 3H), 3,40 (m, 1H), 3,61 (s, 3H), was 4.02 (m, 1H), 4,13 (m, 1H), 4,58 (Tr, 1H), and 4.68 (m, 2H), a 4.83 (m, 2H), 5,35 (m, 4H), 6,00 (m, 2H), 8,10 (m, 1H), 8,14 (m, 1H), by 8.22 (m, 1H), of 9.30 (Shir. s, 1H).

Example 10 (see schemes-carboxylic acid.

To a stirred solution of methyl ester 5-[((2S,4S)-1-allyloxycarbonyl-4-VOS-sulfanilamide-2-ylmethyl)carbarnoyl] pyridine-2-carboxylic acid (10(a)) (991 mg; 2,07 mmol) in dichloromethane are added dropwise TFU (6 ml, 78 mmol). The solution is stirred in an argon atmosphere for 4 hours. The solvent and excess TFU removed in vacuum. The residue is subjected to azeotropic distillation with toluene (210 ml). With minimal exposure to air resulting oil triturated with diethyl ether (20 ml). The resulting solid is washed with cold diethyl ether (10 ml) and dried in vacuum, obtaining the target product 10 in the form of a cream solid product, 654 mg (76%).

[4] has NMR (Dl3; 250 MHz): 1,70 (m, 1H), 1,75 (d, 1H), 2,63-2,77 (m, 1H), 3,15-to 3.50 (m, 3H), 3,90-4,00 (m, 1H), of 4.05 (s, 3H), 4,07-to 4.23 (m, 2H), 4,63 (m, 2H), 5,23 lower than the 5.37 (m, 2H), 5,85-6,03 (m, 1H), they were 8.22 (d, 1H), 8,35 (DD, 1H), 8,95 (Shir.s), 1H), 9,20 (s, 1H).

MS (FAB) m/z 380 (M+N)+.

Analysis. C17H21N3O5S0,33 P2HF3ABOUT2417: 50,9 (50,8), N 5,3 (5,1), N 10,1 (10,1).

The original product (10) was obtained as follows. 2-Methyl ester pyridine-2,5-dicarboxylic acid (10(a)) (9.0 g, 0.05 mol) is added to the mix to thionyl chloride (25 ml) and the mixture is gently boiled with reverse holodilny opnai distillation with toluene (225 ml) receiving methyl ester 5-chlorocarbonyl-2-carboxylic acid (10(b)), which is used crude in the next reaction.

To a stirred solution of compound (15(b)) (example 15)(220 mg, 0.7 mmol) in acetonitrile (6 ml) add a solution of (10(b)) (0.7 mmol) in acetonitrile (4 ml). Add triethylamine (0,29 ml; 2.1 mmol) and the solution stirred for 23 hours. The solvent and excess triethylamine are removed in vacuo and the residue partitioned between chloroform and water. The organic phase is washed with water, aqueous sodium hydrogen carbonate solution and brine, dried over magnesium sulfate and evaporated to dryness. The residual orange resin is subjected to flash chromatography on kieselgel 9385, elwira first isohexanol, then isohexanol with increasing content of ethyl acetate. Target source product 10(C) was isolated as a white foam (200 mg; 60%).

NMR (Dl3; 250 MHz): 1.50 in (C, N), of 1.80 (m, 1H), 2,62 is 2.75 (m, 1H), 3,30-3,37 (m, 1H), 3,39-to 3.50 (m, 1H), 3,68-of 3.80 (m, 1H), 3,83-3,95 (m, 1H), a 4.03 (s, 3H), 4,13-to 4.28 (m, 2H), to 4.62 (m, 2H), 5,20 lower than the 5.37 (m, 2H), by 5.87-of 6.02 (m, 1H), and 8.2 (d, 1H), 8,3 (DD, 1H), 8,87 (s, 1H), and 9.2 (s, 1H).

MS (FAB) m/z 480 (M+H)+.

Analysis. C22H29N3O7S 479: FROM 55.1 (55,1), H 6,4 (6,1), N 8,5 (8,8).

Example 11 (see diagram 11).

Allyl ether (2 To a stirred solution of allyl ester (2S,4S)-2-{[(5-ethoxycarbonylmethyl-2-carbonyl)amino] methyl} -4-VOS-sulfanilamide-1-carboxylic acid (11(b)) (130 mg; 0.26 mmol) in dichloromethane (20 ml) is added TFU (2 ml, 26 mmol). The solution is stirred in an argon atmosphere for 19 hours. The solvent and excess TFU removed in vacuum and the residue is dried in high vacuum, obtaining the target product 11 as a white resin (64%).

NMR (Dl3; 250 MHz): to 1.38 (t, 3H), 1,55-1,70 (m, 1H), 1,75 (d, 1H), 2,60 was 2.76 (m, 1H), 3,10-to 3.50 (m, 3H), 3,80-3,95 (m, 1H), 4,05-of 4.25 (m, 2H), to 4.38 (K, 2N), 4,70 (m, 2H), 5,20-of 5.40 (m, 2H), 5,85-6,05 (m, 1H), 7,47 (d, 1H), 7,73 (d, 1H), charged 8.52 (Shir.s, 1H).

MS (FAB) m/z 399 (M+H)+.

Analysis. C17H22N2O3S20.5 S2HF3O2455: FROM 47.6 (47,5), N 5,2 (4,9), N 6,1 (6,15).

The original product 11(b) are obtained similarly to the equivalent steps in example 10, but with the addition of ethyl ester 5-chlorocarbonate-2-carboxylic acid (11(a)) to the compound (15(b)) (example 15) and with similar chromatographic processing. 11b is a sticky white resin. An output of 60%. Obtaining (11(a)) is described in the Journal of the Amtrican Pharmaceutical Association (Sci. Ed.), Vol. 41, pp. 273-276 (1952).

NMR 11(b) (Dl3; 250 MHz): 1,4 (t, 3H), 1.5 a (s, N), 1,70-of 1.85 (m, 1H), 2.57 m)-by 2.73 (m, 1H), 3,26-to 3.36 (m, 1H), 3,38-to 3.50 (m, 1H), 3,65-a 3.87 (m, 2H), 4,10-of 4.25 (m, 2H), 4,35 (K, 2N) and 4.65 (m, 2H), 5,20 is 5.38 (m, 2H), 5,85-6,04 (m, 1H), 7,47 (d, 1H), 7,72 (d, 1H), 8,45 (Shir.c, 1H).

MC (FAB) m/z 499 (M+N)+another m/z 183.

Analysis. C22N-(3,4-Dichlorobenzyl)-N'-((2S,4S)-4-sulfanilamide-2-ylmethyl)thiophene-2,5-dicarboxamide.

To a stirred solution of N-(3,4-dichlorobenzyl)-N'-((2S,4S)-1-allyloxycarbonyl-4-sulfanilamide-2-ylmethyl)thiophene-2,5-dicarboxamide (12(e)) (59 mg, 0.1 mmol) in dichloromethane (10 ml) in an argon atmosphere add trimethylsilylmethyl (0.35 ml; 0.25 mmol). After aging for 20 hours at room temperature, dichloromethane and excess trimethylsilylmethyl removed in vacuum and the residue is treated with methanol (3 ml). The insoluble product is treated with additional methanol (23 ml) and then triturated with diethyl ether, obtaining a solid product, which is filtered and dried, obtaining the target product 12 as a light brown solid (59%).

NMR (DMSO-d6; 250 MHz): 1,65-1,90 (m, 1H), 2,50-2,62 (m, 1H), 3,20-3,40 (m, 2H), 3,55-3,70 (m, 2H), 3.75 to 3,90 (m, 2H), 4,45 (d, 2H), 7,32 (m, 1H), 7,58 (m, 2H), 7,73 (d, 1H), 7,78 (d, 1H), 8,68 (width, 1H), 8,88 (t, 1H), which 9.22 (t, 1H).

MC (FAB) m/z 444 (M+H)+another 111, 312. Analysis. C18H19Cl2N3O2S21,25HI0,5 C4H10ABOUT 640 TO: FROM 37.6 (37,5), H 3,5 (3,9), N 6,5 (6,6).

The original product (12(e)) obtained as follows. To a stirred solution of 3,4-dichloraniline (of 0.53 ml; 4.0 mmol) in acetone (10 ml), add triethylamine (1,67 ml of 12.0 mmol) and the solution (11(a)) (0.87 g; 4.0 mmol, see example 11) in acetonitrile (20 ml). Restoranina removed in vacuo and the residue partitioned between chloroform and water. The organic phase is washed with water and brine, dried over magnesium sulfate and kept in a vacuum to dryness, obtaining the ethyl ester of 5-(3,4-dichloraniline)thiophene-2-carboxylic acid (12(a)) in the form of a cream solid (90%).

NMR (Dl3; 250 MHz): of 1.40 (t, 3H), of 4.38 (K, 2N), of 4.57 (d, 2H), 6,47 (Shir.t, 1H), 7,28 (m, 1H), 7,42 (m, 2H), of 7.48 (d, 1H), 7,73 (d, 1H).

MC (CI) m/z 358 (M+H)+.

Analysis. C15H13Cl2NO3S 358: FROM 50.4 (50,3), N 3,8 (3,7), N 3,9 (3,9).

Aqueous 1 M sodium hydroxide (of 16.3 ml, 16.3 mmol) is added to the mixed solution (12(a)) (1,17 g; 3.3 mmol) in ethanol (70 ml). The reaction mixture pereshivayut at room temperature for 19 hours, evaporated to small volume, diluted with water and set pH 2 by addition of 2 M hydrochloric acid. The filtered solid portion is washed with water and dried in vacuum, obtaining 5-(3,4-dichloraniline)thiophene-2-carboxylic acid (12(b)) in the form of a solid product (83%).

NMR (DMSO-d6; 200 MHz): 4,43 (d, 2H), 1,3 (DD, 1H), 7,58 (m, 2H), 7,68 (d, 1H), 7,78 (d, 1H), 9.28 are (t, 1H).

MS (CI) m/z 330 (M+H)+.

Analysis. C13H9Cl2NO3S 330: 47,3 (47,3), N 2,7 (2,7), N 4.2 (4,2).

Stir the solution (12(b) (495 mg; 1.5 mmol) in dichloromethane. Astor stirred at room temperature in an argon atmosphere for 4 hours. Dichloromethane and excess oxalicacid removed in vacuum. The residue is subjected to azeotropic distillation with toluene (215 ml) to give 5-(3,4-dichloraniline)thiophene-2-carbonylchloride (12(C)), which is used crude in the next stage.

To stir the mixture (12 ()) (1.5 mmol) in acetonitrile (15 ml), add triethylamine (0,83 ml; 4.5 mmol) and a solution of compound (15(b)) (example 15) (316 mg; 1.0 mmol) and the mixture is stirred at room temperature in an argon atmosphere for 19 hours. The acetonitrile and excess triethylamine are removed in vacuo and the residue partitioned between chloroform and water. The organic phase is washed with water and brine, dried over magnesium sulfate and evaporated in vacuum to dryness, obtaining N-(3,4-dichlorobenzyl)-N'-(2S, 4S)-1-allyloxycarbonyl-4-VOS-sulfanilamide-2-ylmethyl)thiophene-2,5-dicarboxamide (12(d)) as a sticky brown solid (95%).

NMR (Dl3; 200 MHz): 1,5 (, N), 1,65-of 1.85 (m, 1H), 2,47-by 2.73 (m, 1H), 3,25-3,50 (m, 2H), 3,65-of 3.85 (m, 2H), 4,10-to 4.23 (m, 2H), 4,57 (d, 2H), with 4.64 (m, 2H), 5,20-of 5.40 (m, 2H), 5,85-6,05 (m, 1H), 6,45 (t, 1H), 7,20 (DD, 1H), 7,40 (m, 2H), 7,46 (d, 1H), 7,53 (d, 1H), of 8.47 (width, 1H).

MC (FAB) m/z 628 (M+N)+.

Analysis. WITH27t to stir the solution (12(d)) (600 mg; of 0.93 mmol) in dichloromethane (25 ml). The solution was stirred at room temperature in an argon atmosphere for 4 hours, the solvent and excess TFU removed in vacuum and the residue is subjected to azeotropic distillation with toluene, receiving targeted of the original product (12(e)).

NMR (Dl3; 250 MHz): 1,55-1,75 (m, 1H), 1,75 (d, 1H), 2,50-of 2.72 (m, 1H), 3,12-of 3.43 (m, 1H), 3,65-3,90 (m, 2H), 4,03-4,20 (m, 2H), 4,54 (d, 2H), 4,63 (m, 2H), 5.17 to lower than the 5.37 (m, 2H), 5,85-6,03 (m, 1H), 6,63 (Shir. 1H), 7,10-of 7.55 (m, 5H), 8,5 (Shir. 2H).

MC (FAB) m/z 528 (M+N)+.

Analysis. WITH22H23CL2N3O4S20.33 S4H10O0,3C2HF3O2586,5: 49,0 (49,0), N 4,5 (4,6), N 7,2 (7,2).

Example 13 (see scheme 13).

5-[N-(3,4-Dichlorobenzyl)carbarnoyl] -N-((2S, 4S)-4-sulfanilamide-2-ylmethyl)pyridine-2-carboxamide.

5-[N-(3,4-Dichlorobenzyl)carbarnoyl] -N-((2S, 4S)-1-allyloxycarbonyl-4-sulfanilamide-2-ylmethyl)pyridine-2-carboxamide (13(e)) is treated with trimethylsilylimidazole a manner similar to the processing of compound (12(e)) in example 12. Target product 13 receive in the form of a solid medium brown (26%).

NMR (DMSO-d6; 200 MHz): 1,70-to 1.82 (m, 1H), 3.15 and is 3.40 (m , 2H), 3,55-3,90 (m, ?H) to 4.52 (d, 2H), 7,35 (DD, 1H), 7,60 (m, 2H), 8,18 (d, 1H), of 8.47 (DD, 1H), 8,75 (width, 1H), 9,10 (d, 1H), 9.28 are (t +?, 2N), N10ABOUT 655,7: FROM 37.4 (37,2), H 3,4 (3,7), N, 8,1 (8,5).

The original product (13(e)) obtained as follows. Methyl ester 5-chlorocarbonyl-2-carboxylic acid is subjected to reaction with 3,4-dichloraniline in a manner analogous to obtain compound (12) in example 12, receiving the methyl ester of 5-(3,4-dichloraniline)pyridine-2-carboxylic acid (13(a)) in the form of a cream solid (61%).

NMR (Dl3; 250 MHz): of 4.05 (s, 3H), to 4.62 (d, 2H), 6,80 (Shir.t, 1H), 7,22 (DD, 1H), 7,43 (m, 2H), to 8.20 (d, 1H), 8.30 to (m, 1H), remaining 9.08 (d, 1H).

MS (CI) m/z 339 (M+N)+. Analysis. C15H12Cl2N2O3339: 53,2 (53,1), H 3,5 (3,6), N, 8,1 (8,3).

The compound (13) is treated analogously to compound 12(a) in example 12, receiving 5-(3,4-dichloraniline)PI-ridin-2-carboxylic acid (13(b)) in the form of not-quite-white solid product (82%).

NMR (DMSO-d6; 200 MHz): 4,50 (d, 2H), 7,33 (DD, 1H), 7,58 (m, 2H), 8,13 (d, 1H), of 8.37 (DD, 1H), 9,12 (d, 1H), 9,40 (t, 1H). MS (CI) m/z 325 (M+N)+.

Analysis. WITH14H10CL2N2O3H2O 343: 48,9 (48,9), H 3,5 (3,5), 8,0 N (8,2).

The compound (13(b)) is treated analogously to compound (12(b)) in example 12, receiving 5-(3,4-dichloraniline)-pyridine-2-carbonylchloride (13(C)), which is used crude in the shadow (12(C)) in example 12, receiving 5-[N-(3,4-dichlorobenzyl)carbarnoyl] -N-(2S, 4S)-1-allyloxycarbonyl-4-VOS-sulfanilamide-2-ylmethyl)pyridine-2-carboxamide in the form of a light brown solid product (13(d)) (81%).

NMR (Dl3; 250 MHz): 1.50 in (C, N), 1,73-1,90 (m, 1H), 2,50-to 2.65 (m, 1H), 3,20-3,30 (m, 1H), 3,62-of 3.80 (m, 2H), 4,10-4,27 (m, 2H) and 4.65 (d?, 4H), 5,18 is 5.38 (m, 2H), of 5.83-6,05 (m, 1H), 6,80 (Shir.t, 1H), 7,20-7,28 (m, 2H), 7,40-of 7.48 (m, 2H), 8,23 (s, 2H), 8,75 (width, 1H), 8,98 (l?, 1H).

MS (FAB) m/z 623 (M+N)+.

Analysis. WITH28H32CL2N4O6S 623: 53,8 (53,9), N 5,1 (5,2), N 8,9 (9,0); so pl. 136-137,5oC.

The compound (13(d)) is treated analogously to compound 12(d)) in example 12, receiving targeted of the original product (13(e)) as pale brown solid (64%).

NMR (Dl3; 250 MHz): 1,70 (d, 1H), 1,80-2,00 (m, 1H), 2,52-to 2.65 (m, 1H), 3,05-of 3.25 (m, 2H), 3,60-of 3.85 (m, 2H), 4,05-4,20 (m, 2H), 4,60 (l?, 4H), 5,18-5,33 (m, 2H), 5,85-6,03 (m, 1H), 6,80 (width, 1H), 7,20 (DD, 1H), 7,40-7,47 (m, 2H), 8,23 (s, 2H), 8,78 (width, 1H), and 9.0 (s, 1H).

MS (FAB) m/z 523 (M+N)+.

Analysis. WITH23H24CL2N4O4S0,1C2HF3O2534,4: 52,4 (52,1), N 4,6 (4,5), N 10,3 (10,5); so pl. 101-105oC.

Example 14 (see scheme 14).

1-Hydroxy-4-[((2S, 4S)-4-sulfanilamide-2-ylmethyl)aminosulfonyl] naphthalene-2-carboxylic acid.

NMR (DMSO-d6; 250 MHz): 1,45-of 1.62 (m, 1H), 2,25-of 2.45 (m, 1H), 2,90-of 3.25 (m, 3H), 3,45-3,70 (m, 2H), 7,72 (m, 1H), a 7.85 (m, 1H), 8,12 (m, 1H), scored 8.38 at 8.60 (m, 2H), 9,15 (width, 1H).

MS (FAB) m/z 389 (M+N)+.

Analysis. C16H18N2O5S21,25HI0,5 C4H10ABOUT 579: 37,0 (37,3), N 4,1 (4,2), N 4,8 (4,8).

The original product (14) was obtained as follows. Connection (15(b)) (example 15) and 1-hydroxy-4-chlorosulfonyl-naphthalene-2-carboxylic acid (14(a)) combine similar equivalent steps in example 15, receiving 1-hydroxy-4-[((2S, 4S)-1-allyloxycarbonyl-4-VOS-sulfanilamide-2-ylmethyl)aminosulfonyl]naphthalene-2-carboxylic acid (14(b)) in the form of a light brown solid product (80%).

NMR (Dl3; 250 MHz): 1,45 (s, N), 1,50-1,75 (m, 1H), 2,28-to 2.42 (m, 1H), 2,96-3,10 (m, 2H), 3,48-of 3.60 (m, 1H), 3,80-3,90 (m, 1H), 3.95 to of 4.05 (m, 1H), 4,47 (m, 2H), 4.53-in-4,63 (m, 1H), 7,55 (m, 1H), to 7.67 (m, 1H), and 8.50 (m, 2N), to 8.70 (m, 1H). MS (FAB) M+Na+589, another 317, 261. Analysis. C is droxia sodium (5 ml; 10.0 mmol) is added to the mixed solution (14(b)) (333 mg; 0.5 mmol) in methanol (5 ml). After 42 hours, the solution is evaporated to dryness and the residue is dissolved in water (10 ml). Using 2 M hydrochloric acid to set the pH of the solution 2 and the solid portion was separated by filtration, washed with water and dried in vacuum, obtaining the target source product (14) as a white solid (72%).

NMR (Dl3; 200 MHz): 1,48 is 1.70 (m, 2H), 2,38-2,52 (m, 1H), 2,85 is 3.40 (m, ?N), 3,90-of 4.05 (m, 2H), 4,40-4,60 (m, 3H), 5,10 to 5.35 (m, 3H), 5,70-5,95 (m, 2H), 6,20-6,45 (width, 1H), EUR 7.57-of 7.90 (m, 3H), 8,43-to 8.70 (m, 4H).

MS (FAB) m/z 467 (M+N)+.

Analysis. C20H22N2O7S20.5 N2ABOUT 475: FROM 50.6 (50,5), N 4,8 (4,8), N 6,0 (5,9).

Example 15 (see scheme 15).

Methyl ester (2S)-2-{ 3-[([2S, 4S] -4-sulfanilamide-2-ylmethyl)sulfamoyl]benzoylamine}-4-methylsulfonylmethane acid.

TFU (2.0 ml) is added to a stirred solution of methyl ester (2S)-2-{ 3-[([2S, 4S]-4-VOS-sulfanilamide-2-ylmethyl)sulfamoyl]benzoylamine} -4-methylsulfonylmethane acid (15(d)) (101 mg, 0.18 mmol) in CH2Cl2(2.0 ml) at room temperature in argon atmosphere. After 1 hour the reaction mixture is concentrated to dryness, and subjected to azeotropic distillation with toluene (310 ml) and sushi-1,8 (1H, m), 2,0 (1H, d, SH), of 2.1-2.4 (5H, m), 2,52-to 2.65 (3H, m), 3,15 and 3.4 (3H, m), 3.45 points-of 3.65 (1H, m), 3,7-of 3.85 (4H, m), 3,9-4,1 (1H, m), 4,85-5,0 (1H, m), 7,55 to 7.7 (2H, m), and 7.8 (1H, s), and 8.0 (1H, d), 8,1 (1H, d), and 8.3 (1H, s), from 9.0 to 9.4 (1H, s) of 10.0 to 10.4 (1H, s).

MC (ESP+) m/z 462 (M+N)+.

The original product (15(d)) are obtained as follows. The triethylamine (3.0 ml; 21.5 mmol) is added to a stirred suspension of methyl ester of L-methionine as a model HC1 salt (4,37 g and 21.8 mmol) in CH2Cl2(50 ml). The resulting mixture is stirred for 30 min at room temperature, then filtered. The filtrates were then added to a stirred solution of 3-chlorosulfonylbenzoic (5,23 g, 21.9 mmol) and triethylamine (7,6 ml, 54,7 mmol) in CH2Cl2(50 ml) at 0oC in argon atmosphere. The reaction mixture is allowed to warm to room temperature and stew with a mixture of ice-water (100 ml). The organic phase is dried over MgSO4, filtered and concentrated to obtain a viscous brown resin. It then purified flash chromatography on SiO29385 when elution with 50% EtOAc/isohexane, receiving methyl ester (2S)-2-(3-chlorosulfonylbenzoic)-4-methylsulfonylmethane acid (15(a)) in the form of a viscous orange oil; 2,88 g (36%).

1H NMR (Dl3; 250 MHz): 2,1-2,2 (5H, m) to 2.65 (2H, t), 3,83 (3H, s), of 4.95 (1H, m), 7.23 percent (1H, d), 7,74 (1H, t), and 8.2 (2H, m), ml) is added to a stirred solution of allyl ester (2S,4S)-2-aminomethyl-4-VOS-sulfanilamide-1-carboxylic acid (15(b)) (obtained as described in the application for international patent WO 92/17480, see pages 39-41) (1,32 g, 4,18 mmol) and (i-Pr)2NEt (1.5 ml, 9.0 mmol) in CH2Cl2(30 ml) at 0oC in argon atmosphere. The resulting solution allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was then washed with water (100 ml), dried over gSO4, filtered and concentrated to obtain a viscous white resin. It then purified flash chromatography on SiO29385 when elution with mixture of EtOAc/isohexane with EtOAc gradient of 35-50%, receiving allyl ester of (2S, 4S)-4-BOC-effect-free remedy 2-{ [3-([1S]-1-methoxycarbonyl-3-methylsulfinylpropyl)benzosulfimide] methyl} pyrrolidin-1-carboxylic acid (15) as a colourless foam; 2,19 g (81,3%).

1H NMR (Dl3; 200 MHz): 1,5 (N, C) of 1.65 to 1.9 (1H, s), of 2.05 to 2.35 (5H, m), 2,4-2,7 (3H, m), 3,3-3,4 (3H, m), 3,55 of 3.75 (1H, m), and 3.8 (3H, s), 3,9-4,2 (2H, m), 4,55 (2H, d), to 4.98 (1H, m), of 5.15 to 5.35 (2H, m), of 5.8-6.0 (1H, m), and 6.5 (1H, s), and 7.4 (1H, s), 7,55 (1H, t), 7,9-with 8.05 (2H, m), of 8.25(1H, m).

MS (FAB) m/z 646 (M+N)+, 590, 568, 546, 230.

Analysis. Calculated for C27H39N3O9S30,3 CH2Cl2,%, FROM 48.8; H 5,95; N 6,26.

Found,%: Compared To 48.9; H 6,2; N 6,0.

Tri-n-butylaldehyde (565 ml, 2.1 mmol) is added to the mixed solution (15(th mixture is stirred for 10 minutes, dried over gSO4filter and concentrate to the formation of brown oil. It then purified flash chromatography on SiO29385 when elution with mixture of EtOAc/isohexane with EtOAc gradient 0-10%, receiving targeted of the original product 15(d) as a white foam; 751 mg (73%).

1H NMR (Dl3+CD3D; 250 MHz): 1,5 (N, s), 1.85 to of 1.97 (1H, m), 2,1 to 2.35 (5H, m), 2,45-2,7 (3H, m), 3.1 to 3.4 (3H, m), the 3.65-4.25 in (6N, m), 4,9-5,0 (1H, m), 7,63 (1H, t), 7,97-with 8.05 (1H, m), 8,1-8,17 (1H, m), 8,35-8,42 (1H, m).

MS (ESP+) m/z 562 (M+N)+, 462.

Analysis. Calculated for C23H35N3O7S3,%: 49,2; N 6,28; N OF 7.48.

Found,%: C 49,4; H 6,3; N 7,2.

Example 16 (see scheme 16).

(2S)-2-{ 3-[([2S, 4S]-4-Sulfanilamide-2-ylmethyl)sulfamoyl]benzoylamine}-4-methylsulfonylmethane acid.

2 N. NaOH (2.0 ml, 4.0 mmol) is added to a stirred solution of compound (15(d)) (obtained in example 15) (200 mg, 0.36 mmol) in Meon at room temperature in argon atmosphere. After 18 h, the reaction mixture was concentrated to remove the Meon. The resulting residue is dissolved in N2O (2.0 ml) and acidified to pH 3 using 2 N. Hcl. The resulting solution purified HPLC with reversed phase preparative column, 8 m, WITH18, Dynamax), elwira mixture Meon/N2About with gray colorless glassy substance, which is then triturated with Et2O (25 ml), filtered and dried, obtaining the target product 16 as a white powder; to 85.2 mg (54%).

1H NMR (DMSO-d6+CD3COOD; 250 MHz): 1,45-of 1.65 (1H, m), of 2.0-2.2 (5H, m), 2,3-2,7 (3H+DMSO, m), 2.95 and is 3.2 (3H, m), 3,35-4,2 (3H, m), 4,5 with 4.65 (1H, m), 7,65 one-7.8 (1H, m), 7,9-with 8.05 (1H, m), 8,1-of 8.25 (1H, m), 8,3 an 8.4 (1H, m).

MC (FAB) m/z 448 (M+N)+.

Analysis. Calculated for C17H25N3O5S3,%: FROM 45.6; H 5,63; N 9,39.

Found,%: From 45.5; H 5,8; N 9,1.

Example 17 (see scheme 17).

N-(3,4-Dichlorophenyl)-3-[([2S,4S]-4-sulfanilamide-2-yl-methyl)sulfamoyl]benzamid.

N-(3,4-Dichlorobenzyl)-3-[([2S, 4S] -4-VOS-sulfanilamide-2-ylmethyl)sulfamoyl] benzamide (17) is released from the protective group using TFU (similar to the compound (15 (d)) in example 15) to give the desired product 17 with the release of 97% after trituration with Et2O.

1H NMR (Dl3, 200 MHz): 1,5-1,8 (1H, m), 1.8-to 2.2 (2H+H2O, m, SH, NH), 2,5-2,7 (1H, m), 3.1 to the 3.35 (3H, m), 3,4-4,1 (3H, m), 4,55 (2H, d), to 7.15 (1H, DD), 7,2 (1H, s), 7,32 (1H, d), and 7.4 (1H, d), the 7.65 (1H+ h3RHO, m), and 7.9 (1H, m), and 8.2 (1H, m), 8,35 (1H, m), an 8.5 and 9.3 (1H, s, NH), of 10.3 to 10.7 (1H, s, NH).

MC (ESP+) m/z 474 (M+N)+, 279 (PH3RO).

The original product (17) was obtained as follows. 3,4-Dichloraniline combined with 3-Floralife alcholholic (17(a)) with a yield of 28%.

1H NMR (Dl3, 250 MHz): 4,6 (2H, d), and 6.6 (1H, s, NH), 7,2 (1H, DD), to 7.4 and 7.5 (2H, m), of 7.75 (1H, t), 8,15-of 8.25 (2H, m), and 8.4 (1H, m).

MS (FAB) m/z 378 (M+N)+, 380.

Compound 15(b) (example 15) combined with (17) similarly, the equivalent steps in example 15, receiving N-(3,4-dichlorobenzyl)-3-[([2S,4S]-4-VOS-sulfanilamide-2-ylmethyl)sulfamoyl]benzamide (17(b)) with a yield of 72.5%.

1H NMR (Dl3, 200 MHz): 1,5 (N, C), 1,6-1,9 (1H+H2O, m), 2,4-2,6 (1H, m), 3,1-3,3 (3H, m), up 3.6-3.7 (1H, m), of 3.8-4.1 (2H, m), 4,4 (2H, d), and 4.6 (2H, d), 5,1-5,3 (2H, m), 5,7-5,95 (1H, m), between 6.08 (1H, s, NH), 7,2 (1H, DD), 7,35 to 7.7 (4H, m), of 7.95 (1H, d), of 8.15 (1H, d), 8,25-8,35 (1H, s, NH).

MC (FAB) m/z 658 (M+N)+.

Analysis. Calculated for C28H33N3Cl2O7S2,%: 51,1; N. OF 5.05; N 6,38.

Found,%: From 50.8; H 5,2; N 6,2.

Connection (17(b)) is freed from the protective groups in the equivalent steps in example 15, receiving targeted of the original product (17(C)), to yield 70%.

1H NMR (Dl3, 250 MHz): 1,15-of 1.45 (1H, m), 1,5 (N, in), 2.25-2,4 (1H, m), 2,6-2,9 (4H, m), to 3.02 (1H, DD), 3,25-3,4 (2H, m), 3.45 points and 3.6 (1H, m), and 4.6 (2H, m), 7,05 (1H, m), 7,2 (1H, DD), and 7.4 (1H, d), was 7.45 (1H, d), of 7.6 (1H, t), of 7.95 (1H, d) and 8.1 (1H, d), of 8.25 (1H, s).

MC (ESP+) m/z 574 (M+N)+, 574, 279 (PPh3O).

Example 18 (see diagram 18).

N-(3,4-Dichlorobenzyl)-N'-([2S,4S]-4-sulfanilamide (18(e)) released from the protective group using TFU (similar to the equivalent steps in example 15), receiving target product 18 with the release of 100% after trituration with Et2O.

1H NMR (Dl3+CD3D; 250 MHz) of 1.75 to 1.9 (1H, m), 2,6-of 2.75 (1H, m), 3,2-to 3.35 (1H, m), 3.45 points-of 3.65 (1H, m), 3,7-of 3.95 (3H, m), 4,05-to 4.15 (1H, m), and 4.6 (2H, s), 7,2 (1H, DD), and 7.4 (1H, d), at 7.55 (1H, t), 7,95-with 8.05 (1H, m), of 8.1 to 8.2 (1H, m), and 8.4 (1H, m).

MC (ESP+) m/z 438 (M+N)+.

The original product (18(e)) obtained as follows. Suspension nanometrology ester of isophthalic acid (18(a)) (2.65 g, 14.7 mmol) in CH2Cl2(100 ml) and DMF (10 drops) is treated with oxalylamino (2,6 ml, to 29.8 mmol) at 0oC in argon atmosphere. The reaction mixture is allowed to warm to room temperature for 18 h the resulting solution was concentrated and subjected to azeotropic distillation with toluene, receiving a yellow crystalline solid. It then re-dissolved in CH2Cl2(100 ml) and added dropwise to stirred solution of 3,4-dichloraniline (2.6 g, 14.7 mmol) and Et3N (5 ml, or 35.9 mmol) in CHCl2(100 ml) at 0oC in argon atmosphere. The resulting solution allowed to warm to room temperature for 4 hours, washed with 1 N. Hcl (50 ml), saturated aqueous NaHCO3(50 ml), dried over MgSO4filter and concentrate to the formation of the orange oil. It then oecology ester 3-(3,4-dichloraniline)benzoic acid (18(b)) in the form of a pale yellow oil; 3,99 g (80%).

1H NMR (Dl3, 200 MHz): 3,9 (3H, s), 4,6 (2H, d), 6,6-6,8 (1H, t, NH), 7,18 (1H, DD), 7,38 was 7.45 (2H, m), 7,54 (1H, t), with 8.0 and 8.1 (1H, m), 8,13-8,23 (1H, m), 8,35-8,42 (1H, m).

MS (CI) m/z 338 (M+N)+.

Stir the solution (18(b)) (of 3.85 g of 11.4 mmol) in Meon (100 ml) at room temperature in an argon atmosphere is treated with 1 N. NaOH (12 ml, 24 mmol). The reaction mixture was stirred at room temperature for 4 h, concentrated to 1/5 volume and acidified to pH 4 using 2 N. Hcl. The resulting precipitate is then collected by filtration, washed with water (225 ml) and dried in vacuum, obtaining 3-(3,4-dichloraniline)benzoic acid (18) in the form of a white powder, 2.9 g (79%).

1H NMR (DMSO-d6, 200 MHz): 4,49 (2H, d), 7,32 (1H, DD), of 7.5 to 7.7 (3H, m), 8,0-8,2 (2H, m), 8,42 are 8.53 (1H, m), 9,27 (1H, t, NH), 13,0-13,4 (1H, s, COOH).

MS (ESP+) m/z 324 (M+N)+, 159.

Analysis. Calculated for C15H11NO3Cl20,4 H2O%: 54,4; N 3,59; N TO 4.23.

Found.%: FROM 54.0; H 3,2; 4,2 N.

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide as salt with model HC1 (655 mg, 3.4 mmol) and 1-hydroxybenzotriazol (463 mg, 3.4 mmol) is added in parts of mixed solution (18) (1.0 g, 3.1 mmol) in DMF (20 ml) at 0oC in argon atmosphere. After 30 min added dropwise Rast to warm to room temperature for 4 hours. The resulting reaction mixture was concentrated to 1/5 volume and diluted with EtOAc (100 ml). This solution is then washed successively 1 N. citric acid (100 ml), saturated aqueous NaHCO3(100 ml), water (100 ml) and brine (100 ml), dried over MgSO4filter and concentrate to the formation of a white foam. It then purified flash chromatography on SiO29385 when elution with mixture of EtOAc/ithacan with EtOAc gradient of 50-75%, receiving allyl ester of (2S,4S)-4-BOC-sulfanyl-2-{[3-(3,4-dichloraniline)benzoylamine]methyl}pyrrolidin-1-carboxylic acid (18(d)) in the form of a white foam; of 1.57 g (82%).

1H NMR (Dl3, 250 MHz): 1,5 (N, C), 1,6-1,9 (1H, m), 2,55 is 2.75 (1H, m), 3,2-3,6 (2H, m), 3,65 to-3.9 (2H, m), 4,1-of 4.25 (2H, m), 4,5 with 4.65 (4H, m), of 5.15 to 5.35 (2H, m), 5,38 to 6.0 (1H, m), 6.87 in (1H, t, NH), 7,2 (1H, DD), of 7.4 (1H, d), was 7.45 (1H, d), at 7.55 (1H, t), of 7.95 (1H, d),8,07 (1H, d), of 8.25 (1H, s), 8,35 to 8.6 (1H, s, NH).

MC (ESP+) m/z 622 (M+N)+, 566, 522.

Analysis. Calculated for C29H33N3Cl2O6S,% FROM 55.9; H OF 5.34; N 6,75.

Found,%: C 56,1; N 5,6; N 6,6.

Connection (18 (d)) is freed from the protective groups (similar to the equivalent steps in example 15), receiving targeted of the original product (18(e)) with exit 67%.

1H NMR (Dl3, 200 MHz): of 1.2-1.6 (10H, m), 2,25-to 2.55 (2H, m 1H+1NH), 2,9 (1H, K), 3,3-3,7 ESP+) m/z 538 (M+H)+, 438.

Example 19 (see scheme 19).

Allyl ester of (2S, 4S)-4-effect-free remedy 2-[(3-methoxycarbonylmethylene)methyl]pyrrolidin-1-carboxylic acid

Allyl ester of (2S, 4S)-4-BOC-effect-free remedy 2-[(3-methoxycarbonylmethylene)methyl] pyrrolidin-1-carboxylic acid (19) (300 mg, to 0.63 mmol) dissolved in TFU (5 ml) at room temperature in argon atmosphere. The reaction mixture was concentrated and subjected to azeotropic distillation with toluene (320 ml) to give the desired product (19) in the form of colorless viscous resin; 250 mg (105%).

1H NMR (Dl3, 200 MHz): 1,6-of 1.85 (2H, m, CH+SH), 2,55-to 2.85 (2H, m), 3,1-3,6 (3H, m) to 3.92 (3H, Shir. C) of 4.0-4.4 (2H, m) and 4.65 (2H, d), 5,15-5,4 (2H, m), the 5.8 to 6.1 (1H, m), 7,53 (1H, t), with 8.0 and 8.1 (1H, m), 8,1-of 8.25 (1H, m), 8,3-8,7 (2H, m, aromatic H + NH).

MS (FAB) m/z 379 (M+N)+, 163.

The original product (19) is obtained as follows. Suspension nanometrology ester of isophthalic acid (compound 18(a), example 18), (2.5 g, 13,89 mmol) in CH2Cl2(50 ml) and DMF (10 drops) is treated with oxalylamino (1.35 ml of 15.5 mmol) at 0oC in argon atmosphere. The reaction mixture is allowed to warm to room temperature for 18 h the resulting solution was concentrated and subjected to azeotropic distillation with toluene, receiving crystal is applied to the solution of the allyl ether (2S,4S)-2-aminomethyl-4-VOS-sulfanilamide-1-carboxylic acid (compound 15(b), example 15) (2.0 g, 6,33 mmol) and (i-Pr)2NEt (2.2 ml, 12,66 mmol) in CH2Cl2(50 ml) at 0oC in argon atmosphere. The reaction mixture is allowed to warm to room temperature and stirred for 18 hours, then washed with water (250 ml), dried over MgSO4filter and concentrate to form a dark brown oil. It then purified flash chromatography on SiO29385 when elution with mixture of EtOAc/isohexane with EtOAc gradient of 25-50%, receiving targeted of the original product (19) is in the form of a pale yellow viscous oil; 1,81 g (60%).

1H NMR (Dl3, 200 MHz): 1,5 (N, C) of 1.65 to 1.9 (1H, m), 2,55-2,8 (1H, m), and 3.3 (1H, K), 3,4-of 3.65 (1H, m), 3,65 to-3.9 (2H, m), of 3.95 (3H, s), 4,05 is 4.35 (2H, m), 4,6-4,7 (2H, m), 5,15-5,4 (2H, m), the 5.8 to 6.1 (1H, m), 7,52 (1H, t), 8,02 (1H, DD), 8,15 (1H, DD), 8,25 to 8.5 (1H, Shir. s, NH), 8,55 (1H, Shir. C).

MS (FAB) m/z 479 (M+N)+, 423, 163.

Analysis. Calculated for C23H30N2O7S,%: WITH 57.7; H 6,32; N 5,85.

Found,%: 57.5; H 6,4; N 5,7.

Example 20 (see scheme 20).

N-([2S,4S]-4-sulfanilamide-2-ylmethyl)-3-phenoxybenzamide.

3-Phenoxybenzoic acid combined with allyl ether (2S,4S)-2-aminomethyl-4-VOS-sulfanilamide-1-carboxylic acid (compound (15(b), example 15), and then selectively remove the protective N-allyloxycarbonyl the

NMR (Dl3): 1,8 (1H, m), of 2.72 (1H, m), 3,01-of 3.31 (1H, Shir. d), 3,69-of 3.97 (4H, m), 4,3 (1H, Shir. C), 6,92-7,17 (4.5 N, m, aromatic), 7.23 percent was 7.45 (5,5 H, m, aromatic), 7,56 (1H, m), 7,68 (1H, t), 8,02-8,29 (1H, 2T), 9,02-9,29 (1H, 2 Shire. with + simple ether).

Analysis. Calculated for C18H20N2ABOUT2SHI,%: 47,33; N 4,6; N 6,13.

Found,%: C Of 47.8; H 4,5; N 6,1.

Example 21 (see scheme 21).

Dimethyl 5-{ ([2S, 4S]-1-allyloxycarbonyl-4-sulfanilamide-2-ylmethyl)carbarnoyl}isophthalic acid.

Dimethyl ether benzene-1,3,5-tricarboxylic acid combined with allyl ether (2S,4S)-2-aminomethyl-4-VOS-Sul-phenylpyrrolidine-1-carboxylic acid (compound 15(b)), example 15), then remove the group VOS (similar to equivalent stages in example 15) to give the desired product 21.

NMR (Dl3), %: rate of 1.67 (1H, m) 1,75 (1H, d), 2,66-2,89 (3H, m), 3,21 (1H, K), 3.27 to 3,37 (1H, m), 3,5 (1H, m), 3,9 (2H, Shir. C) 3,97 (6N, (C), 4,08-4,27 (2H, m), and 4.68 (2H, d), 5,2-5,4 (2H, m), 5,88-the 6.06 (1H, m), 8,68 (2H, Shir. C) a 8.8 (1H, d).

Analysis. Calculated for C20H24N2O7S,%: 55,0; N 5,54; N, 6.42 PER.

Found,%: From 54.9; H 5, 6; N 5,75.

Example 22 (see diagram 22).

Methyl ester (2S)-2-{ 3-[([2S, 4S] -4-sulfanilamide-2-ylmethyl)amino]benzoylamine}-4-methylsulfonylmethane acid.

1H NMR (Dl3+CD3COOD): 1.7 to 1.9 (1H, m), 2,0-2,4 (6N+CH3COOH, m), of 2.5-2.8 (3H, m), 3,23 (1H, K), 3,45-3,7 (2H, m), 3,7-3,9 (4H, m), 3.95 to to 4.15 (1H, m), 4,8-of 4.95 (1H, m), 6,8 (1H, d), 7,05-to 7.18 (2H, m), 7.23 percent (1H, t).

MS (S) m/z 398 (M+N)+, 235.

Analysis. Calculated for C18H27N3ABOUT3S21,25 TFU,%: FROM 45.6; H 5,27; N 7,78.

Found,%: From 45.2; H 5,3; N 7,4.

Source 22g product obtained as follows.

i) Obtaining allyl ether (2S,4S)-BOC-effect-free remedy 2-formylpyridine-1-carboxylic acid (22b).

TRAR (5,5 mg, 0,0156 mmol) are added to stir the mixture of allyl ether (2S, 4S)-BOC-effect-free remedy 2-hydroxyethylpyrrolidine-1-carboxylic acid (22A) (100 mg, 0.31 mmol) and N-O (56 mg, 0,478 mmol) in CH2Cl2(2.0 ml) and CH3SP (100 μl) containing dried powdered molecular sieve 4 Angstrom (200 mg). The reaction mixture was stirred for 1 h, then concentrated to dryness. The residue is then purified flash chromatography on SiO2(Varian Mega Bond Elut Column with elution with a mixture of 50% EtOAc/isohexane, receiving the connection 22b in the form of a colourless resin; to 66.3 mg (66,7%).

1H NMR (Dl3, 250 MHz): 1,4-1,6 (N, m), a 2.0 to 2.25 (1H, m), 2,45 is 2.75 (1H, m), 3.45 points and 3.6 (1H, m), 3.75 to a 3.9 (1H, MS="ptx2">

ii) Obtaining methyl ester (2S)-2-[(3-aminobenzoyl)amino]-4-methylsulfonylmethane acid (22E).

3-Nitrobenzoic acid (22 ° C) (2.0 g, to 11.9 mmol) is combined with methyl ester hydrochloride L-methionine (2.6 g, 13 mmol) in accordance with the method used for the synthesis of compounds 18a, receiving methyl ester (2S)-2-[(3-nitrobenzoyl)amino]-4-methylsulfonylmethane acid (22d) in the form of a white solid product; 3,15 g (93,4%).

1H NMR (Dl3, 200 MHz): 2,05-of 2.45 (5H, m), 2.63 in (2H, t), 3,82 (3H, c), 4,96 (1H, m), 7,2 (1H, d, NH), the 7.65 (1H, t), 8,18 (1H, m), 8,39 (1H, m), 8,65 (1H, m).

MC (ESP) m/z 313 (M+H)+, 265, 253.

Analysis. Calculated for C13H16N2O5S,% 50,0; H 5,16; N 8,97.

Found,%: From 50.3; H 5,1; N 8,9.

Mix a solution of 22d (500 mg, of 1.62 mmol) in Meon (10 ml) is treated with added parts of decolorizing charcoal (50 mg) and uranyl chloride iron (III) (7 mg, was 0.026 mmol). Then added dropwise N,N-dimethyl hydrazine (1.5 ml, and 19.8 mmol) and the resulting suspension is heated to boiling under reflux for a total time of 18 hours, the Reaction mixture was then concentrated to dryness and the residue purified flash chromatography on SiO2(Varian Mega Bond Elut Column with elution with a solution of 50% EtOAc/isohexane then triturated with Et2O getting 22E in the form of a white powder, which is collected by filtration and dried; 367 mg (81,2%).

1H NMR (Dl3, 250 MHz): 2,0-2,4 (5H, m), a 2.5 to 2.65 (2H, m), and 3.8 (3H, s), 4,9 (1H, m), 6.75 in-6,95 (2H, m, ArH+CONH), 7,05 OF 7.3 (3H, m).

MC (ESP) m/z 283 (M+N)+, 251, 235, 223.

Analysis. Calculated for C13H18N2O3S,%: FROM 55.3; H TO 6.43; N 9,92.

Found,%: C Of 55.5; H 6,6; N 9,8.

iii) Obtaining 22q.

The solution containing 22E (50 mg, 0,17 mmol) and 22b (54 mg, 0,17 mmol) in EtOH (2.5 ml), treated with powdered molecular sieves 4 angstroms (100 mg) and the resulting suspension was stirred at room temperature for 1 h Add acetic acid (10 μl) and cyanoborohydride sodium (17 mg, 0.27 mmol) and the reaction mixture stirred for 18 h at room temperature. The reaction mixture was then partitioned between EtOAc (50 ml) and saturated aqueous NaHCO3(50 ml). The aqueous phase is then washed with EtOAc (50 ml) and the combined organic phases are dried over gSO4filter and concentrate to the formation of the colorless resin. It then purified flash chromatography on SiO2(Varian Mega Bond Elut Column with elution 25-40% solution of EtOAc/isohexane, receiving methyl ester (2S)-2-(3-[([2S,4S]-1-allyloxycarbonyl-4-VOS-sulfanilic is.

1H NMR (Dl3, 200 MHz): 1,45 (N, s, tert-butyl), 1.7 to 1.9 (1H, m), by 2.0-2.4 (5H, m), 2,45-2,7 (3H, m), 3.1 to the 3.35 (2H, m), 3,4-3,6 (1H, m), 3,6-of 3.85 (4H, m), 4,0-4,3 (2H, m), and 4.6 (2H, m), 4,8-of 4.95 (1H, m), 5,15 of 5.4 (2H, m), the 5.8 to 6.1 (1H, m), of 6.75 (1H, d), the 6.5 to 7.3 (5H, m).

MS (ESP) m/z 582 (M+N)+, 482.

Connection 22f freed from the protective groups (similar to the equivalent steps in example 15), receiving the target source 22g product with a yield of 64%.

1H NMR (Dl3+D2O): 1,15-of 1.95 (10H, m), 1,95-2,15 (4H, m, SMe+H), of 2.15 to 2.35 (1H, m), 2,35-2,5 (1H, m) to 2.55 (2H, t), of 2,75 2,95 (1H, m), 2.95 and is 3.15 (1H, m), 3,15-3,55 (3H, m), 3,55 to 3.7 (1H, m), of 3.78 (3H, s, Come), 4,9 (1H, m) of 6.73 (1H, m), 6,98-7,13 (2H, m), 7,2 (1H, t).

MC (ESP) m/z 498 (M+H)+, 398.

Analysis. Calculated for C23H35N3O5S20,35 CH2CL2,%: 52,3; N 6,82; N 7,97.

Found,%: From 53.5; H 7,1: N 7,5.

Example 23 (see scheme 30).

Getting

N-((2S, 4S)-4-sulfanilamide-2-ylmethyl)-3-methyl-N-(2-naphthalene-1-retil)butyramide (compound 9);

(2S, 4S)-2-{ [(3-methoxypropyl)-(2-naphthalene-1-retil)amino] methyl}pyrrolidin-4-thiol (compound 10) and

(2S, 4S)-2-{[(2-(4-methoxyphenyl)methyl)-(2-naphthalene-1-retil)amino]methyl} pyrrolidin-4-thiol (compound 11).

Obtaining the compound (9).

The solution of the original product, N-((2S,4S)-4-SUN-is stirred at room temperature for 10 minutes. Triperoxonane acid is evaporated under reduced pressure and the residue is again dissolved in diethyl ether (90 ml). Add essential model HC1 (1M, 10 ml) and the resulting suspension centrifuged. Diethyl ether is decanted and the residue add ether (90 ml). This mixture is stirred for five minutes and then centrifuged again. The procedure of washing/centrifugation was repeated once more and the resulting white solid is dried under reduced pressure, obtaining the compound (9), (600 mg).

Data on NMR in DMSO-d6: 0,6 (2D, 6N), of 0.95 (d, 1H), 1,7 (m, 3H), of 2.15 (m, 1H), and 1.9 (m, 1H), 3,0-of 3.85 (m, 10H), 7,3 an 8.4 (m, 7H), 8,9 (Shir. s, 1H), 9,5 (Shir. s, 1H).

The microanalysis. Calculated,%: From 64.9, N, 7,7, N, 6,9. (1.00 m HCl).

Found,%: C 64,7, H7,9, N, 6,8.

The original compound (6) obtained as follows. Allyl ester of (2S, 4S)-2-formyl-4-VOS-sulfanilamide-1-carboxylic acid (1) (1.84 g) in dichloromethane (20 ml) is added dropwise during 10 minutes to a mixture of 2-naphthalene-1-ylethylamine (1.0 g), triacetoxyborohydride sodium (1,36 g) and powdered molecular sieves 4 Angstrom (3.0 g) in dichloromethane (130 ml), cooled to -20oAnd mixed in an argon atmosphere. After complete addition, the reaction mixture is allowed to warm to room temp stirred with saturated aqueous sodium bicarbonate (100 ml) for 5 minutes. The mixture was separated, the organic phase is dried over magnesium sulfate and injected into the column for flash chromatography with silica, which is then elute 1) a mixture of ethyl acetate/hexane (50:50), 2) a mixture of ethyl acetate/hexane (80:20), (3) ethyl acetate, getting allyl ester of (2S, 4S)-4-BOC-effect-free remedy 2-[(2-naphthalene-1-ylethylamine)methyl] pyrrolidin-1-carboxylic acid (2) (2.2 g) as a colourless resin.

Data on NMR in Dl3: 1,5 (, N), of 1.85 (m, 1H), 2,5 (m, 1H), 2,8 (m, 1H), 3.0 a (m, 3H), 3,2 (m, 3H), and 3.7 (m, 1H), of 4.05 (m, 2H), 4,55 (d, 2H), 5.25 in (m, 2H), 5,9 (m, 1H), 7,43 (m, 4H), 7.7 (d, 1H), 7,83 (m, 1H), with 8.05 (m, 1H).

A mixture of compound (2) (1.2 g), isovaleraldehyde (0,61 g) and triethylamine (of 0.77 g) in dichloromethane (75 ml) is stirred for 1 hour at room temperature. The reaction mixture is then injected into the column for flash chromatography with silica, which elute with a mixture of ethyl acetate/hexane (20:80) to give compound (3) in the form of a colourless resin (1.3 g).

Tributyltinhydride (6,46 g) is added dropwise during 5 minutes to a stirred mixture of compound (3) (1.23 g) and bis(triphenylphosphine)palladium(0)chloride (20 mg) in dichloromethane (75 ml). This mixture was stirred at room temperature for 30 minutes and then injected into the column for flash chromatography with silica is the first product is introduced into a column IsoluteC18 (10 g) and elute with a mixture of methanol/water (80:20), receiving the original product, the compound (6), in the form of a white solid product (769 mg), so pl. 86oC.

Data on NMR: (Dl3) 0,9 (2D, 6N), 1,3 (m, 1H), 1,5 (, N), 1,8-2,5 (m, 6N), 2,9 (m, 1H), 3,05 to-3.9 (m, N), 7,25-8,35 (m, 7H).

Obtaining the compounds (10).

The solution of the original product, (2S,4S)-2-{[(3-methoxypropyl)-2-(naphthalene-1-retil)amino]methyl}pyrrolidin-4-VOS-thiol (compound 7) (78 mg) in triperoxonane acid is stirred at room temperature for 30 minutes. Triperoxonane acid is removed under reduced pressure and the residue treated with diethyl ether (5 ml). The ether is decanted and the residue is dried under reduced pressure for 24 hours, receiving targeted end product in the form of a colourless resin (compound 10) (70 mg).

Data NMR (Dl3): 1,95 (m, 4H), of 2.05 (m, 1H), 3,16-3,62 (m, 10H), 3,29 (s, 3H), and 3.7 (m, 1H), 4,15 (m, 2H), 7.3 to the 7.65 (m, 4H), to 7.68 (d, 1H), 7,88 (d, 1H), 7,98 (d, 1H), and 11.2 (Shir. s, 2H).

The microanalysis. Calculated,%: 48,2, N 5,13, N 4,32 (2,5 TFU, 0,25 H2O). Found,%: C 48,5, N 5,20, N 4,40.

The original product (compound 7) was prepared as follows.

A solution of 4-methoxybutanol aldehyde (140 mg) in dichloromethane (10 ml) is added dropwise to a mixture of compound (2)(250 is my in argon atmosphere at -20oC. After complete addition (5 minutes) the reaction mixture is allowed to warm to room temperature and stirred for 18 hours. Molecular sieve is separated by filtration and the filtrate washed with saturated sodium bicarbonate solution (20 ml), then brine and dried over magnesium sulfate. The solution is then injected into the column with silica and elute with a mixture of ethyl acetate/hexane (50:50), receiving light resin, the compound (4) (260 mg).

Compound (7) is synthesized from compound (4) similarly, to obtain the compound (6).

Data on NMR: (Dl3) to 1.35 (m, 1H), 1,48 (s, N), of 1.74 (m, 2H), 2,31 (m, 1H), 2,42-3,1 (m, 7H), 3,15 to 3.5 (m, N), the 3.65 (m, 1H), 7,28 to 8.1 (m, 7H).

Obtaining the compounds (11).

The compound (11) are synthesized from the original product, (2S,4S)-2-{[(2-(4-methoxyphenyl)methyl)-(2-naphthalene-1-retil)amino] methyl}pyrrolidin-4-VOS-thiol (compound 8), by the method described for the equivalent stage of obtaining the compound (10).

Data on NMR: (Dl3) to 1.9 (m, 1H), 2.05 is (m, 1H), 2,3 (m, 1H), 3,1-3,8 (m, 8H), 3,82 (s, 3H), 4,25 (m, 3H), of 6.96 (d, 2H), 7,42 (m, 6N), 7,83 (m, 3H).

The microanalysis. Calculated, %: 55,7, N 5,77, N 4,06 (2 TFU, 0.75 in diethyl ether).

Found,%: 56,0, H 5.40, Is N 4,50.

Starting material for compound (11) receive the sodium bicarbonate (5 ml) and dichloromethane (20 ml) was stirred at room temperature for 24 hours. The layers are separated and the organic layer is dried, is introduced into a column for flash chromatography with silica, which is then elute with a mixture of ethyl acetate/hexane (80:20) to give (2S,4S)-1-allyloxycarbonyl-2-{ [(2-(4-methoxyphenyl)methyl)-(2-naphthalene-1-retil)amino] methyl} pyrrolidin-4-VOS-thiol, compound (5), in the form of a colorless gum (140 mg).

Data on NMR: (Dl3) 1,45 (s, N), 2.0 (m, 1H), 2,35 (m, 1H), 2,53-to 4.15 (m, 10H), and 3.8 (s, 3H), 4,6 (m, 4H), 5.25 in (m, 2H), 5,9 (m, 1H), 6,85 (m, 3H), and 7.3 (m, 6N), to 7.75 (m, 2H).

The target of the original product (compound (8)) are synthesized from compound (5) by the same method as used for compound (6) from the compound (3).

Mass spectrum (ESP+) m/e 507,0.

Example 24 (see diagram 31).

Getting

a) 3-methyl-N-(naphthalene-1-ylmethyl)-N-([2S, 4S]-4-sulfanilamide-2-ylmethyl)butanamide (compound 23);

b) N-(naphthalene-1-ylmethyl)-N-([2S, 4S] -4-sulfanilamide-2-ylmethyl)pentanolide (compound 24);

C) N-(naphthalene-1-ylmethyl)-N-([2S,4S]-4-sulfanilamide-2-ylmethyl)-2-(pyridin-3-yl)ndimethylacetamide (compound 27);

g) 3-methyl-N-(naphthalene-1-ylmethyl)-N-([2S, 4S]-4-sulfanilamide-2-ylmethyl)pentanolide (compound 25);

d) 3-methoxy-N-(naphthalene-1-ylmethyl)-N-([2S, 4S]-4-sulfanilamide-2-ylmethyl)propanamide (preprogram the ASS="ptx2">

a) Receiving a connection 23.

The solution of the original product, 3-methyl-N-(naphthalene-1-ylmethyl)-N-([2S,4S]-4-VOS-sulfanilamide-2-ylmethyl)butanamide (compound (18)) (187 mg) in triperoxonane acid (10 ml) was stirred at room temperature for 5 minutes. Triperoxonane acid is evaporated under reduced pressure and the resulting residue is again dissolved in ethyl acetate (5 ml). To the solution add a solution of hydrogen chloride (2 ml/1.0 M), then diethyl ether (5 ml). The mixture is centrifuged, the solvent is decanted and the residue is washed with additional diethyl ether (215 ml) and dried, obtaining cleaners containing hydrochloride salt of the compound (23) in the form of not-quite-white solid product (43 mg).

Data NMR (DMSO-d6): 0,83 (m, 6N), of 0.95 (d, 1H), 1,68 (m, 1H), 2,10 (m, 3H), 2,42 (m, 1H), 3,10 (m, 1H), 3,28-3,90 (m, 5H), 5,20 (m, 2H), was 7.08 (d, 1H), EUR 7.57 (m, 3H), 7,87 (d, 1H), 8,00 (m, 2H), 9,10-9,80 (2 Shire. s, 2H).

The microanalysis. Calculated,%: From 62.7, N 7,52, N 6,97 (1 HC1, 0.5 N2O).

Found,%: From 62.4, N. 7,6, N, 6,7.

The original product, compound (18), was obtained as follows.

A solution of allyl ester (2S,4S)-2-formyl-VOS-sulfanilamide-1-carboxylic acid (compound (1)) (3.11 g) in dichloromethane (60 ml) is added dropwise to peremeshivaemogo (200 ml) in an argon atmosphere at -20oC. the Mixture is stirred for an additional 30 minutes at -20oC and then allowed to warm to room temperature and stirred for another 16 hours. The mixture is filtered and washed with aqueous sodium bicarbonate solution (2200 ml), the organic phase is then washed with water (200 ml), separated, dried over magnesium sulfate and purified column chromatography using a mixture of ethyl acetate/hexane (30:70) as eluent, obtaining allyl ester of (2S,4S)-2-{[naphthalene-1-ylmethyl]amino)methyl}-4-VOS-sulfanilamide-1-carboxylic acid (compound (12)) in the form of a pale yellow oil (2,09 g).

Data NMR (Dl3): 1,50 (s, N), of 1.55 (m, 1H), 1,90 (m, 1H), 2,50 (m, 1H), 2,90 (m, 1H), 3,05 (m, 1H), 3,20 (m, 1H), 3,68 (m, 1H), 4,08 (m, 2H), 4,23 (s, 2H), 4,55 (d, 2H), 5,20 (m, 2H), 5,90 (m, 1H), 7,47 (m, 4H), to 7.77 (m, 1H), 7,86 (m, 1H), 8,13 (m, 1H).

A mixture of compound (12) (507 mg), triethylamine (0.3 ml) and isovaleraldehyde (0,271 ml) in dichloromethane (30 ml) was stirred at room temperature for 1.5 hours and then immediately injected into a column for flash chromatography. Column elute with a mixture of ethyl acetate/hexane (25:75) and ethyl acetate/hexane (35: 65) to give 3-methyl-N-(naphthalene-1-ylmethyl)-N-([2S,4S]-1-allyloxycarbonyl-4-VOS-sulfanilamide-2-ylmethyl)butanamide (compound (13)) in the resin (475 mg).

Tributyltinhydride (2,22 ml) is added dropwise to a mixture of compound (13) (446 mg), bestafootballahand (5.8 mg) in dichloromethane (10 ml). The mixture is stirred at room temperature in an argon atmosphere for 70 minutes and then immediately injected into a column for flash chromatography, which elute (1) a mixture of ethyl acetate/hexane (50:50) and (2) ethyl acetate. The resulting product again chromatographic on column IsoluteC18 (10 g) with elution with a mixture of methanol/water(1) (70:30), (2)(75:25) and (3)(80:20), receiving targeted of the original product (compound (18)) in the resin (197 mg).

Data NMR (DMSO-d6, 373oTo): 0,90 (m, 6N), a 1.45 (m, 5H), to 1.60 (m, 1H), 1,68 (m, 2H), 2,12 (m, 2H), 2,25 (d, 2H), 2.40 a (m, 1H), 2,60-of 3.85 (m, 8H), 5,14 (s, 2H), 7,20 (m, 1H), 7,50 (m, 3H), 7,83 (m, 1H), to 7.93 (m, 1H), 8,03 (m, 1H).

b) Receiving connection 24.

The compound (24) synthesized in the same manner as that used for compound (23), but substituting the appropriate connections as shown in scheme 31.

The connection 24.

Data NMR (DMSO-d6): of 0.85 (m, 3H), 1,15-of 1.75 (m, 5H), 2,28 (t, 2H), 3,10 (m, 1H), 3.33 and-3,95 (m, 6N), 5,18 (m, 2H), 7,20 (2D, 1H), 7,55 (m, 3H), a 7.85 (d, 1H), 8,00 (m, 2H), 8,95-9,90 0, N 6,8.

Connection (14).

Data NMR (Dl3): of 0.90 (m, 3H), 1,12-2,10 (m, 6N), to 1.48 (s, N), and 2.26 (m, 1H), 2,50 (m, 1H), 3.00 and-5,70 (m, N), by 5.87 (m, 1H), 7,07-of 8.06 (m, 7H).

The compound (19).

Data NMR (DMSO-d6, 373oK): 0,84 (m, 3H), of 1.30 (m, 3H), 1,45 (s, N), of 1.55 (m, 2H), 2,34 (m, 3H), 2,80 (m, 2H), 3.45 points (m, 5H), 5,10 (m, 2H), 7,25 (d, 1H), 7,50 (m, 3H), 7,80 (d, 1H), of 7.90 (m, 1H), 8,03 (m, 1H).

C) Obtaining the compound (27).

Compound (27) synthesized in the same manner as in the equivalent stage for the connection (23), from the original product, N-(naphthalene-1-ylmethyl)-N-([2S, 4S]-4-VOS-sulfanilamide-2-ylmethyl)-2-(pyridin-3-yl)ndimethylacetamide (compound (22)).

Compound (27).

Data NMR (DMSO-d6): to 1.70 (m, 1H), 2,50 (m, 1H), 3,14 (m, 1H), 3,28-5,10 (m, 7H), to 5.35 (m, 2H), 7,20-9,00 (m, 11N), 9,20 (Shir. s, 1H), of 10.05-10,50 (2 Shire. s, 1H).

The microanalysis. Calculated,%: C 55,10, N 6,60, N 7,97 (2 HCl, 2,25 H2O, 0,3 diethyl ether).

Found,%: C 54,80, N 6,10, N 7,60.

The original product (compound (22)) was synthesized as follows.

A mixture of compound (12) (345 mg), 4-dimethylaminopyridine (305 mg), hydrochloride 3-pyridyloxy acid (262 mg), and hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (348 mg) in dichloromethane (30 ml) was stirred at room ancrene when elution with a mixture of ethyl acetate/hexane (75:25) and then with ethyl acetate, receiving N-(naphthalene-1-ylmethyl)-N-([2S, 4S] -1-allyloxycarbonyl-4-VOS-sulfanilamide-2-ylmethyl)-2-(pyridin-3-yl)ndimethylacetamide (compound (17)) in the form of a colourless resin (394 mg).

The compound (17).

Data NMR (DMSO-d6, 373o): Of 1.46 (s, N), a 1.75 (m, 1H), 2,50 (m, 1H), 3,17 (K, 1H), 3,50 (m, 1H), 3,75 (m, 4H), Android 4.04 (m, 1H), 4,27 (m, 1H), 4,45 (m, 2H), 5,15 (m, 4H), of 5.83 (m, 1H), 7,25 (m, 2H), 7,43 (t, 1H), 7,52 (m, 2H), 7,58 (m, 1H), 7,82 (d, 1H), 7,95 (m, 2H), 8,40 (d, 2H).

Using the method previously described for the equivalent step in the synthesis of compound 23, compound (17) synthesize the target of the original product (compound (22)).

Compound (22).

Data NMR (DMSO-d6, 373oTo): 1,45 (s, N), of 2.38 (m, 1H), 2,55-4,00 (m, 10H), 5,20 (m, 2H), 7,25 (m, 2H), 7,50 (m, 4H), of 7.90 (m, 3H), 8,40 (m, 2H).

(g) obtaining the compound (25).

The compound (25) synthesized using compounds 12, 15 and 20 as an intermediate product in the same way as in equivalent stages of synthesis of the compound (27) (see scheme 31).

The compound (25).

Data NMR (DMSO-d6): 0,80 (m, 6N), 0,95-4,80 (m, 14N), 5,18 (m, 2H), was 7.08 (d, 1H), 7,55 (m, 3H), 7,95 (m, 3H), 8,90-10,15 (2 Shire. d, 2H).

The microanalysis. Calculated,%: 59,1, N 7,30, N 6,27 (2 HCl, and 0.2 H2O).

Found,%: 59,1, N 6,90, N 5,9.

With whom,90 (m, 1H), 2,17 (m, 1H), 2,30 (m, 1H), 2,50 (m, 1H), 3.15 in (K, 1H), of 3.45 (m, 1H), 3,70 (m, 2H), 4,03 (K, 1H), 4,20 (m, 1H), of 4.44 (d, 2H), 5,10 (m, 4H), 5,80 (m, 1H), 7,20 (m, 1H), 7,50 (m, 3H), 7,80 (d, 1H), of 7.90 (m, 1H), 8,00 (m, 1H).

The compound (20).

Data NMR (DMSO-d6, 373oTo): 0,85 (m, 6N), 1,25 (m, 3H), 1,45 (s, N), of 1.93 (m, 1H), and 2.27 (m, 3H), 3,40 (m, 6N), 5,13 (m, 2H), 7,25 (d, 1H), 7,50 (m, 3H), 7,80 (d, 1H), of 7.90 (m, 1H), 8,04 (m, 1H).

d) Obtaining the compound (26).

The compound (26) synthesized using compounds 12, 16 and 21 as an intermediate product in the same way as in equivalent stages of synthesis of the compound (27) (see scheme 31).

The compound (26).

Data NMR (DMSO-d6): to 1.70 (m, 1H), 2.40 a-to 4.15 (m, 14N), 5,20 (m, 2H), 7,20 (2D, 1H), 7,55 (m, 3H), a 7.85 (m, 1H), 8,00 (m, 2H), 9,05-of 10.25 (2 Shire. d, 2H).

The microanalysis. Calculated,%: 59,5, N 6,99, N 6,93 (2 Hcl, 0.2 g of N2O).

Found,%: C 59,3, N 7,30, N 6,70.

Compound (16).

Data on NMR: (DMSO-d6, 373oK) 1,45 (s, N), of 1.78 (m, 1H), 2,40-of 3.80 (m, N), of 4.00 (m, 1H), 4,20 (m, 1H), 4,45 (m, 2H), 5,10 (m, 4H), 5,80 (m, 1H), 7,20 (m, 1H), 7,45 (t, 1H), 7,50 (m, 2H), 7,80 (d, 1H), of 7.90 (m, 1H), 8,00 (m, 1H).

The compound (21).

Data NMR (DMSO-d6, 373o): Of 1.30 (m, 1H), 1,48 (s, N), is 2.30 (m, 1H), 2,56-3,70 (m, 14N), 5,15 (m, 2H), 7,30 (d, 1H), 7,47 (t, 1H), 7,53 (m, 2H), 7,83 (d, 1H), 7,94 (m, 1H), with 8.05 (m, 1H).

Data NMR (Dl3): 1,5 (m, 1H), 1,75 (Shir. d, 1H), 1,95 (m, 1H), 2,6 (t, 1H), 3,05 (m, 1H), 3,2 (d, 1H), 3,35 (m, 2H), 3,85 (s, 3H), 4.2V (s, 2H), 4,6 (2D, 2H), 6,95 (d, 2H), and 7.4 (d, 2H), 7,6 (m, 4H), 7,9 (m, 3H).

The microanalysis. Calculated,%: 52,0, H 5.40, IS N 3,90 (2,5 TFU, 0,4 diethyl ether).

Found,%: 52,0, N 4,92, N 3,96.

The original product was obtained as follows.

A mixture of compound (12) (240 mg), dimethylformamide (20 ml), anhydrous potassium carbonate (80 mg) and p-methoxybenzylamine (0,143 ml) was stirred at 70oC in argon atmosphere for 4 hours. The solvent is removed under reduced pressure and the residue purified column chromatography with elution with a mixture of ethyl acetate/hexane (20:80) to give a colourless resin, (2S,4S)-1-allyloxycarbonyl-2-[{ N-(4-methoxybenzyl)-N-(naphthalene-1-ylmethyl)amino} methyl] pyrrolidin-4-VOS-thiol (compound (52)), (213 mg).

Data NMR (Dl3): 1,45 (s, N), of 2.15 (m, 1H), 2,5 (m, 1H), 2,8 (m, 1H), 3,05 (m, 1H), 3,5 (m, 2H), 3,8 (Shir. s, 7H), to 3.9 (m, 1H), 4,2 (m, 1H), 4,6 (s, 2H), 5.25 in (m, 2H), 5,9 (is inane (52) and bis(triphenylphosphine)palladium(0)chloride (2 mg) in dichloromethane (10 ml). The solution was stirred at room temperature for 30 minutes. Add the second portion of tributyltinhydride (0,335 ml) and bis(triphenylphosphine)palladium(0)chloride (2 mg) and stirring is continued for an additional 30 minutes. The mixture is injected directly into the column for flash chromatography with silica, which elute with a mixture of ethyl acetate/hexane(25: 75), (50: 50) and at the end of the ethyl acetate. The resulting product is further purified HPLC with reversed-phase C18 column with when elution with a mixture of water/methanol/TFU (20: 80: 0,2), receiving targeted of the original product (compound (53)) as a colourless resin (168 mg).

Data NMR (Dl3): 1,45 (s, N), of 1.55 (m, 1H), 2.0 (m, 1H), 2,5 (m, 1H), 3,1 (d, 1H), 3,4 (m, 3H), 3,6 (t, 1H), and 3.8 (s, 3H), 4,1 (2D, 2H), 4,4 (d, 1H), 4,6 (d, 1H), 6,95 (d, 2H), and 7.4 (d, 2H), 7.5 (m, 4H), to 7.9 (m, 3H).

The microanalysis. Calculated,%: C 54,4 N OF 5.40, N 3,70 (2 TFU).

Found,%: C 55,0, N 5,31, 3,89 N.

Example 25 (see diagram 32).

Getting

a) (2S, 4S)-2-[(N-methylnaphthalene-1-ylamino)methyl]-4-sulfanilamide (compound 36) and

b) N-(naphthalene-1-yl)-N-((2S, 43)-4-sulfanilamide-2-ylmethyl)-3-methylbutanoate (compound 37).

The connection 36.

The mixture of the raw product, (2S,4S)-2-[(N-methylnaphthalene-1-ylamino)methyl] -4-VOS-sulfanyl is giving 1 hour. Triperoxonane acid is removed under reduced pressure and the residue is dried under high vacuum, obtaining the compound (36) as a colourless resin (110 mg).

Data NMR (Dl3): 1,7 (m, 1H), 1,9 (d, 1H), and 2.6 (m, 1H), 2.95 and (s, 3H), 3,1 (2D, 1H), 3,5 (m, 1H), 3,65 (m, 3H), of 4.05 (m, 1H), 7,0 (Shir. s, 1H), and 7.4 (t, 1H), 7,55 (m, 3H), 7.7 (d, 1H), a 7.85 (m, 1H), and 8.2 (m, 1H).

The microanalysis. Found,%: C 45,5, N 4,2, 5,0 N (2,0 TFU, 1,02O).

Calculated,%: 46,3, N 4,67, N 5,4.

Starting material for compound (36) was obtained as follows.

A mixture of allyl ether (2S,4S)-2-formyl-4-VOS-sulfanilamide-1-carboxylic acid (compound (1)) (711 mg), ethanol (25 ml), 1-naphtylamine (333 mg) and molecular sieves 3 Angstrom (4.5 g) is stirred in an argon atmosphere at room temperature for 6 hours. Add acetic acid (0.4 ml) and then cyanoborohydride sodium (170 mg). The mixture was then stirred for an additional 20 hours, after which the sieves are removed by filtration. The filtrate is concentrated under reduced pressure and the residue is introduced into a column with silica and elute with a mixture of ethyl acetate/hexane (20: 80) to give (2S,4S)-1-allyloxycarbonyl-2-[(naphthalene-1-ylamino)methyl] -4-VOS-sulfanilamide (compound (31)) in the form of a light oil (560 mg).

is), 5,95 (m, 1H), 6,55 (m, 1H), 7,2 (d, 1H), and 7.3 (t, 1H), and 7.4 (m, 2H), to 7.75 (m, 1H), 7,9 (m, 1H).

A mixture of compound (31)) (218 mg), dimethylformamide (40 ml), iodomethane (0.6 ml) and anhydrous potassium carbonate (150 mg) was stirred at 80oC for 20 hours. The solvent is removed under reduced pressure and the residue is dissolved in ethyl acetate (30 ml) and washed with water (20 ml). The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure, obtaining the (2S,4S)-1-allyloxycarbonyl-2-[(N-methylnaphthalene-1-ylamino)methyl] -4-VOS-sulfanilamide (compound (32)) as a yellow resin (183 mg).

Data NMR (Dl3): 1,45 (s, N), 2.0 (m, 1H), 2,4 (m, 1H), 2,85 (s, 3H), 3.0 a (2D, 1H), 3,25 (m, 1H), 3,7 (2D, 1H), and 3.8 (m, 1H), 4,1 (m, 2H), and 4.6 (d, 2H), 5,3 (9M, 2H), 5,95 (m, 1H), 7,45 (m, 5H), and 7.8 (m, 1H), of 8.25 (m, 1H).

To a solution of compound (32) (178 mg) in dichloromethane (10 ml) is added tri-n-butylaldehyde (0.2 ml), then bis(triphenylphosphine)pallidiflora (2 mg) and the mixture is then stirred at room temperature. After 10 min and 20 min add the second and third portions of tri-n-butylaldehyde (0.2 ml) and bis(triphenylphosphine)pallidiflora (2 mg) and stirring is continued for an additional 90 minutes, the Reaction solution is injected directly into the column with silica and elute the mixture is odorou elute with a mixture of water/methanol/triperoxonane acid (20:80:0,2), getting the original product (compound (34)) (160 mg) as a colourless resin.

Data NMR (Dl3): 1,45 (s, N), 2,2 (s, 1H), 2,39 (m, 1H), 2,85 (s, 3H), 2,9 (2D, 1H), 3,1 (2D, 1H), 3,25 (m, 2H), 3,4 (m, 1H), 3,6 (m, 1H), 7,15 (d, 1H), 7,45 (m, 4H), and 7.8 (m, 1H), 8,35 (m, 1H).

The microanalysis. Found,%: FROM 50.8, N 5,20, N, 4,6 (2,0 TFU, 0.5 H2O).

Calculated,%: From 49.3, N 5,13, N, 4,6.

b) obtaining the compound (37).

The mixture of the raw product (compound (35)) (187 mg) and triperoxonane acid (5 ml) was stirred at room temperature for 1 hour. Triperoxonane acid is removed under reduced pressure and the residue is dried in high vacuum, obtaining a colorless resin, the compound (37) (200 mg).

Data NMR (Dl3): 0,8 (m, 6N), 1,6-2,2 (m, 5H), and 2.6 (m, 1H), 3,2-5,0 (m, 6N), and 7.6 (m, 5H), and 8.0 (m, 2H).

The microanalysis. Found,%: FROM 48.4, N 4,80, N 4,5 (2,0 TFU, 1,0 H2O).

Calculated,%: 49,0, N 5,14, N 4,76.

The original product was obtained as follows.

Isovalerianic (0,164 ml) is added dropwise during 10 minutes to a stirred solution of compound (31) (297 mg), dichloromethane (50 ml) and triethylamine (0,136 ml). The solution was stirred at room temperature for 24 hours. The solvent is removed under reduced pressure and the residue BBO is Jn-1-yl)-N-((2S,4S)-1-allyloxycarbonyl-4-VOS-sulfanilamide-2-ylmethyl)-3-methylbutanoate (compound (33)) (329 mg).

Data NMR (Dl3): 0,75 (m, 6N), and 1.5 (s, N), of 1.65 to 2.7 (m, 5H), 3,15 to 6.0 (m, N), 7,25 (m, 1H), 7.5 (m, 3H), and 7.7 (m, 1H), 7,9 (m, 2H).

To a solution of compound (33) (296 mg) in dichloromethane (10 ml) is added tri-n-butylaldehyde (0.3 ml), then bis(triphenylphosphine)pallidiflora (2 mg). The solution was stirred at room temperature. After 10 min and 20 min add the second and third portions of tri-n-butylaldehyde (0.3 ml) and bis(triphenylphosphine)pallidiflora (2 mg) and stirring is continued for an additional 30 minutes. The reaction solution was immediately injected into a column with silica, which is then elute with a mixture of ethyl acetate/hexane(25:75), (50:50) and ethyl acetate. The product is further purified HPLC with reversed-phase C18 column with when elution with a mixture of water/methanol/triperoxonane acid (20: 80:0,2), receiving targeted of the original product (compound (35)) (216 mg).

Data NMR (Dl3): 0,8 (m, 6N), for 1.49 (s, N), 1,1-2,2 (m, 6N), a 2.9 to 5.6 (m, 6N), 7,4-8,0 (m, 7H).

The microanalysis. Found,%: 57,0, N 6,20, N 4,80 (1,0 TFU, 0,75 H2O).

Calculated,%: C 56,9 N 6,45, N 4,91.

Example 26 (see scheme 33).

Getting

a) 3-methyl-N-(3,3-diphenylpropyl)-N-([2S, 4S] -4-sulfanilamide-2-ylmethyl)butanamide (compound 43)

b) N-(3,3-diphenylpropyl)-N-([2S, 4S] -4-Sanam way described in example 23, using appropriate starting materials and intermediate products listed in scheme 33.

a) obtaining a compound (43).

Compound (43).

Data NMR (DMSO-d6at 373oTo): 0,9 (d, 6N), and 1.7 (m, 1H), 2,1 (m, 1H), 2,33 (m, 2H), 2,45 (m, 1H), 2,9-4,00 (m, N), 4,2-of 4.95 (m, 2H), and 7.3 to 8.1 (m, 10H), 9,65 (v. Shir. s, 2H).

The microanalysis. Calculated,%: C 64,8, N, 7,7, N 5,9 (1.00 M HCl, 1 N2About%).

Found,%: C 64,5, N, 7,9, N, 6,0.

The original product, 3-methyl-N-(3,3-diphenylpropyl)-N-([2S,4S]-4-VOS-sulfanilamide-2-ylmethyl)butanamide (compound 41), are synthesized from compounds (1) and 3,3-diphenylpropylamine using a method similar to the method indicated in example 23.

Connection (38).

Data NMR (Dl3): 1,5 (, N), and 1.8 (m, 1H), 2,19 (m, 2H), 2,42 (m, 1H), to 2.55 (m, 2H), and 2.7 (m, 1H), 2,82 (m, 1H), 3,19 (m, 1H), to 3.67 (m, 1H), 4,0 (m, 3H), 4,55 (d, 2H), 5,2 (2D, 2H) and 5.9 (m, 1H), 7,2 (m, 10H).

Compound (39).

Data NMR (Dl3): 0,7-1,0 (m, 6N), 1,22 (m, 1H), 1,5 (, N), 1,78-2,02 (m, 2H), 2,3 (m, 4H), 3,2 (m, 3H), 3,4-4,2 (m, 6N), to 4.52 (m, 2H), total of 5.21 (m, 2H), 5,9 (m, 1H), 7,2 (m, 10H).

Compound (41).

Data NMR (Dl3): 0,75-1,00 (m, 6N), 1,25 (m, 1H), 1,5 (, N), of 1.85 to 2.4 (m, 6N), and 2.83 (m, 1H), 3,05-3,47 (m, 6N), and 3.6 (m, 1H), a 3.87 (2T, 1H), 7,25 (m, 10H).

b) Receiving the th NMR (DMSO-d6at 373o): Of 1.65 (m, 1H), 1,85 (s, 3H), 2,32 (K, 2N), of 2.45 (m, 1H), 2,69-4,3 (m, N), to 7.2 (m, 10H), 9,37 (v., Shir. s, 2H).

The microanalysis. Calculated,%: C 63,3, N 7,3, N 6,6 (1.00 M HCl, 0.75, and H2O).

Found,%: C 63,1, N 7,3, N 6,7.

The compound (40).

Data NMR (Dl3): 1,5 (, N), is 1.82 (s, 3H), 1,6-2,5 (m, 4H), 3,2 (m, 3H), 3,32-of 4.25 (m, 6N), of 4.54 (m, 2H), 5,23 (m, 2H), 5,9 (m, 1H), 7.23 percent (m, 10H).

Compound (42).

Data NMR (Dl3): to 1.48 (s, N), and 1.8 (m, 1H), 1,87 (s, 2H), 2,07 (s, 1H), 2,33 (m, 3H), and 2.83 (m, 1H), 3,28 (m, 6N), and 3.6 (m, 1H), 3,85 (m, 1H), 7,25 (m, 10H).

Example 27 (see diagram 34).

Getting

a) 3-methyl-N-(naphthalene-2-ylmethyl)-N-([2S, 4S]-4-sulfanilamide-2-ylmethyl)butanamide (compound 50) and

b) N-(naphthalene-2-ylmethyl)-N-([2S, 4S] -4-sulfanilamide-2-ylmethyl)ndimethylacetamide (compound 51).

Connection (50) and (51) are synthesized using the method described in example 23, using appropriate starting materials and intermediate products listed in scheme 34.

a) Obtaining the compound (50).

The connection 50.

Data NMR (DMSO-d6): 0,75-1,1 (m, 6N), and 1.63 (m, 1H), 2,1 (m, 1H), 2,48 (m, 1H), and 2.83 (m, 3H), 3,0-of 4.95 (m, 8H), 7,17 (m, 7H).

The microanalysis. Calculated,%: From 64.2, N 7,44, N 7,13 (1,0 HC1).

Found,%: C 64,0, N 7,40, N 7,10.

IP is synthesized from compounds (1) and 2-naphthylenediamine.

The compound (45).

Data NMR (Dl3): to 1.48 (s, N), with 1.92 (m, 1H), 2,5 (m, 1H), 2,82 (m, 1H), 2,96 (m, 1H), 3,2 (2D, 1H), 3,7 (m, 1H), 3.96 points (s, 2H), 4,08 (m, 2H), 4,54 (m, 2H), and 5.2 (m, 2H), 5,9 (m, 1H), 7,42 (m, 3H), and 7.8 (m, 4H).

Compound (46).

Data NMR (Dl3): 0,96 (2D, 6N), to 1.48 (s, N), and 1.9 (m, 1H), 2,13-2,6 (m, 4H), 3,3 (m, 1H), and 3.72 (m, 2H), 4,15 (m, 2H), and 4.5 (m, 2H), amounts to 4.76 (m, 1H), 5,2 (m, 2H), 5,9 (m, 1H), of 7.48 (m, 3H), 7,73 (m, 4H).

Connection (48).

Data NMR (Dl3): 0,98 (2D, 6N), 1,3 (m, 1H), 1,48 (s, N), 2,3 (m, 4H), 2,9 (m, 1H), 3,1-3,7 (m, 5H), is 4.85 (m, 2H), 7,15 to 7.9 (m, 7H).

b) obtaining the compound (51).

The characteristic data are given below.

The connection 51.

Data NMR (DMSO-d6at 373oTo): 1,7 (m, 1H), and 2.14 (s, 3H), 2,47 (m, 1H), 2,8-4,00 (m, 6N), and 4.8 (m, 2H), 7,32 to 8.1 (m, 7H).

The microanalysis. Calculated,%: FROM 64.2, N 7,44, N 7,13 (1,00 model HC1).

Found,%: C 64,0, N 7,40, N 7,10.

The compound (47).

Data NMR (Dl3): 1,5 (, N), and 1.9 (m, 1H), 2,12 (s, 2H), 2,29 (s, 1H), 2,5 (m, 1H), 3,18-5 (m, 10H), and 5.2 (m, 2H), 5,95 (m, 1H), 7,2-7,89 (m, 7H).

Compound (49).

Data NMR (Dl3): 1,3 (m, 1H), 1,47 (s, N), of 2.15 (s, 2H), 2,3 (s, 1H), 2,35 (m, 1H), 2,88 (m, 1H), 3,1-3,7 (m, 5H), is 4.85 (m, 2H), and 7.4 to 7.9 (m, 7H).

Example 28 (see diagram 35).

Methyl ester (2S)-2-({ 4-[([2S, 4S] -4-sulfanilyl the>The original product, methyl ester (2S)-2-({4-[([2S,4S]-4-VOS-sulfanilamide-2-ylmethyl)amino] naphthalene-2-Carbo-nil} amino)-4-methylsulfonylmethane acid (30e) (72,1 mg, 0,132 mmol), freed from the protective groups (the same way as the equivalent steps in example 15), receiving specified in the header of the connection 30, 76 mg (97.8 per cent).

1H NMR (Dl3+CD3COOD, 200 MHz): 1,75-2,0 (1H, m), 2.0 to 2.5 (5H+ DMSO, m), 2,55 to 3.0 (3H, m), 3,15 and 3.4 (1H, m), of 3.5-3.7 (1H, m), of 3.7-3.9 (6N, m), 4,2-4,4 (1H, m), 4,9-of 5.05 (1H, m), 7,0-8,1 (6N, m, ArH).

MS (ESP+) m/z 448 (M+N)+.

Analysis. Calculated for C22H29N3S2ABOUT31,25 TFU,%: FROM 49.9; H 5,17; N 7,12.

Found,%: C Of 49.6; H 5,3; N 6,7.

The original product 30e obtained as follows.

Connection 30A.

2-Naphthoic acid nitrous conc. NGO3(Tetrahedron 49, 17, 3655, 1993), receiving a mixture of nitromist 30A containing the target 4-nitro-2-naphthoic acid.

MS (ESP-) m/z 216 (M-N)+.

Compound 30b.

Oxalicacid (6,0 ml of 68.7 mmol) is added dropwise in a mixed solution of a mixture of nitromist 30A (7,3 g, 33.6 mmol) in a mixture of DMF (1.0 ml) and CH2Cl2(100 ml) at 0oC in argon atmosphere. The solution is allowed to warm to room temperaturey the residue is again dissolved in CH2Cl2(100 ml) and cooled to 0oC in argon atmosphere. Add Et3N (7.0 ml, 50 mmol), then added in several portions of the hydrochloride of the methyl ester of L-methionine (7,4 g, 37 mmol) so that the internal temperature did not exceed 10oC. the Reaction mixture is allowed to warm to room temperature and stirred for 18 hours, washed with water (100 ml), dried over gSO4, filtered and concentrated to obtain a viscous brown resin. It then purified flash chromatography on SiO2(Merck 9385), elwira a mixture of 25% EtOAc/isohexane. The appropriate fractions are combined and evaporated, getting 30b in the form of a viscous orange resin, 490 mg (4%).

1H NMR (Dl3, 200 MHz): to 2.1-2.5 (5H, m), 2,55 is 2.75 (2H, m), 3,85 (3H, s), 4,9-5,1 (1H, m), 7,32 (1H, d), and 7.6 to 8.0 (2H, m), with 8.05 (1H, DD), 8,5-of 8.7 (3H, m).

MS (ESD+) m/z 363 (M+N)+.

Compound 30C.

30b (450 mg, 1,24 mmol) restore (the same way as the equivalent steps in example 22), obtaining the corresponding aniline 30C in the form of a yellow resin, 310 mg (75,3%).

1H NMR: (Dl3, 250 MHz) of 2.0 at 2.45 (5H, m), 2,5-2,75 (2H, m), 3,83 (3H, s), 4,3 (2H, Shir. s, NH2), 4,9-of 5.05 (1H, m), 7,0 (1H, d, NHCO), 7,2 (1H, d), 7,45-the 7.65 (2H, m), 7,72 (1H, s), 7,8-8,0 (2H, m).

MS (ESP+) m/z 333 (M+H)+, 271, 170.

When I synthesis 22g, using the Meon as a solvent and in the presence of molecular sieves 3 Angstrom as a dewatering agent, getting a 30d in the form of a yellow resin, 460 mg (76.5 per cent).

MS (S+) m/z 632 (M+N)+.

Connection 30e.

30d (450 mg, 0.7 mmol) freed from the protective groups (the same way as the equivalent stage of example 15), receiving targeted of the original product 30e, 220 mg (56.4 per cent).

1H NMR (Dl3, 200 MHz): 1,4-1,9 (10H+N2Oh, m), 2.0 to 2,75 (N, m), 2,95 (1H, K), 3,1-to 3.35 (1H, m), 3,35-3,55 (2H, m), 3,55-3,8 (2H, m), 3,82 (3H, s, CO2Me), to 4.98 (1H, m), 5,15 (1H, Shir. s, NH), 6,9-7,1 (2H, m, AGN+NHCO), 7,4-7,6 (2H, m), to 7.61 (1H, d), 7,8-8,0 (2H, m).

MS (ESP+) m/z 548 (M+N)+, 448.

Example 29 (see diagram 36).

Getting

a) methyl ester of (2S)-2-({3-[([2S,4S]-4-sulfanilamide-2-ylmethyl)amino] naphthalene-1-carbonyl} amino)-4-methylsulfonylmethane acid (compound 31) and

b) (2S)-2-({3-[([2S,4S]-4-sulfanilamide-2-ylmethyl)-amino]naphthalene-1-carbonyl}amino)-4-methylsulfonylmethane acid (compound 31f).

a) Receiving a connection 31.

31E (55 mg, 0.1 mmol) freed from the protective groups (the same way as the equivalent steps in example 15), then treated with Et2O HCl, receiving specified in the header soy is MHz): 1,05 (1H, t, (CH3CH2)2O), of 1.6-1.8 (1H, m), 1,9-of 2.15 (4H, m), 2,3-2,7 (4H+DMSO, m), 3,0-4,0 (N+(CH3CH2)2O), 4,55-4,7 (1H, m), to 6.95 (1H, s), and 7.1 (1H, s), to 7.15 (1H, t), 7,32 (1H, t), a 7.62 (1H, d), 7,92 (1H, d).

MC (ESP+)m/z 448 (M+H)+.

Analysis. Calculated for C22H29H3S2O32,7 Hcl,0,3 Et2O,%: 49,0; H X 6.15; N 7,39.

Found,%: From 49.1; H 6,1; N 7,2.

Compound 31A.

3-Nitro-1-naphthoic acid (31A) synthesized from 3-nitro-1,8-nataliago anhydride according to method G. J. Leuck et al (Journal of the American Chemical Society, 51, 1831, 1929).

Compound 31b.

3-Nitro-1-naphthoic acid (31A) (5.0 g, 23,04 mmol) is combined with methyl ester hydrochloride L-methionine (same way as the equivalent steps in example 22), receiving 31b in the form of a white crystalline solid product, 2,53 g (30.3 per cent).

1H NMR (Dl3, 200 MHz): 2.0 to 2.5 (5H, m), 2,55 is 2.75 (2H, m), 3,85 (3H, s), of 5.05 (1H, m), 6,9 (1H, d, NH), 7,6-a 7.85 (2H, m), 8,0-of 8.15 (1H, m), 8,3-8,5 (2H, m), 8,83 (1H, m).

MC (ESP+) m/z 363 (M+N)+.

Connection s.

31b (2.3 g, 6,35 mmol) restore (the same way as the equivalent stage of example 22), obtaining the corresponding aniline is in the form of a yellow resin, of 1.75 g (83%).

1H NMR (Dl3

MC (ESP+) m/z 333 (M+N)+, 170.

Connection 31d.

S (1.7 g, 5,12 mmol) is combined with aldehyde 22b (1,76 g, 5,59 mmol) (the same way as the equivalent stage of example 30), receiving 31d as not quite white foam, 2,95 g (91.3 percent).

1H NMR (Dl3+CD3COOD, 250 MHz): 1,5 (N, C), and 1.9 (1H, m), a 2.0 to 2.25 (4H+CH3COOH, m), 2,25 is 2.44 (1H, m), 2,55 is 2.75 (3H, m), 3.25 to of 3.53 (2H, m), 3,55 to 3.7 (1H, m), 3,7-of 3.95 (4H, m), 4,1-of 4.25 (1H, m), 4.25 in and 4.4 (1H, m), 4,55-to 4.8 (2H, m), of 5.03 (1H, m), 5,15-of 5.45 (2H, m), 5,96 (1H, m), the 6.9 to 7.5 (4H+l3, m), 7,66 (1H, m) and 8.1 (1H, m).

MC (S+) m/z 632 (M+N)+.

Compound 31E.

31d (2.0 g, 3,17 mmol) freed from the protective groups (the same way as the equivalent stage of example 15), receiving targeted of the original product 31E in the form of a pale yellow foam, of 1.62 g (93,4%).

1H NMR (Dl3, 300 MHz): 2,4-2,6 (10H, m), of 1.85 (4H, Shir. C), of 2.0-2.2 (4H, m), 2,35 (1H, m), 2,5 (1H, m) to 2.65 (2H, t), 2,9 (1H, m), 3,1 (1H, m), and 3.3 (1H, m), 3,4 (1H, m), 3,55 (1H, m), the 3.65 (1H, m), and 3.8 (3H, s), 5,02 (1H, m), of 6.65 (1H, d), 6,9 (1H, m) and 7.1 (1H, m), 7,2-7,3 (1H+l3, m), and 7.4 (1H, m), a 7.62 (1H, m) and 8.1 (1H, m).

MC (ESP+) m/z 548 (M+H)+,448.

b) Compound 31f.

31E (180 mg, 0.33 mmol) hydrolyzing (analogously to example 16), then purified HPLC with reversed phase preparative column 8 m, C

1H NMR: (DMSO-d6+CD3COOD, 300 MHz) of 1.5-1.8 (1H, m), 1,9-2,1 (5H, m), 2,4-2,7 (3H+DMSO, m), 3,0-3,1 (1H, m), grows 3.4-3.7 (4H, m), 3.75 to a 3.9 (1H, m), of 4.57 (1H, m), 6,9 (1H, m), 7,07 (1H, m), 7,17 (1H, m), 7,35 (1H, m), 7,63 (1H, m), 7,95(1H, m).

MS (ESP+) m/z 434 (M+N)+285.

Analysis. Calculated for C21H27N3S2O31,3 TFU,%: 48,7; N IS 4.9; N 7,22.

Found,%: From 48.6; H Is 4.9; N 7,1.

Example 30 (see diagram 37).

Getting

a) methyl ester (2S)-2-({ 3-phenyl-5-[([2S,4S]-4-sulfanilamide-2-ylmethyl)amino] phenylcarbamoyl} amino)-4-methyl-sulfonylmethane acid (compound 32) and

b) (2S)-2-({ 3-phenyl-5-[([2S,4S]-4-sulfanilamide-2-ylmethyl)amino] phenylcarbamoyl}amino)-4-methylsulfonylmethane acid (compound 32f).

a) Receiving a connection 32.

The original product, the connection a (55 mg, 0,096 mmol), freed from the protective groups (the same way as the equivalent stage of example 15), receiving specified in the title compound 32 as a white foam (56 mg).

1H NMR (Dl3, 250 MHz): 1,6-of 1.85 (1H, m), 1,9-2,4 (6N+CH3WITH5H6), a 2.45-2,7 (3H, m), 3,1-of 3.25 (1H, m), 3,35-4,1 (11N+H2Oh, m), 4.75 V-of 4.95 (1H, m), 6,8 (1H, m), 6,9-7,05 (1H, m) and 7.1-7,55 (6N+CH3WITH6H5+l3, m).

MS (ESP+

Found,%: From 51.6; H 5,2; N 5,1.

The original product a obtained as follows.

Compound 32A.

A saturated aqueous solution of NaHCO3(90 ml) is added to a stirred solution of methyl 3-bromo-5-nitrobenzoate (4.0 g, 15,38 mmol) (Mindl and Vecera, Coll. Czech. Chem. Comm. 38, 3496, 1973) and phenylboronic acid (2.0 g, 16,38 mmol) in dimethoxyethane (180 ml). Add tetrakis(triphenylphosphine)palladium(0) (444 mg, 0.38 mmol) and the mixture is heated to boiling under reflux for 1 h the resulting black solution is allowed to cool to room temperature and then stewed saturated aqueous Panso3(400 ml). The aqueous phase is extracted with EtOAc (200 ml), then acidified to pH 3 using 2 N. Hcl. The resulting suspension is filtered, washed with water and subjected to azeotropic distillation with toluene (325 ml), receiving 32A in the form of not quite white solid product, which was triturated with isohexane, filtered and dried, obtaining 2.6 g (69.5 per cent).

1H NMR (DMSO-d6, 300 MHz): 7,5 (3H, m), 7,8 (2H, m), 8,4-8,7 (3H, m).

MC (ESP-) m/z 242 (M-H)-.

Analysis. Calculated for C13H9NO4,%: FROM 64.2; H TO 3.73; N 5,76.

Found,%: C 64,0; N 3,7; N 5,6.

Compound 32b.

32A (3, example 22), getting 32b, 4.9 g (99%).

1H NMR (Dl3, 200 MHz): 2,1 at 2.45 (5H, m) to 2.65 (2H, t), 3,83 (3H, s), 4,99 (1H, m), a 7.2 to 7.35 (1H+l3, m), 7,4-7,6 (3H, m), and 7.6 to 7.7 (2H, m), scored 8.38 (1H, m), 8,58 (2H, m).

MC (ESP+) m/z 389 (M+N)+.

Analysis. Calculated for C19H20N2O5S,% FROM A HIGH OF 58.8; H 5,19; N 7,21. Found,%: 58.8 X; N 5,1; N 7,2.

Connection 32C.

32b (3.0 g, 7,73 mmol) restore (the same way as the equivalent stage of example 30), receiving the corresponding aniline, 32C, 2,43 g (87.8 per cent).

1H NMR (Dl3, 250 MHz): of 2.0-2.2 (4H, m), 2,2-2,4 (1H, m), and 2.6 (2H, m), and 3.8 (3H, s), 3,9 (2H, Shir. s, NH2), is 4.93 (1H, m), 6,93 (1H, d, NHCO), 7,03 (1H, m), 7,12 (1H, m), 7,3-7,5 (4H, m), 7.5 to the 7.65 (2H, m).

MC (ESP+) m/z 359 (M+N)+.

Connection 32d.

32C (1.0 g, 2.8 mmol) is combined with aldehyde 22b (880 mg, 2.8 mmol) (the same way as the equivalent stage of example 30), receiving 32d, 1.51 g (82.3 per cent).

1H NMR (Dl3+CD3SOOO, 250 MHz): 1,5 (N, C) of 1.8-2.0 (1H,

m), by 2.0-2.4 (5H+CH3COOH, m), 2,5-2,75 (3H, m), 3,2 is-3.45 (2H, m), of 3.5-3.7 (1H, m), 3,7-3,9 (4H, m), of 4.0-4.4 (2H, m), 4,5-of 4.75 (2H, m), 4,9-of 5.05 (1H, m), 5,1-of 5.45 (2H, m), the 5.8 to 6.1 (1H, m), 7,03 (1H, m), 7,1-7,5 (5N+l3, m), 7,55-7,72 N, m).

MS (ESP+) m/z 658 (M+N)+.

Analysis. Calculated for C33H43N3O7
32d (1.1 g, 1,67 mmol) freed from the protective groups (the same way as the equivalent stage of example 15), receiving targeted of the original product e, 800 mg (of 83.4%).

1H NMR (Dl3, 250 MHz): 1,25 (1.5 N, t, CH3PINES3), is 1.4-1.6 (10H, m), 1,9 (2H, Shir. s, NH+H20), a 2.0 2,22 (4N+CH3CH2CO2CH3), 2,23-to 2.55 (2H, m), of 2.51-to 2.65 (2H, m), 2,9 (1H, m), of 3.12 (1H, m), 3,2-of 3.75 (4H, m), and 3.8 (3H, m), 4,13 (1,3 H, K, CH3CH2CO2CH3), of 4.45 (1H, Shir. s, NH), of 4.95 (1H, m), 6,85-7,0 (2H, m, ArH+NHCO), 7,07 (1H, m), 7,2-7,5 (4N+l3, m), 7.5 to the 7.65 (2H, m).

MS (S+) m/z 574 (M+N)+, 474.

Analysis. Calculated for C29H39N3O5S20,5 EtOAc,%: 60,3; N 7,02; N 6,8.

Found,%: C To 59.9; H 7,1; N 6,6.

b) Receiving connection 32f.

The original product e (140 MT, 0,244 mmol) hydrolyzing (the same way as the equivalent stage of example 31), obtaining the target product 32f in the form of a white foam, the 96.3 mg (64,9%).

1H NMR (DMSO-d6+CD3OOD, 250 MHz): 1,5-1,8 (1H, m), 1,9-2,2 (5H, m), 3,05 (1H, K), 3,15-3,6 (7H, m), 3,65 to-3.9 (1H, m), 4,45 with 4.65 (1H, m), 6,95-7,05 (1H, m), 7,05 to 7.2 (1H, m), of 7.25 and 7.5 (4H, m), 7,55 to 7.7 (2H, m).

MC (ESP+) m/z 460 (M+N)+,279.

Analysis. Calculated for C23H29N3S2ABOUT31,3 TFU,%: FROM 50.6; H 5,02; N 6,91.

Nie a).

Example 31 (see diagram 38).

Getting

a) methyl ester (2S)-2-({ 2-phenyl-5-[([2S,4S]-4-sulfanilamide-2-ylmethyl)amino] phenylcarbamoyl} amino)-4-methyl-sulfonylmethane acid (compound 33) and

b) (2S)-2-({ 2-phenyl-5-[([2S,4S]-4-sulfanilamide-2-ylmethyl)amino] phenylcarbamoyl}amino)-4-methylsulfonylmethane acid (compound 33f).

a) Receiving a connection 33.

The original connection e with 53.4 mg, 0,093 mmol) freed from the protective groups (the same way as the equivalent stage of example 31), receiving specified in the title compound 33 as a white solid product, to 43.2 mg (87%).

1H NMR (DMSO-d6+CD3COOD, 300 MHz): 1,5-1,9 (3N+ CH3COOH, m) 1,95 (3H, s), 2,0-2,3 (2H, m), 2.4 to approximately 2.65 (1H+DMSO, m), 3.0 to 3.15 in (1H, m), 3,3-3,9 (8H, m), 4.25 in and 4.4 (1H, m), 6,7 (1H, m), 6,78 (1H, m) and 7.1 to 7.4 (6N, m).

MS (CI+) m/z 474 (M+H)+.

Analysis. Calculated for C24H31N3S2ABOUT31,75 TFU,%: 53.6; H 6,14; N OF 7.82.

Found,%: 53.6; H 6,3; N 7,7.

The original product is obtained in the following way.

Compound 33a.

2-Bromo-5-nitrobenzoic acid (to 12.28 g, 0.05 mmol) is combined with benthivorous acid (6.7 g, by 0.055 mmol) (the same way as the equivalent stage of example 32), is the 7.65 (1H, m), 8,35 (1H, m), to 8.45 (1H, m).

MS (ESP-) m/z 242 (M-N)-, 198.

Compound 33b.

33a (3.58 g, 14.7 mmol) is combined with methyl ester hydrochloride L-methionine (3.25 g, 16.2 mmol) (the same way as the equivalent stage of example 32), receiving 33b in the form of a pale yellow solid product, to 3.02 g (52.6 per cent).

1H NMR (Dl3, 300 MHz): 1.7 to 2.2 (7H, m), and 3.7 (3H, s), 4,7 (1H, m), equal to 6.05 (1H, m, NH), 7,35-7,6 (6N, m), with 8.33 (1H, m), 8,55 (1H, m).

MS (ESP+) m/z 389 (M+N)+.

Connection 33C.

33b (1.0 g, 2.6 mmol) restore (the same way as the equivalent stage of example 30), receiving the corresponding aniline 33C, 725 mg (78,6%).

1H NMR (Dl3, 300 MHz): of 1.6-1.8 (1H, m), 1,8-2,15 (6N, m), and 3.6 (3H, s), of 3.7-3.9 (2H, Shir. s, NH2), 4,6-4,7 (1H, m), of 5.85 (1H, d, NHCO), 6,79 (1H, m), 7,0 (1H, m), to 7.15 (1H, d), 7,2 was 7.45 (5H+l3, m).

MC (ESP+) m/z 359 (M+H)+,196.

Connection 33d.

33 (710 mg, to 1.98 mmol) is combined with aldehyde 22b (625 mg, to 1.98 mmol) (the same way as the equivalent stage of example 30), receiving 33d, 1.1 g (84.4 per cent).

1H NMR (Dl3+CD3COOD, 250 MHz): 1,5 (N, C), 1,6-2,2 (8H+CH3COOH, m), 2,5-2,75 (1H, m), 3,2-3,4 (2H, m), 3.45 points to-3.9 (5H, m), 4,05 is 4.35 (2H, m), 4,5-4,8 (3H, m), 5,15-of 5.45 (2H, m), the 5.8 to 6.1 (1H, m), 6.75 in-6,9 (1H, m), 6,9-7,05 (1H, m) and 7.1-of 7.23 (1H, m), 7,25->S2O7,%: 60,3; N 6,59; N 6,39.

Found,%: C 60,0; N 6,9; N 6,2.

Connection e.

33d (1.0 g, of 1.52 mmol) freed from the protective groups (the same way as the equivalent stage of example 15), receiving targeted of the original product a, 658 mg (75.4 per cent).

1H NMR (Dl3+CD3D, 250 MHz): 1,5 (N, C), 1,6-2,2 (8H+ CH3COOH, m), 2,55 is 2.75 (1H, m), 3.25 to 3,4 (1H, m), 3,5-of 3.75 (5H, m), 3.75 to 4.2V (3H, m), 4,55-of 4.75 (1H, m), 6,7-6,85 (1H, m), 6,85-6,97 (1H, m) and 7.1-of 7.25 (1H, m), 7,25-of 7.48 (5H+SMS3, m).

MC (ESP+) m/z 574 (M+N)+, 474.

Analysis. Calculated for C29H39N3O5S2,%: 60,7; N 6,85; N 7,32.

Found,%: C 60,7; N 7,20; N 7,30.

b) Receiving connection 33f.

The original product e (100 mg, 0,174 mmol) hydrolyzing (the same way as the equivalent stage of example 31), receiving 33f in the form of a white foam, a 64.6 mg (59,8%).

1H NMR (DMSO-d6+CD3COOD, 300 MHz): 1,5-2,0 (6N+CH3COOH, m), 2,0-2,3 (2H, m), 2,3-2,7 (1H+DMSO), 3,0-3,1 (1H, m), the 3.2 to 3.9 (5H, m), 4,2-of 4.35 (1H, m), 6,6-6,9 (2H, m) and 7.1 to 7.4 (6N, m).

MS (ESP+) m/z 460 (M+H)+,311.

Analysis. Calculated for C23H29N3O3S21,4 TFU,%: 50,0; N. OF 4.95; N 6,79.

Found,%: From 49.9; H 5,1; N 6,7.

The original product I get as opisyvaemogo ester (2S)-2-{2-benzyl-5-[(4-sulfanilamide-2-ylmethyl)amino]benzoylamine}-4-methylsulfonylmethane acid (compound 34) and

b) (2S)-2-{ 2-benzyl-5-[(4-sulfanilamide-2-ylmethyl)amino] benzoylamine}-4-methylsulfonylmethane acid (compound 34h).

a) Receiving a connection 34.

The original connection 34 (500 mg, 85 mmol) freed from the protective groups (the same way as the equivalent stage of example 31), receiving specified in the title compound 34 as a white solid product, 454 mg (89.3 per cent).

1H NMR (DMSO-d6+ CD3COOD, 300 MHz): of 1.5-1.7 (1H, m), 1.85 to 2.1 a (5H, m), 2,35-2,6 (3H+DMSO, m), 2,9-3,1 (1H, m), and 3.1 to 3.8 (8H, m), 3.9 to (2N, K), 4,4-4,6 (1H, m), 6,5-6,7 (>1H, m), the 6.9 to 7.0 (1H, m), 7,0-7,3 (6N, m).

MS (ESP+) m/z 488 (M+H)+,325.

Analysis. Calculated for C25H33N3S2O3HCl,%: From 50.3; H Between 6.08; N? 7.04 Baby Mortality.

Found,%: From 50.4; H 6,3; N 7,3.

The original product 34g obtained as follows.

Connection 34a.

A solution of 2-bromo-5-nitrobenzoic acid (9.0 g, 36.6 mmol) in Meon (200 ml) is treated SO2Cl2(2.0 ml) and the resulting solution is heated to boiling under reflux for 18 hours. The reaction mixture was then evaporated, pre-absorb on SiO2(Merck, 9385) and chromatographic, elwira a mixture of 10% EtOAc/isohexane. The appropriate fractions are combined and evaporated, getting 34a in the CH3), a 7.85 (1H, m), 8,18 (1H, m), 8,63 (1H, m).

Compound 34b.

The solution benzylbromide (2.0 ml, 17.3 mmol) in THF (10 ml) is added dropwise at 0oWith to a stirred suspension of zinc dust (1.7 g, 26 mmol) in THF (10 ml), which activate in accordance with the method described by Knochel (J. O. C., 53, 2392, 1988). Mixture is allowed to warm to room temperature and stirred for 3 hours. An aliquot (6.5 mmol) of distilled water containing reactant benzintank, then add to the mix a solution of 34a (1.0 g, of 3.85 mmol) and Pd(PPh3)2Cl2(27 mg, 0,0385 mmol) in THF (10 ml) at room temperature in argon atmosphere. After 1 h, add a second aliquot (6.5 mmol) of the reagent benzilic. The resulting black reaction mixture stew 2n. Model HC1 (250 ml) and extracted with EtOAc (2100 ml). The combined organic layers washed with water (50 ml) and brine (50 ml), filtered through paper, separating the phases, and evaporated to education orange resin. It chromatographic on SiO2(Merck, 9385) with elution with a mixture of 10%tO/ithacan getting 34b in the form of a yellow oil, 590 mg (56.6 per cent).

1H NMR (Dl3, 300 MHz): 3,9 (3H, s, CO2CH3), 4,48 (2H, s, CH2PH), 7,0-7,5 (6N, m) 8,23 (1H, m), is 8.75 (1H, m).

MS (ESP-) m/z ol) in the Meon (10 ml) at room temperature. After 2 hours the reaction mixture is evaporated to remove the Meon and then partitioned between Et2O (20 ml) and 2 N. NaOH (20 ml). The aqueous layer was acidified to pH 2-3 using 2 N. Hcl and extracted with EtOAc (320 ml). The combined organic layers washed with water (20 ml) and brine (20 ml), filtered through paper, separating the phases, and is evaporated by receiving 34C in the form of a white solid product, 453 mg (85,3%).

1H NMR (DMSO-d6, 300 MHz): of 4.45 (2H, s, CH2Ph) of 7.0 to 7.4 (5H, m), 7,55 (1H, m), and 8.3 (1H, m), 8,53 (1H, m).

MS (ESP-) m/z 256 (M-N)-, 212.

Connection 34d.

34C (630 mg, 2.45 mmol) is combined with methyl ester hydrochloride L-methionine (540 mg, 2.7 mmol) (the same way as the equivalent stage of example 32), receiving 34d in the form of a pale yellow solid product, 900 mg (91.3 percent).

1H NMR (DMSO-d6, 250 MHz): 1,9-of 2.25 (5H, m), 2,5-2,75 (2H+ DMSO, m), 3,74 (3H, s, CO2CH3), 4,28 (2N, K, CH2Ph), 4,55-of 4.75 (1H, m), 7,15-to 7.5 (5H, m), and 7.6 (1H, m), 8,2-8,35 (2H, m), 9,13 (1H, d, NHCO).

MS (ESP+) m/z 403 (M+N)+.

Connection e.

SnCl22H2O (2.5 g, 11,08 mmol) is added to the mixed solution 34d (900 mg, 2,24 mmol) in EtOAc (50 ml) and the resulting mixture is heated to boiling under reflux for 18 cha is 8. The resulting heavy white precipitate is removed by filtration through celite (545). The filtrate is evaporated and purified by chromatography (Honey Bond Elut, SiO2) when the elution CH2Cl2and then with a mixture of 50%tO/isohexane, receiving the corresponding aniline e, 595 mg (71,4%).

1H NMR (Dl3, 300 MHz): 1,75-2,2 (5H, m), 2,25-of 2.45 (2H, m), 3,6-3,8 (5H, m, CO2CH3+NH2), 4,08 (2N, K, CH2Ph), 4,65-is 4.85 (1H, m), 6,24 (1H, d, NHCO), 6,7 (1H, m), 6,78 (1H, m), 7,0 (1H, m), 7,05 of 7.3 (5H+l3, m).

MS (ESP+) m/z 373 (M+N)+, 210.

Connection 34f.

E (570 mg, 1.53 mmol) is combined with aldehyde 22b (580 mg, of 1.84 mmol) (the same way as the equivalent stage of example 30), receiving 34f in the form of a crude pale green foam (1.54 g).

MS (ESP+) m/z 672 (M+N)+.

Connection 34g.

34f (1.5 g, 2,24 mmol) freed from the protective groups (the same way as the equivalent stage of example 15), receiving targeted of the original product 34g in the form of a pale brown glassy product, 550 mg (41.9 per cent).

1H NMR (Dl3, 300 MHz): 1,3-1,65 (10H, m), 1.7 to 2.2 (5H+H2O, m), 2,25-2,6 (3H, m), 2,8-3,9 (N, m), 3.9 to 4.25 in (2H, m), 4,6-4,9 (1H, m), and 6.3 (1H, d, NHCO), 6,55 TO 6.8 (2H, m), of 6.9 to 7.4 (5H+l3,m).

MS (ESP+) m/z 588 (M+N)+, 488.

b) Receiving connection 34h.

18Dynamax60A) with elution with a mixture of 50%Meon/N2On (0,1% TFU), receiving 34h in the form of a colorless glassy product of 38.2 mg (56.6 per cent).

1H NMR (DMSO-d6+CD3COOD, 300 MHz): of 1.5-1.7 (1H, m), 1,8-2,1 (5N+CH3COOH, m), 2,3-2,6 (3H+DMSO, m), 2,9-3,1 (1H, m), 3,2-4,1 (7H, m), 4,3-4,5 (1H, m), 6,5-6,7 (2H, m), the 6.9 to 7.0 (1H, m), 7,05-of 7.25 (5H, m).

MC (ESP+) m/z 474 (M+N)+.

Analysis. Calculated for C24H31N3S2ABOUT31,4 TFU,%: FROM 50.8; H 5,16; N 6,14.

Found,%: From 51.0; H 5,3; N 6,7.

The original product is produced as described just above, section a).

Example 33 (see diagram 40).

Getting

a) methyl ester (2S)-{2-benzyl-4-[([2S,4S]-4-sulfanilamide-2-ylmethyl)amino] benzoylamine} -4-methylsulfonylmethane acid (compound 35) and

b) (2S)-{ 2-benzyl-4-[([2S, 4S]-4-sulfanilamide-2-ylmethyl) amino] benzoylamine}-4-methylsulfonylmethane acid (compound 35g).

a) Receiving a connection 35.

Specified in the header of the connection 35 synthesized from methyl 2-bromo-4-nitrobenzoate using methods described in example 32, but using PD2(db)3as the source of catalytic palladium in the reaction of benzylidene.

MC (ESP+) m/z 488 (M+N)+, 325.

Analysis. Calculated for C25H33N3S2ABOUT3HCl,%: 53.6; H 6,29; N To 7.5. Found,%: From 53.5; H 6,5; N 7,3.

b) obtaining a compound 35g.

Compound 35 (100 mg, 0.18 mmol, see (a)) hydrolyzing (the same way as the equivalent stage of example 32), receiving 35g in the form of a white solid product, to 85.8 mg (67,3%).

1H NMR (DMSO-d6+CD3D, 300 MHz): of 1.5-1.7 (1H, m), 1,8-2,1 (5H, m), 2,3-2,6 (3H+DMSO, m), 2,9-3,9 (6N, m), 3.95 to 4.2V (2H, m), 4,3-4,6 (1H, m), 6,4-6,5 (2H, m), 7,0-7,3 (6N, m).

MS (ESP+) m/z 474 (M+H)+, 325.

Analysis. Calculated for C24H31N3S2ABOUT31,3 TFU,%: WITH 51.4; H 5,24; N 6,76.

Found,%: 51,2; N. Of 5.4; N 6,7.

Example 34 (see diagram 41).

Isopropyl ether (2S)-2-{2-benzyl-5-[([2S,4S]-4-sulfanilamide-2-ylmethyl)amino] benzoylamine} -4-methylsulfonylmethane acid (compound 36).

Nitrosoaniline 36b restore to the corresponding aniline, combined with thioproline aldehyde 22b using IPA as a solvent and freed from the protective groups are quite similar manner as in example 32, receiving specified in the header of the connection 36.

1H NMR (DMSO-d

MS (ESP+) m/z 516 (M+N)+, 325.

Analysis. Calculated for C27H37N3S2O32HCl,%: From 55.1; H Of 6.68; N 7,14.

Found,%: From 54.9; H 7,0; N 7,1.

Compound 36A.

The solution 34d (25,24 g, 62,78 mmol) in Meon (500 ml) is treated with 2 N. NaOH (35 ml, 70 mmol). The resulting solution is then evaporated to dryness and the solid residue partitioned between Et2O (200 ml) and water (500 ml). The aqueous phase is then acidified to pH 2 using 2 ad model HC1 and extracted with EtOAc (2250 ml). The combined organic layers washed with water (2100 ml), brine (100 ml), filtered through paper, separating the phases, and is evaporated by receiving 36A in the form of a white solid product, 23,57 g (96.8 per cent).

1H NMR (DMSO-d6, 300 MHz): 1.8-to 2.2 (5H, m), 2,3-2,6 (2H+DMSO, m), 4,1-4,3 (2H, m), 4,4-4,6 (1H, m), 7,1-7,3 (5H, m), 7,4-7,6 (1H, m), 8,1-8,3 (2H, m), 8,9-9,0 (1H, m, NHCO).

MS (ESP) m/z 387 (M-N)+.

Connection 36b.

Sulfurylchloride (5.0 ml, 62 mmol)is added to a stirred suspension 36A (19.2 g, 50 mmol) in IPA (500 ml). The resulting mixture was then heated to boiling under reflux for 16 hours. The reaction mixture was then evaporated to 1/5 of the volume and partitioned between EtOAc (1 l) and saturated aqueous Panso3(500 ml). The organization is evaporated, getting 36b in the form of a white solid product, each holding 21.25 g (100%).

1H NMR (DMSO-d6, 300 MHz): 1,0-1,3 (6N, m), 1.8-to 2.2 (5H, m), 2,3-2,6 (2H+DMSO, m), 4,1-4,3 (2H, m), 4,4-4,6 (1H, m), 4,8-5,0 (1H, m), 7,1-7,3 (5H, m), 7,4-7,6 (1H, m), 8,1-8,3 (2H, m), and 9.0 (1H, m, NHCO).

MC (ESP+) m/z 43 (M+N)+.

Example 35 (see diagram 42).

Isopropyl ether (2S)-2-{ 2-benzyl-5-[N-([2S,4S]-4-sulfanilamide-2-ylmethyl)-N-(3-methoxypropyl)amino] benzoylamine} -4-methylsulfonylmethane acid (compound 37).

The original product 37b is released from the protective group using methods equivalent to the stages described in example 32, receiving specified in the header of the connection 37.

1H NMR (DMSO-d6+CD3COOD, 300 MHz): 1,0-1,3 (6N, m), of 1.5-1.7 (1H, m), 1,8-2,1 (5H, m), 2,2-2,6 (5H+DMSO, m), 2,9-3,95 (10H, m), 4,0-4,2 (3H, m), 4,4-4,6 (1H, m), 4,8-5,0 (1H, m), 7,0-7,5 (8H, m).

MC (ESP+) m/z 602 (M+N)+.

Analysis. Calculated for C31H43N3S2O31,5 HCl,%: 56.7 G; N 6,83; N 6,4.

Found,%: C Of 56.7; H 7,0; N 6,0.

The original connection was obtained as follows.

EEDQ (530 mg, of 2.15 mmol) is added to the mixed solution 36d (1.5 g, of 2.15 mmol; see example 34) and 3-methoxypropionate acid (220 ml, 2.36 mmol) in CH2Cl2(15 ml). The mixture is stirred in the Noah acid (200 ml) and EtOAc (100 ml). The organic layers washed with saturated aqueous Panso3(50 ml), water (50 ml) and brine (50 ml), filtered through paper, separating the phases, and evaporated, obtaining a pale yellow resin. It then purified flash chromatography on SiO2(Merck 9385) with elution with mixture of EtOAc/isohexane with gradient EtOAc 0-50%. Appropriate fractions filtered and evaporated, getting the original product 37b in the form of a colourless resin, 1,14 g (67.7 percent).

MS (ESP+) m/z 786 (M+N)+.

Example 36 (see diagram 43).

Getting

a) N-([2S, 4S]-4-sulfanilamide-2-ylmethyl)-3,3-dimethyl-N-(2-naphthalene-1-retil)butyramide (compound 56) and

b) N-([2S, 4S] -4-sulfanilamide-2-ylmethyl)-N-(2-naphthalene-1-retil)-2-pyridin-3-ylacetamide (compound 57).

a) Receiving a connection 56.

The method described in example 23 for the synthesis of compounds (6), is used for connection (56), as shown in scheme 43.

Data on NMR in Dl3: of 0.91 (s, N), 1,5 (m, 1H), 1,75 (m, 1H), 1,82 (d, 1H), 1.91 a (d, 1H), 2,52 (m, 1H), 2,92 (m, 1H), 3.33 and (m, 3H), and 3.72 (m, 4H), to 4.15 (m, 1H), 7,26 (d, 1H), 7,41 (t, 1H), 7,56 (m, 2H), and 7.8 (d, 1H), 7,9 (2D, 2H), remaining 9.08 (Shir. s, 1H).

Microanalysis: % of theoretical From 64.2, N Of 7.97, N 6,5 (1.00 M HCl, 0.5 H2O); % found From 64.4, N Of 7.90, N 6,3.

The original product, the compound (ptx2">

Data on NMR in Dl3: 1,00 (2C, N), of 1.46 (d, N), of 1.95 (m, 2H), 2,4 (m, 2H), 3,3 (m, 4H), and 3.7 (m, 3H), 4.00 points (m, 3H), of 4.57 (d, 2H), 5,22 (2D, 2H), 5,90 (m, 1H), 7.24 to a 8.4 (m, 7H).

The compound (54).

Data on NMR in Dl3: 1,00 (2C, N), of 1.35 (m, 1H), 1,49 (s, N), 1,89 (Shir. s, 1H), 1,95 (d, 1H), 2,3 (m, 1H), 2,32 (d, 1H), 2,88 (2s, 1H), 3,1-3,9 (m, N), 7,25-8,31 (m, 7H).

b) Receiving connection 57.

The method described in example 24 synthesis of compound (27), is used in a similar manner to obtain the compound (57).

Data on NMR in Dl3: 1,2 (m, 1H), 2,00 (m, 1H), and 2.6 (m, 2H), 3,15-and 4.40 (m, 10H), 7,28-to 8.70 (m, 11N), and 9.4 (Shir. s, 1H).

Microanalysis: % of theoretical With 56,0, N 6,20, N 8,17 (2 HCl, 2 H2O); % found From 56.4, N 6,46, N 7,70.

The original product, compound (55), are synthesized analogously to the method of example 24, using the appropriate intermediates.

Compound (53).

Data on NMR in Dl3: to 1.48 (s, N), of 1.84 (m, 1H), 2,42 (m, 1H), 2,87 is-3.45 (m, 5H), 3,63-4.26 deaths (m, 7H), 4,55 (d, 2H), 5,22 (2D, 2H) and 5.9 (m, 1H), 7,1-to 8.7 (m, 11N).

Compound (55).

Data on NMR in Dl3: of 1.34 (m, 1H), 1,5 (, N), of 1.95 (m, 1H), 2,32 (m, 2H), 2,72-4,00 (m, 10H), and 7.1 and 8.6 (m, 11N).

Example 37 (see diagram 44).

Getting

a) N-(2,2-diphenylether)-N-([2S, 4S]-4-sulfanilamide-2-ylmethyl)-3-methylbutylamine (68 CE);

C) N-(2,2-diphenylether)-N-([2S, 4S]-4-sulfanilamide-2-ylmethyl)-2-pyridin-3-ylacetamide (compound 69) and

g) N-(2,2-diphenylether)-N-([2S, 4S]-4-sulfanilamide-2-ylmethyl)-6-methoxynicotinate (compound 70).

a) Receiving a connection 67.

The method described in example 23 synthesis of compound (6) use a similar manner to obtain the compound (67) using the appropriate intermediates, see figure 44.

Data on NMR in DMSO-d6: 0,75 (m, 6N), of 1.55 (m, 1H), 1,87 (m, 2H), 2.05 is at 2.45 (m, 1H), 3,05 (m, 1H), 3.25 to 3,70 (m, 6N), of 4.05 (m, 2H), 4,20-4,55 (m, 1H), 7,30 (m, 10H), 8,80-9,80 (2 Shire. s, 2H).

Microanalysis: % of theoretical From 63.9, N Of 7.82, N 6,21 (1.00 M HCl, 1,00 N2O); % found From 64.1, N Of 7.70, N 6,00.

Connection (58).

Data on NMR in Dl3: 1,50 (s, N), or 1.77 (m, 1H), 2.40 a (m, 1H), 2,75 (m, 1H), 3,00 (m, 1H), 3,14 (K, 1H), 3,24 (d, 2H), to 3.67 (m, 1H), 3,93 (m, 1H), 4,10 (m, 2H), 4,54 (d, 2H), 5.25 in (m, 2H), 5,90 (m, 1H), 7,25 (m, 10H).

Compound (59).

Data on NMR in Dl3: 0,85 (m, 6N), to 1.48 (m, N), of 1.80 (m, 2H), 2,10 (m, 2H), 2.40 a (m, 1H), 2,80 is 4.35 (m, N), 4,55 (m, 2H), 5.25 in (m, 2H), 5,90 (m, 1H), 7,25 (m, 10H).

Connection (63).

Data on NMR in Dl3: 0,85 (2D, 6N), 1,24 (m, 1H), 1,48 (s, N), by 1.68 (m, 1H), 1,81 (d, 1H), of 1.95 to 2.35 (m, 3H), 2,75-the 3.65 (m, 6N), 3,90-4,55 (m, 3H), 7,25 (m, 10H).

b) Policeme 44.

The compound (68).

Data on NMR in DMSO-d6: 0,85 (m, N), of 1.55 (m, 1H), 1,74-of 2.27 (m, 2H), is 2.37 (m, 1H), 3,05 (m, 1H), 3.45 points (m, 6N), of 4.05 (m, 2H), 4,18-4,55 (m, 1H), 7,28 (m,10H), 8,90-9,90 (m, 2H).

Microanalysis: % of theoretical With 64,6, N 8,02, N 6,02 (1,0 HCl, 1,0 H2O);% found 64,8, N 8,30, N 5,70.

Connection (60).

Data on NMR in Dl3: 0,93 (m, N), 1,50 (s, N), is 1.82 (m, 2H), 2,35 (m, 3H), 2,90 is 4.35 (m, 8H), 4,55 (m, 2H), 5.25 in (m, 2H), 5,90 (m, 1H), 7,25 (m, 10H).

The compound (64).

Data on NMR in Dl3: 0,93 (s, N), 1,24 (m, 1H), 1,48 (s, N), 1,80 (K, 1H), 2,23 (d, 1H), 2,30 (m, 1H), 2,75-3,70 (m, 6N), 3,90-4,60 (m, 3H), 7,25 (m, 10H).

C) Obtaining connection 69.

Compound (69) was synthesized from compound (61) (see figure 44) similarly to the method described in example 24 to obtain the compound (27).

Data on NMR in Dl3: 1,95 (m, 1H), 2.40 a (m, 1H), 2,60 (m, 1H), 3,15-4,50 (m, 11N), 7,28 (m, 10H), to 7.67 (m, 1H),8,05 (m, 1H), and 8.50 (m, 1H), 8,71 (m, 1H), 9,10-10,20 (Shir. d, 2H).

Microanalysis: % of theoretical From 55.1, N 5,51, N 7,01 (2,0 HCl, 0.75 in TFU, 0.5 H2O); % found 55,0, N the ceiling of 5.60, N 6,90.

Compound (61).

Data on NMR in Dl3: 1,47 (s, N), of 1.80 (m, 1H), 2,30 with 4.65 (m, 14N), 5,23 (m, 2H), 5,90 (m, 1H), 7,25 (m, N), 8,10-8,55 (m, 2H).

The compound (65).

Data on NMR in Dl3: 1,25 (m, 1H), 1,48 (s, N), is 2.30 (m, 1H), 2,70-the unity (70) are synthesized from compound (62), using the appropriate intermediates.

Data on NMR in Dl:3to 1.67 (m, 1H), 2,15 (d, 1H), 2,47 (m, 1H), and 3.16 (Shir. s, 1H), 3,50 (m, 2H), 3,85-and 4.40 (m, 8H), 5,22 (Shir. s, 1H), 6,56 (d, 1H), 7,00-7,35 (m, 11N), of 7.90 (s, 1H), cent to 8.85-10,75 (2 Shire. s, 2H).

Microanalysis: % of theoretical From 57.2, N 5,91, N 7,70 (2,0 HC1, 0.5 H2O)%; found 57.5, N the ceiling of 5.60, N 7,30.

Compound (62).

Data on NMR in Dl3: 1,50 (s,N), to 1.60 (m, 1H), 2,47 (m, 1H), 3,00-4,50 (m, N), 4,58 (d, 2H), 5.25 in (m, 2H), 5,90 (m, 1H), 6,53 (d, 1H), 6,95 (m, 1H), 7,25 (m, 11N).

Connection (66).

Data on NMR in Dl3: 1,20 (m, 1H), 1,45 (s, N), is 2.30 (m, 1H), 2,66 (m, 1H), 3.00 and is-3.45 (m, 4H), 3,55 (m, 1H), 3.95 to of 4.25 (m, 5H), 4,47 (m, 1H), 6,55 (d, 1H), 7,25 (m, 11N), the 7.65 (m, 1H).

Example 38 (see figure 45).

Getting

a) N-([2S, 4S]-4-sulfanilamide-2-ylmethyl)-3-methyl-N-(2-naphthalene-2-retil)butyramide (compound 80);

b) N-([2S, 4S]-4-sulfanilamide-2-ylmethyl)-3,3-dimethyl-N-(2-naphthalene-2-retil)butyramide (compound 81);

C) N-([2S, 4S] -4-sulfanilamide-2-ylmethyl)-N-(2-naphthalene-2-retil)-2-pyridin-3-ylacetamide (compound 82) and

g) N-([2S, 4S] -4-sulfanilamide-2-ylmethyl)-2-(4-methoxyphenyl)-N-(2-naphthalene-2-retil)ndimethylacetamide (compound 83).

a) Receiving a connection 80.

The method described in example 23 to synthesize coedine, 1H), 2,02 (d, 1H), 3,03 (m, 3H), 3,20-of 3.80 (m, N), of 7.48 (m, 3H), of 7.75 (d, 1H), a 7.85 (m, 3H), 8,90-9,90 (Shir. d, 2H).

Microanalysis: % of theoretical From 64.9, N Of 7.68, N 6,88 (1.00 M HCl); % found From 64.9, N 7,50, N 6,80.

The original product, the compound (76), are synthesized analogously to example 23, using the appropriate intermediates, see figure 45.

Compound (71).

Data on NMR in Dl3: 1,50 (s, N), of 1.85 (m, 1H), 2,50 (m, 1H), 2,80 (m, 1H), 3,00 (m, 5H), 3,20 (m, 1H), 3,65 (m, 1H), 4.00 points (m, 1H), 4,10 (m, 1H), 4.53-in (d, 2H), 5,20 (m, 2H), 5,90 (m, 1H), 7,32 (m, 1H), 7,42 (m, 2H), 7,63 (s, 1H), 7,80 (m, 3H).

Connection (72).

Data on NMR in Dl3: 0,90 (m, 7H), 1,00-2,60 (m, 14N), to 3.00 (m, 2H), 3,10-4,20 (m, 7H), 4,60 (m, 2H), 5.25 in (m, 2H), 5,90 (m, 1H), 7,30-to 7.50 (m, 2H), 7,60 (m, 1H), 7,80 (m, 3H).

Connection (76).

Data on NMR in Dl3: 0,90 (m, 6N), 1,10-of 2.50 (m, 15 NM), 2,80-of 3.80 (m, N), 7,26-to 7.50 (m, 3H), 7,60 (m, 1H), 7,80 (m, 3H).

b) Receiving connection 81.

Connection (81) synthesized from compounds (73) as shown in scheme 45, similarly to the production method of compound 80 (see above).

Data on NMR in DMSO-d6: 1,08 (d, N), of 1.80 (m, 1H), 2,15 (m, 2H), 2,65 (m, 1H), 3,00-4,00 (m, 10H), 7,63 (m, 3H), of 7.90 (s, 1H), 8,03 (m, 3H), 9,50 (Shir. d, 2H).

Microanalysis: % of theoretical From 64.9, N Of 7.93, N 6,58 (1,0 HCl, 0.25 N2O); % found 64,8, N 8,10, N 6,50.

Connection (77).

Data on NMR in DMSO-d6(100oS): 0,95 (m, N), of 1.35 and 1.75 (m, N), of 2.15 (s, 2H), 2.40 a (m, 1H), 2,60-3,90 (m, N), 7,40 (m, 3H), of 7.70 (m, 1H), 7,80 (m, 3H).

C) Obtaining connection 82.

Connection (82) are synthesized from compound (74), as shown in scheme 45, in a manner similar to the method described in example 24 to obtain the compound (27).

Connection (82).

Data on NMR in DMSO-d6: of 1.65 (m, 1H), 2,90-to 4.15 (m, 14N), 7,35-8,90 (m, 11N), 9,50 (Shir. d, 2H).

Microanalysis: % of theoretical With 51.9, N 5,19, N 6,99 (2,0 HCl, 1,0 TFU, 0,5% H2O); found From 52.2, H 5.40, Is N 7,00.

Connection (74).

Data on NMR in DMSO-d6(100oS): 1,45-of 1.75 (m, 10H), 2,85-of 3.85 (m, 11N), a 4.03 (m, 1H), 4,20 (m, 1H), 4,45 with 4.65 (m, 2H), 5,20 (m, 2H), 5,90 (m, 1H), 7.23 percent (m, 1H), 7,45 (m, 4H), to 7.67 (s, 1H), 7,80 (m, 3H), 8,35 (m, 2H).

Compound (78).

Data on NMR in DMSO-d6(100oS): 1,30-of 1.75 (m, N), is 2.40 (m, 1H), 2,55-3,90 (m, 14N), 7,10-to 8.45 (m, 11N).

d) receiving the connection 83.

Similarly, the compound (83) synthesized from compounds (75) using the appropriate intermediates, as indicated in scheme 45.

The compound (85).

Data on NMR in DMSO-d6: of 1.65 (m, 1H), 2.95 points (m is eroticheskii From 62.7, N 6,57, N 5,62 (1,5 HCl, 0.5 H2O); % found From 62.4, N 6,50, N of 5.40.

Connection (75).

Data on NMR in DMSO-d6(100oS): 1,45 (s, N), a 1.75 (m, 1H), 2,75-of 3.85 (m, 14N), of 4.00 (m, 1H), 4,14 (m, 1H), 4,45 with 4.65 (m, 2H), 5,20 (m, 2H), 5,90 (m, 1H), 6,80 (m, 2H), 7,05 (m, 2H), 7,33 (m, 1H), 7,45 (m, 2H), 7,63 (s, 1H), 7,80 (m, 3H).

Compound (79).

Data on NMR in DMSO-d6(100oS): 1,30-of 1.75 (m, N), to 2.35 (m, 1H), 2,60-3,90 (m, 17H), 6,78 (m, 2H), 7,05 (m, 2H), 7,40 (m, 3H), of 7.65 (m, 1H), 7,80 (m, 3H).

Example 39 (see diagram 46).

Getting

a) methyl ester of (2S)-2-({2-phenyl-4-[((2S,4S)-4-sulfanilamide-2-ylmethyl)amino] phenylcarbamoyl} amino)-4-methyl-sulfonylmethane acid (compound 38) and

b) (2S)-2-({ 2-phenyl-4-[((2S,4S)-4-sulfanilamide-2-ylmethyl)amino] phenylcarbamoyl}amino)-4-methylsulfonylmethane acid (compound 38f).

a) Receiving a connection 38.

Methyl 2-bromo-4-nitrobenzoate combine with phenylboronic acid (similar to the equivalent stage of example 30), then combined and freed from the protective groups, as previously described in example 32, receiving specified in the header of the connection 38.

1H NMR: (DMSO-d6, 250 MHz) of 1.35 and 1.75 (3H, m), 1.8 m (3H, s), 1,9-2,2 (2H, m), 2,25-2,5 (2H+DMSO, m), 2,75 to-3.9 (10H, m), 4,0-of 4.25 (1H, m), 5,0-5,9 (5H, Shir. C, H2About), and 6.3 and 6.6 (2H, m), 7,0 is 7.3 (7H, m), 7,95 1N3ABOUT3S22l1,5 H2O%: FROM 50.3; H 6,3; N 7,3.

Found,%: From 50.4; H 6,1; N 7,3.

b) obtaining a compound 38f.

Compound 38 hydrolized to the corresponding acid (similar to the equivalent stage of example 33), receiving 38f.

1H NMR (DMSO-d6+CD3D, 300 MHz): 1,5-1,9 (3N+CD3D, m) 1,95 (3H, s), of 2.05 to 2.35 (2H, m), 2,4-2,6 (2H+DMSO, m), 3,0-3,1 (1H, m), 3,2-3,9 (4H, m), 4,2-4,3 (1H, m), 6,5-6,7 (2H, m), 7,2-7,4 (6N, m).

MC (ESP+) m/z 460 (M+H)+, 311.

Analysis. Calculated for C23H29N3ABOUT3S21,35 TFU,%: FROM 50.3; H 4,99; N 6,85.

Found,%: From 50.2; H 5,1; N 6,8.

Example 40. Pharmaceutical compositions.

Below is a representative pharmaceutical form of the invention, as defined here (the active ingredient called "Compound X"), for therapeutic or prophylactic use for people:

a) Tablet I mg/tablet

Compound X - 100

Lactose Ph.Eur. - 182,75

Sodium salt croscarmellose to 12.0

Pasta maize starch (5% wt./about.) was 2.25

Magnesium stearate - 3,0

b) II Tablet mg/tablet

Compound X - 50

Lactose Ph. Eur. - 223,75

Sodium salt croscarmellose - 6,0

Maize starch - 15,/BR> Compound X - 1,0

Lactose Ph. Eur. - 93,25

Sodium salt croscarmellose - 4,0

Pasta maize starch (5% wt./about.) - 0,75

Magnesium stearate - 1,0

g) Capsule mg/capsule

Connection X - 10

Lactose Ph. Eur. - 488,5

Magnesium - 1,5

Injection I (50 mg/ml)

Connection X to 5.0% wt./about.

1 M sodium hydroxide solution, 0.1 M hydrochloric acid (to establish a pH of 7.6) - 15% wt./about.

The polyethylene glycol 400 - 4.5% wt./about.

Water for injection up to 100%

Injection II (10 mg/ml)

Compound X 1.0% wt./about.

Sodium phosphate BP 3.6% of wt./about.

0.1 M sodium hydroxide solution to 15.0% vol./about.

Water for injection up to 100%

Injection III - 1 mg/ml, buffered to pH 6

Compound X 0.1% wt./about.

Sodium phosphate BP 2.26 and% wt./about.

Citric acid - 0,38% wt./about.

The polyethylene glycol 400 and 3.5% wt./about.

Water for injection to 100% -

Aerosol I mg/ml

Compound X - 10,0

Trioleate sorbitan - 13,5

Trichlorofluoromethane - 910,0

DICHLORODIFLUOROMETHANE - 490,0

Aerosol II - mg/ml

Compound X - 0,2

Trioleate sorbitan - 0,27

Trichlorofluoromethane - 70,0

DICHLORODIFLUOROMETHANE - 280,0

Dichlorotetrafluoroethane - 1094,0

Dichlorotetrafluoroethane to 191.6

Aerosol IV - mg/ml

Compound X IS 2,5

Soy lecithin - 2,7

Trichlorofluoromethane is 67.5

DICHLORODIFLUOROMETHANE - 1086,0

Dichlorotetrafluoroethane to 191.6

Ointment - ml

Compound X 40 mg

Ethanol - 300 ál

Water - 300 ál

1-Dodecylsulfate-2-he - 50 ál

Propylene glycol to 1 ml

Note. Above the finished formulation can be obtained by conventional means, well known in the pharmaceutical field. The tablets (a)-(C) can be covered intersolubility shell by conventional means, for example, for the formation of shell mixed acetate and cellulose phthalate. Spray the finished formulation (h)-(k) can be used in conjunction with standard aerosol devices for delivery of measured doses and suspendresume agents trioleate sorbitan and soya lecithin may be replaced by another suspendium agent such as monooleate sorbitan, sesquioleate sorbitan, Polysorbate 80, of the polyglycerol oleate or oleic acid.

Example 41 (see diagram 47).

Getting

a) (2S)-4-carbarnoyl-2-({ 2-phenyl-5-[([2S, 4S]-4-sulfanilamide-2-ylmethyl)amino]phenylcarbamoyl}amino)butyric acid (compounds is rbony}amino)oil acid (compound 39).

a) Receiving a connection 39.

Compound 39A.

32A (1.5 g, 6.2 mmol) is combined with methyl ester of L-glutamine (similar to the equivalent stage of example 30), receiving the connection 39A in the form of a white solid product, 1.2 g (50.5 per cent).

MS (S)+ m/z 386 (M+N)+.

Connection 39.

39A restore, combined with the aldehyde (22b) and selectively released from the protective group using the same methodology as previously described for example 32, receiving specified in the header of the connection 39.

MS (S+) m/z 471 (M+N)+.

Analysis. Calculated for C24H30N4O4S3l0,25N2O%: FROM 49.3; H 5,8; N 9,6.

Found,%: C And 49.2; H 5,9; N 9,2.

b) obtaining a compound 39e.

39 hydrolyzing (similar to the equivalent stage of example 32), receiving specified in the title compound 39e.

MS (ESP) m/z 455 (M-N)+.

Analysis. Calculated for C23H28N4O4S2,% TO 47.4; H TO 4.4; N, 8,2.

Found,%: C 47,0; N 4,5; N Is 7.9.

1. Derivatives of 4-mercaptopyridine any of the following classes of i), ii) and iii), represented by the following formula:

< / BR>
where X1selected from the group including H, C1-6-alkoxo1-61-6alkyl;

X3selected from H, C1-6of alkyl;

X4selected from C1-6alkylsulfanyl, carbamoyl;

< / BR>
where X5selected from-C (O) -C1-4alkyl-PH, -C (O)- C1-6of alkyl, -C (O)-C1-C1-4alkylpyridine, Ph and pyridyl optionally substituted by the Deputy, is selected from C1-4of alkyl, C1-4alkoxy, C1-4alkalosis1-4of alkyl;

And means naphthyl;

R3selected from the group comprising H; HE; NO2; (CH2)nCOOR8where n is 0-3 and R8represents H, C1-4alkyl, C2-4alkenyl;

-CONR9R10where R9and R10independently represent H, C1-4alkyl, C1-3alkylen Ph, optionally mono - or disubstituted by halogen;

-CON(R11OR12where R11and R12independently represent H, C1-4alkyl, C2-4alkenyl, a group of the formula II

- CONR13- CHR14- COOR17,

where R13represents N or C1-4alkyl, R17represents N or C1-6alkyl, R14means carbamoyl1-4alkyl;

p is 0-3, and R3may be the same or different;

< / BR>
where X6has any value, particularly the), selected from the group comprising FROM1-4alkyl, C1-4alkoxy;

And is Ph or naphthyl;

R3and R such as defined above,

or its N-oxide, MES, ester, pharmaceutically acceptable salt.

2. Connection on p. 1, where in the compounds of class (i) X1selected from N and C1-6alkoxy, C1-6of alkyl; X2selected from H; phenyl and phenyl C1-6of alkyl; X4selected from C1-6alkylsulfanyl; a is selected from phenyl or naphthyl; in the compounds of class ii) p is 0 and in the compounds of class (iii) X7is Ph; And is Ph; R is 0.

3. Connection on p. 1, representing a compound selected from the group including

methyl ester (2S)-2-{ 2-benzyl-5-[([2S,4S]-4-sulfanilamide-2-ylmethyl)amino]benzoylamine}-4-methylsulfonylmethane acid;

(2S)-2-{ 2-benzyl-5-[([2S,4S]-4-sulfanilamide-2-ylmethyl)amino]benzoylamine}-4-methylsulfonylmethane acid;

methyl ester (2S)-2-(2-phenyl-5-[([2S, 4S] -4-sulfanilamide-2-ylmethyl)amino]phenylcarbamoyl}amino)- 4-methylsulfonylmethane acid;

(2S)-2-({2-phenyl-5-[([2S,4S]-4-sulfanilamide-2-ylmethyl)amino]phenylcarbamoyl}amino)-4-methylsulfonylmethane acid;

methyl ester (2S)-2-({ 3-[([2S, 4S] -43-[([2S,4S]-4-sulfanilamide-2-ylmethyl)amino]naphthalene-1-carbonyl}amino)-4-methylsulfonylmethane acid;

methyl ester (2S)-2-(3-phenyl-5-[([2S,4S]-4-sulfanilamide-2-ylmethyl)amino]phenylcarbamoyl}amino)-4-methylsulfonylmethane acid;

(2S)-2-({ 3-phenyl-5-[([2S, 4S] -4-sulfanilamide-2-yl-methyl) amino] phenylcarbonylamino)-4-methylsulfonylmethane acid;

(2S, 4S)-2-[{N-(4-methoxybenzyl)-N-(naphthalene-1-ylmethyl)-amino}methyl]pyrrolidin-4-thiol;

N-(naphthalene-1-ylmethyl)-N-([2S, 4S] -4-sulfanilamide-2-ylmethyl)pentamid;

N-(naphthalene-1-ylmethyl)-n-([2S, 4S] -4-sulfanilamide-2-ylmethyl)-2-(pyridin-3-yl)ndimethylacetamide;

N-((2S, 4S)-4-sulfanilamide-2-ylmethyl)-3-methyl-N-(2-naphthalene-1-retil)butyramide;

N-([2S, 4S]-4-sulfanilamide-2-ylmethyl)-N-(2-naphthalene-1-retil)-2-pyridin-3-ylacetamide;

(2S,4S)-2-[{(3-methoxypropyl)-(2-naphthalene-1-retil)amino] methyl}pyrrolidin - 4-thiol;

N - ([2S, 4S] -4-sulfanilamide-2-ylmethyl)-2-(4-methoxyphenyl)-N-(2-naphthalene-2-retil)ndimethylacetamide;

N-(2,2-diphenylether)-N-([2S, 4S] -4-sulfanilamide-2-ylmethyl)-3-methylbutyrate;

N-([2S, 4S]-4-sulfanilamide-2-ylmethyl)-3,3-dimethyl-N-(2-naphthalene-2-retil)butyramide;

N-(2,2-diphenylether)-N-([2S, 4S] -4-sulfanilamide-2-ylmethyl)-3,3-dimethylbutyramide;

(2S)-2-{ 3-[([2S, 4S] -4-sulfanilamide-2-ylmethyl)-(3-methoxypropyl)amino]benzoylamine}-4-methylsulfonylmethane bamol-2-({ 2-phenyl-5-[([2S, 4S]-4-sulfanilamide-2-ylmethyl)amino]phenylcarbamoyl}amino)butyric acid;

methyl ester (2S)-4-carbarnoyl-2-({ 2-phenyl-5-[([2S, 4S]-4-sulfanilamide-2-ylmethyl)amino]phenylcarbamoyl}amino)butyric acid;

or their pharmaceutically acceptable salts.

4. The pharmaceutical composition inhibiting the enzyme farnesyltransferase containing compounds according to any one of paragraphs.1-3 in an effective amount together with a pharmaceutically acceptable diluent or carrier.

5. The pharmaceutical composition under item 4 in the form of tablets.

6. The method of obtaining the compounds defined in paragraph 1, are represented by i), ii) or iii), consisting in the removal of the protective group of the compounds of formula VI

< / BR>
where X8is the right side of the connection class i), ii) or iii), as defined in paragraph 1;

WG1represents H or aminosidine group;

WG2represents H or thosewithout group and any functional group X8optional protected, provided that there is at least one protective group,

and, optionally, if necessary, subsequently converting the thus obtained product in its pharmaceutically acceptable salt.

 

Same patents:

The invention relates to amide derivative of the General formula I, the symbols in the formula have the following meanings: D is pyrazolidine group which may have 1-3 halogenated derivatives or unsubstituted lower alkyl group as the Deputy(I)her is fenelonov or topendialog group, X represents a group of formula-NH-CO - or-CO-NH -, and a represents a phenyl group which may be substituted by one or more halogen atoms, or a five - or six-membered monocyclic heteroaryl group which may be substituted by one or more of lower alkyl groups

The invention relates to new compounds of the formula (I)

< / BR>
where AG represents a radical selected from formulas (a) and (b) below:

< / BR>
R1represents a halogen atom, -CH3CH2OR SIG7, -OR SIG7, СОR8, R2and R3taken together form a 5 - or 6-membered ring, R4and R5represent H, a halogen atom, a C1-C10-alkyl, R7represents H, R8represents H orX represents the radical-Y-C-, r' and r" is H, C1-C10alkyl, phenyl, Y represents S(O)nor SE, n = 0, 1, or 2, and salts of compounds of formula (I)

The invention relates to new derivatives of 2- (iminomethyl) aminobenzoyl General formula (I) where a represents either a radical represented by the formula of the invention in which R1and R2denote, independently, a hydrogen atom, a group HE, a linear or branched alkyl or alkoxy having from 1 to 6 carbon atoms, R3means a hydrogen atom, a linear or branched alkyl with 1-6 carbon atoms or the radical COR4, R4means a linear or branched alkyl with 1-6 carbon atoms, or radicals represented by the formula of the invention, R5means a hydrogen atom, a group HE or linear or branched alkyl or alkoxy with 1-6 carbon atoms, means thienyl, X means Z1-, -Z1-CO-, -Z1-NR3-CO, -CH=CH-CO - or a simple bond, Y represents a radical chosen from the radicals Z2-Q, piperazinil, homopiperazine, -NR3-CO-Z2-Q-, -NR3-O-Z2-, -O-Z2Q-in which Q means a simple bond, -O-Z3and-N(R3)-Z3-, Z1, Z2and Z3means independently a simple link or a linear or branched alkylene with 1-6 carbon atoms, preferably Z1, Z2and Z3means -(CH2)m-, and m is an integer, R

The invention relates to new derivatives of barbituric acid and a pharmaceutical composition having activity of inhibiting metalloprotease

The invention relates to CIS-isomers of N,N'-bis-(4-hydroxy-2,3,4,5-tetrahydrothiophene-3-yl)diamines of the formula I and their salts, where a-g, i-m R=H; a-C X= 0; and n=3; b n=4; n=5; n=6; d n=7; n=8; W n=9; h R=Ac, n=6; and n=6, and X = disuccinate; X = ditartrate; X l = diacetyltartaric; m X = 6-sulfoxylate dehydroabietic acid; n X = glycyrrhizinate; X = dichlorhydrate

The invention relates to new derivatives of arylethanolamine formula I or its pharmaceutically acceptable salts, which have a high affinity for endothelin and can find application in medicine

The invention relates to new derivatives of azabicycloalkanes possessing biological activity, in particular to derivatives of N - substituted 3-azabicyclo[3.2.0]heptanol

The invention relates to new derivatives of azetidinone General formula (I) in which R, R1, Ar1-Ar3X, Y, m, n, q and r are specified in the claims values, and their pharmaceutically acceptable salts, which are the active ingredient of the pharmaceutical composition with anti-atherosclerotic or hypocholesterolemic activity

The invention relates to new derivatives of piperidine-ketocarboxylic acids of the formula (I), where R1- COR4or SO2R4, R4means of alkenyl, substituted phenyl or pyridine, naphthyl, honokalani, chinoline, benzothiophene, dihydroxyphenyl or pyridyl, substituted with allmineral, R2- C1-C6-alkyl which can be substituted by phenyl or pyridium, R3group-OR6or other6where R6means hydrogen, C1-C6-alkyl, which may be a phenyl, pyridine or morpholinium, their tautomeric and isomeric forms, and salts

The invention relates to a sodium salt of omeprazole form B, which can be used as a proton pump inhibitor, i.e

The invention relates to amide derivative of the General formula I, the symbols in the formula have the following meanings: D is pyrazolidine group which may have 1-3 halogenated derivatives or unsubstituted lower alkyl group as the Deputy(I)her is fenelonov or topendialog group, X represents a group of formula-NH-CO - or-CO-NH -, and a represents a phenyl group which may be substituted by one or more halogen atoms, or a five - or six-membered monocyclic heteroaryl group which may be substituted by one or more of lower alkyl groups

The invention relates to S-omeprazole in a neutral form, which is effective as an inhibitor of the secretion of gastric acid and is useful as an antiulcer agent

The invention relates to new compounds of the formula (I), where R0- phenyl, R1- phenyl, heteroaryl, lower alkyl which may be substituted or unsubstituted, R2substituted or unsubstituted phenyl, lower alkyl, R3is hydrogen, acyl group, sulfonylurea group, X and Y independently represent a nitrogen atom or a carbon atom, Z is methylene group

The invention relates to N-(N'-substituted glycyl)-2-cyanopyrrolidine formula I, where R denotes: a)1R1aN (CH2)m-, where R1means pyridinoline or pyrimidinyl fragment, optional one - or disubstituted independently of one another by halogen, trifluoromethyl, cyano - or nitro-group; R1adenotes hydrogen or C1-C8alkyl, m is equal to 2,3, b)3-C12cycloalkyl, optional one-deputizing in position 1 WITH1-C3hydroxyalkyl,) R2(CH2)n- where either R2denotes phenyl, optional one-, two - or tizamidine selected independently of each1-C4alkoxygroup, halogen or phenylthiourea, optional one-deputizing in the phenyl ring with hydroxymethyl; or denotes a C1-C8alkyl, [3.1.1] bicyclic carbocyclic fragment, optional single or mnogozalny1-C8the alkyl, pyridinoline or nattily fragment, or cyclohexenyl, or substituted and n is 1-3, or R2denotes fenoxaprop; and n is 2; d) (R3)2CH(CH2)2-, where each R3independently represents phenyl; d) R4(CH2)p-, where R4ebony in position 1 WITH1-C3hydroxyalkyl, W) R5that means indanyl piperidinyl fragment, optionally substituted benzyl, and [2.2.1] or [3.1.1] bicyclic carbocyclic fragment, optional single or mnogozalny1-C8by alkyl, substituted or1-C8alkyl, optionally one or mnogozalny independently from each other hydroxy-group, hydroxymethyl or phenyl, optional one - or disubstituted independently selected from each other WITH1-C4the alkyl, C1-C4alkoxygroup or halogen, in free form or in the form of an acid additive salt

The invention relates to 4-(allumination)-2,4-dihydropyrazol-3-Onam General formula I, where R1denotes benzyl, alkoxybenzyl with 1-3 C-atoms in the alkyl part, unsubstituted or substituted once to three - fold amino, acyl, halogen, nitro, CN, AO, carboxyla, carbamoyl, N-allylcarbamate, N, N-dialkylammonium (with 1-6 C-atoms in the alkyl part), A-CO-NH-, AND-O-CO-NH-, AND-O-CO -, NA-, SO2NR4R5(R4and R5can denote H or alkyl with 1-6 C-atoms or NR4R5represents 5 - or 6-membered ring, optionally with other heteroatoms, like N, or O, which may be substituted),-CO-NH-SO2-, A-CO-NA-SO2- (AND-SO2-)2N-, tetrazolium phenyl; or pyridyl; R2denotes alkyl with 1-5 C-atoms, ethoxycarbonylmethyl, hydroxycarbonylmethyl; R3denotes unbranched or branched alkyl with 1-5 C-atoms, unbranched or branched alkoxy with 1-5 C-atoms or CF3And denotes unbranched or branched alkyl with 1-6 C-atoms or CF3and their salts

The invention relates to new compounds of the formula (I) or their salts, where X, Y independently is hydrogen, halogen; Z is oxygen; Q is chosen among the Q1-Q9described in the claims and containing heterocycles with nitrogen, and sulfur; Ar is pyridyl, pyrimidyl, pyridazinyl, triazolyl, thiazolyl, isothiazole or phenyl, or pyridyl, pyrimidyl, pyridazinyl, triazolyl, thiazolyl, isothiazole or phenyl substituted with up to five substituents, when Q - Q3or Q6substituted phenyl is excluded

The invention relates to new bicyclic to carboxamide formula (i) in which (1) X represents N and (a) Z is =CR1-CR2and Y is N, Z is =CR1and Y represents O, S or NR4or (C) Z is = CR1-N= and Y represents CR2or (2), X represents NR4Z represents CR1= and Y is N, Q is O, R1and R2are СОR6, C(= NOR6R13, alkyl-C(=NOR6R13, NR8R9, CF3or R6, R3is1-6alkoxygroup, R4represents H or alkyl, R5is heteroaryl, optionally substituted with halogen, alkyl, CONR11R12, CF3or CN, aryl, substituted with halogen; R6represents H, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, arylalkyl, heteroaromatic or heteroseksualci, R7represents alkyl, hydroxy, OR10, NR8R9CN, CO2H, CO2R10, CONR11R12, R8and R9represent H or alkyl, or NR8R9represents a heterocyclic ring, optionally substituted by R14, R10represents an alkyl, heterocycle, R11and R12represent H or alkyl, and the salts
The invention relates to N-methyl-N-/(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidine-1-yl)-ethyl/-2,2-diphenylacetamide, which can be used in the treatment of inflammatory bowel disease
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