Hydroxyethylamino sulfonamides heterocyclicamines amino acids, inhibiting retroviral protease

 

(57) Abstract:

Describes new hydroxyethylamino sulfonamides heterocyclicamines amino acids represented by the General formula (I) or their pharmaceutically acceptable salt, where n = 0; R1is alkyl with 1 to 5 carbon atoms; R2- aralkyl, in which alkyl has 1 to 3 carbon atoms; R3is alkyl with 1 to 5 carbon atoms; R4group of the formula (II), where a and b each independently is oxygen; R6is hydrogen; R7- hydrogen. The new compounds are effective as inhibitors of retroviral proteases and in particular as inhibitors of HIV protease. 7 C. and 5 C.p. f-crystals, 40 PL.

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The invention relates to inhibitors of retroviral proteases, in particular to new compounds, compositions and method for inhibiting retroviral proteases such as protease of human immunodeficiency virus (HIV, HIV). The invention in particular relates to hydroxyethylamine sulfonamidnuyu connections heterocyclicamines amino acids, which inhibit proteases, composition and method for inhibiting retroviral proteases, prophylactic prevention (prophylaxis) retroviral infection or the spread of the retrovirus and retroviral treatment in the tick connections used in these ways.

During the replication cycle of retroviruses products of transcription of the gag and gag-pol gene are translated as proteins. These proteins then are processed viral kolorowanki protease (or proteinase) obtaining a viral enzymes and structural proteins of the nucleus of the virus. Most often, the proteins gag precursors are processed in the core protein, and proteins, the pol precursors are processed in viral enzymes such as reverse transcriptase and retroviral protease. It was shown that the correct processing of protein precursors retroviral protease is required for Assembly of infectious Mironov. For example, it was shown that mutations shift the frame in by region of the pol gene of HIV (HIV) prevent the processing of the protein of the gag precursor. It was also shown by site-directed mutagenesis of aspartic acid residue in the active site of HIV protease, the protein processing of the gag precursor is prevented. Therefore, attempts were made to inhibit viral replication inhibition of retroviral proteases.

Inhibition of retroviral protease typically includes a transition-state mimetic, whereby the retroviral protease is subjected to the pol proteins, thereby inhibiting specific processing of the structural proteins and the release of retroviral protease itself. Thus, it is possible to effectively inhibit the replication of the retroviral proteases.

There were several classes of compounds, in particular for the inhibition of proteases, such as, for example, for the inhibition of HIV protease. Such compounds include isostere (isosteres) hydroxyethylamine and restored isosteric amide. For example, EP 0346847; EP 0342541; Roberts et al, "Rational Design of Peptide-Based Proteinase Inhibitors", Science, 248, 358 (1990); and Erickson et al, "Design Activity, and 2.8 a Crystal Structure of a C2Symmetric Inhibitor Complexed to HIV-I Protease", Science, 249, 527 (1990). US 5157041, WO 94/04491, WO 94/04492, WO 94/04493, WO 94/05639, WO 92/08701 and Application for Pat. The U.S. Ser. N 08/294468, filed August 23, 1994, (each of which is incorporated here by reference), describe inhibitors of retroviral protease containing hydroxyethylamine, hydroxyethylamino or hydroxyethyl sulfonamide isaster.

There are several classes of compounds that are useful as inhibitors of proteolytic enzyme renin. For example, US N 4599198; UK 2184730; GB 2209752; EP 0264795; GB 2200115 and the U.S. SIR H725. Of them GB 2200115, GB 2209752, EP 0264795, U.S. SIR H725 and US 4599198 reveal michelinstarred hydroxyethylamine inhibitors of renin. In EP 468641 opisaniya hydroxyethylamino connection such as 3-(t-butoxycarbonyl) amino-cyclohexyl-1-(phenylsulfonyl)amino-2(5)-butanol. In Pat. GB 2200115 described sulfanilamide hydroxyethylamino renin inhibitors and EP 0264795 revealed some sulfonamides hydroxyethylamine inhibitors of renin. However, it is known that, although renin and HIV protease both are classified as aspartyl protease, compounds that are effective as inhibitors of renin, usually it is impossible to predict whether they will be effective for the inhibition of HIV protease.

This invention relates to certain compounds which are inhibitors of retroviral proteases, their analogues and their pharmaceutically acceptable salts, esters and prodrugs. The proposed compounds are characterized as compounds inhibitors, representing hydroxyethylamino sulfonamides heterocyclicamines amino acids. Compounds of the invention mainly inhibit retroviral proteases such as protease of human immunodeficiency virus (HIV). Therefore, this invention also includes pharmaceutical compositions, methods of inhibiting retroviral proteases and methods of treatment or prophylaxis of retroviral infections such as HIV infection. Objawienie in such ways.

In this invention the proposed connection, inhibiting a retroviral protease, of the formula:

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or its pharmaceutically acceptable salt, prodrug or ester, where n = 0 or 1;

R1represents alkyl, alkenyl, quinil, hydroxyalkyl, alkoxyalkyl, cianelli, imidazolidinyl, -CH2CONH2, -CH2CH2CONH2, -CH2S(O)2NH2, - CH2SCH2, -CH2S(O)CH3, -CH2S(O)2CH3, -C(CH3)2SCH3, -C(CH3)2S(O)CH3or-C(CH3)2S(O)2CH3group; preferably R1represents alkyl with 1-5 carbon atoms, alkenyl with 2-5 carbon atoms, quinil with 2-5 carbon atoms, hydroxyalkyl with 1-3 carbon atoms, alkoxyalkyl, in which the alkyl has 1-3 carbon atoms, and alkoxy has 1-3 carbon atoms, cianelli, in which the alkyl has 1-3 carbon atoms, imidazolidinyl, -CH2CONH2, -CH2CH2CONH2, -CH2S(O)2NH2, -CH2SCH3, -CH2S(O)CH3, -CH2S(O)2CH3,

-C(CH3)2SCH3, -C(CH3)2S(O)CH3or-C(CH3)2S(O)2CH3group; more preferably R1represents alkyl with 1-4 at the 2CONH2, -CH2CH2CONH2, -CH2S(O)2NH2, -CH2SCH3, -CH2S(O)CH3, -CH2S(O)2CH3, -C(CH3)2SCH3, -C(CH3)2S(O)CH3or-C(CH3)2S(O)2CH3group; most preferably R1is sec-butyl, tert-butyl, ISO-propyl, 3-PROPYNYL, or-C(CH3)2S(O)2CH3;

R2represents alkyl, aralkyl, alkylthiomethyl, alltoall or cycloalkenyl; preferably R2represents alkyl with 1-5 carbon atoms, aralkyl, in which the alkyl has 1-3 carbon atoms, alkylthiomethyl, in which the alkyl has 1-3 carbon atoms, alltoall, in which the alkyl has 1-3 carbon atoms, or cycloalkenyl, in which the alkyl has 1-3 carbon atoms, the ring has 3-6 carbon atoms; more preferably R2represents alkyl with 3 to 5 carbon atoms, arylmethyl, alkylthiomethyl, in which the alkyl has 1-3 carbon atoms, arithimetic or cycloalkenyl, in which the ring has 5-6 carbon atoms; still more preferably R2represents isobutyl, n-butyl, CH3SH2CH2-, benzyl, phenylthiomethyl, (2 naphthylthio)methyl, 4-methoxyphenethyl, 4-hydroxyphenylethyl, 4-performancerelated; most preferably, R2represents benzyl; R3represents alkyl, cycloalkyl or cycloalkenyl; preferably R3is alkyl having 1-5 carbon atoms, cycloalkyl with a 5-8-membered ring or cycloalkenyl, in which the ring has 3 to 6 carbon atoms; more preferably R3represents propyl, isoamyl, isobutyl, butyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexyl or cycloheptyl; more preferably R3represents isobutyl or cyclopentylmethyl;

R4represents aryl, heteroaryl or heterocycle; preferably R4represents aryl, benzododecinium 5-6 membered heteroaryl ring or benzododecinium with a 5-6 membered heterocycle; or

R4represents a group of the formula:

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where A and B each independently represents O, S, SO or SO2; preferably A and B each represent O;

R4represents deuterium, alkyl or halogen; preferably,

R6represents deuterium, alkyl with 1-5 carbon atoms, fluorine or chlorine; more preferably R6represents deuterium, methyl, ethyl, propyl, isopropyl or fluoro;

R7represents hydrogen, deuterium, alkyl or halo is preferably R7represents hydrogen, deuterium, methyl or fluoro, or R6or R7each independently represents fluorine or chlorine and preferably R6or R7each is fluorine; or

R4represents a group of the formula:

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where Z represents O, S or NH; and R9represents a group of the formula:

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where Y represents O, S or NH; X represents a bond, O or NR21;

R20represents hydrogen, alkyl, alkenyl, quinil, aralkyl, heteroalkyl, heteroseksualci, aminoalkyl, N-monosubstituted or N,N-disubstituted aminoalkyl, where these substituents are alkyl or aralkyl, carboxylic, alkoxycarbonylmethyl, cianelli or hydroxyalkyl; preferably R20represents hydrogen, alkyl with 1-5 carbon atoms, alkenyl with 2-5 carbon atoms, quinil with 2-5 carbon atoms, aralkyl with 1-5 carbon atoms, heteroalkyl with 5-6 members in the ring, in which the alkyl has 1-5 carbon atoms, heteroseksualci with 5-6 members in the ring, in which the alkyl has 1-5 carbon atoms, aminoalkyl with 2 to 5 carbon atoms, N-monosubstituted or N,N-disubstituted aminoalkyl, in which alkyl has 2 to 5 carbon atoms, where these substituents are alkyl with 1-3 atoms of placil with 1-5 carbon atoms, cianelli with 1-5 carbon atoms or hydroxyalkyl with 2-5 carbon atoms; more preferably R20represents hydrogen, alkyl with 1-5 carbon atoms, phenylalkyl, in which the alkyl has 1-3 carbon atoms, heteroseksualci with 5-6 members in the ring, in which the alkyl has 1-3 carbon atoms, or N-monosubstituted or N,N-disubstituted aminoalkyl with 2-3 carbon atoms, where these substituents are alkyl with 1-3 carbon atoms; and most preferably R20represents hydrogen, methyl, ethyl, propyl, isopropyl, isobutyl, benzyl, 2-(1-pyrrolidinyl) ethyl, 2-(1-piperidinyl)ethyl, 2-(1-piperazinil)ethyl, 2-(4-methylpiperazin-1-yl)ethyl, 2-(1-morpholinyl)ethyl, 2-(1-thiomorpholine)ethyl or 2-(N,N-dimethylamino)ethyl;

R21represents hydrogen or alkyl; preferably R21represents hydrogen or alkyl with 1-3 carbon atoms; more preferably R21represents hydrogen or methyl; and most preferably21represents hydrogen; or a group of the formula-NR20R21is heterocycle; preferably a group of formula-NR20R21is a heterocycle of 5-6 members in the ring; more preferably a group of formula-NR20R21is pyrrolidinium, piperidinium/SUP> represents alkyl or R20R21N-alkyl; preferably R22represents alkyl or R20R21N-alkyl, where alkyl has 1-3 carbon atoms; and more preferably R22represents alkyl with 1-3 carbon atoms;

and preferably R4represents phenyl, 2-naphthyl, 4-methoxyphenyl, 4-hydroxyphenyl, 3,4-acid, 3-AMINOPHENYL, 4-AMINOPHENYL, benzothiazol-5-yl, benzothiazol-6-yl, 2-amino-benzothiazol-5-yl, 2-(methoxycarbonylamino)benzothiazol-5-yl, 2-aminobenzothiazole-6-yl, 2-(methoxycarbonylamino)benzothiazol-6-yl, 5-benzoxazolyl, 6-benzoxazolyl, 6-benzopyranyl, 3,4-dihydrobenzofuran-6-yl, 7-benzopyranyl, 3,4-dihydrobenzofuran-7-yl, 2,3-dihydrobenzofuran-5-yl, benzofuran-5-yl, 1,3-benzodioxol-5-yl, 2-methyl-1,3-benzodioxol-5-yl, 2,2-dimethyl-1,3-benzodioxol-5-yl, 2,2-dideuterio-1,3-benzodioxol-5-yl, 2,2-debtor-1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, 5-benzimidazolyl, 2-(methoxycarbonylamino)the benzimidazole-5-yl, 6-chinoline, 7-chinoline, 6-ethenolysis or 7-ethenolysis; more preferably R4represents phenyl, 2-naphthyl, 4-methoxyphenyl, 4-hydroxyphenyl, benzothiazol-5-yl, benzoxazol-6-yl, benzoxazol-5-yl, 2,3-dihydrobenzofuran-5-yl, benzofuran-5-yl, 1,3-benzodioxol-5-yl, 2-methyl-1,3-benzodioxol-5-yl-6-yl, 2-(methoxycarbonylamino)benzothiazol-5-yl, 2-(methoxycarbonylamino) benzothiazol-6-yl or 2-(methoxycarbonylamino)benzimidazole-5-yl; and more preferably R4represents phenyl, 4-methoxyphenyl, 4-hydroxyphenyl, benzothiazol-5-yl, benzoxazol-6-yl, 2,3-dihydrobenzofuran-5-yl, benzofuran-5-yl, 1,3-benzodioxol-5-yl, 2-methyl-1,3-benzodioxol-5-yl, 2,2-dimethyl-1,3-benzodioxol-5-yl, 2,2-dideuterio-1, 3-benzodioxol-5-yl, 2,2-debtor-1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, 2-(methoxycarbonylamino)benzothiazol-6-yl or 2-(methoxycarbonylamino)benzimidazole-5-yl;

R10represents hydrogen, alkyl with 1-3 carbon atoms, benzyl, phenylmethanesulfonyl, tert-butoxycarbonyl or 4-methoxyphenylacetylene; preferably R10represents hydrogen, methyl or benzyl; most preferably R10represents hydrogen;

R11represents hydrogen, hydroxyalkyl or alkoxyalkyl, where alkyl has 1-3 carbon atoms; preferably R11represents hydrogen;

R12and R13each independently represents hydrogen, hydroxy, alkoxy, 2-hydroxyalkoxy, hydroxyalkyl or alkoxyalkyl, preferably R12and R13each independently represents hydrogen, hydroxy, alkoxy, 2UP>12and R13each independently represents hydrogen, hydroxy, methoxy or ethoxy; or

R11and R12or R12and R13together with the carbon atoms to which they are connected, are anthropou, which is optionally substituted by at least one hydroxy or alkoxy with 1-3 carbon atoms; preferably R11and R12together with the carbon atoms to which they are connected, are anthropou, which is optionally substituted by at least one hydroxy or methoxy.

The absolute stereochemistry of the carbon atom-CH(OH)-group is preferably (R). The absolute stereochemistry of the carbon atom-CH(R1) group is preferably (S). The absolute stereochemistry of the carbon atom of CH(R2) group is preferably (S).

The group of compounds described by formula I, of special interest includes compounds of formula II:

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or their pharmaceutically acceptable salts, prodrugs or esters, where n, R1, R2, R3, R4and R10are as defined above.

The group of compounds described by formula II, of special interest includes compounds of formula III:

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or f is P>10are as defined above.

A more preferred group of compounds described by formula III include compounds or their pharmaceutically acceptable salts, prodrugs or esters, where n is 0;

R1is sec-butyl, tert-butyl, ISO-propyl, 3-PROPYNYL, or-C(CH3)2S(O)2CH3;

R2represents benzyl;

R3represents propyl, isoamyl, isobutyl, butyl, cyclohexyl, cycloheptyl, cyclopentylmethyl or cyclohexylmethyl;

R4is as defined above; and

R10represents hydrogen, methyl or benzyl.

Compounds of interest are as follows: 2S-[[(pyrrolidin-2-yl)carbonyl] amino]-N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl] (2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethyl-butanamide;

2S-[[(pyrrolidin-2-yl)carbonyl] amino] -N-[2R-hydroxy-3- [[(1,3-benzodioxol-5-yl)sulfonyl] (2-methylpropyl)amino] -1S- (phenylmethyl)propyl]-3-methyl-butanamide;

2S-[[(pyrrolidin-2-yl)carbonyl] amino] -N-[2R-hydroxy-3- [[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S- (phenylmethyl)propyl]-3S-methyl-pentanone;

2S-[[(pyrrolidin-2-yl)carbonyl] amino] -N-[2R-hydroxy-3- [[(1,3-benzodioxol-5-is-[2R-hydroxy-3 [[phenylsulfonyl] (2-methylpropyl)amino]-1S-(phenylmethyl)propyl] -3,3-dimethyl-butanamide;

2S-[[(pyrrolidin-2-yl)carbonyl]amino]-N-[2R-hydroxy-3- [[phenylsulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl] -3-methyl-butanamide;

2S-[[(pyrrolidin-2-yl)carbonyl]amino]-N-(2R-hydroxy-3- [[phenylsulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl] -3S-methyl-pentanone;

2S-[[(pyrrolidin-2-yl)carbonyl]amino]-N-[2R-hydroxy-3- [[phenylsulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl] -4-partyname;

2S-[[(pyrrolidin-2-yl)carbonyl] amino] -N-[2R-hydroxy - 3-[[(4-methoxyphenyl)sulfonyl] (2-methylpropyl)amino]-1S- (phenylmethyl)propyl]-3,3-dimethyl-butanamide;

2S-[[(pyrrolidin-2-yl)carbonyl] amino]-N-[2R-hydroxy-3- [[(4-methoxyphenyl)sulfonyl] (2-methylpropyl)amino] -1S- (phenylmethyl)propyl]-3-methyl-butanamide;

2S-[[(pyrrolidin-2-yl)carbonyl] amino] -N-[2R-hydroxy-3- [[(4-methoxyphenyl)sulfonyl] (2-methylpropyl)amino] -1S- (phenylmethyl)propyl] -3S-methyl-pentanone;

2S-[[(pyrrolidin-2-yl)carbonyl] amino] -N-[2R-hydroxy-3- [[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S- (phenylmethyl)propyl]-4-partyname;

2S-[[(pyrrolidin-2-yl)carbonyl] amino] -N-[2R-hydroxy-3- [[(2,3-dihydrobenzofuran-5-yl)sulfonyl] (2-methylpropyl)amino] -1S-(phenylmethyl)propyl]-3,3-dimethyl-butanamide;

2S-[[(pyrrolidin-2-yl)carbonyl] amino] -N-[2R-hydroxy-3- [[(2,3-dihydrobenzofuran] amino] -N-[2R-hydroxy-3- [[(2,3-dihydrobenzofuran-5-yl)sulfonyl] (2-methylpropyl)amino] -1S-(phenylmethyl)propyl]-3S-methyl-pentanone;

2S-[[(pyrrolidin-2-yl)carbonyl] amino] -N-[2R-hydroxy-3- [[(2,3-dihydrobenzofuran-5-yl)sulfonyl] (2-methylpropyl)amino] -1S-(phenylmethyl)propyl]-4-partyname;

2S-[[(pyrrolidin-2-yl)carbonyl]amino]-N-[2R-hydroxy-3- [[(benzothiazol-6-yl)sulfonyl] (2-methylpropyl)amino]-1S- (phenylmethyl)propyl] -3,3-dimethyl-butanamide;

2S-[[(pyrrolidin-2-yl)carbonyl]amino]-N-[2R-hydroxy-3- [[(benzothiazol-6-yl)sulfonyl] (2-methylpropyl)amino]-1S- (phenylmethyl)propyl] -3-methyl-butanamide;

2S-[[(pyrrolidin-2-yl)carbonyl]amino]-N-[2R-hydroxy-3- [[(benzothiazol-6-yl)sulfonyl] (2-methylpropyl)amino]-1S- (phenylmethyl)propyl] -3S-methyl-pentanone;

2S-[[(pyrrolidin-2-yl)carbonyl]amino]-N-[2R-hydroxy-3- [[(benzothiazol-6-yl)sulfonyl] (2-methylpropyl)amino]-1S- (phenylmethyl)propyl] -4-partyname;

2S-[[(pyrrolidin-2-yl)carbonyl] amino] -N-[2R-hydroxy-3- [[(2-naphthyl)sulfonyl] (2-methylpropyl)amino] -1S-(phenylmethyl) propyl]-3,3-dimethyl-butanamide;

2S-[[(pyrrolidin-2-yl)carbonyl] amino] -N-[2R-hydroxy-3- [[(2-naphthyl)sulfonyl] (2-methylpropyl)amino] -1S-(phenylmethyl) propyl]-3-methyl-butanamide;

2S-[[(pyrrolidin-2-yl)carbonyl] amino] -N-[2R-hydroxy-3- [[(2-naphthyl)sulfonyl] (2-methylpropyl)amino] -1S-(phenylmethyl) propyl]-3S-methyl-pentanone;

2S-[[(pyrrolidin-2-yl)carbonyl] amino] -N-[2R-hydroxy-3- [[(Mino]-N-[2R-hydroxy-3- [[(1,4-benzodioxan-6-yl)sulfonyl] (2-methylpropyl)amino] -1S- (phenylmethyl)propyl]-3,3-dimethyl-butanamide;

2S-[[(pyrrolidin-2-yl)carbonyl] amino]-N-[2R-hydroxy-3- [[(1,4-benzodioxan-6-yl)sulfonyl] (2-methylpropyl)amino] -1S- (phenylmethyl)propyl] -3-methyl-butanamide;

2S-[[(pyrrolidin-2-yl)carbonyl] amino]-N-[2R-hydroxy-3- [[(1,4-benzodioxan-6-yl)sulfonyl] (2-methylpropyl)amino] -1S- (phenylmethyl)propyl]-3S-methyl-pentanone and

2S-[[(pyrrolidin-2-yl)carbonyl] amino]-N-[2R-hydroxy-3- [[(1,4-benzodioxan-6-yl)sulfonyl] (2-methylpropyl)amino] -1S- (phenylmethyl)propyl]-4-pentamid.

Used herein, the term "alkyl", alone or in combination, means a straight or branched alkyl radical containing preferably from 1 to 8 carbon atoms, more preferably from 1 to 5 carbon atoms, most preferably 1-3 carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl, octyl, etc., the Term "alkenyl", alone or in combination, means a straight or branched hydrocarbon radical having one or more double bonds and containing preferably from 2 to 10 carbon atoms, more preferably from 2 to 8 carbon atoms, most preferably from 2 to 5 carbon atoms. Examples of suitable alkenyl radicals include ethynyl, Oh or branched hydrocarbon radical, having one or more triple linkages and containing preferably from 2 to 10 carbon atoms, more preferably from 2 to 5 carbon atoms. Examples etkinlik radicals include ethinyl, PROPYNYL (propargyl), butynyl, etc., the Term "alkoxy", alone or in combination, means a radical Olkiluoto ether, where the term alkyl has the same meaning as above. Examples of suitable radicals alilovic esters include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, out-butoxy, sec-butoxy, tert-butoxy etc.

The term "cycloalkyl", alone or in combination, means a saturated or partially saturated monocyclic, bicyclic or tricyclic alkyl radical, where each of the cyclic portion contains preferably from 3 to 8 carbon atoms in the ring, more preferably from 3 to 7 carbon atoms in the ring, most preferably from 5 to 6 carbon atoms in the ring, and which can be not necessarily benzododecinium system, which is optionally substituted as set forth in the definition of "aryl". Examples of such cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, octahydronaphthalene, 2,3-dihydro-1H-indenyl, substituted, etc., Ispace as naphthyl and - -carbolines, and substituted ring systems, such as biphenyl, phenylpyridine, naphthyl and diphenylpiperazine.

The term "cycloalkenyl" means an alkyl radical, as defined above, which is substituted cycloalkenyl radical, as defined above. Examples of such cycloalkenyl radicals include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 1-cyclopentylmethyl, 1-cyclohexylethyl, 2-cyclopentylmethyl, 2-cyclohexylethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, etc., the Term "benzo", alone or in combination, means the divalent radical (C6H4= derived from benzene.

The term "aryl", alone or in combination, means a phenyl or nattily radical, which is optionally substituted by one or more substituents selected from alkyl, alkoxy, halogeno, hydroxy, amino, nitro, cyano, haloalkyl, carboxy, alkoxycarbonyl, cycloalkyl, heterocycle, alkanolamine, amido, amidino, alkoxycarbonyl, N-alkylamide, alkylamino, dialkylamino, N-alkylamino, N,N-dialkylamide, alcoxycarbenium, alkylthio, alkylsulfonyl, alkylsulfonyl, etc., Examples of aryl radicals include phenyl, p-tolyl, 4-methoxyphenyl, 4-(tert-butoxy) the Nile, 2-methyl-3-acetamidophenyl, 4-CF3-phenyl, 2-methyl-3-AMINOPHENYL, 3-methyl-4-AMINOPHENYL, 2-amino-3-methyl-phenyl, 2,4-dimethyl-3-AMINOPHENYL, 4-hydroxyphenyl, 3-methyl-4-hydroxyphenyl, 1-naphthyl, 2-naphthyl, 3-amino-1-naphthyl, 2-methyl-3-amino-1-naphthyl, 6-amino-2-naphthyl, 4,6-dimethoxy-2-naphthyl, piperazineethanol etc.

The terms "aralkyl and arakaki", alone or in combination, means an alkyl or alkoxy radicals, as defined above, in which at least one hydrogen atom substituted on the aryl radical, as defined above, such as benzyl, benzyloxy, 2-phenylethyl, dibenzylamine, hydroxyphenylethyl, methylphenylethyl, diphenylmethyl, diphenylmethoxy, 4-methoxyphenylacetic, etc., the Term "arelaxation", alone or in combination, signifies a group of formula aralkyl-O-C(O)-, in which the term "aralkyl" has the meaning given above. Examples alcoxycarbenium radical are benzyloxycarbonyl and 4-methoxyphenyl-methoxycarbonyl. The term "aryloxy" means a group of the formula aryl-O-, in which the term "aryl" has the meaning given above. The term "alkanoyl", alone or in combination, means an acyl radical derived from alkenylboronic acids, examples of which include acetyl, propionyl, butyryl, valeryl, 4-methylmalonyl etc.

The term "aroyl" means an acyl radical derived from arylcarbamoyl acid, and "aryl" has the values listed above. Examples of such rolnych radicals include substituted and unsubstituted benzoyl or naphtol, such as benzoyl, 4-chlorobenzoyl, 4-carboxybenzoyl, 4-(benzyloxycarbonyl)benzoyl, 1-naphtol, 2-naphtol, 6-carboxy-2-naphtol, 6-(benzyloxycarbonyl)-2-naphtol, 3-benzyloxy-2-naphtol, 3-hydroxy-2-naphtol, 3-(benzyloxycarbonyl)-2-naphtol etc.

The term "heterocycle", alone or in combination, means a saturated or partially unsaturated monocyclic, bicyclic or tricyclic heterocyclic radical containing at least one, preferably 1-4, more preferably 1-2, nitrogen atoms, color is every ring and most preferably 5-6 atoms in each ring.

"Heterocycle" group includes sulfones, sulfoxidov, N-oxides of tertiary nitrogen ring and condensed carbocyclic and benzoquinoline ring system. Such heterocyclic groups can be optionally substituted with at least one, preferably 1-4, more preferably 1-2, carbon atoms by halogen, alkyl, alkoxy, hydroxy, oxo, aryl, aralkyl, heteroaryl, heteroalkyl, amidino, N-alkylamide, alkoxycarbonyl, alkylsulfonyl, etc. and/or on a secondary nitrogen atom (i.e.- NH-) hydroxy, alkyl, alcoxycarbenium, alkanoyl, heteroalkyl, phenyl or phenylalkyl, and/or tertiary nitrogen atom (i.e., =N-) oxido group.

"Heteroseksualci" means an alkyl radical, as defined above, in which at least one hydrogen atom substituted by a heterocyclic radical, as defined above, such as pyrrolidinyl, tetrahydrocannibinol, pyridylmethyl, etc., the Term "heteroaryl", alone or in combination, means an aromatic heterocyclic radical, as defined above, which is optionally substituted as defined above in the definitions of "aryl" and "heterocycle".

Examples of such heterocyclic is alil, imidazolyl (for example, imidazol-4-yl, 1-benzyloxycarbonylamino-4-yl, and so on), pyrazolyl, pyridyl (e.g. 2-(piperidinyl)pyridyl and 2-(4-benzylpiperazine-1-yl-1-pyridinyl, and so on), pyrazinyl, pyrimidinyl, furyl, tetrahydrofuryl, thienyl, tetrahydrofuryl and its sulfoxide and sulfadiazine, triazolyl, oxazolyl, thiazolyl, indolyl (e.g., 2-indolyl, and so on), chinoline (for example, 2-chinoline, 3-chinoline, 1 oxido-2-chinoline and so on), ethenolysis (for example, 1-ethenolysis, 3-ethenolysis and so on), tetrahydroquinoline (for example, 1,2,3,4-tetrahydro-2-chinolin and so on), 1,2,3,4-tetrahydroisoquinoline (for example, 1,2,3,4-tetrahydro-1-oxo-ethenolysis and so on), honokalani, carboline, 2-benzofuranyl, 1-, 2-, 4 - or 5-benzimidazolyl, methylenedioxyphenyl-4-yl, methylendioxyphenyl-5-yl, atlanticcity, benzothiazolyl, benzopyranyl, benzofuran, 2,3-dihydrobenzofuran, benzoxazolyl, thiophenyl etc.

The term "cycloalkylcarbonyl" means an acyl group derived from cycloalkylcarbonyl acid formula cycloalkenyl-of-COOH, where cycloalkenyl has the value given above. The term "aryloxyalkyl" means an acyl radical of the formula aryl-O-alkanoyl, where aryl and alkanoyl have the meanings given above. The term g is lcil has the meaning this above. The term "heterocyclochain" means an acyl group derived from geterotsiklicheskikh acid, where "heterocycle" has the meaning given above.

The term "geterotsiklicheskikh" means an acyl radical derived from heteroseksualci-Of-COOH, where "heterocycle" has the meaning given above. The term "heteroarylboronic" means an acyl radical derived from a carboxylic acid represented by the formula heteroaryl-Of-COOH, where heteroaryl has the values given above. The term "aminocarbonyl", alone or in combination, means aminosilane carbonyl (carbamoyl) group, where the amino group may be primary, secondary or tertiary amino group containing substituents selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, etc., the Term "aminoalkyl" means an acyl group derived from aminosilanes alkalicarbonate acid, where the amino group may be primary, secondary or tertiary amino group containing substituents selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, etc., the Term "halogen" means fluorine, chlorine, bromine or iodine.

The term "haloalkyl" means an alkyl radical having this bischloromethyl, 1-bromacil, vermeil, deformity, trifluoromethyl, 1,1,1-triptorelin, etc., the Term "leaving group" (L or W) generally refers to groups readily replaced by a nucleophile such as an amine, thiol or alcohol. Such leaving groups are well known in the field. Examples of such leaving groups include, but are not limited to, N-hydroxysuccinimide, N-hydroxybenzotriazole, halides, triflate, tozilaty, etc., the Preferred leaving group is specified, where appropriate.

Methods for obtaining compounds of formula I are given below.

It should be noted that the General method shown in the example of obtaining compounds having a specific stereochemistry, for example, where the absolute stereochemistry relative to the hydroxyl group is designated as (R). However, such methods are generally applicable to compounds of the opposite configuration, for example, where the relative stereochemistry of the hydroxyl group is designated as (S). In addition, the compounds having the (R) stereochemistry, can be used to produce compounds having the (S) stereochemistry. For example, the compound having the (R) stereochemistry, can be converted in connection with the (S) stereochemistry using well known methods.

Obtaining compounds formulary, schematically shown in Schemes I and II (see below).

N-protected derivative chlorcon amino acids, having the formula:

< / BR>
where P represents aminosidine group, and R2defined above, to restore to the corresponding alcohol using a suitable reducing agent. Suitable aminosidine groups are well known in this area and these include carbobenzoxy, t-butoxycarbonyl, etc. Preferred aminosidine group is carbobenzoxy. Preferred N-protected chloroethanol is N-benzyloxycarbonyl-L-phenylalanine chloro-methyl ketone. Preferred regenerating agent is borohydride sodium. The reduction is carried out at a temperature of from -10oC to about 25oC, preferably at about 0oC, in a suitable solvent system, such as, for example, tetrahydrofuran, etc., N-protected chloretone commercially available, for example, from Bachem. Inc., Torrance, California. Alternatively, chloretone can be obtained according to methods described by S. J. Fittkau, J. Pract. Chem., 315, 1037 (1973), and further applying techniques for N-protection, which is well known in this field.

Halogen-substituted alcohol, you can use nepokretnosti, with a suitable base in a suitable solvent system, to obtain the N-protected aminoamide formula:

< / BR>
where P and R2such as defined above. Suitable solvent systems to obtain aminoethoxy include ethanol, methanol, isopropanol, tetrahydrofuran, dioxane, etc., and mixtures thereof. Suitable bases to obtain the epoxide from the restored chloretone include potassium hydroxide, sodium hydroxide, t-piperonyl potassium, DBU, etc., the Preferred base is potassium hydroxide.

Alternatively, the protected aminoethoxy can be obtained, as described in co-filed and simultaneously considering the PCT patent application N PCT/US93/04804 (WO 093/23388) and PCT/US94/12201, and the application for Pat. US Patent Application Attorney Docket) N C-2860, each of which is given here as a reference, where disclosed methods of obtaining chiral epoxide, chiral cyanohydrin, chiral amine and other chiral intermediates used to obtain inhibitors of retroviral proteases, which are used as starting reagent DL-, D - or L-amino acid, which reacts with a suitable aminosidine group in a suitable solvent with the receipt of ester amino is the substance protected L-amino acid of the following formula:

< / BR>
where P3is carboxylamide group, for example methyl, ethyl, benzyl, tertiary butyl, 4-methoxyphenethyl etc.;2is as defined above; and P1and P2and/or P3independently selected from aminosidine groups, including, but not limited to, aralkyl, substituted aralkyl, cycloalkenyl and substituted cycloalkenyl, allyl, substituted allyl, acyl, alkoxycarbonyl, arelaxation and silyl. Examples of aralkyl include, but are not limited to, benzyl, ortho-methylbenzyl, trityl and benzhydryl, which may be optionally substituted with halogen, C1-C8the alkyl, alkoxy, hydroxy, nitro, alkylene, amino, alkylamino, acylamino and acyl, or their salts, such as salts of phosphonium and ammonium. Examples of aryl groups include phenyl, naphthalenyl, indanyl, anthracene, brenil, 9-(9-phenylfluorene) and phenanthrene, cycloalkenyl or substituted cycloalkenyl containing C6-C10cycloalkyl. Suitable acyl groups include carbobenzoxy, t-butoxycarbonyl, isobutoxide, benzoyl, substituted benzoyl, butyryl, acetyl, three-florouracil, three-chloroacetyl, phthaloyl, etc., Preferably P1and P2independently selected from ar is omnitele, P1and/or P2and/or P3the protective group may form a heterocyclic ring with the nitrogen to which they are attached, for example, 1,2-bis(methylene) benzene, phthalimide, succinimide, maleimide, etc., and where these heterocyclic groups, which may optionally include attached aryl and cycloalkyl rings. In addition, the heterocyclic group can be mono-, di - or tri - substituted, for example, nitrophthalimide. The term silyl refers to the silicon atom, optionally substituted by one or more alkyl, aryl or aranceles groups.

Suitable silyl protective groups include, but are not limited to, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, dimethylphenylsilane, 1,2-bis(dimethylsilane) benzene, 1,2-bis(dimethylsilane) ethane and diphenylmethylsilane. Similarobama amine functional groups with obtaining mono - or bis-desilylation can provide derivatives of amerosport, amino acids, esters of amino acids and amides of amino acids. In the case of amino acids, esters of amino acids and amides of amino acids, reduction of carbonyl functional groups give the desired mono - or bis-silyl amerosport. Sililar group of the silyl functional group of simple ether is easily accomplished by processing, for example, a metal hydroxide or ammonium fluoride, either in a separate reaction stage, or in situ during retrieval aminoaldehydes reagent. Suitable similitudine agents are, for example, trimethylsilyl chloride, tert-butyl dimethylsilane chloride, phenyldimethylsilane chloride, diphenylmethylsilane chloride or the products of their connection with imidazole or DMF. How sililirovanie amines and remove silyl protective groups are well known to specialists in this field. Methods of obtaining these amine derivatives of the corresponding amino acids, amides of amino acids or esters of amino acids are well known to specialists in the field of organic chemistry, including the chemistry of amino acids/esters of amino acids or aminoalcohols.

Then the ether aminosidine L-amino acid restores to the corresponding alcohol. For example, ether aminosidine L-amino acids can be restored diisobutylaluminium hydride at -78oC in a suitable solvent, such as toluene. To preferred regenerating agents include lithium alumoweld, lithium borohydride, borohydride sodium, borane, lithium tri-tert-butoxylated, the complex of borane/THF. Most preferably vosstanavlivajusa the power Swern oxidation, in the appropriate aldehyde of the formula:

< / BR>
where P1, P2and R2are as defined above. Thus, a solution of alcohol in dichloromethane is added to a cooled (-75 to -68oC) the solution of oxalyl chloride in dichloromethane and DMSO in dichloromethane and stirred for 35 minutes.

To an acceptable oxidizing reagents include, for example, a complex of a sulfur trioxide-pyridine and DMSO, oxalyl chloride and DMSO, acetyl chloride or anhydride and DMSO, TRIFLUOROACETYL chloride or anhydride and DMSO, methanesulfonyl chloride and DMSO or tetrahydro-thiophene-S-oxide, toluensulfonyl chloride and DMSO, triptorelin-sulfonyl anhydride (triflic anhydride and DMSO, pentachloride phosphorus and DMSO, dimethylphosphoric chloride and DMSO and isobutylacetate and DMSO. The oxidation conditions specified in Reetz et al [Angew. Chem., 99, p. 1186, (1987)], Angew. Chem. Int. Ed. Engl. , 26, p. 1141, 1987), which used oxalyl chloride and DMSO at -78oC.

The preferred method of oxidation described in this invention is a method of using a complex of a sulfur trioxide-pyridine, triethylamine and DMSO at room temperature. This system provides excellent yields of the target chiral protected aminoaldehyde that you can use without clear, the operations on a large scale become less dangerous. Reaction at room temperature also eliminates the necessity of using low-temperature reactor, which makes the method more acceptable for commercial production.

The reaction can be conducted in an atmosphere of inert gas, such as nitrogen or argon, or in a normal or dry air, at atmospheric pressure or in a sealed reaction vessel under positive pressure. Preferred is a nitrogen atmosphere. Alternative bases amines include, for example, three-butyl amine, tri-isopropyl amine, N-methylpiperidine, N-methyl morpholine, azabicycloalkanes, diisopropylethylamine, 2,2,6,6-tetramethylpiperidine, N,N-dimethylaminopyridine or mixtures of these bases. The triethylamine is the preferred base. Alternative pure DMSO solvents include a mixture of DMSO with or aprotic halogenated solvents, such as tetrahydrofuran, ethyl acetate, toluene, xylene, dichloromethane, ethylene dichloride, etc., Dipolar aprotic co-solvents include acetonitrile, dimethylformamide, dimethylacetamide, ndimethylacetamide, tetramethyl urea and its cyclic analogue, N-organic, sulfolan, etc. Instead of N,N-dibenzyl-the military above, to obtain the corresponding N-monosubstituted [or P1or P2= H] or N,N-disubstituted aldehyde.

In addition, to obtain aldehydes can be recovering the amide or hydride hard-ether derivative of the corresponding benzyl (or another suitable protective group) asutamisega phenylalanine, substituted phenylalanine or cycloalkyl analogue derivative of phenylalanine. Hydride transfer is an additional method of synthesis of aldehyde under conditions when avoid condensations of aldehydes, for example, oxidation of Obenauer (Oppenauer Oxidation).

The aldehydes of this method can also be obtained by recovering protected phenylalanine and analogues of phenylalanine or its amide or difficult-ether derivatives, for example, by treatment with sodium amalgam with HCl in ethanol or lithium, or sodium, or potassium, or calcium in ammonia. The reaction temperature may be from about -20oC to about 45oC and preferably from about 5oC to about 25oC. Two additional ways of obtaining asutamisega aldehyde include oxidation of the corresponding alcohol bleach in the presence of catalytic amount of 2,2,6,6-tetramethyl-1-pyridyloxy with whom propylammonium of perruthenate in the presence of N-methylmorpholin-N-oxide.

Alternatively, chloranhydride protected derivative of phenylalanine or a derivative of phenylalanine, disclosed above, can be restored with hydrogen and a catalyst such as Pd on barium carbonate or barium sulphate, with or without additional agent for the catalyst under normal conditions (moderating agent, such as sulfur or thiol (Recovery of Rosenmund, Rosenmund Reduction).

The aldehyde obtained in the oxidation Swarna (Swern), then subjected to interaction with glomerulitis-reagent generated in situ by the interaction alkyllithium or abilitiesa connection with dihalomethane represented by the formula X1CH2X2where X1and X2independently represent I, Br or Cl. For example, a solution of aldehyde and chloroiodomethane in THF cooled to -73oC and add a solution of n-utility in hexane. The resulting product is a mixture of diastereomers of the corresponding aminosidine epoxides of formula:

< / BR>
and

< / BR>
The diastereomers can be divided, for example, chromatographic, or, alternatively, immediately after they will react in subsequent stages. D-amino acid can be used instead of L-amino acids, to obtain the compounds and promotility to the chiral aminoaldehyde is highly diastereoselective. Preferably, hermeticity or promotility was generated in situ by reaction dihalomethane and n-utillity. To an acceptable halomethanes to methyltyrosine are chloridometer, bromochloromethane, dibromomethane, diiodomethane, Braverman etc. Sulphonate ester product of accession, for example, hydrogen bromide to formaldehyde, is also methyltyrosine agent. Tetrahydrofuran is the preferred solvent, however, alternative solvents, such as toluene, dimethoxyethane, ethylene dichloride, methylene chloride, can be used in the form of pure solvents or mixtures thereof. Dipolar aprotic solvents, such as acetonitrile, DMF, N-organic, are used as solvents or as part of a mixture of solvents. The reaction can be conducted in an atmosphere of inert gas, such as nitrogen or argon. n-Utility can replace other organometallics reagents, such as motility, tert-utility, second-utility, finality, phenyl sodium, etc., the Reaction can be conducted at temperatures from about -80oC and 0oC, but preferably from about -80oC to -20oC. Most preferably the reaction temperature is in the which cases preferred. The preferred pressure of the reaction is atmospheric, but the positive pressure under certain conditions, more predominantly, for example, in the case of the environment with high humidity.

Alternative ways of turning into the epoxides of this invention include the substitution of another type of charged methylaminophenol predecessor with the subsequent processing of the base with the receipt of the same anion. Examples of such compounds include trimethylsulfoxonium toilet or triflate, Tetramethylammonium halide, methylvinylsiloxane halide in which the halide is chloride, bromide or iodide.

The conversion of aldehydes of this invention in their epoxy derivative can also be multi-stage. For example, adding anion thioanisole obtained from, for example, butyl or abilitiesa reagent to secure aminoaldehyde, oxidation of the obtained protected aminosilica alcohol is well known oxidizing agents such as hydrogen peroxide, tert-butylhypochlorite, bleach or periodate sodium, obtaining sulfoxide. Alkylation sulfoxide, for example, methyl iodide or bromide, methyl tosylate, methyl, mesago or inorganic bases. Alternatively, the protected aminomethyl alcohol can be alkylated, for example, the above-mentioned alkylating agents with obtaining salts of sulfone, which are then converted into epoxides by treatment of tert-amine or mineral bases.

The desired epoxides are formed, when using the most preferred conditions, diastereoselective in quantitative (weight) ratio of at least about 85:15 (S:R). The product can be purified by chromatography to obtain diastereomers and enantiomerically pure product, but most of all, to obtain inhibitors of retroviral proteases product is used directly without purification. The above method is applicable both to obtain mixtures of optical isomers, and to obtain the separated compounds. If you want a specific optical isomer, it can be selected by selection of source materials, for example, L-phenylalanine, D-phenylalanine, L-phenylalaninol, D-phenylalaninol, D-hexahydrocannabinol, etc., or may be conducted by the division into intermediate or final stages. Chiral excipients, such as one or two equivalent camphorsulfonic acid, citric acid, camphoric acid, 2-Soedinenii of the present invention. These compounds or derivatives can crystallize or can be separated by chromatography, using either chiral or achiral column, as is well known to experts in this field.

Amino epoxides are then subjected to interaction, in a suitable solvent system, with an equal amount or preferably with an excess of the required amine of formula R3NH2where R3is hydrogen or takes the values defined above. The reaction can be carried out in a wide temperature range, for example from about 10oC to about 100oC, and preferably, but not necessarily, carried out at the temperature at which the solvent begins to boil. A suitable solvent system include proton, not proton and dipolar aprotic organic solvents, such as, for example, systems in which the solvent is an alcohol, such as methanol, ethanol, ISO-propanol and so on, ethers such as tetrahydrofuran, dioxane, etc., and toluene, N, N-dimethylformamide, dimethylsulfoxide and mixtures thereof. The preferred solvent is isopropanol. The resulting product is a derivative of 3-(N-protected amino)-3-(R2)-1-(OTHER3)-propan-2-ol (here the/SUP>, P2, R2and R2such as described above. Alternatively, instead of aminoethoxy you can use galasport.

The above-defined amerosport then subjected to interaction in a suitable solvent with sulfonyl chloride R4SO2Cl, sulfonyl bromide R4SO2Br or with the appropriate sulfonyl anhydride, preferably in the presence of an acid acceptor. Suitable solvents that can be used for the reaction include methylene chloride, tetrahydrofuran, etc. Suitable acid acceptors include triethylamine, pyridine, etc., derived sulfonamida can be represented, depending on the epoxide, formulas;

< / BR>
< / BR>
where P, P1, P2, R2, R3and R4such as described above. These intermediate products used to produce compounds are inhibitors of the present invention.

Sulfonyl halides of the formula R4SO2X can be obtained by the interaction of the appropriate aryl, heteroaryl and benzododecinium heterocyclic Grignard reagent or a lithium reagent with sulfurylchloride or sulfur dioxide with subsequent oxidation by halogen, preferably chlorine. Aryl, Goethe is sootvetstvujushij halide (such as chlorine or bromine) compounds, which are commercially available or can be easily obtained from commercially available starting materials using known in the field methods. Also, thiols can oxidize in sulfonyl chlorides using chlorine, in the presence of water under carefully controlled conditions. In addition, sulfonic acid, such as arylsulfonic acid, can be turned into sulfonil a halide, using reagents such as PCl5, SOCl2, ClC(O)C(O)Cl, etc., and also the anhydrides, using suitable dehydrating reagents. Sulfonic acid, in turn, can be obtained using well-known in the field methods. Some sulfonic acid commercially available. To obtain compounds in which-SO2part replaced-SO - or-S - part, respectively, instead of sulfonyl halides, can be used sulfinil halides (R4SOX) or sulfenyl halides (R4SX). Arylsulfonate acid, benzododecinium heterocyclic sulfonic acid or heteroarylboronic acid can be obtained by sulfonation of the aromatic ring are well known in this field means, such as by reaction with sulfuric acid, SO3, SO3complexes, such as the s derived from aromatic compounds by interaction with DMF (SO3and SOCl2or ClC(O)C(O)Cl. The reaction can be conducted Paladino or in the same vessel.

Arylsulfonate acid, benzododecinium heterocycle sulfonic acid, heteroaryl sulfonic acid, arylmercury, benzododecinium heterocycle mercaptans, heteroaromatic, aryl halides, benzododecinium generalcologne, heteroarylboronic, etc. are commercially available or can be easily obtained from commercially available starting materials using standard, well-known in the field methods. For example, the number of sulfonic acids (R4SO3H) represented by the formula:

< / BR>
and

< / BR>
where A, B, Z, R6, R7and R9such as defined above, can be obtained from 1,2-benzodithiol, 2-mercaptoethanol, 1,2-bentolila, 2-aminobenzothiazole, benzothiazole, 2-aminobenzimidazole, benzimidazole, etc., which are commercially available, Carter, Pat. USA 4595407; Ehrenfreund et al. Pat. USA 4634465; Yoder et al., J. Heterocycl. Chem. 4:166-167 (1967); Cole et al., Aust. J. Chem. 33:675-680 (1980); Cabiddu et al. Synthesis 797-798 (1976); Ncube et al. , Tet. Letters 2345-2348 (1978); Ncube et ai., Tet. Letters 255-256 (1977); Ansink & Cerfontain, Rec. Trav. Chim. Pays-Bas 108:395-403 (1989); and Kajihara & Tsuchiya, EP 638564 Al, which are incorporated here by reference. For example, 1,2-benzodithiol, 2-Mer, predpochtitelno Br or I, in the presence of a base, such as hydroxide, or R6R7C= O in the presence of acid, such as toluensulfonate acid, or P2O5pick substituted benzododecinium heterocycle of the formula:

< / BR>
which can then be sulfonated in the above-mentioned sulfonic acid. For example, CF2Br2or CD2Br2can be subjected to the interaction of 1,2-benzodithiol, 2-mercaptoethanol or 1,2-bentolila in the presence of a base to obtain connections:

< / BR>
or

< / BR>
accordingly, where A and B are O or S, and D is a deuterium atom. In addition, when A and/or B represent S, the sulfur can oxidize, using the following methods, in sulfon or sulfoxide derivatives.

After deriving sulfonamida, aminosidine group P or P1and P2aminosidine group is removed under conditions which will not have actions on the rest of the molecule. These methods are well known in this field and include acid hydrolysis, hydrogenolysis, etc., the Preferred method includes removing the protective group, for example, removing carbobenzoxy group by hydrogenolysis with apologia protecting group is t-butoxycarbonyl group, it can be removed using an inorganic or organic acid, for example HCl or triperoxonane acid, in a suitable solvent system, such as dioxane or methylene chloride. The resulting product is derived amine salt.

After neutralization of the amine salt is then associated with the DL-, D-, or L-amino acid corresponding to the formula PNHCH(R1)COOH, where P and R1such as defined above, followed by removing protection from the amine, as described above, and the binding of cyclic amino acids of formula:

< / BR>
(when R10H) or

< / BR>
where n, P, R10, R11, R12and R13such as defined above, and L represents a leaving group such as halide, anhydride, active ester, etc., for Example, when R11, R12and R13are, each, hydrogen, it is possible to use N-protected or N-substituted Proline of NOT active ester, N-protected or N-substituted pipecolinate (pipecolinic) acid N-hydroxysuccinimide active ester, etc.

Alternatively, the intermediate compounds

< / BR>
you can unprotect the interaction with R10L, where R10represents alkyl or benzyl, or an appropriate aldehyde or to the
where n, R1, R2, R3, R4, R10, R11, R12and R13such as defined above.

Cyclic amino acids of formula:

< / BR>
are commercially available, such as Proline, 4-hydroxyproline, N-methylpropan, indolin-2-carboxylic acid and so on; or they can be easily obtained from commercially available starting materials using standard, well-known in the field methods, such as, for example, Proline, 4-hydroxyproline, 4-hydroxyquinolin-2-carboxylic acid, 3-gidroksipropanova acid, indolin-2-carboxylic acid, 5-methoxyindole-2-carboxylic acid, kainic acid, 4-methoxy-2-quinoline-carboxylic acid, etc., alternatively, a cyclic amino acids can be easily obtained by cyclization of aminecontaining alpha-ketone carboxylic acids or esters in a circular Imin and subsequent reduction, for example, cyanoborohydride sodium, etc. in a cyclic amine as shown in Scheme III (see the end of the description), or alternatively, the cyclization of amino acids having an appropriate leaving group L, such as chlorine, bromine, toilet, mesilate, etc. as shown in Scheme IV (see end of description), where n, P3, R10, R11R12

Alternatively, after neutralization of the salt, the amine is then associated with the DL-, D-, or L-amino acid corresponding to the formula:

< / BR>
(when R10H) or

where n, P, R1, R10R11, R12and R13such as defined above, which can be obtained in a manner analogous to the method of binding, described above, of the DL-, D - or L-amino acid corresponding to the formula NH2CH(R1)COOP3where P3and R1such as defined above.

DL-, D - or L-amino acid corresponding to the formula PNHCH(R1)COOH or NH2CH(R1)COOP3where R, P3and R1such as defined above, are commercially available (Sigma Chemical Co.) or it can be easily obtained using standard, well-known in this field ways, from readily available starting materials. Preferably P is benzyloxycarbonyl or t-butoxycarbonyl, and P3represents benzyl or tert-butyl. Standard linking techniques you can use to bind amino acids and amines. The group of carboxylic acid is subjected to interaction with the formation of the anhydride, a mixed anhydride, galodamadruga, such as chlorine or bromohydrin, Il the design and engineering methods and conditions. Appropriate systems of solvents include tetrahydrofuran, ethyl ether, methyl tert-butyl ether, methylene chloride, N,N-dimethylformamide, etc., and mixtures thereof.

Alternatively, the protected amerosport obtained by opening of the epoxide may be further protected by the newly introduced amino group with a protective group P', which is not deleted when deleting aminosidine groups P or1and P2, i.e., P' is selectively removed by the group. The person skilled in the art can select appropriate combinations of P', P, P1and P2. For example, suitable combinations are P=Cbz and P'=Boc; P'=Cbz and P=Boc; P'=Cbz, P2=benzyl and P'=Boc; and P'= P2=benzyl and P'=Boc. The obtained compound represented by the formula:

< / BR>
or

< / BR>
may be subjected to additional transformations to obtain the compounds of formula:

< / BR>
or

< / BR>
where n, P, P' R1, R2, R3, R10, R11, R12and R13such as defined above. Additional to the above transformations may include, if necessary, the introduction of required residues or groups directly or introduction prior molecule more than one residue or group within one study is about synthesis. At this stage it is also possible synthetic transformations. The protective group P' is then selectively removed and the resulting amine interacts with sulfonyl chloride R4SO2Cl, sulfonyl bromide R4SO2Br or with the appropriate sulfonyl anhydride, preferably in the presence of an acid acceptor, to form compounds of this invention:

< / BR>
where n, R1, R2, R3, R4, R10, R11, R12and R13such as defined above. Selective removal of the protection and transformation of the sulfonamide can be done either at the end of the synthesis, or at any intermediate stage, if required.

The above chemical reaction is usually open, based on their most extensive use to obtain the compounds of the present invention. Sometimes the reaction may not be applicable as described to each compound included in the scope of the invention. Connection for which it is easily recognized experts in this field. In all such cases, either the reactions can be successfully performed using standard modifications, known to specialists in this field, for example, by using the appropriate protection of affected groups, pogut to be applied to other reactions disclosed here or undisclosed standard, to obtain the compounds of the present invention. In all preparative methods, all of the original substances are known or can easily be obtained from known starting materials.

It is obvious that the person skilled in the art, using this description, you may realize the invention to the full extent. So below is the preferred specific variants of embodiment of the invention should be considered as merely illustrative and not limiting in any way the scope of the present invention.

All reagents were used without purification. All proton and carbon NMR spectra were obtained either on a Varian VXP-300 or VXR-400 nuclear magnetic resonance spectrometer.

The following examples illustrate the formation of compounds inhibitors of this invention and intermediates used in the preparation of the compounds are inhibitors of the present invention.

EXAMPLE 1

< / BR>
Receipt of 2S-[Bis(phenylmethyl)amino]benzodiapine

Method 1: Obtain 2S-[Bis(phenylmethyl)amino] benzodiapines Dibal recovery phenylmethylene ether N,N-bis(phenylmethyl)-L-phenylalanine

Stage 1:

A solution of L-favout to 97oC. and Then slowly added benzyl bromide (108,5 ml, 0,605 mol) (add - 25 min). The mixture was stirred at 97oC for 30 minutes in nitrogen atmosphere. The solution is cooled to room temperature and extracted with toluene (2 x 250 ml). The combined organic layers washed with water and brine, dried over magnesium sulfate, filtered and concentrated to oil. The product identification is confirmed as follows. Analytical TCX (TLC) (10% ethyl acetate/hexane, silica gel) shows the main component at the Rf value of 0.32, which corresponds to the desired tribenzylamine connection, phenylmethanone ether, N,N-(phenylmethyl)-L-phenylalanine. This compound can be purified by column chromatography (silica gel, 15% ethyl acetate/hexane). Usually the product is sufficiently pure to be used directly in the next stage without additional purification. 1The NMR spectrum corresponds published in the literature.1The NMR spectrum (CDCl3) , 3.00 and 3.14 (ABX-system, 2H, JAB=14.1 Hz, JAB=7,3 Hz and JBX=5,9 Hz), 3,54, and to 3.92 (AB-System, 4H, JAB=a 13.9 Hz), 3,71 (t, 1H, J=7,6 Hz), 5,11 and 5,23 (AB-System, 2H, JAB= 12.3 Hz), 7,18 (m, 20N). AIMS (EIMS): m/z 434 (M-1).

Stage 2:

FeNi is Le (750 ml) and cooled to -55oC. a 1.5 M solution of DIBAL in toluene (443,9 ml, 0,666 mol) is added in such a rate as to maintain the temperature -55 to -50oC (add -1 hour). The mixture is stirred for 20 minutes in an atmosphere of nitrogen and then the reaction is terminated by -55oC by slow addition of methanol (37 ml). Then cool the solution is poured into cold (5oC) 1.5 N HCl solution (1.8 l). Precipitated precipitated solid (approx. 138 g) is filtered off and washed with toluene. The solid is suspended in a mixture of toluene (400 ml) and water (100 ml). The mixture is cooled to 5oC and treated with 2.5 N NaOH (186 ml) and then stirred at room temperature until until the solid has dissolved. Toluene layer is separated from the aqueous phase and washed with water and brine, dried over magnesium sulfate, filtered and concentrated to a volume of 75 ml (89 g). To the residue is added ethyl acetate (25 ml) and hexane (25 ml), after which the desired alcohol product begins to crystallize. After 30 minutes an additional 50 ml of hexane added in order to further accelerate the crystallization. The solid is filtered off and washed with 50 ml of hexane, getting to 34.9 g of the first portion of the product. The second portion of the product produce by re-filtering the fallopian Rast is ylmethyl)amino] benzoylpropionate, 40% of output in the calculation of L-phenylalanine. Additional 7 g (7%) of the product can be obtained by recrystallization of the concentrated mother liquor. TLC (TLC) product Rf=0,23 (10% ethyl acetate/hexane, silica gel);1NMR (CDCl3and of 2.44 (m, 1H), 3,09 (m, 2H), 3.33 and (m, 1H), 3,48, and to 3.92 (AB-System, 4H, JAB=13.3 Hz), 3,52 (m, 1H) and 7.23 percent (m, 15 NM); []25D+ 42,4 (1.45, CH2Cl2); DSC (DSC) 77,67oC; Elemental anal. The expect. for C23H25ON: C, 83,34; H, 7,60; N, 4,23. Found: C, 83,43; H, To 7.59; N, 4,22. HPLC (HPLC) on a chiral stationary phase: Cyclobond I SP column (250 x 4.6 mm C. D. (I. D.)), mobile phase: methanol/triethylamine acetate buffer pH of 4.2 (58:42, V/V), flow rate 0.5 ml/min, detection by the detector at 230 nm and a temperature of 0oC. retention Time: 11,25 min, retention time enantiomer of the desired product: 12,5 minutes

Method 2: Obtain S-2-[Bis(phenylmethyl)amino]benzodiapine by N, N-dibenzylamine L-phenylalaninol

L-phenylalaninol (176,6 g 1,168 mol) is added to a mixed solution of potassium carbonate (484,6 g 3,506 mol) in 710 ml of water. The mixture is heated to 65oC in nitrogen atmosphere. The solution benzylbromide (400g, 2,339 mol) in 3A ethanol (305 ml) is added at a rate that allows to maintain the temperature 60-68oC. Dujfasp lichdom stirring. The oily product solidifies into small granules. The product was diluted with 2.0 l of tap water and stirred for 5 minutes to dissolve the inorganic by-products. The product distinguish filtration under reduced pressure and washed with water until until the pH reaches 7. The crude product is dried in air over night, receiving semi-solid (407 g) which is recrystallized from 1.1 l of a mixture of ethyl acetate/heptane (1:10 by volume). The product distinguish filtering (if -8oC), washed with 1.6 l of cold mixture (-10oC) ethyl acetate/heptane (1:10 by volume) and dried in the air, getting 339 g S-2-[Bis(phenylmethyl)amino]benzoylpropionate, So pl. = 71,5-73,0oC. If necessary, an additional amount of product can be obtained from the mother liquor. Other analytical characteristics are identical to the compound obtained as described in Method 1.

EXAMPLE 2

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Receipt of 2S-[Bis(phenylmethyl)amino]benzoylpropionate

Method 1:

2S-[Bis(phenylmethyl)amino]benzodiapines (200 g, 0,604 mol) is dissolved in triethylamine (300 ml, of 2.15 mol). The mixture is cooled to 12oC and add a solution of the complex trioxide silver/pyridine (380 g, 2,39 mol) in DMSO (1.6 l) with a room temperature in a nitrogen atmosphere for 1.5 hours, after which, according to TLC analysis, the reaction is finished (33% ethyl acetate/hexane, silica gel). The reaction mixture is cooled with ice water and the reaction stopped by the addition of 1.6 l of cold water (10-15oC) for 45 minutes. The resulting solution was extracted with ethyl acetate (2.0 l), washed with 5% citric acid (2.0 l) and brine (2.2 l), dried over MgSO4(280 g) and filtered. The solvent is removed on a rotary evaporator at 35-40oC and then dried in vacuum, obtaining 198,8 g of 2S-[Bis-(phenylmethyl)amino] benzoylpropionate in the form of a pale yellow oil (99.9 percent). The crude product is sufficiently pure to be used directly in the next stage without purification. Analysis data of the compounds are in accordance with the published literature. []25D= -92,9o(1,87, CH2Cl2); 1H NMR (400 MHz, CDCl3) , to 2.94 and 3.15 (ABX-System, 2H, JAX= a 13.9 Hz, JAX= 7,3 Hz and JBX= 6.2 Hz), of 3.56 (t, 1H, 7,1 Hz), 3,69, and is 3.82 (AB-System, 4H, JAB=to 13.7 Hz), 7,25 (m, 15 NM) and 9,72 (s, 1H); WCMC (HRMS) Expect. for (M+1) C23H24NO 330,450 found: 330,1836. Elem. anal. The expect. for C23H23ON: C, 83,86; H,? 7.04 BABY MORTALITY; N, 4.25 IN. Found: C, 83,64; H, 7,42; N, 4,19. HPLC (HPLC) on a chiral stationary phase: (S,S) Pirkle-Whelk-O 1 column (250 x what'or at 210 nm. The retention time of the target S-isomer: 8,75 min, the retention time of the R-enantiomer to 10.62 min

Method 2:

The solution of oxalyl chloride (8,4 ml, 0,096 mol) in dichloromethane (240 ml) is cooled to -74oC. a Solution of DMSO (DMCO) (12.0 ml, 0,155 mol) in dichloromethane (50 ml) is then added slowly with such a rate as to maintain the temperature of -74oC (add 1.25 hours). The mixture is stirred for 5 min, followed by a solution of S-2-[bis(phenylmethyl)amino]benzoylpropionate (0,074 mol) in 100 ml of dichloromethane (addition of 20 min, temp. from -75oC to -68oC). The solution was stirred at -78oC for 35 minutes in a nitrogen atmosphere. Then add triethylamine (41,2 ml, 0,295 mol) for 10 minutes (temp. from -78oC to -68oC), and at this time, the precipitated ammonium salt. The cold mixture is stirred for 30 min and then add water (225 ml). The dichloromethane layer is separated from the aqueous phase and washed with water, brine, dried over magnesium sulfate, filtered and concentrated. The residue is diluted with ethyl acetate and hexane and then filtered to further remove the ammonium salt. The filtrate is concentrated and receiving S-[bis(phenylmethyl)amino]benzoylpropionic. The aldehyde used in the next stage without ochistki of the research, of 2.27 g of molecular sieves (4A) and 9.1 ml of acetonitrile added 53 mg (0.15 mmol) tetrapropylammonium of perruthenate (TRAR). The mixture is stirred for 40 minutes at room temperature and concentrate under reduced pressure. The residue is suspended in 15 ml of ethyl acetate, filtered through a silica substrate. The filtrate is concentrated under reduced pressure, obtaining a product containing approximately 50% of S-2-[bis(phenylmethyl)amino]benzoylpropionate in the form of a pale yellow oil.

Method 4:

To a solution of 1.0 g (to 3.02 mmol) of S-2-[bis(phenylmethyl)amino]benzodiapine 9.0 ml of toluene added 4,69 mg (0.03 mmol) of 2,2,6,6-tetramethyl-1-piperidinyloxy in the form of a free radical (TEMPO), 0.32 g (3.11 mmol) of sodium bromide, and 9.0 ml of ethyl acetate and 1.5 ml of water. The mixture is cooled to 0oC and an aqueous solution 2,87 ml of 5% bleach for household use containing 0,735 g (is 8.75 mmol) of sodium bicarbonate and 8,53 ml of water is added slowly over 25 minutes. The mixture was stirred at 0oC for 60 minutes. Two additional portions (1,44 ml each) mixture, followed by stirring for 10 minutes. Two-phase mixture is allowed the opportunity to split. The aqueous layer was extracted twice with 20 ml of ethyl acetate. The combined organic layer washed with brine. The organic solution is dried over magnesium sulfate, filtered and concentrated under reduced pressure, obtaining of 1.34 g of crude oils containing a small amount of the target aldehyde, S-[bis(phenylmethyl)amino]benzoylpropionate.

Method 5:

Using the techniques described in Method 1 of this Example, except that uses 3.0 equivalent of a complex of sulfur trioxide-pyridine, emit S-[bis(phenylmethyl)amino]benzoylpropionic with comparable outputs.

EXAMPLE 3

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Obtaining N,N-dibenzyl-3(S)-amino-1,2-(S)-epoxy-4-phenylbutane

Method 1:

A solution of S-[Bis(phenylmethyl)amino] benzoylpropionate (191,7 g of 0.58 mol) and chloroiodomethane (of 56.4 ml, 0.77 mol) in tetrahydrofuran (1.8 ml) is cooled to -30o- -35oC (lower temperature such as -70oC also acceptable, but higher temperatures easier achievable with operations in industrial scale) in the reactor of stainless steel in an atmosphere of nitrogen. A solution of n-utility in hexane (1.6 M, 365 ml of 0.58 mol) is then added at a speed that allows you to maintain the temperature below -25oC. After the addition the mixture is stirred at a temperature of from -30 to - 35oC for 10 minutes. Then add utility (110 ml), at < -25oC. After the addition the mixture is stirred at -30 to -35oC for 10 minutes. The operation is repeated once. (2) Add an additional number chloroiodomethane (8.5 ml, 0.11 mol), then n-utility (55 ml, 0,088 mol) at < -25oC. After the addition the mixture is stirred at a temperature of from -30 to -35oC for 10 minutes. Operation is repeated 5 times. (3) Add an additional number chloroiodomethane (8.5 ml, 0.11 mol), then n-utility (37 ml, 0,059 mol) at < -25oC. After the addition the mixture is stirred at a temperature of from -30 to -35oC for 10 minutes. The operation is repeated once. Stop external cooling, and the mixture is heated to ambient temperature for 4 to 16 hours, when the data TLC (silica gel, 20% ethyl acetate/hexane) indicated that reaction was completed. The reaction mixture is cooled to 10oC and the reaction stopped by the addition of 1452 g of a 16% solution of ammonium chloride (obtained by dissolving 232 g of ammonium chloride in 1220 ml of water), keeping the temperature below 23oC. the Mixture is stirred for 10 minutes and the organic and aqueous layers separated. Excite phase is further extracted with ethyl acetate (2 x 500 ml). An ethyl acetate layer combined with tetrahydrofuranate at 65oC. the Brown oil residue is dried at 70oC in vacuum (0.8 x 105PA, 0.8 bar) for 1 hour, receiving 222,8 g of the crude substance. (The weight of the crude residue was > 100%. Because of the relative instability of the product on silica gel, the crude product is usually directly used in the next stage without purification). The ratio of diastereoisomers in the crude mixture is determined using proton NMR: (2S)/(2R): 86:14. Minor (secondary) and primary epoxy diastereoisomer in this mixture identified using the method TLC (silica gel, 10% ethyl acetate/hexane), Rf=0,29 & 0,32 respectively. An analytical sample of each of the diastereomers is obtained by purification by chromatography on silica gel (3% ethyl acetate/hexane) and is characterized as follows:

N,N, S-Tris(phenylmethyl)-2S-oxiranemethanol

1H NMR (400 MHz, CDCl3) 2,49 and 2.51 (AB-System, 1H, JAB=2,82), was 2.76 and 2.77 (AB-System, 1H, and 2.83 (m, JAB=4,03), and 2.83 (m, 2H), 2,99 & 3,03 (AB-System, 1H, JAB=10.1 Hz) and 3.15 (m, 1H), to 3.73 & 3,84 (AB-System, 4H, JAB= 14,00), 7,21 (m, 15H); 13C NMR (400 MHz, CDCl3) 139,55, 129,45, 128,42, 128,14, 128,09, 126,84, 125,97, 60,32, 54,23, 52,13, 45,99, 33,76; WCMC (HRMC) Expect. for24H26NO (M+1) 344,477 Found 344,2003.

N,N, S-Tris(phenylmethyl)-2R-oxirane is H). HPLC (HPLC) on a chiral stationary phase: Pirkie-Wheik-O 1 column (250 x 4.6 mm C. D.), mobile phase: hexane/isopropanol (99,5 level:0.5, V/V), flow rate: 1.5 ml/min, detection with UV detector at 210 nm. Retention time (8): 9,38 min, the retention time of enantiomer (4): of 13.75 minutes

Method 2:

A solution of the crude aldehyde 0,074 mole and chloroiodomethane (7.9 ml, 0,096 mol) in tetrahydrofuran (285 ml) is cooled to -78oC in nitrogen atmosphere. 1.6 M solution of n-utility in hexane (25 ml, 0.040 mol) is then added with such speed that allows you to keep the temperature at -75oC (add 15 minutes). After the first add adds extra chloroiodomethane (1.6 ml, of 0.022 mol), and then n-utility (23 ml, 0,037 mol), keeping the temperature -75oC. the Mixture is stirred for 15 minutes Each of the reagents, chloridometer (0,70 ml 0,010 mol) and n-utility (5 ml 0,008 mol) is added 4 more times over 45 min at -75oC. Then the cooling bath removed and the solution is heated to 22oC for 1.5 hours. The mixture is then poured into 300 ml of a saturated aqueous solution of ammonium chloride. Tertrahydrofuran ring layer is separated. The aqueous phase is extracted with ethyl acetate (1 x 300 ml). The combined organic layers washed with brine the form in the next stage without purification. The desired diastereoisomer can be purified by recrystallization at a later stage. Product usually also purify by chromatography.

Method 3:

A solution of S-[Bis(phenylmethyl)amino]benzoylpropionate (178,84 g, 0.54 mol) and bremgarten (46 ml, 0.71 mol) in tetrahydrofuran (1.8 l) is cooled to -30oC (-35oC) (lower temperature such as -70oC also acceptable, but higher temperatures easier achievable with operations in industrial scale) in the reactor of stainless steel in an atmosphere of nitrogen. A solution of n-utility in hexane (1.6 M, 340 ml, 0.54 mol) were then added, at a speed that allows you to maintain the temperature below -25oC. After the addition the mixture is stirred at a temperature of from -30 to -35oC for 10 minutes. Subsequent additions of the reagents carried out as follows: (1) Add a further quantity chloroiodomethane (14 ml), then n-utility (102 ml) at < -25oC. After the addition the mixture is stirred at a temperature of from -30 to -35oC for 10 minutes. The operation is repeated once. (2) Add an additional number chloroiodomethane (7 ml, 0.11 mol), then n-utility (51 ml, 0,082 mol) at < -25oC. After addition the mixture was stirred at temperaturemonitor (7 ml, 0.11 mol), then n-utility (51 ml, 0,082 mol) at < -25oC. After the addition the mixture is stirred at a temperature of from -30 to -35oC for 10 minutes. The operation is repeated once. Stop external cooling and the mixture is heated to ambient temperature for 4 to 16 hours, when the data TLC (TLC) (silica gel, 20% ethyl acetate/hexane) indicated that reaction was completed. The reaction mixture is cooled to 10oC and the reaction stopped by adding 1452 g of a 16% solution of ammonium chloride (obtained by dissolving 232 g of ammonium chloride in 1220 ml of water), keeping the temperature below 23oC. the Mixture is stirred for 10 minutes and the organic and aqueous layers separated. The aqueous phase is extracted with ethyl acetate (2 x 500 ml). An ethyl acetate layer combined with tetrahydrofuranyl layer. The combined solution is dried over magnesium sulfate (220 g), filtered and concentrated on a rotary evaporator at 65oC. the Brown oil residue is dried at 70oC in vacuum (0.8 x 105PA, 0.8 bar) for 1 hour, receiving 222,8 g of the crude substance.

Method 4:

Use the techniques described in Method 3 of this Example, except that the reaction temperature is -20oC. the Obtained N,N, S-Tr is the FDS 3.

Method 5:

Use the techniques described in Method 3 of this Example, except that the reaction temperature is from -70 to -78oC. the Obtained N,N, S-Tris(phenylmethyl)-2S-oxiranemethanol is diastereomers mix, which is directly used in the next stage without purification.

Method 6:

Use the techniques described in Method 3 of this Example, except that the continuous addition of bremgarten and n-utillity carried out at a temperature from -30 to -35oC. After the reaction and processing operations described in Method 3 of this Example, allocate N,N, S-Tris(phenylmethyl)-2S-oxiranemethanol with comparable yields and comparable purity.

Method 7:

Use the techniques described in Method 2 of this Example, except that instead of chloroiodomethane use dibromethane. After the reaction and processing operations described in Method 3 of this Example, receive N,S N-Tris(phenylmethyl)-2S-oxiranemethanol.

EXAMPLE 4

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Obtaining N-[3(S)-[N, N-bis(phenylmethyl)amino]-2(R)- hydroxy-4-phenylbutyl]-N-isobutylamine

To a solution of the crude N,N-dibenzyl-3(S)-amino-1,2(S)-epoxy-4-phenylbutane (388,5 g, 1.13 mol) in isopropanol (2.7 l) (or those who P>C. the Solution is heated to 82oC and stirred at this temperature for 1.5 hours. Warm the solution is concentrated under reduced pressure at 65oC. the remainder of the brown oil is transferred into a 3-liter flask and dried in vacuo (0.8 mm Hg) for 16 hours, getting 450 g of 3S-[N,N-bis(phenylmethyl)amino]-4-phenylbutane-2R-ol in the form of crude oil.

An analytical sample of the desired primary diastereomeric product is obtained by purification of a small sample of the crude product by chromatography on silica gel (40% ethyl acetate/hexane. TLC analysis: silica gel, 40% ethyl acetate/hexane; Rf=0.28 in; HPLC

(HPLC) analysis; column ultraspherical ODS, 25% dianilino-/phosphate buffer pH 3 - acetonitrile, flow rate 1 ml/min, UV detector, retention time 7,49 min; WCMC (HRMC) Expect. for C28H27N2O (M+1) 417,616 found 417,2887. An analytical sample diastereomeric product, 3S-[N, N-bis(phenylmethyl)amino] -1-(2-methylpropyl) amino-4-phenylbutane-2S-ol, also get cleaning small sample of the crude product by chromatography on silica gel (40% ethyl acetate/hexane).

EXAMPLE 5

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Getting salt of N-[3(S)-[N,N-bis(phenylmethyl)amino]-2(R)- hydroxy-4-phenylbutyl]-N-isobutylamine oxalic acid

To a solution of shch1-(2-methylpropyl)amino-4-phenylbutane-2(R)-ol (39,68 g), which contains about 25,44 g (61,06 mmol) of 3(S), 2(R) isomer and about of 4.49 g (10,78 mmol) of 3(S) 2(S) isomer, ethyl acetate (90 ml) for 15 minutes. The mixture is stirred at room temperature for about 2 hours. The solid is separated by filtration, washed with ethyl acetate (2 x 20 ml) and dried in vacuum for approximately 1 hour, receiving 21,86 g (allocation of 70.7% isomer) salt 97% diastereomeric purity (based on space HPLC peak). HPLC analysis: Vydec-peptide/protein C18 column, UV detector 254 nm, flow rate 2 ml/min, gradient {A=0,05% triperoxonane acid in water, B=0.05% of triperoxonane acid in acetonitrile, 0 min, 75% A/25% B, 30 min, 10% A/90% B, 35 min, 10% A/90% B, 37 min, 75% A/25%}; retention Time is 10.68 min (3(S), 2(R) isomer) and 9,73 min (3(S) 2(S) isomer). So pl. = 174,99oC; Elem. analysis: Expect. C 71,05%, H 7,50%, N Of 5.53%; Found: C 71,71%, H Of 7.75%, N 5,39%.

Alternatively, the dihydrate of oxalic acid (119 g of 0.94 mol) is placed in a 5000 ml round-bottom flask equipped with a mechanical stirrer and addition funnel. Add methanol (1000 ml) and the mixture is stirred until until dissolution is complete. A solution of crude 3(S)-[N,N-bis(phenyl-methyl)amino] -1-(-2-methylpropyl) amino-4-phenylbutane-2(R)-ol in ethyl acetate (1800 ml, 0,212 g isomers of amerosport/ml, 0,9160 malthusianism six portions at 400 rpm Each portion was washed with 125 ml of ethyl acetate. Then salt is harvested and dried over night at 1 Torr, getting 336,3 g of product (71%, based on the total amerosport). HPLC/MS (elektrorazpredelenie) correspond to the desired product (m/z 417 [M+H]+).

Alternatively, the crude 3(S)-[N, N-bis(phenylmethyl)amino] -1-(2-methylpropyl)amino-4-phenylbutane-2(R)-ol (5 g) is dissolved in methyl tert-butyl ether (MTBE) (10 ml) and added oxalic acid (1 g) in methanol (4 ml). The mixture is stirred for about 2 hours. The obtained solid is filtered off, washed with cold MTBE and dried, obtaining 2.1 g of a white solid substance that 98.9% diastereomeric purity (based on space HPLC peak).

EXAMPLE 6

Getting salt of N-[3(S)-[N, N-bis(phenylmethyl)amino]2(R)- hydroxy-4-phenylbutyl]-N-isobutylamine acetic acid

To a solution of crude 3(S)-[N,N-bis(phenylmethyl)amino]-1-(2 - methylpropyl)amino-4-phenylbutane-2(R)-ol in methyl tert-butyl ether (MTBE) (45 ml, 1.1 g of isomers amerosport/ml) is added dropwise acetic acid (6.9 ml). The mixture is stirred for about 1 hour at room temperature. The solvent is removed in vacuum, obtaining the product as a brown oil 85% diastereomeric purity (iastoricon when heated, obtaining a clear solution, the second solvent added to until the solution becomes turbid, the mixture is heated again to transparency, make the seed approximately 99% diastereomeric pure product, cooled to room temperature and then store in the refrigerator over night. The crystals are filtered, washed with a second solvent and dried. Diastereomer purity is calculated from the area of the HPLC peak. The results are presented in Table 1.

Alternatively, the crude 3(S)-[N,N-bis(phenylmethyl) amino]-1-(2-methylpropyl)amino-4-phenylbutane-2(R)-ol { 50.0 g, which contains about 30,06 g (76,95 mmol) of 3(S), 2(R) isomer and about to 5.66 g (of 13.58 mmol) of 3(S) 2(S) - isomer}, is dissolved in methyl tert-butyl ether (45,0 ml). To this solution was added acetic acid (6,90 ml, 120,6 mmol) for about 10 minutes, the Mixture is stirred at room temperature for about 1 hour and concentrated under reduced pressure. The oily residue is purified by recrystallization from methyl tert-butyl ether (32 ml) and heptane (320 ml). Solid allocate filtration, washed with cold heptane and dried in vacuum for approximately 1 hour, receiving 21,34 g (selection 58,2% isomer) 96% diastereomers 75,53%, H 8,39%, N By 5.87%; Found: C 75,05%, H 8,75%, N 5,71%.

EXAMPLE 7

Getting salt of N-[3(S)-[N,N-bis(phenylmethyl)amino]-2(R)- hydroxy-4-phenylbutyl]-N-isobutylamine L-tartaric acid

The crude 3(S)-[N,N-bis(phenylmethyl)amino]-1- (2-methylpropyl)amino-4-phenylbutane-2(R)-ol (10,48 g, which contains about 6,72 g (16,13 mmol) of 3(S), 2(R) isomer and about 1.19 g (2,85 mmol) of 3(S) 2(S) isomer) is dissolved in tetrahydrofuran (10.0 ml). To this solution was added L-tartaric acid (2.85 g, 19 mmol) in methanol (5.0 ml) for about 5 minutes the Mixture is stirred at room temperature for about 10 min and concentrated under reduced pressure. To the oily residue add methyl tert-butyl ether (20,0 ml) and the mixture is stirred at room temperature for about 1 hour. The solid is separated by filtration, receiving 7.50 g of the crude salt. The crude salt is purified by recrystallization from ethyl acetate and heptane at room temperature, receiving of 4.13 g (selection 45,2% isomer) 95% diastereomeric pure salt L-tartaric acid (based on space HPLC peak). Microanalysis: Expect To.: C 67,76%, H 7,41%, N 4,94%; Found: C 70,06%, H 7,47%, N 5,07%.

EXAMPLE 8

Getting salt of N-[3(S)-[N,N-bis(phenylmethyl)amino]-2 (R)-hydroxy-4-phenylbutyl]-N-isobutyl-4-phenylbutane-2(R)-ol (10.0 g, which contains about 6,41 g (15,39 mmol) of 3(S), 2(R) isomer and about 1.13 g (2,72 mmol) of 3(S) 2(S) isomer) is dissolved in tetrahydrofuran (20,0 ml). To this solution was added hydrochloric acid (20 ml of 6.0 N) for approximately 5 minutes, the Mixture is stirred at room temperature for about 1 hour and concentrated under reduced pressure. The residue is recrystallized from ethanol at 0oC, receiving 3,20 g (selection 42.7 percent isomer) 98% diastereomeric pure salt dichloroisoproterenol acid (based on space HPLC peak). Elem. analysis: Expect to.: C 68,64%, H 7,76%, N 5,72%; Found: C 68,79%, H 8,07%, N Of 5.55%.

EXAMPLE 9

Getting salt of N-[3(S)-[N,N-bis(phenylmethyl) amino]-2(R)-hydroxy-4-phenylbutyl]-N-isobutylamine toluenesulfonic acid

The crude 3(S)-[N, N-bis(phenylmethyl) amino]-1-(2-methyl-propyl)amino-4-phenylbutane-2(R)-ol (5.0 g, which contains about 3,18 g (7,63 mmol) of 3(S), 2(R) isomer and about 0.56 g (1.35 mmol) of 3(S) 2(S) isomer) is dissolved in methyl tert-butyl ether (10.0 ml). To this solution add a solution of toluenesulfonic acid (2.28 g, 12 mmol) in methyl tert-butyl ether (2.0 ml) and methanol (2.0 ml) for about 5 minutes the Mixture is stirred at room temperature for about 2 hours and concentrate when s is trout, washed with cold heptane and dried in vacuum, obtaining 1.85 g (allocation of 40% isomer) 97% diastereomeric pure salt of montrealcanada (based on space HPLC peak).

EXAMPLE 10

Getting salt of N-[3(S)-[N,N - bis(phenylmethyl)Anino]-2(R)-hydroxy-4-phenylbutyl]-N-isobutylamine methansulfonate

The crude 3(S)-[N, N-bis(phenylmethyl)amino]-1-(2-methyl-propyl)amino-4 - phenylbutane-2(R)-ol (1.68 g, which contains approximately 6.85 g (16/44 mmol) of 3(S), 2(R) isomer and about to 1.21 g (2,90 mmol) of 3(S) 2(S) isomer) is dissolved in tetrahydrofuran (10.0 ml). To this solution add methansulfonate acid (1.25 ml, (Jn 19: 26 mmol). The mixture is stirred at room temperature for about 2 hours and concentrated under reduced pressure. The oily residue is recrystallized from methanol and water at 0oC, filtered, washed with cold mixture of methanol/water (1:4) and dried in vacuum, obtaining of 2.40 g (selection 28.5% isomer) 98% diastereomeric pure salt monoethanolamines acid (based on space HPLC peak).

EXAMPLE 11

Obtain N-benzyl-L-phenylalaninol

Method 1:

L-Phenylalaninol (89,51 g, 0,592 mol) is dissolved in 375 ml of methanol in an atmosphere of inert gas, add 35,52 g (0,592 mol) glacial acetic sour is the super 15oC and add a solution 134,6 g (2.14 mol) of lamborginid sodium in 700 ml of methanol for about 40 minutes, maintaining the temperature between 15oC to 25oC. the Mixture is stirred at room temperature for 18 hours. The mixture is concentrated under reduced pressure and partitioned between 1 l of 2 M ammonium hydroxide solution and 2 l of ether. The ether layer is washed with 1 l of 1 M ammonium hydroxide solution, twice with 500 ml water, 500 ml of brine and dried over magnesium sulfate for 1 hour. The ether layer was filtered, concentrated under reduced pressure and the crude solid product is recrystallized from 110 ml of ethyl acetate and 1.3 l of hexane, getting 115 g (81% yield) of N-benzyl-L-phenylalaninol in the form of a white solid.

Method 2:

L-Phenylalaninol (5 g, 33 mmol) and 3,59 g (33,83 mmol) of benzaldehyde are dissolved in 55 ml of 3A ethanol in an inert atmosphere in a Parr apparatus for shaking, and the mixture is heated to 60oC for 2.7 hours. The mixture is cooled to approximately 25oC and add 0,99 g of 5% platinum on coal and the mixture hydronaut when the hydrogen pressure 4,219 kg/cm2(60 psi) and 40oC for 10 hours. The catalyst is filtered off, the reaction mixture was concentrated under reduced pressure and the product - neocidin the form of a white solid.

EXAMPLE 12

Obtain N-(t-Butoxycarbonyl)N-benzyl-L - phenylalaninol

N-benzyl-L-phenylalaninol (2.9 g, 12 mmol) dissolved in 3 ml of triethylamine and 27 ml of methanol and add a 5.25 g (24,1 mmol) di-tert-butyl dicarbonate. The mixture is heated to 60oC for 35 minutes and concentrated under reduced pressure. The residue is dissolved in 150 ml ethyl acetate and washed with twice 10 ml of cold (0-5oC), dilute hydrochloric acid (pH of 2.5-3), 15 ml of water, 10 ml of brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product in the form of oil purified by chromatography on silica gel (ethyl acetate:hexane, 12:3 as eluting solvent) to give 3.98 g (97% yield) of colorless oil.

EXAMPLE 13

Obtain N-(t-Butoxycarbonyl)-N-benzyl-L-phenylalaninol

Method 1:

To a solution of 0.32 g (0,94 mmol) of N-(t-butoxycarbonyl)- N-benzyl-L-phenylalaninol 2.8 ml of toluene added 2.4 mg (0.015 mmol) of 2,2,6,6-tetramethyl-1 - piperidinyloxy in the form of a free radical (TEMPO), 0.1 g (0.97 mmol) of sodium bromide, and 2.8 ml of ethyl acetate and 0.34 ml of water. The mixture is cooled to 0oC and added slowly an aqueous solution of 4.2 ml of 5% bleach for household use containing 0,23 g (3.0 ml, 2,738 mmol) bicarbonate lime added, followed by stirring for 10 minutes after each addition, to spend all the original substance. Two-phase mixture is allowed the opportunity to split. The aqueous layer was extracted twice 8 ml of toluene. The combined organic layer was washed with 1.25 ml of a solution containing 0.075 g of potassium iodide, sodium bisulfate (0.125 g) and water (1.1 ml), 1.25 ml of 10% aqueous sodium thiosulfate solution, 1.25 ml of phosphate buffer with pH 7 and 1.5 ml of brine. The organic solution is dried over magnesium sulfate, filtered and concentrated under reduced pressure, getting 0.32 g (100% yield) of N-(t-Butoxycarbonyl)-N-benzyl-L-phenylalaninol.

Method 2:

To a solution of 2.38 g (6,98 mmol) of N-(t-butoxycarbonyl)-N-benzyl-L-phenylalaninol 3.8 ml (to 27.2 mmol) of triethylamine in 10oC add solution to 4.33 g (to 27.2 mmol) of a complex of sulfur trioxide-pyridine in 17 ml of dimethylsulfoxide. The mixture is heated to room temperature and stirred for one hour. Add water (16 ml) and the mixture is extracted with 20 ml ethyl acetate. The organic layer is washed with 20 ml of 5% citric acid, 20 ml water, 20 ml of brine, dried over magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure, getting 2.37 g (100% yield) of N-(t-butoxycarbonyl)-N-benzyl-L-phenylalaninol.

EXAMPLE 14

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Getting 3(S)-[N-(t-butoxycarbonyl)-N-Ben is nylalanine and 0.72 ml chloroiodomethane in 35 ml of THF is cooled to -78oC. with 4.64 ml n-utility (1.6 M in hexane, 7,42 mmol) is added slowly, keeping the temperature below -70oC. the Mixture is stirred for 10 minutes at a temperature of from -70 to -75oC. Two additional portions to 0.22 ml chloroiodomethane and 1.4 ml of n-utility added successively and the mixture is stirred for 10 minutes while maintaining the temperature from -70 to -75oC after each addition. Four additional portions of 0.11 ml chloroiodomethane and 0.7 ml of n-utility added successively and the mixture is stirred for 10 minutes while maintaining the temperature from -70 to -75oC after each addition. The mixture is heated to room temperature for 3.5 hours. The reaction is stopped when the temperature is below 5oWith the addition of 24 ml of ice water. Two-phase layers are separated and the aqueous layer was extracted twice with 30 ml of ethyl acetate. The combined organic layers are washed with three times 10 ml of water, then 10 ml of brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure, obtaining 2.8 g of a yellow crude oil. Crude oil (> 100% yield) is a mixture of diastereomeric epoxides N, S-bis(phenylmethyl)-N-(t - butoxycarbonyl)-2S-oxiranemethanol and N, S-bis(Fe the stage without purification.

Method 2:

To a suspension of 2.92 g (13,28 mmol) trimethylsulfoxonium iodide in 45 ml of acetonitrile add 1,49 g (13,28 mmol) t-butoxide potassium. Add a solution of 3.0 g (cent to 8.85 mmol) of N-(t-butoxycarbonyl)-N-benzyl-L-phenylalaninol in 18 ml of acetonitrile and the mixture is stirred at room temperature for one hour. The mixture is diluted with 150 ml of water and extracted with twice 200 ml of ethyl acetate. The organic layers are combined and washed with 100 ml of water, 50 ml brine, dried over sodium sulfate, filtered and concentrated under reduced pressure, obtaining 3.0 g crude yellow oil. The crude product is purified by chromatography on silica gel (ethyl acetate/hexane: 1:8 as the eluting solvent), receiving of 1.02 g (32,7% yield) of a mixture of two diastereomers N, S-bis(phenylmethyl)-N-(t-butoxycarbonyl)-2S - oxiranemethanol and N, S-bis(phenylmethyl)-N-(t-butoxycarbonyl) -2R-oxiranemethanol.

Method 3:

To a suspension of 0.90 g (4,42 mmol) trimethylsulfonium iodide in 18 ml of acetonitrile add 0,495 g (4,42 mmol) t-butoxide potassium. Add a solution of 1.0 g (2,95 mmol) of N-(t-butoxycarbonyl)-N-benzyl-L-phenylalaninol in 7 ml of acetonitrile and the mixture is stirred at room temperature for one hour. The mixture is diluted with 80 ml of water and extragonadal sodium, filter and concentrate under reduced pressure, obtaining 1.04 g of a yellow crude oil. The crude product is a mixture of two diastereomers N, S-bis (phenylmethyl)-N-(t-butoxycarbonyl)-2S-oxiranemethanol and N, S-bis(phenylmethyl)-N-(t-butoxycarbonyl)-2R-oxiranemethanol

EXAMPLE 15

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Getting 3(S)-[N-(t-Butoxycarbonyl)-N-(phenylmethyl) amino] -1-(2-methylpropyl)amino-4-phenylbutane-2R-ol

To a solution of 500 mg (of 1.42 mmol) of the crude epoxide (mixture of two stereomono N, S-bis(phenylmethyl)-N-(t-butoxycarbonyl) -2S-oxiranemethanol and N, S-bis(phenylmethyl)-N-(t-butoxycarbonyl)-2R-oxiranemethanol) in 98 ml of isopropanol added to 0.71 ml (7,14 mmol) isobutylamine. The mixture is heated under reflux at 85-90oC for 1.5 hours. The mixture is concentrated under reduced pressure and the product in the form of oil purified by chromatography on silica gel (chloroform: methanol, 100:6 as eluting solvents) to give 330 mg of 3S-[N-t-butoxycarbonyl)-N-(phenylmethyl)amino]-1-(2 - methylpropyl)amino-4-phenylbutane-2R-ol as a colourless oil (54,5% yield). Just allocate 3S-[N-t-butoxycarbonyl)-N- (phenylmethyl)amino] -1-(2-methylpropyl)amino-4-phenylbutane-2S-ol. When the initial substance use purified N, the propyl) amino-4-phenylbutane-2R-ol emit after purification by chromatography with 86% yield.

EXAMPLE 16

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Receipt of 3S-(N-t-Butoxycarbonyl)amino-4-phenylbutane-1,2 R-diol

To a solution of 1 g (3,39 mmol) of 2S-(N-t-butoxycarbonylamino - 1S-hydroxy-3-phenylbutanoate acid (commercially available from Nippon Kayaku, Japan) in 50 ml THF at 0oC add 50 ml of the complex of borane-THF (liquid, 1.0 M in THF), keeping the temperature below 5oC. the Reaction mixture is heated to room temperature and stirred for 16 hours. The mixture is cooled to 0oC and slowly add 20 ml of water to destroy the excess BH3and to stop the reaction, maintaining the temperature below 12oC. the Reaction mixture is stirred for 20 minutes and concentrated under reduced pressure. The product mixture is extracted three times with 60 ml of ethyl acetate. The organic layers are combined and washed with 20 ml of water, 25 ml of a saturated aqueous solution of sodium chloride and concentrated under reduced pressure, obtaining 1.1 g of crude oil. The crude product is purified by chromatography on silica gel (chloroform/methanol, 10: 6 as eluting solvents) to give 900 mg (94,4% yield) of 3S-(N-t - butoxycarbonyl)amino-4-phenylbutane-1,2 R-diol as a white solid.

EXAMPLE 17

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Receipt of 3S-(N-t-butoxycarbonyl)amino-2R-1,2 R-diol in 13 ml of pyridine at 0oC add 914 mg toluensulfonyl chloride in one portion. The mixture was stirred at 0oC-5oC for 5 hours. A mixture of 6.5 ml of ethyl acetate and 15 ml of 5% aqueous sodium bicarbonate solution is added to the reaction mixture and stirred for 5 minutes. The resulting mixture is extracted with three times 50 ml of ethyl acetate. The organic layers are combined and washed with 15 ml of water, 10 ml of a saturated solution of sodium chloride and concentrated under reduced pressure to yield about 1.1 g of a yellow solid substance in the form of lumps. The crude product is purified by chromatography on silica gel (ethyl acetate/hexane 1: 3 as eluting solvents) to give 850 mg (74% yield) of 3S-(N-t-butoxycarbonyl)amino-2R - hydroxy-4-phenylbut-1-yl of toluensulfonate in the form of a white solid.

EXAMPLE 18

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Receipt of 3S-[N-(t-butoxycarbonyl)amino] -1-(2 - methylpropyl)amino-4-phenylbutane-2R-ol

To a solution of 90 mg (0,207 mmol) of 3S-(N-t-butoxycarbonyl)amino-2R-hydroxy-4-phenylbut-1-yl of toluensulfonate in 0,143 ml of isopropanol and 0.5 ml of toluene added 0,103 ml (to 1.034 mmol) isobutylamine. The mixture is heated to 80-85oC and stirred for 1.5 hours. The product mixture was concentrated under reduced pressure at 40-50oC and purifying chromatography oxycarbonyl)amino]-1-(2-methylpropyl)amino-4-phenylbutane-2R - diol as a white solid.

EXAMPLE 19

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Obtaining N-[3(S)-benzyloxycarbonylamino-2(R)-hydroxy - 4-phenylbutyl] -N-isobutylamine

Part a:

To a solution of 75.0 g (0,226 mol) N-benzyloxycarbonyl-L-phenylalanine chloromethyl ketone in a mixture of 807 ml of methanol and 807 ml of tetrahydrofuran at -2oC add 13,17 g (0,348 mol, 1.54 equiv.) solid sodium borohydride over a period of 100 minutes. The solvents are removed under reduced pressure at 40oC and the residue is dissolved in ethyl acetate (approx. 1 l). The solution is washed successively 1 M solution of acid potassium sulfate, saturated sodium bicarbonate solution and then a saturated solution of sodium chloride. After drying over anhydrous magnesium sulfate and filtering, the solvent is removed under reduced pressure. To the resulting oil is added hexane (approx. 1 l) and the mixture heated to 60oC with vortex mixing. After cooling to room temperature, the solid collected and washed with 2 l of hexane. The obtained solid is recrystallized from hot ethyl acetate and hexane, obtaining and 32.3 g (43% yield) of N-benzyloxycarbonyl-3(S)-amino-1 - chloro-4-phenyl-2(S)-butanol, T. pl. 150-151oC and M+Li+= 340.

Part:

To a solution of 6.52 g (0,116 mol, 1.2 EQ.) potassium hydroxide in 968 ml assle stirring for fifteen minutes the solvent is removed under reduced pressure and the solids dissolved in methylene chloride. After washing with water, drying over magnesium sulfate, filtration and evaporation, receive 27.9 g of a white solid. Recrystallization from hot ethyl acetate and hexane gives 22,3 g (77% yield) of N-benzyloxycarbonyl-3(S)-amino-1,2(S)-epoxy-4-phenylbutane, so pl. 102-103oC and MN+298.

Part C:

A solution of N-benzyloxycarbonyl-3(S)-amino-1,2(S)-epoxy-4-phenylbutane (1,00 g, to 3.36 mmol) and isobutylamine (4,90 g,67,2 mmol, 20 EQ.) in 10 ml of isopropyl alcohol is heated to the boiling temperature under reflux for 1.5 hours. The solution is cooled to room temperature, concentrated in vacuo and then poured into 100 ml of stirred hexane, whereupon the product crystallizes from the solution. The product is separated by filtration and dried in the air, getting 1.18 g, 95% N-[[3(S)-formethylcarbamoyl) amino-2(R)-hydroxy-4-phenylbutyl] N- [(2-methylpropyl)] amine, C23H30N2O3so pl. 108,0-109,5oC, MH+m/z = 371.

EXAMPLE 20

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Getting phenylmethyl[2R-hydroxy-3-[(3-methylbutyl) (phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]carbamate

By the reaction of N[3(S)-benzyloxycarbonylamino-2(R)-hydroxy-4 - phenylbutyl] N-isoamylamine (1.47 g, 3.8 mmol), triethylamine (528 μl, 3.8 mmol) and benzosulphochloride. Column chromatography on silica gel, with elution with chloroform containing 1% of ethanol gives the pure product. Elem. anal, Expect. for C29H36N2O5S: C, 66,39; H, 6,92; N, 5,34. Found: C, 66,37; H, 6,93; N, 5,26.

EXAMPLE 21

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Getting 2R-hydroxy-3-[[(4-AMINOPHENYL)sulfonyl] (2-methylpropyl)amino] -1S-(phenylmethyl)Propylamine

Part a: Getting phenylmethylene ether 2R-hydroxy-3- [[(4-nitrophenyl)sulfonyl] (2-methylpropyl)amino] -1S-(phenylmethyl) propellerbuying acid.

To a solution of 4.0 tonnes (up 10.8 mmol) of N-[3S - benzyloxycarbonylamino-2R-hydroxy-4-phenyl] -N-isobutylamine in 50 ml of anhydrous methylene chloride added to 4.5 ml (3,27 g, 32,4 mmol) of triethylamine. The solution is cooled to 0oC and add 2,63 g (11.9 mmol) of 4-nitrobenzene of sulphonylchloride, stirred for 30 minutes at 0oC, then for 1 hour at room temperature. Add ethyl acetate, washed with 5% citric acid, saturated sodium bicarbonate, brine, dried and concentrated, gaining 5.9 g of the crude substance. It is recrystallized from a mixture of ethyl acetate/hexane, receiving of 4.7 g of pure phenylmethylene ether 2R-hydroxy-3-[[(4-nitrophenyl)sulfonyl] (2-methylpropyl)amino] - 1S-(phenylmethyl)propellerbuying Kisler)Propylamine

A solution of 3.0 g (5.4 mmol) phenylmethanol ether 2R-hydroxy-3-[[(4-nitrophenyl)sulfonyl](2-methylpropyl)amino]-1S- (phenylmethyl)propellerbuying acid in 20 ml of ethyl acetate hydronaut 1.5 g of 10% palladium-on-coal catalyst at a pressure of hydrogen 2,461 kg/cm2(35 psig) for 3.5 hours. The catalyst was removed by filtration and the solution is concentrated and receiving of 2.05 g of the desired 2R-hydroxy-3-[[(4-AMINOPHENYL)sulfonyl] (2-methylpropyl)amino] -1S- (phenylmethyl)Propylamine, m/e = 392 (M+H).

EXAMPLE 22

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Getting 2R-hydroxy-3[[(3-AMINOPHENYL) sulfonyl](2-methylpropyl) amino-1S-(phenylmethyl)Propylamine

Part 1: Getting phenylmethylene ether [2R-hydroxy-3-[(3-nitrophenyloctyl)(2 - methylpropyl)amino]-1S-(phenylmethyl)propellerbuying acid

To a solution of 1.1 g (3.0 mmol) of N-[3S-benzyloxycarbonylamino - 2R-hydroxy-4-phenyl] -N-isobutylamine in 15 ml of anhydrous methylene chloride add 1.3 ml of 0.94 g, 9.3 mmol) of triethylamine. The solution is cooled to 0oC and add to 0.67 g (3.0 mmol) of 3-nitrobenzene of sulphonylchloride, stirred for 30 minutes at 0oC, then for 1 hour at room temperature. Add ethyl acetate, washed with 5% citric acid, saturated sodium bicarbonate, brine, dried and the tea 1.40 g of pure phenylmethylene ether [2R-hydroxy-3-[(3-nitrophenyloctyl)(2-methylpropyl)amino] - 1S-(phenylmethyl)propyl-carbamino acid, m/e = 562 (M+Li).

Part B: Getting [2R-hydroxy-3-[[(3-AMINOPHENYL)sulfonyl] (2-methylpropyl)amino]-1S-(phenylmethyl)Propylamine

A solution of 1.33 g (2.5 mmol) phenylmethanol ether [2R-hydroxy-3- [(3-nitrophenyloctyl)(2-methylpropyl)amino] -1S-(phenylmethyl) propellerbuying acid in 40 ml 1:1 methanol/tetrahydrofuran hydronaut in the presence 0,70 g of 10% palladium-on-coal at a gauge pressure of hydrogen 2,812 kg/cm2(40 psig) for 1.5 hours. The catalyst was removed by filtration and the solution concentrated, receiving 0.87 g of the desired [2R-hydroxy-3- [[(3-AMINOPHENYL)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)Propylamine.

EXAMPLE 23

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Getting 2R-hydroxy-3[[(2,3-dihydrobenzofuran-5-yl)sulfonyl] (2-methylpropyl)amino]-1S-(phenylmethyl)Propylamine

Part a: Obtain 5-(2,3-dihydrobenzofuranyl)sulfonyl chloride

To the solution at 3.35 g of anhydrous N,N-dimethylformamide at 0oC in nitrogen atmosphere add 6,18 g Sulfuryl chloride, after which a solid substance. After stirring for 15 minutes, add 4,69 g of 2,3-dihydrobenzofuran and the mixture is heated at 100oC for 2 hours. The reaction mixture is cooled, poured into ice water, extra is crystallizability of ethyl acetate, receiving of 2.45 g of 5-(2,3-dihydrobenzofuranyl)sulfonyl chloride.

Part B: Getting phenylmethylene ether 2R-hydroxy-3-[[(2, 3-dihydrobenzofuran-5-yl)sulfonyl](2-methylpropyl)amino]- 1S-(phenylmethyl)propellerbuying acid.

To a solution of 1.11 g (3.0 mmol)of N-[3S-benzyloxycarbonylamino-2R - hydroxy-4-phenyl] -N-isobutylamine in 20 ml of anhydrous methylene chloride add 1.3 ml of 0.94 g, 9.3 mmol) of triethylamine. The solution is cooled to 0oC and added 0.66 g of 5-(2,3-dihydrobenzofuranyl)sulfonyl chloride, stirred for 15 minutes at 0oC, then for 2 hours at room temperature. Add ethyl acetate, washed with 5% citric acid, saturated sodium bicarbonate, brine, dried and concentrated, obtaining of 1.62 g of the crude substance. It is recrystallized from diethyl ether, receiving 1,17 g of pure phenylmethylene ether [2R-hydroxy-3-[[(2,3-dihydrobenzofuran-5-yl)sulfonyl] (2-methylpropyl) amino]-1S-(phenylmethyl)propellerbuying acid.

Part C: Getting [2R-hydroxy-3-[[(2,3-dihydrobenzofuran-5-yl) sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)Propylamine

A solution of 2.86 g of phenylmethanol ether [2R-hydroxy-3- [[(2,3-dihydrobenzofuran-5-yl)sulfonyl] (2-methylpropyl)amino] -1S-(penile batocina hydrogen pressure 3,515 kg/cm2(50 psig) for 16 hours. The catalyst was removed by filtration and the filtrate is concentrated and receiving of 1.99 g of the desired [2R-hydroxy-3-[[(2,3 - dihydrobenzofuran-5-yl)sulfonyl](2-methylpropyl)amino]-1S- (phenylmethyl)Propylamine.

EXAMPLE 24

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Obtaining N-[(1,1-dimethylethyl)carbonyl] -N-[2 - methylpropyl] -3S-(N1(phenylmethanesulfonyl)amino] -2R-hydroxy-4-phenylbutyramide

To a solution of 7.51 g (20.3 mmol) of N-[3S-[(phenylmethanesulfonyl)amino]-2R-hydroxy-4-phenylbutyl] -2 - methylpropylamine in 67 ml of anhydrous tetrahydrofuran added 2.25 g (of 22.3 mmol) of triethylamine. After cooling to 0oC add 4.4 g (20.3 mmol) of di-tert-BUTYLCARBAMATE and stirring is continued at room temperature for 21 hours. Volatiles are removed in vacuo, add ethyl acetate, then washed with 5% citric acid, saturated sodium bicarbonate, brine, dried over magnesium sulfate, filtered and concentrated, gaining 9.6 g of the crude product. Chromatography on silica gel using a mixture of 30% ethyl acetate/hexane yields of 8.2 g of pure N-[[3S-(formethylcarbamoyl)amino] -2R-hydroxy-4 - phenyl] -1-[(2-methylpropyl)amino-2-(1,1-dimethylethyl)carbonyl] butane, mass spectrum m/e = 477 (M+Li).

EXAMPLE 25

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Obtaining N is methylbutylamine

Part a:

To a solution of N-CBZ-L-tert-leucine (450 mg, 1.7 mmol) and N-hydroxybenzotriazole (260 mg, 1.7 mmol) in DMF (10 ml) is added EDC (307 mg, 1.6 mmol). The solution is stirred for 60 minutes at room temperature and then add 2R-hydroxy-3-[N-(3-methylbutyl)-N-(phenylsulfonyl)amino] -1S-(phenylmethyl) Propylamine (585 mg, 1.5 mmol) in DMF (2 ml). The reaction mixture is stirred for 16 hours at room temperature, then poured into 50% saturated sodium bicarbonate solution (200 ml). The aqueous mixture is extracted three times with ethyl acetate (50 ml). United an ethyl acetate layers washed with water (50 ml) and saturated NaCl solution (50 ml), then dried over magnesium sulfate. Filtration and concentration gives an oil, which chromatographic on silica gel (50 GM), elwira 20% ethyl acetate in hexane. Get phenylmethyl [1S-[[[2R - hydroxy-3-[(3-methylbutyl)phenylsulfonyl)amino]-1S-(phenylmethyl)propyl] amino] carbonyl] -2,2-dimethylpropyl]carbamate in the form of solids. Elem. anal. The expect. for C35H47N3O6S: C, 65,91; H, THE 7.43; N, 6,59. Found: C, 65.42 Per; H, 7,24; N, 6,55.

Part B:

The solution phenylmethyl [1S-[[[2R-hydroxy-3-[(3-methylbutyl) (phenylsulfonyl)amino] -1S-(phenylmethyl)propyl] amino] carbonyl] -2,2 - dimethylpropyl] carbamate (200 is altroot through diatomaceous earth and concentrated to oil.

EXAMPLE 26

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Obtaining cleaners containing hydrochloride salt of N1-[2R-hydroxy-3-[N2-(2-methylbutyl)-N2- (phenylsulfonyl)amino]-1S-(phenylmethyl) propyl]-2S-amino-3S-methylpentadiene

Part a:

To a solution of 2R-hydroxy-3-[N-(3-methylbutyl)-N- (phenylsulfonyl)amino]-1S-(phenylmethyl)Propylamine (2,79 g, 7.1 mmol) in 27 ml of dioxane add (2.3 g, 7.1 mmol) of the ester of N-tert-butylcarbamoyl-L-isoleucine-N-hydroxysuccinimide and the reaction mixture was stirred in nitrogen atmosphere for 16 hours. The reaction mixture was concentrated in vacuo and the residue is dissolved in ethyl acetate, washed with acidic potassium sulfate (5% water), saturated sodium bicarbonate and saturated sodium chloride. The organic layer is dried over magnesium sulfate, filtered and concentrated, obtaining 4.3 g of the crude substance, which chromatographic using a 3:1 mixture of ethyl acetate:hexane, getting 3,05 g, 72% yield 2S-[[(1,1-dimethylmethoxy)carbonyl]amino]-N- [2R-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)amino] -1S- (phenylmethyl)propyl] -3-methylpentanoic.

Part B:

(3,05 g, 5.0 mmol) of product from Part A was dissolved in 20 ml of 4N HCl in dioxane and stirred under nitrogen atmosphere for 1.5 hours. The content was concentrated in vacuo and washed with diethyl ether. Naoci salt.

EXAMPLE 27

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Obtaining N1-[2R-hydroxy-3-[N2-(2-methylpropyl)-N2- (4-methoxybenzenesulfonyl)amino]-1S-(phenylmethyl)propyl]-2S - amino-3S-methylpentanoic

Part a:

To a solution of 2R-hydroxy-3-[(2-methylpropyl)(4-methoxybenzenesulfonyl) amino] -1S-(phenylmethyl)Propylamine (1.70 g, 4,18 mmol) in 40 ml dichloromethane added ester N-carbobenzoxy-N-isoleucine-N - hydroxysuccinimide (1.51 g, 4,18 mmol) and the solution stirred under nitrogen atmosphere for 16 hours. The content was concentrated in vacuo and the residue re-dissolved in ethyl acetate. An ethyl acetate solution is washed with aqueous solution of 5% KHSO4, saturated sodium bicarbonate, saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated, obtaining 2,47 g of the crude product. The product was then purified by chromatography on silica gel using as eluent a mixture of 2:1 hexane:ethyl acetate, obtaining 2.3 g (84% yield) of 2S-[(carbobenzoxy)amino] -N-[2R - hydroxy-3-[(3-methylpropyl)(4-methoxybenzenesulfonyl)amino]-1S- (phenylmethyl)propyl]-3S-methylmethanamine.

Part B:

(1.18 g, 1.8 mmol) of the product of Part A is dissolved in 50 ml of methanol and to it add 250 mg of 10% palladium on coal in a stream of nitrogen. Suspension hydronaut using izbytochnoi and concentrated in vacuo, getting 935 mg of 2S-(amino)-N-[2R-hydroxy-3-[(3 - methylpropyl)(4-methoxybenzenesulfonyl)amino]- 1S-(phenylmethyl)propyl]-3S-methylpentylamino, which is used without further purification.

EXAMPLE 28

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Getting phenylmethylene ether 2R-hydroxy-3-[[(2-amino - benzothiazol-6-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl) propellerbuying acid.

Fenilmetilovy ether 2R-hydroxy-3-[[(4-AMINOPHENYL)sulfonyl] (2-methylpropyl)amino] -1S-(phenylmethyl)propellerbuying acid of 0.30 g (0,571 mmol) are added to a well mixed powder of anhydrous copper sulfate (1.20 g) and potassium thiocyanate (1.50 g), and then add dry methanol (6 ml) and the resulting black-brown suspension is heated under reflux for 2 hours. The reaction mixture is filtered and the filtrate is diluted with water (5 ml) and heated under reflux. To the reaction mixture ethanol, cooled and filtered. After concentration of the filtrate get the remainder, which chromatographic (ethyl acetate:hexane 80:20),

getting 0.26 g (78%) of target compound in the form of a solid substance.

EXAMPLE 29

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Getting phenylmethylene ether 2R-hydroxy-3- [[(benzothiazol-6-yl)sulfonyl] (2-methylpropyl)amino] -1S- (fenil the l) sulfonyl] (2-methylpropyl)amino] -1S-(phenylmethyl) propellerbuying acid (0.25 g, 0,429 mmol) are added to a solution of isoamylamine (0,116 ml, 0,858 mmol) in dioxane (5 ml) and the mixture is heated at 85oC. After termination of nitrogen, the reaction mixture was concentrated and the residue purified by chromatography (hexane: ethyl acetate 5: 3), receiving 0,130 g (53%) of the desired product as a solid substance.

Method 2:

The crude benzothiazole-6-sulfonyl chloride in ethyl acetate (100 ml) are added to N-[3S-benzyloxycarbonylamino-2R - hydroxy-4-phenyl]-N-isobutylamine (1,03 g, 2,78 mmol) and then N-methylmorpholine (4 ml). After stirring at room temperature for 18 hours, the reaction mixture was diluted with ethyl acetate (100 ml), washed with citric acid (5%, 100 ml), sodium bicarbonate (saturated, 100 ml) and brine (100 ml), dried (MgSO4) and concentrated in vacuo. The remainder chromatographic (silica gel, ethyl acetate:hexane 1:1), receiving 0,340 g (23%) of the target product.

EXAMPLE 30

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and

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Getting phenylmethylene ether 2R-hydroxy-3-[[(2 - aminobenzothiazole-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl) propellerbuying acid and phenylmethanol ether 2R-hydroxy-3-[[(2-aminobenzothiazole-7-yl)sulfonyl](2-methylpropyl)amino]- 1S-(phenylmethyl)propellerbuying koloti

Phenylmethyl is 36 g (0,685 mmol) are added to a well mixed powder of anhydrous copper sulfate (1.44 g) and potassium thiocyanate (1,80 g) followed by addition of dry methanol (10 ml) and the resulting black-brown suspension is heated under reflux for 2 hours. The reaction mixture is filtered and the filtrate is diluted with water (5 ml) and heated under reflux. To the reaction mixture ethanol, cooled and filtered. After concentration of the filtrate get the remainder, which chromatographic (ethyl acetate: hexane 1:1) to give 0.18 g (45%) 7-isomer in the form of solids. Further elution of the column with a mixture (ethyl acetate: hexane 3: 2) gives 0,80 g (20%) received 5-isomer in the form of a solid substance.

EXAMPLE 31

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Getting 3S-amino-1-[N-(2-methylpropyl)-N-(4-methoxyphenyl - sulfonyl] amino]-4-phenyl-2R-butanol

Part a: N-benzyloxycarbonyl-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol

To a solution of N-benzyloxycarbonyl-L-phenylalanine chloromethyl ketone (75 g 0.2 mol) in a mixture of 800 ml of methanol and 800 ml of tetrahydrofuran, add borohydride sodium (13,17 g, 0,348 mol, 1.54 equiv.) for 100 minutes, the Solution was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue is dissolved in 1000 ml of ethyl acetate and float 1N KHSO4saturated aqueous NaHCO3, saturated aqueous NaCl, dried over anhydrous MgSO4, filtered and concentrated in vacuo, obtaining oil. The crude product is dissolved in 1000 ml of hexane at 60oC and give opportunities which provide abundant quantities of hexanol. Then, the resulting solid is recrystallized from hot ethyl acetate and hexanol getting 32,3 g 43% N-benzyloxycarbonyl-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol, T. pl. 150-151oC, the Belarusian library Association (FAB) MC:MLi+= 340.

Part B: 3(S)-[N-(benzyloxycarbonyl)amino]-1,2(S)- epoxy-4-phenylbutane

A solution of potassium hydroxide (6,52 g, 0,116 mol, 1.2 EQ.) in 970 ml of absolute ethanol is treated with N-benzyloxycarbonyl-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol (32,3 g, 0,097 mol). The solution was stirred at room temperature for 15 minutes and then concentrated in vacuo, getting a white solid. The solid is dissolved in dichloromethane and washed with water, dried over anhydrous MgSO4filtered and concentrated in vacuo, getting a white solid. The solid is crystallized from hexanol and ethyl acetate, getting 22,3 g 77% 3(S)-[N-(benzyloxycarbonyl)amino]-1,2(S)-epoxy-4 - phenylbutane, so pl. 102-103oC, THE BELARUSIAN LIBRARY ASSOCIATION (FAB) MC:MN+= 298.

Part C: N-[3(S)-benzyloxycarbonylamino-2(R)-hydroxy - 4-phenyl]N-isobutylamine

A solution of N-benzyloxycarbonyl-3(S)-amino-1,2-(S) -epoxy-4-phenylbutane (50.0 g, has 0.168 mol) and isobutylamine (246 g, 3,24 mol, 20 equivalents) in 650 ml of isopropyl alcohol is heated under reflux in teeniesfemale hexane, whereupon the product crystallizes from the solution. The product is separated by filtration and dried in the air, getting 57,56 g, 92% N[(S)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenyl] -N-isobutylamine, so pl. 108,0-109,5oC, MN+m/z = 371.

Part D: Phenylmethyl [2(R)-hydroxy-3-[N-(2-methylpropyl)- N-(4-methoxybenzenesulfonyl)amino]-1S-(phenylmethyl)propyl]carbamate

Amin Part C (936,5 mg, 2,43 mmol) and triethylamine (288,5 mg, 2,85 mmol) was dissolved in 20 ml dichloromethane and treated with 4-methoxybenzenesulfonyl chloride (461 mg, 2,61 mmol). The solution was stirred at room temperature for 16 hours and then concentrated in vacuo. The residue is dissolved in ethyl acetate and the solution washed with 1N KHSO4saturated aqueous NaHCO3brine, dried over anhydrous MgSO4, filtered and concentrated, obtaining a clear oil 1,234, the Oil is crystallized from a mixture of ether and hexanol, 729,3 mg, 56.5% of so pl. 95-99oC, THE BELARUSIAN LIBRARY ASSOCIATION (FAB) MS:MN+= 511.

Part E: 3(S)-amino-1-[N-(2-methylpropyl)-N-(4 - methoxybenzenesulfonyl)amino]-4-phenyl-2R-butanol

The solution phenylmethyl [2(R)-hydroxy-3-[N-(2-methylpropyl)-N-(4 - methoxybenzenesulfonyl)amino] 1-S-(phenylmethyl)propyl carbamate (671,1 mg, 1,31 mmol) of Part D in 10 ml of methanol hydronaut in the presence of 50 mg of 10% palladium on coal Fri filtered through diatomaceous earth and the filtrate is concentrated, getting a white foam, 474,5 mg, 96% of the Belarusian library Association (FAB) MS:MN+= 377.

EXAMPLE 32

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Obtaining 1,3-benzodioxol-5-sulfonyl chloride

Method 1:

To a solution of 4.25 g of anhydrous N,N-dimethylformamide at 0oC in argon atmosphere add to 7.84 g Sulfuryl chloride, after which a solid substance. After stirring for 15 minutes, add 6,45 g of 1,3-benzodioxole and the mixture is heated at 100oC for 2 hours. The reaction mixture is cooled, poured into ice water, extracted with methylene chloride, dried over magnesium sulfate, filtered and concentrated, getting to 7.32 g of the crude substance in the form of a black oil. It chromatographic on silica gel using 20% methylene chloride/hexane, receiving of 1.9 g of (1,3-benzodioxol-5-yl)sulfonyl chloride.

Method 2:

In a 22-liter round-bottom flask equipped with a mechanical stirrer, a refrigerator, a heating jacket and a dropping funnel with a balanced pressure, put the sulfur trioxide-DMF complex (2778 g, 18,1 mol). Then add dichloroethane (4 liters) and begin mixing. Then through an addition funnel for five minutes add 1,3-benzodioxol (1905, 15.6 mol). Then the temperature was raised to 75oC and maintained for 22 cabassut oxalyl chloride (2290 g, 18,1 mol) at such a speed as to maintain the temperature below 40oC (1.5 hours). The mixture is heated to 67oC for 5 hours and then cooled to 16oC in a bath with ice. The reaction mixture was quenched with water (5 l) at a speed that allows you to maintain the temperature below 20oC. After adding water, the mixture is stirred for 10 minutes. The layers are separated and the organic layer washed twice (5 l) H2O. the Organic layer is dried with magnesium sulfate (500 g) and filtered to remove the desiccant. The solvent is removed in vacuum at 50oC. Received a warm liquid allow to cool, and at this time begins to form a solid substance. After one hour, the solid is washed with hexane (400 ml), filtered and dried, obtaining the required sulfonyl chloride (2823 g). Washing hexane water concentrated and the obtained solid is washed with 400 ml of hexane, gaining additional sulfonyl chloride (464 g). The total yield is 3287 g (95.5% of per 1,3-benzodioxol).

Method 3:

1,4-benzodioxan-6-sulfonyl chloride get under way, opened in EP 583960, which is included here as a reference.

EXAMPLE 33

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Obtain 1-[N-[1,3-benzodiox ml, 3-necked flask equipped with a mechanical stirrer, are placed salt of N-[3(S)-[N,N-bis(phenylmethyl)amino]-2(R)-hydroxy-4 - phenylbutyl]-N-isobutylamine oxalic acid (354,7 g, 0.7 mol) and 1,4-dioxane (2000 ml). Then add a solution of potassium carbonate (241,9 g of 1.75 mol) in water (250 ml). The obtained heterogeneous mixture is stirred for 2 hours at room temperature followed by the addition of 1,3-benzodioxol-5-sulfonyl chloride (162,2 g, 0,735 mol) dissolved in 1,4-dioxane (250 ml) during 15 minutes. The reaction mixture was stirred at room temperature for 18 hours. Charged to the reactor in ethyl acetate (1000 ml) and water (500 ml) and continue stirring for another 1 hour. The aqueous layer was separated and then extracted with ethyl acetate (200 ml). United an ethyl acetate layers are washed with 25% brine (500 ml) and dried over anhydrous magnesium sulfate. After filtration and washing of magnesium sulfate with ethyl acetate (200 ml), the solvent in the filtrate is removed under reduced pressure, obtaining the desired sulfonamide as a viscous yellow foamy oil (440,2 g, 105% yield). HPLC/MS (HPLC/MS) (elektrorazpredelenie) (m/z 601 [M+H]+].

EXAMPLE 34

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Getting salt of 1-[N-[(1,3-benzodioxol-5-yl)sulfonyl]-N- (2-methylpropyl)amino]-3(S)-amino-4-phenyl-2(R)-BU the amino] -3(S)-[bis(phenylmethyl)amino] -4-phenyl-2(R)-butanol (6.2 g, 0,010 mol) is dissolved in methanol (40 ml). Then to the solution was added methanesulfonyl acid (0,969 g 0,010 mol) and water (5 ml). The mixture is placed in a 500 ml Parr reactor for hydrogenation containing 20% Pd(OH)2coal (255 mg, 50% water content). The reactor is placed in hydrogenator and rinsed 5 times with nitrogen and 5 times with hydrogen. Allow the reaction at 35oC at a pressure of hydrogen 4,43 kg/cm2(63 PSI) for 18 hours. Add additional catalyst (125 mg) and, after blowing, the hydrogenation continued for another 20 hours. The mixture is filtered through celite, which is washed with methanol (2 x 10 ml). Approximately one third of the methanol is removed under reduced pressure. The remaining methanol is removed by azeotropic distillation with toluene at 80 Torr. Toluene add portions 15, 10, 10 and 10 ml. of the Product crystallizes from the mixture and it is filtered off and washed twice with 10 ml portions of toluene. The solid is dried at room temperature under 1 Torr for 6 hours, getting an amine salt (4.5 g, 84%). HPLC/MS (elektrorazpredelenie) corresponds to the desired product (m/z 421 [M+H]+).

Method 2:

Part a: Salt N-[3(S)-[N,N-bis(phenylmethyl)amino]- 2(R)-hydroxy-4-phenylbutyl] -N-isobutylamine oxalic acid (2800 g of 5.53 mg, a 13.9 mol) dissolved in water (2.8 l) and added to the THF suspension. The mixture was then stirred for one hour. 1,3-benzodioxol-5 - sulfonyl chloride (1281 g, 5.8 mol) is dissolved in THF (1.4 l) and added to the reaction mixture over 25 minutes. Use an additional 200 ml of THF in order to rinse the addition funnel. The reaction mixture is stirred for 14 hours and then add water (4 l). This mixture is stirred for 30 minutes and the layers give the opportunity to split. The layers are removed and the aqueous layer was washed twice THF (500 ml). The combined THF layers dried with magnesium sulfate (500 g) for one hour. The solution is then filtered to remove the desiccant, and its use in subsequent reactions.

Part B: To the THF solution of the crude 1-[N-[(1,3 - benzodioxol-5-yl) sulfonyl] -N-(2-methylpropyl)amino] -3(S)-[bis (phenylmethyl) amino]-4-phenyl-2(R)-butanol add water (500 ml), and then methanesulfonyl acid (531 g, 5.5 mol). The solution is stirred to ensure complete mixing, and placed in 5-gallon (USA, 18,93 l) autoclave. Pearlman catalyst (200 g of 20% Pd(OH)2C/50% water) is added to the autoclave with the aid of THF (500 ml). The reactor was rinsed four times with nitrogen and four times with hydrogen. The reactor is loaded with hydrogen at isbutton is on a small number monobenzylether intermediate product is still present. Add additional catalyst (50 g) and the reaction continued overnight. Then the solution is filtered through celite (500 g) to remove the catalyst and concentrated in vacuo five portions. To each portion add toluene (500 ml) and removed in vacuo azeotropic remove residual water. The obtained solid is divided into three portions and each was washed with methyl t-butyl ether (2 l) and filtered. Residual solvent is removed at room temperature in a vacuum oven at less than 1 Torr, getting 2714 g target salt.

If desired, the product may be further purified by the following method. Only 500 ml of methanol and 170 g of the substance of the above is heated under reflux until then, until it is completely dissolved. The solution is cooled, add 200 ml of isopropanol and then 1000-1300 ml of hexane, after which the precipitated white solid. After cooling to 0oC this precipitate is collected and washed with hexane, getting 123 g of a target substance. Through this procedure, the original substance, which was a 95:5 mixture of alcohol diastereomers, is a mixture of more than hanil] (2-methylpropyl)amino]-1S-(phenylmethyl)Propylamine

Part a: Getting phenylmethylene ether 2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S- (phenylmethyl)propellerbuying acid

To a solution 3,19 g (8.6 mmol) of N-[3S-benzyloxycarbonyl-amino-2R-hydroxy-4-phenyl] -N-isobutylamine in 40 ml of anhydrous methylene chloride added 0.87 g of triethylamine. The solution is cooled to 0oC and add 1,90 t (1,3-benzodioxol-5-yl) sulfonyl chloride, stirred for 15 minutes at 0oC, then for 17 hours at room temperature. Add ethyl acetate, washed with 5% citric acid, saturated sodium bicarbonate, brine, dried and concentrated, obtaining the crude substance. It is recrystallized from a mixture of diethyl ether/hexane, receiving 4.77 g of pure phenylmethylene ether 2R-hydroxy-3-[[(1,3-benzodioxol-5-yl) sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl) propellerbuying acid.

Part B: Getting 2R-hydroxy-3-[[(1,3-benzodioxol-5-yl) sulfonyl] (2-methylpropyl)amino]-1S-(phenylmethyl)Propylamine

A solution of 4.11 g phenylmethylene ether 2R-hydroxy-3-[[(1,3 - benzodioxol-5-yl)sulfonyl] (2-methylpropyl)amino] -1S- (phenylmethyl)propellerbuying acid in 45 ml of tetrahydrofuran and 25 ml of methanol hydronaut in the presence of 1.1 g of 10% philydraceae and the filtrate is concentrated, getting to 1.82 g of the desired 2R-hydroxy-3-[[(1,3-benzodioxol-5-yl) sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)Propylamine.

EXAMPLE 36

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Getting Benzothiazole-6-sulfonyl chloride

Part a: Obtaining N-(4-sulfonatophenyl)thiourea

A mixture of sulfanilamide (86 g, 0.5 mol), ammonium thiocyanate (76,0 g, 0.5 mol) and diluted hydrochloric acid (1.5 N, 1 l) was mechanically stirred and heated under reflux for 2 hours. About 200 ml of distilled water and the concentration of the reaction mixture gives a solid substance. The solid is filtered off and washed with cold water and dried in the air, getting to 67.5 g (59%) of the desired product as a white powder.

Part B: Getting 2-amino-6-sulphametoxazole

Bromine (43,20 g, 0.27 mol) in chloroform (200 ml) added dropwise within 1 hour to a suspension of N-(4-sulfonatophenyl)thiourea (27,72 g, 0,120 mol) in chloroform (800 ml). After the addition, the reaction mixture was heated under reflux for 4.5 hours. The chloroform is removed in vacuo and the residue re-distil with additional quantities of chloroform. The obtained solid is treated with water (600 ml), and then ammonium hydroxide (to make it bases which provide water and dried in air, getting 22,0 g (80%) of the desired product as a white powder.

Part C: Getting Benzothiazole-6-sulfonic acid

A suspension of 2-amino-6-sulphametoxazole (10.0 g, 43,67 mmol) in dioxane (300 ml) heated under reflux. Soliditet (24 ml) is added in two portions to the reaction mixture. There is a vigorous evolution of gas (the reaction is carried out behind the screen as a precaution) and after 2 hours, a red precipitate is deposited in the reaction vessel. The reaction mixture is filtered hot, the solid is washed with dioxane and dried. The solid is recrystallized from methanol-water. A small amount of precipitate formed after 2 days. The precipitate is filtered off and the mother liquor was concentrated in vacuo, obtaining the pure product (8.0 g, 85%) as a pale red-orange solid.

Part D: getting a 6-chlorosulfonylbenzoic

Thionyl chloride (4 ml) are added to the suspension benzothiazole-6-sulfonic acid (0,60 g, and 2.79 mmol) in dichloroethane (15 ml) and the reaction mixture is heated under reflux and the reaction mixture is added dimethylformamide (5 ml) to give a clear solution. After 1.5 hours boiling under reflux, the solvent UDA is
Obtaining cleaners containing hydrochloride salt of N-[2R-hydroxy-3-[[(1,3 - benzodioxol-5-yl)sulfonyl] (2-methylpropyl)amino-1S-(phenylmethyl) propyl]-2S-[(2S-pyrrolidinylcarbonyl)amino] -3,3 - dimethylbutyramide

Part a: Obtaining N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl] (2-methylpropyl)amino-1S-(phenylmethyl)propyl] -2S-[(phenylmethanesulfonyl) amino]-3,3-dimethylbutyramide

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To a solution of 118.8 g (0,776 mol) of N-hydroxybenzotriazole and 137,1 g (0.52 mol) of N-carbobenzoxy-L-relatina in 750 ml of anhydrous DMF (DMF) at 0oC in nitrogen atmosphere add 109,1 g (or 0.57 mol) of EDC. After stirring at 0oC for 2 hours, add a solution of 273 g (of 0.53 mole) of 2R-hydroxy-3-[[(1,3-benzodioxol-5-yl) sulfonyl] (2-methylpropyl)amino] -1S-(phenylmethyl)Propylamine of methansulfonate, pre-neutralized 228 ml (210 g, 2,08 mol) 4-methylmorpholine, in 250 ml of anhydrous DMF. After stirring at 0oC for 30 minutes, the mixture is stirred at room temperature for 18 hours. The solvents are removed under reduced pressure at 45oC add 1.5 l of ethyl acetate, washed with 5% citric acid, saturated sodium bicarbonate, brine, dried over anhydrous magnesium sulfate, filtered and concentrated, gaining 400 g of the crude prophetic is Xan as eluent, getting 320 g of purified substances, m/e = 674 (M+Li), 98% by HPLC.

Part B: Obtaining N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl) sulfonyl] (2-methylpropyl)amino]-1S-(phenylmethyl)propyl]- 2S-amino-3,3-dimethylbutyramide

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A solution of 312 g of Cbz connections from the previous part in 1 l of tetrahydrofuran hydronaut in the presence of catalyst, 100 g of 4% palladium-on-coal at a gauge pressure of hydrogen 4,219 kg/cm2(60 psig) for 6 hours at room temperature. The catalyst was removed by filtration and the solvents removed under reduced pressure, receiving 240 g of the desired compound.

Part C: Obtaining N-[2R-hydroxy-3-[[(1,3-benzodioxol-5 - yl)sulfonyl] (2-methylpropyl)amino] -1S-(phenylmethyl)propyl] - 2S-[[1-phenylmethanesulfonyl)pyrrolidin-2S-ylcarbonyl]amino]-3,3 - dimethylbutyramide

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a 250 ml round bottom flask equipped with a magnetic stirrer in the form of a rod and inlet for N2download 1.6 g of Cbz-L-Proline (1.15 EQ.) in 40 ml of DMF. The reaction mixture was cooled to 0oC and load 0.88 g Hobt (1.5 EQ.) 1.25 g of EDC (1.15 EQ. ). The reaction mixture is stirred for 40 minutes at room temperature, then add a solution of 3.0 g of 2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl] (2-methylpropyl)amino]-1S-(phenylmethyl)propyl amine and 1.85 ml of N-metil vacuum and the residue distributed between ethyl acetate and saturated aqueous bicarbonate Na. The organic layers washed with 5% aqueous acidic potassium sulfate and brine, dried over Na2SO4and concentrated in vacuo, obtaining of 4.25 g (95%) of a white foam; RP HPLC > 97% purity.

Part D: Getting cleaners containing hydrochloride salt of N-[2R-hydroxy-3-[[(1,3 - benzodioxol-5-yl)sulfonyl] (2-methylpropyl)amino] -1S-(phenylmethyl)propyl] - 2S-[(2S-pyrrolidinylcarbonyl)amino]-3,3-dimethylbutyramide

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300 ml vessel Fischer-porter (Fisher-Porter), equipped with a magnetic stirrer in the form of a rod, download N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl] (2-methylpropyl)amino] - 1S-(phenylmethyl)propyl]-2S-[[1-phenylmethanesulfonyl)pyrrolidin - 2S-ylcarbonyl]amino]-3,3-dimethylbutyramide (1,15 g) and 10% Pd-C (wet) in 150 ml MeOH. The reaction mixture hydronaut when 3,515 kg/cm2(50 psi) for 6 hours, then filtered through Celite. The filtrate was concentrated in vacuo to 3,36 g of white foam. The residue is dissolved in 50 ml of CH3CN and process of 0.96 ml (2 EQ.) concentrated HCl. The reaction mixture was concentrated in vacuo to a solid, triturated with ether and filtered, obtaining 3.1 g of pure desired product.

EXAMPLE 37A

Obtaining cleaners containing hydrochloride salt of N-[2R-hydroxy-3-[[(1,3-benzodioxol - 5-yl)sulfonyl](2-methylpropyl)amino)-1S-(phenylmethyl)impregnated ropyl)amino] 1S-(phenylmethyl)propyl] -2S-[[1-phenylmethanesulfonyl)pyrrolidin-2S-ylcarbonyl] amino]-3,3-dimethylbutyramide

Bis-protected compound

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Example 43 was dissolved in dioxane/HCl and the solution is stirred for approximately 2 hours at room temperature. The solvent is removed and the residue is dried in vacuum, obtaining Amin

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Part B: the remainder of the amine of Part A was stirred in ethyl acetate, add 1.3-benzodioxol-5-yl sulfonyl chloride of Example 32, and then triethylamine. The mixture is stirred at about room temperature. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate and brine, dried (MgSO4) and concentrated, obtaining the target product. The remainder chromatographic, if you require additional cleaning

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Part C: 300 ml vessel Fischer-porter, equipped with a magnetic stirrer in the form of a rod, download N-[2R-hydroxy-3-[[(1,3 - benzodioxol-5-yl)sulfonyl] (2-methylpropyl)amino] -1S-(phenylmethyl) propyl] -2S-[[1-(phenylmethanesulfonyl)pyrrolidin-2S-ylcarbonyl] amino] -3,3-dimethylbutyramide

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(1,15 g) and 10% Pd-C (wet) in 150 ml MeOH. The reaction mixture hydronaut when 3,515 kg/cm2(50 psi) for 6 hours, then filtered through Celite. The filtrate was concentrated in vacuo to 3,36 g of white foam. The residue is dissolved in 50 ml of CH3CN and process of 0.96 ml (2 EQ.) concentrated is the learn of 3.1 g of pure desired product

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EXAMPLE 38

Obtaining cleaners containing hydrochloride salt of N-[2R-hydroxy-3-[[(1,3-benzodioxol - 5-yl)sulfonyl] (2-methylpropyl)amino] -1S-(phenylmethyl) propyl]-2S-amino-3S-methylbenzamide

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Part a: Obtaining N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl] (2-methylpropyl)amino] -1S-(phenylmethyl)propyl] - 2S-[[(1,1-dimethylmethoxy)carbonyl]amino]-3S-methylpentanoic

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To a cooled solution of N-t-BOC-L-isoleucine 2,02 g (a total of 8.74 mmol) and 2.00 g (13,11 mmol) N-hydroxybenzotriazole in 17 ml of N,N-dimethylformamide added 1.84 g (being 9.61 mmol) of EDC and stirred at 0oC for one hour. To the reaction mixture add a solution to 3.67 g (a total of 8.74 mmol) of 2R-hydroxy-3-[[(1,3-benzodioxol-5 - yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl amine in 6 ml N,N-dimethylformamide and the solution is stirred for 16 hours. The solvent is removed in vacuum, replace with ethyl acetate and washed with saturated sodium bicarbonate, 5% citric acid solution. The organic layers are dried over magnesium sulfate, filtered and concentrated, obtaining of 6.1 tons of crude product, which chromatographic on silica gel using 1: 1 ethyl acetate:hexane eluent, obtaining 4.3 g (78% yield) of N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl] (2-methylpropyl)amino] - 1S-(phenylmethyl)R-hydroxy-3- [[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S- (phenylmethyl)propyl]-2S-amino-3S-methylpentanoic

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N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl] (2 - methylpropyl)amino] -1S-(phenylmethyl)propyl] -2S-[[(1,1-dimethylmethoxy) carbonyl]amino] -3S-methylpentane (4,29 g, 6,77 mmol) was dissolved in 20 ml of 4N HCl in dioxane and stirred for 20 minutes. Landed product otparivat twice from diethyl ether and the crude cleaners containing hydrochloride salt use in subsequent reactions.

EXAMPLE 39

Obtaining N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl] (2-methylpropyl)amino] -1S-(phenylmethyl)propyl]-2S-[(2S-pyrrolidinylcarbonyl) amino]-3S-methylpentanoic

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Part a: Obtaining N-[2R-hydroxy-3-[[(1,3-benzodioxol - 5-yl)sulfonyl] (2-methylpropyl)amino]-1S-(phenylmethyl)propyl] -2S-[[1-(phenylmethanesulfonyl)pyrrolidin-2S-ylcarbonyl]amino]- 3S-methylpentanoic

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A solution of 0.5 g (2.2 mm) M-CEZ-L-Proline in 10 ml of anhydrous DMF is cooled to 0oC and add 0.4 g (2.8 mm) NOWT and 0.4 g (2.2 mm) of EDC. Bath with ice removed after 20 minutes and stirring is continued for another 40 minutes. Add a solution of 1.0 g (1.9 mm) cleaners containing hydrochloride salt of N-[2R-hydroxy-3-[[(1,3-benzodioxol-5 - yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl-2S - amino-3S-methylpentanoate and 0.6 g (5.6 mm) 4-methylmorpholine in 15 ml of anhydrous DMF and the mixture is stirred during the acid sulphate of potassium. The layers are separated and the organic layer was washed with 50 ml each of saturated sodium bicarbonate solution, water and brine, then dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo, obtaining 1.5 g of the crude substance. Cleaning is performed using flash chromatography on silica gel using 70-80% ethyl acetate/hexane, obtaining 1.3 g (90%) of the desired product as a white solid, m/e = 771 (M+Li).

Part B: Obtaining N-[2R-hydroxy-3-[[(1,3-benzodioxol - 5-yl)sulfonyl] (2-methylpropyl)amino] -1S-(phenylmethyl)propyl] -2S-[(2S-pyrrolidinylcarbonyl)amino]-3S-methylpentanoic

Into the flask Fischer-porter, equipped with a magnetic stirrer in the form of a rod, load 1.2 g (1.5 mm) of the product of Part A and 25 ml THF. The solution hydronaut in the presence of 1 g of 10% palladium catalyst on coal (50% water by weight) at a gauge pressure of hydrogen 3,515 kg/cm2(50 psig) for 16 hours at room temperature. The catalyst was removed by filtration and the solvent is removed under reduced pressure, obtaining 0.9 g of the crude substance. Cleaning is performed using flash chromatography on silica gel, using 1-4% methanol/methylene chloride, and obtain 0.8 g (80%) of the desired product, m/e = 637 (M+H).

EXAMPLE 40

Obtaining N-[2R-GI
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Part a: Obtaining N-[2R-hydroxy-3-[(1,3-benzodioxol-5-yl) sulfonyl] (2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S- [(phenylmethanesulfonyl)amino]-3-methylbutylamine

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In a 250 ml round bottom flask, equipped with a magnetic stirrer in the form of a rod, download N-Cbz-L-Valine (4,22 g, a 16.8 mmol) in 20 ml of DMF. The solution is cooled to 0oC and added HoBt (2,96, 21.9 mmol) and EDC (3,22 g, a 16.8 mmol) and stirred for 1 hour. In the reaction mixture was then added N-methylmorpholine (1.7 g, a 16.8 mmol) of 2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl] (2-methylpropyl) amino]-1S-(phenylmethyl)Propylamine (of 7.55 g, 14.6 mmol) in 30 ml DMF. The reaction mixture was stirred over night at room temperature, then concentrated in vacuo and distributed between ethyl acetate and 5% citric acid. The combined organic layers are washed with saturated sodium bicarbonate and brine and dried over sodium sulfate. Concentration in vacuo gives 10 g of the crude product. Cleaning Prep (Prep) HPLC (20-40% ethyl acetate/hexane) to give 5.8 g (61%) of the desired compound.

Part B: Obtaining N-[[2R-hydroxy-3-[(1,3-benzodioxol-5 - yl)sulfonyl] (2-methylpropyl)amino]-1S-(phenylmethyl)propyl]- 2S-amino-3-methylbutanoic

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In a 300-ml round-bottom vessel equipped with an magnanimity)propyl]- 2S-[(phenylmethanesulfonyl)amino] -3-methylbutanoic (5.8 g), 2.3 g of 10% Pd-C in 75 ml of tetrahydrofuran. In the reaction mixture is passed 3,515 kg/cm2(50 psi) H2and hydronaut during the night. The reaction mixture was filtered through Celite and concentrated in vacuo, obtaining 4.4 g of a white foam, which is used in subsequent reactions without further purification.

EXAMPLE 41

Obtaining cleaners containing hydrochloride salt of N-[[2R-hydroxy - 3-[(1,3-benzodioxol-5-yl)sulfonyl] (2-methylpropyl)amino] -1S- (phenylmethyl)propyl] -2S-amino-3-(methylsulphonyl)propanamide

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Part a: Obtaining N-[[2R-hydroxy-3-[(1,3-benzodioxol - 5-yl)sulfonyl] (2-methylpropyl)amino] -1S-(phenylmethyl)propyl] -2S-[[(1,1-dimethylmethoxy)carbonyl]amino-3-(methylthio)propanamide

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N-t-BOC-S-methyl-(L)-cysteine (2,80 g, to 11.9 mmol), 1-hydroxybenzotriazole hydrate (1.92 g, 12.5 mmol) and 1-(3-dimethylaminopropyl)-3-3-ethylcarbodiimide hydrochloride of 2.27 g of 11.9 mmol) are mixed in N,N-dimethylformamide (30,0 ml) at 0oC for 10 minutes Add N-methylmorpholine (3.03 g, 33.0 mmol) and the solution stirred an additional 10 min at 0oC. Add 2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2 - methylpropyl)amino]-1S-(phenylmethyl)Propylamine (5,00 g, to 11.9 mmol) and the solution warmed to room temperature and stirred for 2 hours. The reaction mixture is mm sodium bicarbonate (3 x 100 ml) and brine (2 x 100 ml). The organic layer is dried over sodium sulfate and filtered through a layer of silica gel (50 g). Get the desired product (7,13 g, to 11.9 mmol, 93% yield) as white solids removal of solvent under reduced pressure; m/e expect. 637; found (M+Li) 644.

Part B: Obtaining N-[[2R-hydroxy-3-[(1,3-benzodioxol - 5-yl)sulfonyl] (2-methylpropyl)amino] -1S-(phenylmethyl)propyl] -2S-[[(1,1-dimethylmethoxy)carbonyl]amino-3-(methylsulphonyl) propanamide

< / BR>
N-[[2R-hydroxy-3-[(1,3-benzodioxol-5-yl)sulfonyl] (2-methylpropyl)amino] -1S-(phenylmethyl)propyl] -2S- [[(1,1-dimethylmethoxy)carbonyl]amino] -3-(methylthio)propanamide (7,10 g, 11.1 mmol) dissolved in methanol (150 ml). The solution Oksana(20,8 g, to 33.9 mmol) in water (150 ml) is added dropwise to the solution at room temperature for 1.5 hours. The solution becomes turbid, and during the addition a precipitate. The reaction mixture was stirred for an additional hour and add tetrahydrofuran (200 ml). After stirring for an additional hour, the solution was poured into ethyl acetate (1000 ml) and washed with water (3 x 200 ml), then brine (2 x 300 ml). The organic layer is dried over anhydrous sodium sulfate and the solvent is removed under reduced pressure. Get ASS="ptx2">

Part C: Getting cleaners containing hydrochloride salt of N-[[2R-hydroxy-3- [(1,3-benzodioxol-5-yl) sulfonyl](2-methylpropyl)amino]-1S- (phenylmethyl)propyl]-2S-amino-3-(methylsulphonyl)propanamide

< / BR>
N-[[2R-hydroxy-3-[(1,3-benzodioxol-5-yl)sulfonyl] (2-methylpropyl)amino] -1S-(phenylmethyl)propyl] -2S-[[(1,1 - dimethylmethoxy)carbonyl]amino] -3-(methylsulphonyl)propanamide (5.5 g, 8.20 mmol) was dissolved in dichloromethane (100 ml) at room temperature. Anhydrous hydrochloric acid is bubbled through the solution for 15 minutes the Solution was stirred at room temperature for 2 hours and the solvent is removed under reduced pressure. Get the desired product (4,91 g, 8,10 mmol, 99% yield) as a white solid; m/e expect. 569; found (M+Li) 576.

EXAMPLE 42

Obtaining cleaners containing hydrochloride salt of N-[[2R-hydroxy-3- [(1,3-benzodioxol-5-yl)sulfonyl] (2-methylpropyl)amino] -1S- (phenylmethyl)propyl]-2S-amino-3-methyl-3-(methylsulphonyl) propanamide

< / BR>
Part a: Obtaining N-[[2R-hydroxy-3-[(1,3-benzodioxol-5 Il)sulfonyl] (2-methylpropyl)amino] -1S-(phenylmethyl)propyl] - 2S-[[(1,1-dimethylmethoxy)carbonyl]amino]-3-(methylthio)butanamide

< / BR>
Salt-N-t-boc-3-methyl-L-penicillamine of dicyclohexylamine (4,00 g, 9,00 mmol), 1-hydroxybenzotriazole hydrate (amide (60,0 ml) at room temperature. The heterogeneous mixture is stirred for 1 hour and add 2R-hydroxy-3-[[(1,3-benzodioxol-5-yl) sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)Propylamine (of 3.78 g, 9,00 mmol) and the heterogeneous mixture is stirred for 16 hours. The solution was poured into ethyl acetate (600 ml) and washed with 10% aqueous citric acid (2 x 300 ml), saturated aqueous sodium bicarbonate (2 x 300 ml) and brine (300 ml). The solution is dried over sodium sulfate and the solvent is removed in vacuum. The desired product clean flash chromatography (0-80% ethyl acetate-hexane on silica gel). Receive the product (a total of 5.21 g, 7,83 mmol, 87% yield) as a white foam; m/e expect. 665; found (M+Li) 672.

Part B: Obtaining N-[[2R-hydroxy-3-[(1,3-benzodioxol - 5-yl)sulfonyl] (2-methylpropyl)amino] -1S-(phenylmethyl)propyl] -2S-[[(1,1-dimethylmethoxy)carbonyl]amino]-3-methyl-3- (methylsulphonyl)butanamide

< / BR>
N-[[2R-hydroxy-3-[(1,3-benzodioxol-5-yl)sulfonyl] (2 - methylpropyl)amino] -1S-(phenylmethyl)propyl] -2S-[[(1,1 - dimethylmethoxy)carbonyl]amino] -3-methyl-3-(methylthio)butanamide (5,01 g, 7,53 mmol) dissolved in tetrahydrofuran (250 ml). The solution oxone (13.8 g, and 22.6 mmol) in water (250 ml) is added dropwise to the solution at room temperature for 2 hours. The solution becomes turbid, and at the time the Addendum is). The organic layer is dried over anhydrous sodium sulfate and the solvent is removed in vacuum. Receive the product (4.72 in) 6,77 mmol, 89% yield) as a white foam; m/e expect. 697; found (M+Li) 704.

Part C: Getting cleaners containing hydrochloride salt of N-[[2R-hydroxy-3- [(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S- (phenylmethyl)propyl]-2S-amino-3-methyl-3-(methylsulphonyl)butanamide

< / BR>
N-([2R-hydroxy-3-[(1,3-benzodioxol-5-yl)sulfonyl] (2 - methylpropyl)amino] -1S-(phenylmethyl)propyl] -2S-[[ (1,1-dimethylmethoxy)carbonyl]amino] -3-methyl-3-(methylsulphonyl) butanamide (4,51 g, 6,46 mmol) dissolved in dichloromethane (200 ml) at room temperature. Anhydrous hydrochloric acid is bubbled through the solution for 30 minutes the Solution was stirred at room temperature for 1 hour and the solvent is removed in vacuum. Receive the product (as 4.02 g, 6,35 mmol, 99% yield) as a white solid; m/e expect. 697; found (M+Li) 704.

EXAMPLE 43

Obtaining N-[2R-hydroxy-3-[[(1,1-dimethylmethoxy) carbonyl](2-methylpropyl)amino] -1S-(phenylmethyl)propyl] -2S- [[1-(phenylmethanesulfonyl)pyrrolidin-2S-ylcarbonyl]amino]-3,3 - dimethylbutyramide

< / BR>
Part a: Obtaining N-[(1,1-dimethylethyl)carbonyl]-N- [2-methylpropyl] -3S-[N1(phenylmethoxy-4-phenylbutyl] -N-(2-methylpropyl)amine (18.5 g, 50 mmol), BOC-ON (12,35 g, 50 mmol) and triethylamine (7 ml) in tetrahydrofuran (400 ml) was stirred at room temperature for 18 hours and then concentrated in vacuo. The residue is dissolved in dichloromethane (1 l) and washed with sodium hydroxide (5%, 2 × 200 ml) and brine, dried (MgSO4) and then concentrated in vacuo, obtaining of 23.5 g (quantitative yield) of pure desired product.

< / BR>
Part B: Obtaining N-[2R-hydroxy-3-[[(1,1 - dimethylmethoxy)carbonyl](2-methylpropyl)amino] -1S-(phenylmethyl) propyl]-2S-[(phenylmethanesulfonyl)amino] -3,3-dimethylbutyramide

< / BR>
N-[(1,1-dimethylethyl)carbonyl]-N-[2-methylpropyl]-3S- [N1(phenylmethanesulfonyl)amino] -2R-hydroxy-4-phenylbutyramide in ethanol hydronaut at a gauge pressure of hydrogen 3,164 kg/cm2(45 psig) in the presence of 5% Pd(C) catalyst, obtaining N-[(1,1-dimethylethyl)carbonyl]-N-[2-methylpropyl] -3S-[N1(phenylmethanesulfonyl)amino]-2R-hydroxy-4-phenylbutyramide. After standard processing, the crude amine (12,24 g, 36, 42 mmol) is added to a mixture of N-carbobenzoxy-L-tert-leucine (9,67 g, 36,42 mmol), NOT (4,92 g, 36,42 mmol) and EDC (6,98 g, 36,42 mmol) in DMF (300 ml), once the mixture is stirred at room temperature for 1 hour. The mixture is stirred during the course the house of sodium (5%, 2 x 200 ml) and brine (200 ml), dried and concentrated, gaining 21 g (quantitative) of the desired product.

Part C: Obtaining N-[2N-hydroxy-3-[[(1,1 - dimethylmethoxy)carbonyl][2-methylpropyl]amino]-1S-(phenylmethyl) propyl]-2S-amino-3,3-dimethylbutyramide

< / BR>
N-[2R-hydroxy-3-[[(1,1-dimethylmethoxy)carbonyl] [2 - methylpropyl]amino]-1S-(phenylmethyl)propyl] -2S- [(phenylmethanesulfonyl)amino] -3,3-Dimethylbutane (20 g, 34,29 mmol) in methanol (250 ml) hydronaut at room temperature in the presence of Pd/C (10%, 5 g). The catalyst is filtered off and the filtrate is concentrated, obtaining 13.8 g (90%) of pure desired product.

Part D: Obtaining N-[2R-hydroxy-3-[[(1,1-dimethylmethoxy) carbonyl][2-methylpropyl]amino]-1S-(phenylmethyl)propyl]-2S-[[1- (phenylmethanesulfonyl)pyrrolidin-2S-ylcarbonyl]amino]-3,3 - dimethylbutyramide

Cbz-L-Proline is dissolved in DMF in a nitrogen atmosphere under stirring at about 0oC. Add hydroxybenzotriazole (peso, NRT), and then add the EDC. The reaction mixture was stirred at room temperature, add the amine of Part C and add N-methyl-morpholine. The reaction mixture is stirred for about one day. The reaction mixture was concentrated in vacuo and the residue partitioned between ethyl is Aliya and brine, dried over Na2SO4and concentrated in vacuo, getting

< / BR>
EXAMPLE 44

Getting phenylmethylene ether 2R-hydroxy-3- [[(1,4-benzodioxan-6-yl)sulfonyl] (2-methylpropyl)amino] -1S- (phenylmethyl)propellerbuying acid

< / BR>
To a solution of N-[3S-[(phenylmethanesulfonyl)amino]-2R-hydroxy - 4-phenylbutyl]-N-(2-methylpropyl)amine (0.5 g, 1.35 mmol) in CH2Cl2(5.0 ml) containing Et3N (0.35 ml, 2.5 mmol), added 1,4-benzodioxan-6-sulfonyl chloride (0.34 g 1,45 mmol) and stirred at 0oC within 30 minutes After stirring at room temperature for 1 hour, the reaction mixture was diluted with CH2Cl2(20 ml), washed with cold 1N HCl (3 x 20 ml), water (2 x 20 ml), saturated NaHCO3(2 x 20 ml) and water (3 x 20 ml), dried (Na2SO4) and concentrate under reduced pressure. The resulting residue is purified flash chromatography using 35% EtOAc in hexane, obtaining the desired product as a white amorphous solid which crystallized from MeOH as a white powder (0.65 g, 84% yield); so pl. 82-84oC, VRMS-the Belarusian library Association (HRMC-FAB): expect. for C30H37N2O7S 569,2321 (MN+found 569,2323.

EXAMPLE 45

Getting [2R-hydroxy-3-[(benzothiazole-6 - sulfonyl)(2-methyl-prop is-[(4 - aminophenylalanine)(2-methylpropyl)amino]-1S-(phenylmethyl) propellerbuying acid

< / BR>
A mixture of [2R-hydroxy-3-[(4-aminophenylalanine)(2-methylpropyl) amino] -1S-(phenylmethyl)Propylamine 3.7 g (of 9.45 mmol) and BOC-ON (2,33 g of 9.45 mmol) and triethylamine (0,954 g of 9.45 mmol) in tetrahydrofuran (60 ml) is stirred for 16 hours and concentrated in vacuo. The residue is dissolved in dichloromethane (200 ml), washed with sodium hydroxide (1N, 100 ml) and citric acid (5%, 100 ml), dried (MgSO4and concentrate, receiving 1.18 g (94%) of the desired product as a white solid.

Part B: Getting t-butyl ether [2R-hydroxy-3-[[(2 - aminobenzothiazole-6-yl)sulfonyl](2-methylpropyl)amino]-1S- (phenylmethyl)propellerbuying acid

< / BR>
t-Butyl ether [2R-hydroxy-3-[(4-aminophenylalanine) (2-methylpropyl)amino] -1S-(phenylmethyl)propellerbuying acid (1,12 t, 2,279 mmol) are added to a well mixed powder of anhydrous copper sulfate (4,48 g) and potassium thiocyanate (the ceiling of 5.60 g) followed by addition of dry methanol (35 ml) and the resulting black-brown suspension is heated under reflux for 2 hours. The reaction mixture turns grey. The reaction mixture is filtered and the filtrate is diluted with water (50 ml) and heated under reflux. To the reaction mixture ethanol, cool and filter the I 0,80 g (78%) unprotected (after removal protection) connection in the form of solids. Connection re right protects the following way: (2.25 g, 5,005 mmol) of BOC-ON (1.24 g) and triethylamine (worn: 0.505 g, 5,005 mmol) in tetrahydrofuran (20 ml) was stirred at room temperature for 18 hours. The reaction mixture was concentrated and the residue is dissolved in dichloromethane (200 ml) and washed with sodium hydroxide (1N, 100 ml) and citric acid (5%, 100 ml), dried (MgSO4) and concentrated, obtaining a residue that chromatographic (ethyl acetate:hexane 3:1) to give 1.8 g (65%) of the desired product as a solid.

Part C: Getting t-butyl ether [2R-hydroxy-3- [[(benzothiazol-6-yl)sulfonyl](2-methylpropyl)amino]-1S- (phenylmethyl)propellerbuying acid

< / BR>
t-Butyl ether [2R-hydroxy-3-[[(2-aminobenzothiazole-6-yl) sulfonyl] (2-methylpropyl)amino] -1S-(phenylmethyl)propellerbuying acid (1.80 g, 3,2755 mmol) are added to a solution of isoamylamine (0,88 ml) in dioxane (20 ml) and the mixture is heated at 85oC. After termination of nitrogen, the reaction mixture was concentrated and the residue purified via chromatography (hexane: ethyl acetate 1: 1) to give 1.25 g (78%) of the desired product as a solid.

Part D: Getting cleaners containing hydrochloride salt, [2R-hydroxy-3 [[(benzothiazol-6-yl)sulfonyl](2-methylpr(2-methylpropyl)amino] -1S-(phenylmethyl)propellerbuying acid (1.25 g, 2,3385 mmol) are added to a mixture of dioxane/HCl (4N, 10 ml) and stirred at room temperature for 2 hours and concentrated. Excess HCl displace toluene, receiving 1.0 g (quantitative yield) of the desired product.

EXAMPLE 46

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Receipt of 2S-Amino-N-[2R-hydroxy-3-[[{1,3-benzodioxol-5 - yl)sulfonyl] (2-methylpropyl)amino]-1S-(phenylmethyl)propelent-4-enamide

Part a: Getting 2S-[[(1,1-dimethylmethoxy)carbonyl]amino] -N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl] (2-methylpropyl) amino] -1S-(phenylmethyl)propyl]Penta-4-enamide

< / BR>
To a cooled solution of N-t-Boc-L-propargyl glycine (5.0 g of 23.4 mmol) and 4.7 g (1.5 EQ.) N-hydroxybenzotriazole in 40 ml of N,N-dimethylformamide added 4.6 g (23,4 mmol) of EDC and stirred at 0oC for one hour. To the reaction mixture add a solution 12,10 g (23,4 mmol) of 2R-hydroxy-3-[[(1,3 - benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S- (phenylmethyl)Propylamine in 6 ml N,N-dimethylformamide and the solution is stirred for 16 hours. The solvent is removed on a rotary evaporator, add ethyl acetate, washed with saturated sodium bicarbonate, 5% citric acid and brine. The organic layer is dried over magnesium sulfate, filtered and concentrated, gaining 13.3 g of the crude PL] amino] -N-[2R - hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl] (2-methylpropyl)amino]-1S-(phenylmethyl)propyl]Penta-4-enamide.

Part B: Getting 2S-amino-N-[2R-hydroxy-3-[[(1,3 - benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl) propyl]Penta-4-enamide

< / BR>
5.0 g (8,12 mmol) of product from Part A was dissolved in 20 ml of 4 N HCl in dioxane and stirred for 30 minutes. Landed product twice otparivat diethyl ether and the crude cleaners containing hydrochloride salt use in subsequent reactions.

EXAMPLE 47

Getting dihydrobromide salt of N-[2R-hydroxy - 3-[[(benzothiazol-6-yl)sulfonyl] (2-methylpropyl)amino] -1S- (phenylmethyl)propyl] -2S-(amino) - 3,3-dimethylbutyramide

< / BR>
Part a: Obtaining N-[2R-hydroxy-3-[[(benzothiazol-6-yl) sulfonyl](2-methylpropyl)amino] -1S-(phenylmethyl)propyl] -2S- [[(N-benzyloxy)carbonyl] amino]-3,3-dimethylbutyramide

< / BR>
A mixture of N-benzyloxycarbonyl-t-butylglycol (2.0 g, 7,538 mmol), NOT (1,02 g of 7.55 mmol) and EDC (1.45 g, at 7.55 mmol) in DMF (20 ml) was stirred at room temperature for 1 hour. Then add 2R-hydroxy-3-[[(benzothiazol-6-yl)sulfonyl] (2-methylpropyl)amino]-1S-(phenylmethyl)Propylamine hydrochloride (3,825 g, rate of 7.54 mmol) and N-methylmorpholin (3.80 g) and continued stirring for 18 hours. DMF is removed under vacuum, the residue is dissolved in dichloromethane (500 ml) and washed with citric acid (1N, 100 ml),hydroxy-3- [[(benzothiazol-6-yl)sulfonyl] (2-methylpropyl)amino]-1S- (phenylmethyl)propyl] -2S-[N-(phenylmethanesulfonyl)amino]-3,3 - dimethylbutyramide.

Part B: Getting dihydrobromide salt of N-[2R-hydroxy-3- [[(benzothiazol-6-yl)sulfonyl] (2-methylpropyl)amino]-1S- (phenylmethyl)propyl] -2S-(amino)-3,3-dimethylbutyramide

A solution of N-[2R-hydroxy-3-[[(benzothiazol-6-yl)sulfonyl] (2-methylpropyl)amino] -1S-(phenylmethyl)propyl)-2S-[N-(phenyl-methoxycarbonyl) amino] -3,3-dimethylbutyramide (4,69 g, 6,89 mmol) in dichloroethane (200 ml) is treated with HBr (48% in acetic acid, and 7.1 ml) and the reaction mixture is stirred for 2 hours at room temperature. The reaction mixture was concentrated and the residue is washed several times with diethyl ether, receiving 4,88 g of the desired dihydrobromide product in powder form: the Belarusian library Association-MS high resolution: expect. for C27H38N4O4S2; 547,2413 found: 547,2429 (M+H).

EXAMPLE 48

Getting 5-chlorosulfonyl-2-carbomethoxyamino-benzimidazole

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A solution of 2-carbomethoxyamino-benzimidazole (5.0 g, was 0.026 mmol) in chlorosulfonic acid (35,00 ml) stirred at 0oC for 30 minutes and at room temperature for 3 hours. The obtained dark-colored reaction mixture is poured into a mixture of ice-water (200 ml) and stirred at room temperature for 30 minutes. The precipitate is filtered and washed with cold is getting 5-chlorosulfonyl-2-carbomethoxyamino-benzimidazole (5.9 g, 78%) as a gray powder.1H NMR (DMSO-d6) : the 3.89 (s, 3H), 7,55 (d, J=8,4 Hz,1H), 7,65 (d, J=8,4 Hz, 1H), 7,88 (s, 1H). (German Patent DE 3826036).

EXAMPLE 49

Getting phenylmethylene ester of N-[2R-hydroxy-3-[N1-[(2-carbomethoxyamino-benzimidazol-5-yl)sulfonyl] -N1-(2-methylpropyl)amino] -1S-(phenylmethyl)propyl]carbamino acid

< / BR>
To a cold solution of N-[3S-[(phenylmethanesulfonyl)amino]- 2R-hydroxy-4-phenylbutyl] -N-(2-methylpropyl)amine (5.0 g, 13.5 mmol) in dichloromethane (70 ml), add triethylamine (5,95 t, 54,0 mmol) followed by addition of 5-chlorosulfonyl-2 - carbomethoxyamino (4,29 g, 14,85 mmol) in small portions as a solid substance. The reaction mixture was stirred at 0oC for 30 minutes and at room temperature for 2.5 hours after the reaction amerosport will be completed. The mixture is cooled and filtered and the filtrate concentrated. The resulting residue is dissolved in EtOAc (200 ml), washed successively with cold 5% citric acid (3 x 50 ml), saturated aqueous sodium bicarbonate (3 x 50 ml) and water (3 x 100 ml), then dried (Na2SO4), concentrated and dried in vacuum. The residue is triturated with methanol, cooled, filtered, washed with MeOH-EtOAc (1:1, V/V) and dried in a desiccator, drank)amino] -1S-(phenylmethyl)propyl)carbamino acid (6,02 g, 72%) as a light brown powder: BAMS (FABMC): m/z = 630 (M+Li); VRMS (HRMS): expect. for31H38N5O5S (M+N) 624,2492 found 624,2488.

EXAMPLE 50

Getting 2R-hydroxy-3-[[(2-amino-benzimidazole-5-yl) sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)Propylamine

< / BR>
The solution phenylmethylene ester of N-[2R-hydroxy-3-[[(2 - carbomethoxyamino-benzimidazole-5-yl)sulfonyl](2-methylpropyl) amino]-1S-(phenylmethyl)propyl)carbamino acid (0.36 g, of 0.58 mmol) in 2.5 N solution of KOH in methanol (2.00 ml) is heated at 70oC in nitrogen atmosphere for 3 hours. The reaction mixture was diluted with water (10 ml) and extracted with EtOAc (3 x 15 ml). The combined organic extracts washed with brine, dried (Na2SO4) and concentrate. The resulting residue is purified HPLC with reversed phase, using 10-90% CHCN/H2O gradient (30 min) at a flow rate of 70 ml/min. and the Appropriate fractions are combined and freeze-dried, obtaining pure 2R-hydroxy-3-[[(2-aminobenzimidazole-5 - yl)sulfonyl](2-methyl-propyl)amino] -1S-(phenylmethyl)Propylamine (0,22 g, 58%) as a white powder: the Belarusian library Association-MS m/z = 432 (M+H); VRMS (HMRS): expect. for21H30N5O3S (M+N) 432,2069 found 432,2071.

EXAMPLE 51

Getting phenylmethylene ester of N-[2R-you

< / BR>
To a solution of 2R-hydroxy-3-[[(2-amino-benzimidazole-5-yl) sulfonyl](2-methylpropyl)amino] -1S-(phenylmethyl)Propylamine (0,22 g, 0.33 mmol) in THF (3,00 ml), add triethylamine (0.11 g, 1.1 mmol) and benzyloxycarbonyl succinimide (0.09 g, 0.36 mmol) and the reaction mixture was stirred at room temperature for 16 hours. The solution is concentrated and the residue partitioned between EtOAc (15 ml) and saturated aqueous sodium bicarbonate. The organic phase is washed with brine, dried (Na2SO4) and concentrate. The resulting residue is purified HPLC with reversed phase, using 10-90% CH3CN/H2O gradient (30 min) at a flow rate of 70 ml/min. and the Appropriate fractions combined and dried by freezing, getting clean fenilmetilovy ester of N-[2R-hydroxy-3-[[(2-amino-benzimidazole-5-yl)sulfonyl](2-methylpropyl) amino] -1S- (phenylmethyl)propyl)carbamino acid (0.12 g, 61%) as a white powder: the Belarusian library Association-MS m/z = 566 (M+H); VRMS (HMRS): expect. for C29H36N5O5S 3566, 2437 (M+H), found 566, 2434.

EXAMPLE 52

Getting 2R-hydroxy-3-[[(2-carbomethoxyamino 5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)Propylamine

< / BR>
The solution phenylmethylene ester of N-[2R-hydroxy-3-[[(2 - carbomethoxyamino and THF (50 ml) hydronaut in the presence of 10% Pd/C (1.2 g) at room temperature under 4,219 kg/cm2(60 psi) for 16 hours. The catalyst was removed by filtration and the filtrate concentrated under reduced pressure. Then the obtained solid is washed with ether and dried in vacuum, obtaining 2R-hydroxy-3-[[(2-carbomethoxyamino-5-yl)sulfonyl] (2 - methylpropyl)amino]-1S-phenylmethyl)Propylamine (1.5 g, 77%) as a white powder: Rt= 12,8 min; the Belarusian library Association-MS m/z = 490 (M+H); VRMS (HMRS): expect. for C23H32N5O5S 490,2124 (M+H), found 490,2142.

EXAMPLE 53

Obtaining N-[2R-hydroxy-3-[[(2 - carbomethoxyamino-benzimidazole-5-yl)sulfonyl] (2-methylpropyl) amino]-1S-(phenylmethyl)propyl]-2S-amino-3,3-dimethylbutyramide

< / BR>
Part a: Obtaining N-[2R-hydroxy-3-[N1-[(2 - carbomethoxyamino-benzimidazole-5-yl) sulfonyl]-N1-(2 - methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S- [(phenylmethanesulfonyl)amino]-3,3-dimethylbutyramide

< / BR>
To a solution of N-carbobenzoxy-L-tert-leucine (0.65 g, 2.45 mmol) in DMF (10 ml) is added HOBt (0.5 g, up 3.22 mmol) and EDC (0,49 g, 2.55 mmol) and the resulting mixture was stirred at 0oC for 2 hours. Then add a solution of 2R-hydroxy-3{ [(2 - carbomethoxyamino-benzimidazole-5-yl) sulfonyl] (2-methylpropyl)amino] -1S-(phenylmethyl)Propylamine (1.2 g, 2.45 mmol) in DMF (4 ml) and N-methylmorphine and the remaining residue is partitioned between cold 1N aqueous HCl (100 ml) and EtOAc (200 ml). The organic phase is washed successively with cold 1N HCl (2 x 50 ml), brine (2 x 50 ml), 0.25 N NaOH (3 x 50 ml), brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue is purified flash chromatography on a column of silica gel using EtOAc as este eluent, obtaining 1.5 g (83%) of pure N-[2R-hydroxy-3- [[(2-carbomethoxyamino-benzimidazole-5-yl) sulfonyl] (2-methylpropyl)amino] -1S-(phenylmethyl)propyl] -2S- [(phenylmethanesulfonyl)amino] -3,3-dimethylbutyramide:t= 21,2 min; the Belarusian library Association-MS m/z = 737 (M+H); VRMS (HMRS): expect. for C37H49N6O8S 737,3333 (M+H), found 737,3334.

Part B: Obtaining N-[2R-hydroxy-3-[[(2-carbomethoxyamino-benzimidazole-5-yl)sulfonyl] (2-methylpropyl)amino] -1S-(phenylmethyl)propyl] -2S-amino-3,3-dimethylbutyramide

A solution of N-[2R-hydroxy-3-[[(2-carbomethoxyamino-benzimidazole-5-yl) sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2S- [(phenylmethanesulfonyl)amino]-3,3-dimethylbutyramide (4.0 g, 5.4 mmol) in MeOH (15 ml) and THF (65 ml) hydronaut in the presence of 10% Pd/C (2.0 g) at room temperature under 3,515 kg/cm2(50 psi) for 16 hours. The catalyst was removed by filtration and the filtrate concentrated under reduced pressure. The resulting residue is triturated with ether and filtered. The solid residue of pripremi)amino]-1S-(phenylmethyl)propyl]-2S-amino-3,3-Dimethylbutane (2.9 g, 88%) as pale yellow powder. A portion of the product is distilled HPLC (HPLC) with reversed phase, using 10-90% CH3N/H2O gradient (30 min) at a flow rate of 70 ml/min. and the Appropriate fractions combined and dried by freezing to produce pure N-[2R-hydroxy-3-[[(2-carbomethoxyamino-benzimidazole-5-yl) sulfonyl] (2-methylpropyl)amino]-1S-(phenylmethyl)propyl-2S - amino-3,3-dimethylbutyramide in the form of a white powder: Rt= a 13.9 min; the Belarusian library Association-MS m/z = 609 (M+Li); 603 (M+H); VRMS (HMRS): expect. for C29H43N6O6S 603,2965 (M+H); found 603,2972.

EXAMPLE 54

According to the methods of the previous Examples can be obtained compounds are shown in Tables 2-9 (see the end of the description).

EXAMPLE 55

The compounds of this invention are effective inhibitors of HIV protease. According to the data of enzymatic analysis, described below, compounds provided in examples described here, inhibit HIV enzyme. Preferred compounds of this invention and calculated IC50values (50% inhibitory concentration, i.e. the concentration at which the compound is an inhibitor reduces enzyme activity by 50%) are presented in Table 10. Method of enzymatic analysis described below. Sub is(1989)]. Conditions of the analysis are the following:

Buffer for analysis: 20 mm sodium phosphate, pH 6,4; 20% glycerol; 1 mm add; 1 mm DTT; 0.1% of CHAPS.

The above substrate was dissolved in DMSO, then diluted 10 times with buffer for analysis. The final concentration of substrate in the analysis is equal to 80 μm. HIV protease was diluted with a buffer for analysis to the end of 12.3 nanomolar concentrations of the enzyme, based on the molecular weight 10780.

The final concentration of DMSO is 14% and the final concentration of glycerol is 18%. The test compound dissolved in DMSO and diluted with DMSO to 10x on the concentration of the test; add 10 μl of the enzyme preparation, the substances are mixed and then the mixture is incubated at ambient temperature for 15 minutes. The enzymatic reaction is initiated by adding 40 μl of the substrate. The increase in fluorescence is fixed at 4 points in time (0, 8, 16 and 24 minutes) at ambient temperature. Each analysis is performed in two holes.

The preceding examples can be reproduced with similar success by substituting the usual and specifically described reactants and/or conditions of the method of the present invention the reagents and/or the processing conditions used in the preceding pretermitting analysis and SEM cell analysis.

The method of analysis of HIV inhibition acutely infected cells is an essentially automatic colorimetric analysis using connection tetryzoline, which is described Pauwles et al, J. Virol. Methods, 20, 309-321 (1988). Tests conducted in 96-well tablets for tissue culture. CEM cells, CD4+cell line grown in RPMI-1640 medium (Gibco), supplemented with 10% fetal calf serum, and then treated polybrene (2 μg/ml). an 80 μl volume of medium containing 1 to 104cells dispersed in each hole of the tablet for tissue culture. To each well was added 100 μl of test compound dissolved in tissue culture medium (or medium without test compound as a control) to achieve the desired final concentration and the cells incubated at 37oC for 1 hour. A frozen culture of HIV-1 was diluted in culture medium to a concentration of 5 x 104TCID50per ml (TCID50= the dose of virus that infects 50% of cells in tissue culture), and 20 μl samples of the virus (containing 1000 TCID50virus) is added to wells containing test compound and to wells containing only medium (infected control cells). Several holes ademowo connection is determined by adding the environment without the virus in several holes, containing the test compound. In General, tablets with tissue culture contained the following experiments. (see tab. A).

In experiments 2 and 4 final concentration of the test compounds were 1, 10, 100, and 500 μl/ml as a positive drug control include either azidothymidine (AZT) or dideoxyinosine (ddI). Test compounds dissolved in DMSO and diluted with tissue culture medium so that in any case the final concentration of DMSO did not exceed 1.5%. DMSO and added to all control wells at the appropriate concentration.

After the introduction of the virus to cells incubated at 37oC in humidified 5% CO2the atmosphere within 7 days. The test compounds are usually added on day 0, 2 and 5, if necessary. On day 7 after infection, the cells in each well is re-suspended and select 100 ál sample of each cell suspension for analysis. To each 100 μl of cell suspension, add 20 ál of 5 mg/ml solution of 3-(4,5-dimethylthiazol-2-yl)-2,5 - diphenyltetrazolium bromide (MMT) and the cells incubated for 4 hours at 27oC in an environment containing 5% CO2. During incubation, MTT metabolities restored living cells, private Na 0.01 N HCl for lizirovania cells and samples incubated over night. For each sample, determine the absorbance at 590 nm using a Molecular Devices microplate reader. The absorption values for each row of holes is compared in order to assess viral control the infection, the response of uninfected control cells and test compound on the cytotoxicity and antiviral effectiveness.

The compounds of this invention are effective antiviral compounds and, in particular, effective retroviral inhibitors, as shown above. Thus, the inventive compounds are effective inhibitors of HIV protease. Assume that the inventive compounds can also inhibit other retroviruses, such as other lentiviruses, in particular other strains of HIV, for example, WC-2, the virus T-cell leukemia human respiratory syncytial virus, human immunodeficiency virus monkeys, feline immunodeficiency virus, cytomegalovirus and picornavirus. Thus, the claimed connection is effective for the treatment, prophylaxis of retroviral infections and/or prevent the spread of retroviral infections.

The inventive compounds are also effective to prevent the growth of retroviruses in solution. As the cell to the number of well-known goals, such as research methods and diagnosis, including calibration and control. Before and during growth and storage of cell cultures, the claimed compounds can be added to the cell culture medium at a concentration effective to prevent unexpected or unwanted replication of a retrovirus, which may accidentally, inadvertently or intentionally be present in cell culture. The virus may be present initially in cell culture, for example, it is known that HIV is present in T-lymphocytes of humans long before its discovery in the blood, or during exposure to the virus. Such use of the claimed compounds prevents unknown or accidental exposure to potentially lethal retrovirus researcher or practitioner.

The compounds of this invention can contain one or more asymmetric carbon atoms and can therefore exist in the form of optical isomers, as well as in the form of racemic or narramissic mixtures thereof. The optical isomers can be obtained by separation of racemic mixtures by standard methods, for example, education diastereoisomeric salt processing optically active acid or base and SATAII of these salts. Examples of appropriate acids are tartaric, diatsetilvinny, dibenzoyltartaric, ditawarkannya and camphorsulfonic acid. Another method of separation of optical isomers involves the use of columns for chiral chromatography, optimally chosen to maximize the separation of enantiomers. The following is an acceptable method involves synthesis of covalent diastereoisomeric molecules by interaction of the compounds of formula I with an optically pure acid in an activated form or an optically pure isocyanate. Synthesized diastereoisomer can be divided in the usual way, such as chromatography, distillation, crystallization or sublimation, and then hydrolyze to release the enantiomerically pure compound. Optically active compounds of formula I can also be obtained by using optically active educt. These isomers can be in the form of a free acid, free base, complex, ester or salt.

The compounds of this invention can be used in the form of salts derived from inorganic and organic acids. Such salts include, but are not limited to, the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzo is aconsultant, glucoheptonate, glycyrrhizinate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-econsultant, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, mesilate, undecanoate. Additionally, basic nitrogen-containing groups can be quaternity such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutil and diamyl sulfates, halides, long-chain, such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides, such as benzyl and phenethyl bromides, and others. You get a water or oil-soluble or dispersible products.

Examples of acids that can be used to obtain pharmaceutically acceptable salts of the accession of the acid include inorganic acids as hydrochloric acid, sulfuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid. Other examples of Agni, or with organic bases.

The total daily dose, administered to a patient in single or divided by total dose (repeated at intervals of time) may be the number, for example, from 0.001 to 10 mg/kg body weight daily, and usually from 0.01 to 1 mg Composition standard dose may contain such number of sub-multiple doses that make up the daily dose.

The amount of active ingredient which can be combined with substances-carriers in order to obtain a single dosage form, usually varies from patient to be treated, and the particular method of administration.

The regimen of medicines for the treatment of painful conditions compounds and/or compositions of this invention are chosen in accordance with several factors, including the type, age, weight, sex, diet and medical condition of the patient, the severity of the disease, route of administration, pharmacological characteristics, such as the activity, efficacy, pharmacokinetic and toxicology profiles of the particular used compounds are the delivery system for the drug or compound is administered as part of combination is and can vary widely and therefore may deviate from the preferred dosage regimen, above.

The compounds of this invention can be administered orally, parenterally, by inhalation spray, rectally, or topically in a formulation in the form of single doses containing standard non-toxic pharmaceutically acceptable carriers, adjuvants and diluents, if necessary. Local administration can also involve the use of transdermal administration, such as transdermal patches or devices for medicinal electrophoresis. Used herein, the term " parenteral includes subcutaneous injections, intravenous, intramuscular, vnutriserdecnuu (intrasternal) injection or infusion techniques.

Injectable preparations, for example a sterile aqueous or oily suspension for injection, can be prepared according to known in the field methods using suitable dispersing or wetting agents and suspendresume agents. A sterile preparation for injection may also be a sterile solution or suspension for injection in a non-toxic parenterally acceptable diluent or solvent, for example in 1,3-butanediol. To an acceptable carriers or solvents that can be used, autosets suspendiruetsa environment typically use sterile, non-volatile oils. For this purpose, can be used any soft fixed oils, including synthetic mono - or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of drugs for injection.

Suppositories for rectal administration of medicinal remedies can be obtained by mixing the drug with a suitable, not causing irritation excipient, such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at rectal temperature and therefore, melt in the rectum and release the drug.

Solid dosage forms for oral administration may include capsules, tablets, pills, powders and granules. In such solid dosage forms the active compound may be mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms can also include, in normal practice, additional substances, in addition to inert diluents, for example, lubricants such as magnesium stearate. In the case of capsules, tablets and pills, the dosage forms may also include sabatinivka dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in this field, such as water. Such compositions can also include adjuvants such as wetting agents, emulsifying and suspendresume agents, and sweetening agents, tools, gives taste and aroma.

Although the compounds of this invention can be entered as the sole active pharmaceutical agent, they can also be used in combination with one or more immunomodulators, antiviral agents or other anti-infective funds. For example, the compounds of this invention can be introduced in combination with AZT, DDI, DDC or glucosidase inhibitors, such as N-butyl-1-deoxynojirimycin, or in the form of their prodrugs for the prevention and/or treatment of AIDS. When used in combination therapeutic agent can be formulated as separate compositions that provide at the same time or at different times, or therapeutic agent can be introduced in the form of a single composition.

The above is only an illustration of this invention and it is implied that the invention is not limited to the disclosed compounds. the m and the essence of the present invention, which is defined in the following claims.

From the above description specialists in this field can easily set the essential characteristics of this invention and, without going beyond being and scope of the invention, it is possible to make various changes and modifications of the present invention to adapt it to various usages and conditions.

1. Hydroxyethylamino sulfonamides heterocyclicamines amino acids represented by the General formula

< / BR>
or their pharmaceutically acceptable salt,

where n = 0;

R1- alkyl with 1-5 carbon atoms;

R2- aralkyl, in which the alkyl has 1-3 carbon atoms;

R3- alkyl with 1-5 carbon atoms;

R4group of the formula

< / BR>
where a and b each independently is oxygen;

R6is hydrogen or deuterium;

R7is hydrogen or deuterium.

2. Connection on p. 1, or its pharmaceutically acceptable salt, where R1with 1-4 carbon atoms; R2- arylmethyl.

3. Connection on p. 2, or its pharmaceutically acceptable salt, where R1- ISO-propyl, sec-butyl, tert-butyl, R2is benzyl, R3- propyl, isoamyl, isobutyl, butyl, R4- 1,3-binarisation acid, salt, sulfuric acid salt, phosphoric acid salt, oxalic acid salt, maleic acid salt, succinic acid salt of citric acid or salt methanesulfonic acid.

5. Salt p. 4, where the specified pharmaceutically acceptable salt is a salt of hydrochloric acid, a salt of oxalic acid, a salt of citric acid or salt methanesulfonic acid.

6. Connection on p. 1, which is a 2S-[[(pyrrolidin-2-yl)carbonyl] amino] -N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)-sulfonyl] (2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethyl-butanamide;

2S-[[pyrrolidin-2-yl)carbonyl] amino] -N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl] (2-methylpropyl)amino]-1S(phenylmethyl)propyl]-3S-methyl-pentanone.

7. The composition having inhibitory activity against retroviral protease containing compound under item 1 and a pharmaceutically acceptable carrier.

8. A method of inhibiting retroviral proteases, including the introduction of an effective amount of the compounds under item 1.

9. A method of treating a retroviral infection, comprising introducing an effective amount of the composition under item 7.

10. The method of preventing replication of a retrovirus, including the of rovirosa in vitro, including the introduction of an effective amount of the compounds under item 1.

12. A method of treating AIDS comprising introducing an effective amount of the composition under item 7.

Priority points:

07.06.1995 on PP.1,2,5,6 and 8-12;

10.03.1995 on PP.3,4 and 7.

 

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