Cyclic urea, a method of inhibiting the growth of retroviruses and pharmaceutical composition

 

(57) Abstract:

Describes the new cyclic urea of General formula /I/, where W, R4, R4A, R5, R6, R7, R7Aand n described in paragraph (1 formulas, suitable as protease inhibitors of retroviruses. Describes a pharmaceutical composition based on compounds of the formula /I/, and the method of inhibiting the growth of retroviruses using compounds of the formula /I/. 5 C. and 15 C.p. f-crystals, 2 PL.

This application is a partial continuation of patent application U.S. 07/883944, filed may 15, 1992, which is a partial continuation of patent application U.S. 07/776491, filed October 11, 1991

The present invention relates to substituted cyclic CARBONYLS and their derivatives, useful as protease inhibitors of retroviruses, containing such compounds, pharmaceutical compositions and to methods of using such compounds for the treatment of viral infections.

Currently in treatment of viral diseases usually involves the introduction of compounds that inhibit the synthesis of viral DNA. The current treatment of AIDS (AVDS) Dagani, Chem. Eng. News, November 23, 1987, pp. 41 - 49/ includes introduction of such soy is 1,2,4-triazole-3-carboxamide, 3'-azido-3'-deoxythymidin /AZT/ and adriamycin, which inhibits viral DNA synthesis, such compounds as AZ - 721 and polymannuronate, which can prevent the entry of HIV into host cells, and compounds that treat appropriate infection caused by the immunosuppression caused by HIV infection. As shown, none of the currently available treatments of AIDS is not fully effective in the treatment and/or reversal of the disease. In addition, many of the compounds that are used currently for the treatment of AIDS, cause harmful side effects, including low levels of platelets, renal toxicity and cytopenia and bone marrow. Proteases are enzymes that break down proteins at specific peptide bonds. Many biological functions are controlled by, or are carried out by proteases and their complementary protease inhibitors. For example, proteiny renin cleaves peptide angiotensinogen to obtain peptide angiotensin I. Angiotensin I is further cleaved protease angiotensin converting enzyme /angiotensin converting enzyme/ education hypotensive peptide angiotensin II. Inhibitors of renin and ACE are known to reduce high because of problems of accessibility with oral admission and stability in vivo.

The genomes of retroviruses encode a protease, which is responsible for the proteolytic enter one or more of polyproteins predecessors, such as poI and gag gene products. Cm. Wellink, Arch. Virol. 98, 1 /1988/. Protease retroviruses often impose gag-precursor in the middle of the protein and lead pol-predecessor in reverse transcriptase and retroviral protease.

Correct entry predecessors polyproteins at the expense of the retroviral protease is required for Assembly of infectious virions. It was shown that in vitro mutagenesis, in which are formed protease-defective viruses, leads to the production of immature internal forms that are not infectious ability. Cm. Crawford J. Virol. 53 899 /1985/; Katoh et. al., Virology 145 280 /1985/.

Therefore, the inhibition of retroviral proteases leads to the desired target for antiviral therapy. Cm. Mitsuya, Nature 325 775 /1987/. Moore, Biochem. Biophys. Res. Commun. 159 420 /1989/ reveals peptidyl inhibitors of HIV protease. Erickson, European Patent Application N WO 89/10752 discloses derivatives of peptides that are inhibitors of HIV protease.

U.S. patent N 4652552 discloses derivatives of methylketones of tetrapeptides as inhibitors of viral proteases. U.S. patent N 4644055 reveals GE N WO 87/07836 disclosed gamma monohydroxylic L-glutamic acid as an anti-virus agent.

The ability to inhibit viral protease provides a method for blocking virus replication and, consequently, the treatment of such viral diseases as AIDS, which can give fewer side effects, be more efficient and can provide less prone to addiction to drugs compared to the current treatment.

The object of the present invention are substituted cyclic CARBONYLS and derivatives thereof, and those compounds which are able to inhibit viral protease and is thought to serve as a means of combating such viral diseases as AIDS. Substituted cyclic CARBONYLS and derivatives thereof, presented in this invention provide a significant improvement in comparison with well-known specialists protease inhibitors. A large number of compounds, as reported, are inhibitors of proteases such as renin, but they suffer from lack of adequate bioavailability, and therefore are not useful as therapeutic agents, especially in case of need of oral administration. So weak activity attributed to the relatively high molecular weight of most protease inhibitors, napthol the x in vivo and which usually cause significant binding to molecules in human serum. Substituted cyclic CARBONYLS and derivatives described here, give this plan a number of advantages, including that they do not contain peptide bonds have low molecular weight and can be hydrophilic, already inhibiting viral proteiny enzyme.

In addition, known inhibitors of other, non-HIV-protease, does not inhibit HIV protease. The structural requirements for the activity of these inhibitors differ from the requirements for inhibitors of HIV protease. Substituted cyclic CARBONYLS and derivatives thereof of the present invention are particularly useful as inhibitors of HIV protease and similar retroviral proteases.

Other HIV-protease inhibitors have been described, but to date none of them proved to be clinically effective. This inapplicability lies partly in the previously discussed factors for inhibitors of renin, especially due to low biospiritual. Compounds of the present invention offer a valuable solution to this problem, in the sense that they are of low molecular weight and so many have good absorption in oral introduction mammals, providing 1 - 100% absolute oral receptivity.

In this izobreteny/BR> where R4and R7independently vibirut from hydrogen, C1-C8of alkyl, substituted 0 - 3 R11; C2-C8-alkenyl, substituted with 0 to 3 R11; C2-C8-quinil, substituted with 0 to 3 R11; C3-C8-cycloalkyl, substituted with 0 to 3 R11; C6-C10-bicycloalkyl, substituted with 0 to 3 R11; aryl, substituted with 0 to 3 R12; C6-C14-carbocyclic residue substituted with 0 to 3 R12; heterocyclic system substituted with 0 2 R12consisting of 5 to 10 atoms including at least one atom of nitrogen, oxygen, or sulfur;

R4Aand R7Aindependently selected from hydrogen, C1-C4-alkyl substituted by halogen or C1-C2-alkoxy; benzyl, substituted by halogen or C1-C2-alkoxy;

R4and R4Amay not necessarily be connected with the formation of 5 - to 7-membered carbocyclic ring, substituted with 0 2 R12;

R7and R7Amay not necessarily be connected with the formation of 5 - to 7-membered carbocyclic ring, substituted with 0 2 R12;

n = 0, 1, or 2;

R5selected from fluorine, Diptera, =O, C1-C3the alkyl or or20;

R6n = 1, selected from hydrogen, =O, fluorine, Diptera, C1-C3the alkyl or-OR21;

R5and R6can be an alternative connected with the formation of the epoxide ring; -OCH2SCH2O; -OS/=O/O-; -OC/=O/O; -OCH2O-; -OC/=S/O-; -OC/=O/C/=O/O-; -OC/CH3/2O-; -OC/OCH3//CH2CH2CH3/O-; or any group that after the introduction of the connection mammals split with the formation of free dihydroxyl;

R20and R21independently selected from hydrogen, C1-C6of alkyl, substituted 0 - 3 R11; C3-C6-alkoxyalkyl, substituted with 0 to 3 R11; C1-C6-alkylsulphonyl, substituted with 0 to 3 R11; C1-C6-alkoxycarbonyl, substituted with 0 to 3 R11; benzoyl substituted with 0 to 3 R12; phenoxycarbonyl, substituted with 0 to 3 R12; phenylenecarbonyl, substituted with 0 to 3 R12; or any group that after entering the connection mammals split with the formation of free hydroxyl;

R11choose from one or more of the following groups: keto, halogen, cyano, -CH2NR13R14, -NR13R14, -CO2R13, -OC/=O/R13, -OR13C2-C6alkoxyalkyl, -S/O/mR13, -NHC/=NH/HR13, -C/=NH/OTHER13, -C/=O/NR13R14, -NR14C/SUP>SO2NR13R14, -NR14SO2R13, -SO2NR13R14C1-C4of alkyl, C2-C4alkenyl, C3-C6cycloalkyl,

C3-C6cycloalkenyl; 1 to 3 amino acids linked by an amide bonds, and linked with R4or R7via the amine or carboxylate end; C5-C14-carbocyclic residue substituted with 0 to 3 R12; aryl, substituted with 0 to 3 R12; or heterocyclic ring system, substituted with 0 2 R12consisting of 5 to 10 atoms, containing at least one atom of nitrogen, oxygen, or sulfur;

R12when he is Deputy on carbon, selected from one or more of the following groups: phenyl, benzyl, Venetia, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4of alkyl, C3-C6cycloalkyl, C3-C6cycloalkenyl, C7-C10arylalkyl, C1-C4alkoxy, -CO2H, hydroxamic acid, hydrazide, oxime, boric acid, sulfonamida, promila, C3-C6cycloalkane, OR13C1-C4of alkyl, substituted-NR13R14, -NR13R14C2-C6alkoxyl, C1-C4hydroxyalkyl, methylenedioxy is aryloxy, C1-C4alkylsulphonyl, C1-C4alkylcarboxylic, -S/O/mR13, -SO2NR13R14, -NHSO2R14, -OCH2-CO2H, 2-/1-morpholino/ethoxy; or 5 - or 6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur; or R12can be 3 - or 4-carbon chain attached to adjacent carbons of the ring with the formation of a condensed 5 - or 6-membered ring, with the specified 5 - or 6-membered ring optionally substituted on the aliphatic carbons with halogen, C1-C4the alkyl, C1-C4alkoxy, hydroxy, or-NR13R14; or, if R12attached to a saturated carbon atom, it may be carbonyl or thiocarbonyl; R12if he is a Deputy from nitrogen, are selected from one or more of the following groups: phenyl, benzyl, Venetia, hydroxy, C1-C4hydroxyalkyl, C1-C4alkoxy, C1-C4of alkyl, C3-C6cycloalkyl, C3-C6cycloalkenyl, -CH2NR13R14, -NR13R14,

C2-C6alkoxyalkyl, C1-C4haloalkyl, C1-C4alkoxycarbonyl, -CO2H, C1-CKyl, or C3-C6alkoxyalkyl;

R14- OH, H, C1-C4alkyl or benzyl;

R13and R14can be an alternative connected with education/CH2/-CH2/5-, -CH2CH2N/R15/CH2CH2- or-CH2CH2OCH2CH2-;

R15- H or CH3; m = 0, 1, or 2;

W is selected from-N/R22/C/= Z/N/R23/-; -N/R22/S/=O/N/R23-; -OC/=Z/O-; -N/R22/C/= Z/O; -C/R25//R26/C/= Z/C/R27//R28/-' -N/R22/C/=Z/C/R27//R28/-; -C/R25//R26/C/= Z/O; N/R22/C/=O/C/=O/N/R23/-; -C/R25//R26/C/F2/C/R27//R28/-;

-C/R25//R26//R26/N/CH3//O/C/R27/ /R28/-;

-C/R25//R26/N/OR29/C/R27// R28/-; -C/R25//R26/C/=Z/S;

where Z = O, S or NR24;

R22and R23independently selected from hydrogen, C1-C8of alkyl, substituted 0-3 R31; C2-C8alkenyl, substituted 0-3 R31; C2-C8the quinil, substituted 0-3 R31; C3-C8cycloalkyl, substituted 0-3 R31; C6-C10bicycloalkyl, substituted 0-3 R31; aryl, substituted 0-3 R32; C6-C14carbocyclic residue, Samedan at least one atom of nitrogen, oxygen, or sulfur;

R24selected from: hydroxy; amino; C1-C4of alkyl, C1-C4alkoxy, C1-C4aminoalkyl; cyano; nitro; benzyloxy;

R25and R27independently selected from the following groups: hydrogen; C1-C8of alkyl, substituted 0-3 R31; C2-C8alkenyl, substituted 0-3 R31; C2-C8the quinil, substituted 0-3 R31; C3-C8cycloalkyl, substituted 0-3 R31; C6-C10bicycloalkyl, substituted 0-3 R31; aryl, substituted 0-3 R32; C6-C14carbocyclic residue substituted 0-3 R32; heterocyclic ring system, substituted 0-2 R32consisting of at least from 5 to 10 atoms including at least one nitrogen atom of oxygen or sulfur;

R26and R28independently selected from hydrogen, C1-C4of alkyl, substituted by halogen or C1-C4alkoxy; benzyl, substituted by halogen or C1-C2alkoxy;

R29selected from hydrogen, C1-C4of alkyl, substituted by halogen or C1-C2alkoxy; benzyl, substituted by halogen or C1-C2alkoxy;

or in another embodiment, R22, R2512;

or in another embodiment, R23, R27or R28independently can be joined with R7or R7Awith the formation of five - or six-membered condensed heterocyclic, aromatic, alicyclic ring, substituted 0-2 R12;

or in another embodiment, W may be connected to R5or R6with the formation of three - to semichasnoho condensed heterocyclic or carbocyclic ring, substituted 0-2 R12;

R31choose from one or more of the following groups: keto, halogen, cyano, -CH2NR13R14, -NR13R14-, -CO2R13, -CO/=O/R13, -OR13C2-C6-alkoxyalkyl, -S/O/mR13, -NHC/= NH/OTHER13, -C/= NH/OTHER13, -C/=O/NR13R14, -NR14C/=O/R13, = NOR14, -NR14C/= O/OR14, -OC/=O/NR13R14, -NR13C/=O/NR13R14, -NR14SO2NR13R14, -R14SO2R13, -SO2NR13R14C1-C4-alkyl, C2-C4alkenyl, C3-C6-cycloalkyl,

C3-C6-cycloalkenyl; 1-3 amino acids, linked together by an amide bonds, and linked to R4or R7through amine or carboxy; or heterocyclic ring system, substituted 0-2 R32containing 5 to 10 atoms including at least one nitrogen atom, oxygen or sulfur; R32if he is Deputy on carbon, selected from one or more of the following groups: phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4-alkyl, C3-C6-cycloalkyl, C3-C6-cycloalkenyl, C7-C10-arylalkyl, C1-C4-alkoxy, -CO2H, hydroxamic acid, hydrazide, oxime, baronova acid, sulfonamide, formyl, C3-C6-cycloalkane, -OR13C1-C4alkyl, substituted-NR13R14, -NR13R14C2-C6-alkoxyalkyl, C1-C4-hydroxyalkyl, methylenedioxy, Ethylenedioxy, C1-C4-haloalkyl, C1-C4-haloalkoxy, C1-C4-alkoxycarbonyl, C1-C4-alkylcarboxylic, C1-C4-alkylsulphonyl, C1-C4-alkylcarboxylic, -S/O/mR13, -SO2R13R14,

-NHSO2R14, -OCH2CO2H, 2-/1-morpholino/-ethoxy, - C/R14/=N,/OR14/; or five - or six-membered heterocyclic ring containing 1 to 4 heteroatoms, wybranie carbons of the ring with the formation of a condensed five - or six-membered ring, moreover, the specified five - or six-membered ring may be optionally substituted on the aliphatic carbons with halogen, C1-C4-alkyl, C1-C4-alkoxy, hydroxy, or-NR13R14; or, if R32attached to a saturated carbon atom, it may be carbonyl or thiocarbonyl; R32if he is a Deputy from nitrogen, are selected from one or more of the following groups: phenyl, benzyl, phenethyl, hydroxy, C1-C4-hydroxyalkyl, C1-C4-alkoxy, C1-C4-alkyl, C3-C6-cycloalkyl, C3-C6-cycloalkenyl, -CH2NR13R14, -NR13R14, -NR13R14C2-C6-alkoxyalkyl,

C1-C4-haloalkyl, C1-C4-alkoxycarbonyl, -CO2H, C1-C4-alkylcarboxylic,

C1-C4-alkylaryl, -C/R14/=N,/OR14/; provided that R4, R4A, R7and R7Aare not hydrogen; if W is-OC/=Z/O-, R4and R7are not hydrogen; if R4and R4Aboth hydrogens, at least one of the following is not hydrogen: R22, R23, R25- R28.

Preferred compounds of the present from carstvo,

where R4and R7independently selected from hydrogen, C1-C4of alkyl, substituted 0-3 R11; C3-C4-alkenyl, substituted 0-3 R11; C3-C4-quinil, substituted 0-3 R11;

R4Aand R7Ais hydrogen;

n = 0 or 1;

R5selected from fluorine, Diptera, = O, or-OR20;

R6from hydrogen, =O, fluorine, Diptera or or21;

R5and R6can be an alternative connected with the formation of the epoxide ring; -OCH2S CH2O-; -OS/=O/O-; -OC/=O/O-; -OCH2O-; -OC/=S/O-; -OC/=O/C/= O/O-, -OC/CH3/2O-; -OC/OCH3//CH2CH2CH3/O-; or can be any group that, when the introduction of a drug to a mammal split with the formation of free dihydroxyl;

R20and R21independently selected from hydrogen;

C1-C6-alkylcarboxylic; C1-C6-alkoxycarbonyl, benzoyl or any group that, when the introduction of a drug to a mammal split with the formation of free hydroxyl;

R11choose from one or more of the following groups: keto, halogen, cyano, -CH2NR13R14, -NR13R14, -CO2R13, -OC/=O/R13, -OR13C -C6-cycloalkyl; C5-C14-carbocyclic residue substituted 0-3 R12; aryl, substituted 0-3 R12; or heterocyclic ring system, substituted 0-2 R12containing 5 to 10 atoms including at least one nitrogen atom, oxygen or sulfur;

R12if he is a Deputy at the carbon atom, selected from one or more of the following groups: phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4-alkyl, C3-C6-cycloalkyl, C3-C6-cycloalkenyl, C7-C10-arylalkyl, C1-C4-alkoxy, -CO2H, hydroxamic acid, hydrazide, oxime, baronova acid, sulfonamide, formyl, C3-C6-cycloalkane, -OR13C1-C4-alkyl, substituted-NR13R14, NR13R14C2-C6-alkoxyalkyl, C1-C14-hydroxyalkyl, methylenedioxy, Ethylenedioxy, C1-C4-haloalkoxy, C1-C4-alkoxycarbonyl, C1-C4-alkylcarboxylic, C1-C4-alkylsulphonyl, C1-C4-alkylcarboxylic, -S/O/mR13-SO2NR13R14, -NHSO2R14; or five - or six-membered heterocyclic ring containing 1 to who ever got carbon atoms, attached to adjacent carbon ring with the formation of a condensed 5 - or 6-membered ring, with the specified 5 - or 6-membered ring may be optionally substituted on the aliphatic carbons with halogen, C1-C4-alkyl, C1-C4alkoxy, hydroxy, or-NR13R14; or, if R12attached to a saturated carbon atom, it may be carbonyl or thiocarbonyl; R12if he is Deputy on the nitrogen are selected from one or more of the following groups: phenyl, benzyl, phenethyl, hydroxy, C1-C4-hydroxyalkyl, C1-C4-alkoxy, C1-C4-alkyl, C3-C6-cycloalkyl, C3-C6-cycloalkenyl, -CH2NR13R14, -NR13R14C2-C6-alkoxyalkyl, C1-C4-haloalkyl, C1-C4-alkoxycarbonyl, C1-C4-alkylcarboxylic, C1-C4-alkylsulphonyl, -CO2H, R13is H, C1-C6-alkyl or C3-C6-alkoxyalkyl; R14is OH, H, C1-C4-alkyl or benzyl; R13and R14can be an alternative connected with education/CH2/4-, -/CH2/5-, -CH2CH2N/R15/CH2CH W is selected from-N/R22/C/= Z/N/R23/ ; N/R22/C/=Z/O-; -C/R25//R26/C/= Z/C/R27//R28/-; -N/R22/C/= Z/C/R27//R28/-; -C/R25//R26/C/=Z/O-; -N/R22/C/= O/C/= O/N/R23/-; -C/R25//R26/C/F2/C/R27//R28/-; where Z = O, S, N-CN, N-OH, N-OCH3; R22and R23independently selected from the following groups: hydrogen, C1-C8-alkyl, substituted 0-3 R31; C3-C8alkenyl, substituted 0-3 R31; C3-C8-quinil, substituted 0-3 R31; C3-C6-cycloalkyl, substituted 0-3 R31; R25and R27independently selected from hydrogen, C1-C8of alkyl, substituted 0-3 R31; C2-C8-alkenyl, substituted 0-3 R31; C3-C8-quinil, substituted 0-3 R31; R26and R28is hydrogen;

R31choose from one or more of the following groups: keto, halogen, cyano, -CH2NR13R14, -NR13R14, -CO2R13, -OC/=O/R13, -OR13C2-C4-alkoxyalkyl, -S/O/mR13C1-C4-alkyl, C2-C4alkenyl, C3-C6-cycloalkyl; C5-C14-carbocyclic residue substituted 0-3 R12; aryl, substituted 0-3 R32; or heterocyclic ring is whether sulfur;

R32when he is Deputy on carbon, selected from one or more of the following groups: phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4-alkyl, C3-C6-cycloalkyl, C3-C6-cycloalkenyl, C7-C10-arylalkyl, C1-C4-alkoxy, -CO2H, hydroxamic acid, hydrazide, oxime, baronova acid, sulfonamide, formyl, C3-C6-cycloalkane, -OR13C1-C4-alkyl, substituted-NR13R14, -NR13R14C2-C6-alkoxyalkyl, C1-C4-hydroxyalkyl, methylenedioxy, Ethylenedioxy, C1-C4-haloalkyl, C1-C4-haloalkoxy, C1-C4-alkoxycarbonyl, C1-C4-alkylcarboxylic, C1-C4-alkylsulphonyl, C1-C4-alkylcarboxylic,

-S/O/mR13, -SO2NR13R14, -NHSO2R14-THE C/R14/=N,/OR14; or 5 - or 6-membered heterocyclic ring containing 1 heteroatom selected from oxygen, nitrogen or sulfur; or R32may be a chain of 3 or 4 carbon atoms, prisoedinennykh to the adjacent carbon ring with the formation of a condensed 5 - or 6-membered ring, etc is B>4
-alkyl, C1-C4-alkoxy, hydroxy, or-NR13R14; or, if R32attached to a saturated carbon atom, it may be carbonyl or thiocarbonyl R32if he is Deputy on the nitrogen are selected from one or more of the following groups: phenyl, benzyl, phenethyl, hydroxy, C1-C4-hydroxyalkyl, C1-C4-alkoxy, C1-C4-alkyl, C3-C6-cycloalkyl, C3-C6-cycloalkenyl, -CH2NR13R14, -NR13R14,

C2-C6-alkoxyalkyl, C1-C4-haloalkyl, C1-C4-alkoxycarbonyl, C1-C4-alkylcarboxylic, C1-C4-alkylsulphonyl, -CO2H-C/R14/=N,/OR14/; provided that R4, R4A, R7and R7Anot all are hydrogen; when W is-OC/= Z/O-, R4and R7are not hydrogen; if R4and R4Aboth hydrogens, at least one of the following is not hydrogen: R22, R23, R25- R28.

Other preferred compounds of the present invention according to formula I are:

The compound of formula (II)

< / BR>
where R4and R7independently selected from hydrogen, C1-C4- Is UP>; R6- hydrogen or-OR21; R20and R21independently are hydrogen or any group that, when the introduction of a drug to a mammal cleaved with the formation of free hydroxyl; R11choose from one or more of the following groups: keto, halogen, -CH2NR13R14, -NR13R14, -OR13C2-C4-alkoxyalkyl, C1-C4-alkyl, C2-C4alkenyl, C3-C6-cycloalkyl; aryl, substituted 0-3 R12; or heterocyclic ring system, substituted 0-2 R12consisting of 5 to 10 atoms including at least one nitrogen atom, oxygen, sulfur; R12if he is Deputy on carbon, selected from one or more of the following groups: phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, C1-C4-alkyl, C7-C10-arylalkyl, C1-C4-alkoxy, -CO2H, hydroxamic acid, hydrazide, oxime, baronova acid, sulfonic, formyl, C3-C6-cycloalkane, -OR13C1-C4-alkyl, substituted-NR13R14, -NR13R14methylendioxy, C1-C4-haloalkyl, C1-C4-alkylsulphonyl, C1-C4-alkylcarboxylic, hydroxy, hertta or sulfur; R12if he is Deputy on nitrogen, is selected from benzyl or methyl; R13is H, C1-C2-alkyl or C3-C6-alkoxyalkyl; R14- OH, H or C1-C2-alkyl; R13and R14in another embodiment, can be connected with education/CH2/4-, -/CH2/5, -CH2CH2/R15/CH2CH2-, or CH2CH2OCH2CH2-;

W is selected from-N/R22/C/= Z/ /R23/-; -C/R25//R26/C/=Z/C/R27//R28/-; -N/R22/C/= Z/C/R27//R28/-; -C/R25//R26/C/=Z/O-; where Z Is O, S or N-CN; R22and R23independently selected from hydrogen, C1-C4of alkyl, substituted 0-3 R31; C3-C4-alkenyl, substituted 0-3 R31; R25and R27independently selected from hydrogen, C1-C4of alkyl, substituted 0-3 R31; C3-C4-alkenyl, substituted 0-3 R32; R26and R28is hydrogen; R31choose from one or more of the following groups: keto, halogen, -CH2NR13R14, -NR13R14, -OR13C2-C4-alkoxyalkyl, C1-C4-alkyl,

C2-C4alkenyl, C3-C6-cycloalkyl; aryl, substituted 0-3 R32; or heteros is nitrogen, oxygen or sulfur; R32if it is the Deputy of carbon, selected from one or more of the following groups: phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, C1-C4-alkyl, C7-C10-arylalkyl, C1-C4-alkoxy, -CO2H, hydroxamic acid, hydrazide, oxime, baronova acid, sulfonamide, formyl, C3-C6-cycloalkane, -OR13C1-C4-alkyl, substituted-NR13R14, -NR13R14methylendioxy, C1-C4-haloalkyl, C1-C4-alkylsulphonyl, C1-C4-alkylcarboxylic, hydroxy, hydroxymethyl, -C/R14/=N,/OR14/; or 5 - or 6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur; R32if he is Deputy on nitrogen, is selected from benzyl or methyl; provided that, if R4and R7both are not hydrogen; if R4is hydrogen, at least one of the following is not hydrogen: R22, R23, R25- R28.

More preferred compounds of the present invention of the above are compounds in which R4and R7independently selected from hydrogen, C1<>0and R21independently are hydrogen or any group that, when the introduction of a drug to a mammal split with the formation of free hydroxyl; R11choose from one or more of the following groups: halogen, OR13C1-C4-alkyl, C3-C5-cycloalkyl; aryl, substituted 0-2 R12; or heterocyclic ring system selected from pyridyl, pyrimidyl, triazinyl, furanyl, teinila, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, indolyl, chinoline, ethanolamine, R12if he is Deputy on carbon, selected from one or more of the following groups: benzyloxy, halogen, methyl, C1-C4-alkoxy, CF3, 2-/1-morpholino/ethoxy, -CO2H, hydroxamic acid, hydrazide, oxime, cyano, baronova acid, sulfonamide, formyl, C3-C6-cycloalkane, C1-C4-alkyl, substituted-NR13R14, -NR13R14, hydroxy, hydroxymethyl; or R12if he is Deputy nitrogen, is stands; R13- H or methyl; R14- OH, H or stands; R13and R14can be an alternative connected with education/CH2/4-/CH2/5-, -CH2CH23or N/R22/C/=N CN/N/R23/-; R22and R23independently selected from hydrogen, C1-C4of alkyl, substituted 0-1 R31; C3-C4-alkenyl, substituted 0-1 R31; R31choose from one or more of the following groups: halogen, -OR13C1-C4-alkyl, C3-C5-cycloalkyl; aryl, substituted 0-2 R32; or heterocyclic ring system selected from pyridyl, pyrimidinyl, triazinyl, furanyl, teinila, perrella, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, indolyl, chinoline, izochinolina R32if he is Deputy of carbon, selected from one or more of the following groups: benzyloxy, halogen, methyl, C1-C4-alkoxy, CF3, 2-/1-morpholino/ethoxy-CO2H, hydroxamic acid, hydrazide, oxime, cyano, baronova acid, sulfonamide, formyl, C3-C6-cycloalkane, C1-C4-alkyl, substituted-NR13R14-, -NR13R14, hydroxy, hydroxymethyl, -C/R14/ = N,/OR14/; or R32if he is a Deputy from nitrogen, is stands, provided that if R4is hydrogen, R7is not hydrogen; if R4is hydrogen, at least one of slidename of the present invention of the above are compounds wherein R4and R7are benzyl; R5- OH; R6- hydrogen or-OH; R13- H or stands; R14- H or stands; W is-N/R22/C/=O/N/R23or N/R22/C/=N CN/N/R23/-; R22and R23independently selected from hydrogen, C1-C4of alkyl, substituted 0-1 R31; R31choose from one or more of the following groups: C3-C5-cycloalkyl; aryl, substituted 0-2 R32; or heterocyclic ring system selected from pyridyl, tanila of chinoline or izochinolina; R32if he is Deputy of carbon, selected from one or more of the following groups: CONH2, -CO2H, -CHO, -CH2NHOH, -CH2NR13R14, -NR13R14, hydroxy, hydroxymethyl, -C/R14/= N,/OR14/; or R32if he is a Deputy from nitrogen, is stands.

Preferred are also the compounds of formula /IIa/

< / BR>
where R22and R23independently selected from the group consisting of hydrogen, allyl, propyl, cyclopropylmethyl, n-butyl, ISO-butyl, CH2CH=CH/CH3/2, pyridylmethyl, Metallica, n-pentile, out-pentile, hexyl, benzyl, pyridylmethyl, isoprenyl, propargyl, picoline, marinellie, the vinyloxyethyl, pentafluorobenzyl, hyalinella, carboxybenzene, chlorothene, picoline, benzyloxybenzyl, phenylbenzyl, adamantylamine, cyclopropylmethanol, ethoxybenzyl, hydroxybenzyl, hydroxymethylbenzene, aminobenzyl, formylmethyl, cyanobenzyl, cinnamyl, allyloxymethyl, tormentil, cyclobutylmethyl, formaldoxime, cyclopentylmethyl, nitrobenzyl, nitrosobenzene, carboxylatomethyl, carbomethoxyamino, tetracarbonyl, dimethylallyl.

Most preferred are the compounds of formula /IIa/

< / BR>
selected from the group consisting of the compounds of formula /IIa/

where R22and R23- allyl;

R22and R23- propyl;

R22and R23- cyclopropylmethyl;

R22and R23- n-butyl;

R22and R23- CH2CH=CH/CH3/2;

R22and R23- out-of pentyl;

R22and R23- 4-pyridylmethyl;

R22and R23- 2-methallyl;

R22and R23- n-pentyl;

R22and R23- isobutyl;

R22and R23- benzyl;

R22and R23- 3-pyridylmethyl;

R22- allyl, R23- isoprenyl;

R22and R23- 3-propargyl;

Rmethyl;

R22and R23- 3,3-dimethyl-1-butyl;

R22and R23- 2-ethoxyethyl;

R22- 3-methyl-5-oxazolidinyl, and R23is hydrogen;

R22- 1-naphthylmethyl, and R23- 1-naphthylmethyl;

R22and R23- 3-methyloxazolidine;

R22and R23- 2-vinyloxyethyl;

R22and R23- 2,3,4,5,6-pentafluorobenzyl;

R22is benzyl, and R23- 2-hyalinella;

R22and R23- 4-carboxybenzoyl;

R22and R23- 5-chloro-2-thienyl;

R22and R23- 2-hyalinella;

R22- 2-propyl, and R23- 2-picoline;

R22and R23- 3-benzyloxybenzyl;

R22- 4-phenylbenzyl, and R23- phenylbenzyl;

R22- 2-adamantylamine, and R23- 2-adamantylidene;

R22is hydrogen, and R23- cyclopropylmethyl;

R22- 2-picoline, and R23- 2-naphthylmethyl;

R22- 3-allyl, and R23is hydrogen;

R22- 3-allyl, and R23- 2-picoline;

R22- 3-allyl, and R23- 4-picoline;

R22- 3-benzyloxybenzyl, and R23- 3-benzyloxybenzyl;

R22and R23- 3-cyclopropylmethoxy;

R22and R23- 3-ethoxybenzyl;

R22and R23- 4-benzile the 22
and R23- 3-hydroxymethylene;

R22and R23- 4-hydroxymethylbenzene;

R22and R23- 3-aminobenzyl;

R22and R23- 3-carboxybenzoyl;

R22and R23- 3-formylmethyl;

R22and R23- 3-cyanobenzyl;

R22and R23- 2-naphthylmethyl;

R22- n-butyl, and R23- benzyl;

R22- allyl, and R23- cyclopropylmethyl;

R22- n-butyl, and R23- cyclopropylmethyl;

R22- 3-methallyl, and R23- benzyl;

R22is benzyl, and R23- ethyl;

R22is benzyl, and R23- 4-picoline;

R22- cyclopropylmethyl, and R23- 4-picoline;

R22is benzyl, and R23- cyclopentylmethyl;

R22- cyclopropylmethyl, and R23- cyclopentylmethyl;

R22is benzyl, and R23- n-propyl;

R22- cyclopropylmethyl, and R23- cinnamyl;

R22- cyclopropylmethyl, and R23-2 - naphthylmethyl;

R22- cyclopentylmethyl, and R23-2-naphthylmethyl;

R22is benzyl, R23-2 - naphthylmethyl;

R22- cyclopropylmethyl, R23- 2-picoline;

R22and R23- 3-cyanobenzyl;

R22- 3-allyl, R23- 2-naphthylmethyl;

R22P> - 2-naphthylmethyl;

R22- 4-picoline, R23- 2-naphthylmethyl;

R22- 3-allyl, R23- cyclopentylmethyl;

R22- 3-allyl, R23- 2-hyalinella;

R22- 3-picoline, R23- cyclopropylmethyl;

R22- 3-picoline, R23- 2-naphthylmethyl;

R22- 3-allyloxymethyl, R23- 3-allyloxymethyl;

R22- 3-allyloxymethyl, R23- 3-hydroxybenzyl;

R22- 3-picoline, R23- 3-picoline;

R22- 2-naphthylmethyl, and R23- 4-terbisil;

R22and R23- 3-carbomethoxybiphenyl;

R22and R23- 4-formylmethyl;

R22and R23- 4-cyanobenzyl;

R22- 4-hydroxybenzyl, and R23- n-propyl;

R22- 3-hydroxybenzyl, and R23- n-propyl;

R22and R23- 3-carboxybenzoyl;

R22and R23- cyclobutylmethyl;

R22and R23- cyclopentylmethyl;

R22- n-butyl, and R23- 3-methallyl;

R22- n-butyl, and R23- cyclopentylmethyl;

R22and R23- 3-formaldoxime;

R22- cyclopropylmethyl, and R23- 3-hydroxybenzyl;

R22- cyclopropylmethyl, and R23- 4-hydroxybenzyl;

R22and RAminobenzyl;

R22- 2-naphthylmethyl, and R23- 3-hydroxybenzyl;

R22- 4-hydroxymethylbenzene, and R23- 3-hydroxybenzyl;

R22and R23- N-methyl-/3-amido-benzyl;

R22- N-methyl-/3-amido/benzyl, and R23- 3-/amidino/-benzyl;

R22- 3-/5-tetrazolyl/benzyl, and R23- cyclopropylmethyl;

R22and R23- 3-/5-tetrazolyl/benzyl;

R22and R23- phenylmethyl-3-baronova acid.

Especially preferred are the following compounds of formula (I), in which the IC50(IR50or values of Ki< 10 nm for the inhibition of HIV protease: a compound of the formula /IIa/,

where R22and R23- allyl;

R22and R23- propyl;

R22and R23- cyclopropylmethyl;

R22and R23- n-butyl;

R22and R23- CH2CH=CH/CH3/2;

R22and R23- out-of pentyl;

R22and R23- 2-methallyl;

R22and R23- n-pentyl;

R22and R23- benzyl;

R22- allyl, and R23- isoprenyl;

R22and R23- 3-hydroxybenzyl;

R22and R23- 4-hydroxybenzyl;

R22and R23- 3-hydroxymethyl-benzyl;

R22and R23- 4-R22and R23- 3-formylmethyl;

R22and R23- 3-cyanobenzyl;

R22and R23- 2-naphthylmethyl;

R22- n-butyl, R23- benzyl;

R22- allyl, and R23- cyclopropylmethyl;

R22- n-butyl, and R23- cyclopropylmethyl;

R22- 3-methallyl, and R23- benzyl;

R22is benzyl, and R23- ethyl;

R22is benzyl, and R23- 4-picoline;

R22- cyclopropylmethyl, and R23- 4-picoline;

R22is benzyl, and R23- cyclopentylmethyl;

R22- cyclopropylmethyl, and R23- cyclopentylmethyl;

R22is benzyl, and R23- n-propyl;

R22- cyclopropylmethyl, and R23- cinnamyl;

R22- cyclopropylmethyl, and R23- 2-naphthylmethyl;

R22is benzyl, and R23- 2-naphthylmethyl;

R22- cyclopropylmethyl, and R23- 2-picoline;

R22and R23- 3-cyanobenzyl;

R22- 3-allyl, and R23- 2-naphthylmethyl;

R22- n-propyl, and R23- 2-naphthylmethyl;

R22- n-butyl, and R23- 2-naphthylmethyl;

R22- H, and R23- 2-naphthylmethyl;

R22- 4-picoline, and R23- 2-naphthylmethyl;

R22- 3-allyl, and R23- cyclopentylmethyl;

R22- 3-picoline, and R23- 2-naphthylmethyl;

R22- 3-allyloxymethyl, and R23- 3-allyloxymethyl;

R22- 3-allyloxymethyl, and R23- 3-hydroxybenzyl;

R22and R23- 3-picoline;

R22- 2-naphthylmethyl, and R23- 4-terbisil;

R22and R23- 3-carbomethoxybiphenyl;

R22and R23- 4-cyanobenzyl;

R22and R23- 4-formylmethyl;

R22and R23- 4-cyanobenzyl;

R22- 4-hydroxybenzyl, and R23- n-propyl;

R22- 3-hydroxybenzyl, and R23- n-propyl;

R22and R23- 3-carboxybenzoyl;

R22and R23- cyclobutylmethyl;

R22and R23- cyclopentylmethyl;

R22- n-butyl, and R23- 3-methallyl;

R22- n-butyl, and R23- cyclopentylmethyl;

R22and R23- 3-formaldoxime;

R22- cyclopropylmethyl, and R23- 3-hydroxybenzyl;

R22- cyclopropylmethyl, and R23- 4-hydroxybenzyl;

R22and R23- 3-/N-methylamino/-benzyl;

R22and R23- 3-acetylbenzo;

R22and R23- 3-hydroxylamines;

R22- 2-naphthylmethyl, and R23- 3-hydroxybenzyl;

R22- 4-the P>22
- N-methyl-/3-amido-benzyl, and R23- 3-/amidino/benzyl;

R22- 3-/5-tetrazolyl/benzyl, and R23- cyclopropylmethyl;

R22and R23- 3-/5-tetrazolyl/benzyl;

R22and R23- phenylmethyl-3-baronova acid.

The following preferred compounds of formula (I), for which the value of the IC90(IR90) < 10 mg/ml to inhibit the growth of HIV: the connection formula /IIa/,

where R22and R23- allyl;

R22and R23- cyclopropylmethyl;

R22and R23- n-butyl;

R22and R23- CH2CH=CH/CH3/2;

R22and R23- propyl;

R22and R23- out-of pentyl;

R22and R23- benzyl;

R22and R23- 3-hydroxybenzyl;

R22and R23- 4-hydroxybenzyl;

R22and R23- 3-hydroxymethylene;

R22and R23- 4-hydroxymethylbenzene;

R22and R23- 3-aminobenzyl;

R22and R23- 3-carboxybenzoyl;

R22and R23- 3-formylmethyl;

R22and R23- 3-formaldoxime;

R22and R23- 3-/N-methylamino/-benzyl;

R22and R23- 3-acetylbenzo;

R22and R23- 3-hydroxylamine which R23- 3-hydroxybenzyl;

R22and R23- N-methyl/3-amido/benzyl;

R22- N-methyl/3-aminobenzyl/, and R23- 3-amidino/benzyl;

R22- 3-/5-tetrazolyl/benzyl, and R23- cyclopropylmethyl;

R22and R23- 3-/5-tetrazolyl/benzyl;

R22and R23- phenylmethyl-3-baronova acid.

Preferred in the present invention are the compounds of formula /Ib/

< / BR>
or their pharmaceutically acceptable salts or prodrugs,

where R22and R23independently selected from hydrogen, cyclopropylmethyl, CH2/C6H4/-p-OCH2C6H5CH2/C6H4/-p-OH, cyclopentylmethyl, allyl, n-butyl,

beta naphthylmethyl, benzyl, CH2/C6H4/-m-OCH2C6H5p-nitrobenzyl, m-nitrobenzyl, CH2/C6H4/-m-OH, p-aminobenzyl m-aminobenzyl, p-nitrobenzyl, m-nitrobenzyl, dimethylallyl, cyclohexylmethyl, cyclobutylmethyl, propyl, 3-methyl-1-butyl, carboxamides and formaldoxime.

More preferred are the following compounds of formula I, in which the values of the IC50or Ki< 10 nm for the inhibition of HIV protease: the compounds of formula /Ib/, in which R22
or their pharmaceutically acceptable salts, or prodrugs,

where R33- OH, halogen, H, N3;

R22and R23independently selected from hydrogen, allyl, propyl, cyclopropylmethyl, n-butyl, ISO-butyl, CH2CH=CH/CH3/2, pyridylmethyl, Metallica, n-pentile, out-pentile, hexyl, benzyl, pyridylmethyl, isoprenyl, propargyl, picoline, methoxyethyl, cyclohexylmethyl, dimethyl-butyl, ethoxyethyl, methyloxazolidine, naphthylmethyl, methyloxazolidine, vinyloxyethyl, pentafluorobenzyl, hyalinella, carboxybenzene, chloranil, picoline, benzyloxybenzyl, phenylbenzyl, adamantylamine, cyclopropylmethanol, ethoxybenzyl, hydroxybenzyl, hydroxymethylbenzene, aminobenzyl, formylmethyl, cyanobenzyl, cinnamyl, allyloxymethyl, tormentil, cyclobutylmethyl, formaldoxime, cyclopentylmethyl, nitrobenzyl, nitrosobenzene, carboxylatomethyl, carboxymethylamino and dimethylallyl.

In the present invention it was found that the above listed compounds are useful as inhibitors of HIV protease and similar retroviral proteases, and therefore, for the treatment of HIV infection and similar retrov the Oia of HIV, pharmaceutically effective amount of the compounds of formula I, as described earlier.

The described compounds may have asymmetric centers. In the scope of the present invention includes all chiral, diastereoisomers and racemic forms. In the compounds described here can meet many geometric isomers of olefins, C= N double bond, etc., and all such stable isomers are also part of the present invention.

When any variable (for example, R1- R28, R4Aand R7A, m, n, w, z and so on) occurs more than one time in any constituent or in formula /I/ or /II/, or in any other frequent this formula, its definition in each case depends on its definition in each of the other cases. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

The term "alkyl" used in the description includes both branched and unbranched aliphatic saturated hydrocarbon group containing the specified number of carbon atoms; "alkoxy" represents an alkyl group with the specified number of carbon atoms attached through an oxygen bridge; "the cycle, cloepfil and cyclooctyl; and "bicycloalkyl" include saturated bicyclic groups such as [3.3.0] bicicletta, [4.3.0]bicycleand, [4.4.0]bellocan/decalin/, [2.2.2]bicicletta and so on, the term "alkenyl" refers to a branched or unbranched hydrocarbon chain containing one or more unsaturated carbon-carbon bonds, which may reside anywhere in the chain, for example, Attila, propenyl, etc. and the term "quinil" refers to a branched or unbranched hydrocarbon chains, containing one or more triple carbon-carbon bond, which may reside anywhere in the chain, for example, atenolo, PROPYNYL, etc., "Halogen" is used to denote a fluorine, chlorine, bromine and iodine; the term "counterion" is used to denote a small, negatively charged particles, for example, chloride, bromide, hydroxide, acetate, sulfate, etc.

The term "aryl" or "aromatic residue" is used to denote a phenyl or naphthyl; "carbocyclic" refers to any stable 5-7-membered monocyclic or bicyclic, or 7-14 membered bicyclic or tricyclic carbon ring, and any of them may be saturated, partially anticline" refers to a stable 5 to 7-membered monocyclic or bicyclic, or 7-10-membered bicyclic heterocyclic ring which may be saturated or unsaturated, and which consists of carbon atoms and 1-3 heteroatoms selected from the group consisting of nitrogen atoms, oxygen and sulfur, and nitrogen atoms and sulfur may optionally be oxidized, and the nitrogen may optionally be quaternity, and includes any bicyclic group in which any of the above heterocyclic rings condensed with the benzene ring. The heterocyclic ring can be attached to it hanging down the group at any heteroatom or carbon atom that results in the formation of a stable structure. Described here heterocyclic ring can be substituted on the carbon atoms or nitrogen, if the resulting compound is stable. Examples of such heterocycles include, but are not limited to/ pyridyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, benzothiophene, indolyl, indolinyl, chinoline, ethenolysis or benzimidazolinyl, piperidinyl, 4-piperidinyl, pyrrolidinyl, 2-pyrrolidinyl, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroisoquinoline, decahydroquinoline or octahedrite the form specified group, provided that the normal valency of the specified atom is not exceeded, and that this substitution leads to the formation of stable compounds.

By "stable compound" or "stable structure" is meant a compound which is sufficiently stable to withstand the selection with the desired degree of purity from a reaction mixture, and the transformation into an effective therapeutic agent.

The term "pharmaceutically acceptable salt and prodrug" refers to derivatives of the disclosed compounds that are modified due to the transfer of acidic or basic salts, or by modifying functional groups present in the compound so that these modifications can be split either in a known manner, either in vivo, before obtaining the parent compounds. Examples include but are not limited to, salts of mineral or organic acids such basic residues as amines; alkali or organic salts acid residues such as carboxylic acids; acetates, formats, and benzoate derivatives of alcohols and amines; etc.

Pharmaceutically acceptable salts of the compounds of the present invention can be obtained by interaction of the form of the free acid or o in an organic solvent, or mixtures thereof; usually non-aqueous environment, such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, is more preferable. A list of suitable salts can be found in Remington's, Pharmaceutical Science, 17th ed., Mack Publishing Company, Easton, PA, 1985, p. 1418.

Compounds of the present invention can be obtained using the General methods of synthesis described hereinafter. Each of these sources is included here as a reference.

Compounds of the present invention, in which W is-N/R22/C/=Z/N/R23/ or N/R22/C/= O/C/= O/N/R23/-; R5- -OR20or H; R6- -OR21or H and n=1, can be obtained from diamines of formula (III:

< / BR>
The diamines of formula (III can be obtained by the method described in U.S. patent 5294720 (issued 15.03.1994).

Other methods for obtaining compounds /III/ described in European patent publication 40266A1, in U.S. patent 4837204 and in the patent application Canada 2026832.

The compounds of formula (III can be cilitate to obtain compounds of formula (I) in circumstances which are usually used to obtain cyclic ureas, which are known in the art. Use reagents J/C=Z/-J', where J and J' represent otsepleniya group, preferably, in a relatively dilute condition /for example, to Maintain the many examples J and J', preferred carbonyldiimidazole, thiocarbonyldiimidazole, phosgene, thiophosgene, diphenylcarbonate or diphenylthiourea. In addition, for compounds where W is-N/R22/C/=O/C/= O/N/R23/-, the compounds of formula (III can be subjected to interaction with activated derivatives of oxalic acid, preferably with oxalylamino in the previously mentioned conditions, to obtain diamide.

For compounds of the present invention, in which R20or R21represents-OH, it is advantageous to protect the free hydroxyl before cyclization. Used protective groups include any of those listed in Greehe, Protective Groups in Organic Synthesis, Chapter 2, Wiley. NY /1981/. Preferred protective groups are trimethylsilylmethyl /SAM/, methoxyethoxymethyl /mA'am/ or methoxymethyl /IOM/.

Cyclization of compounds of formula (III results framework /IV/,

< / BR>
i.e. patterns /I/, where W is the N/R22/C/=O/C/=O/N/R23/ - and n=1/.

Another preferred method of obtaining the compounds of formula /IV/, if R22and R23associated with the respective nitrogen atoms through CH2is the cyclization of the compounds of formula (III, where R22and R23are Vodnik method. The preferred base is sodium hydride, and the preferred alkylating agents are R22Y and R23Y, where Y is halogen, triflate or mesilate, preferably bromide or iodide. Preferred conditions include polar aprotic solvents and temperature from 0 to 100oC.

After removal of the protective groups /if they are/ get the structure of formula I, where R5and R6represent hydroxyl.

If R5and R6different from OR20and OR21may need some chemical modification of functional groups to obtain the compounds of formulas /III/ or /IV/, it is clear that professionals in the field of organic synthesis. The following are examples of such methods.

Methods for producing compounds in which R5is OH, and R6is OR21include protection of nitrogen /if necessary/ subsequent interaction diol with one equivalent of base and one equivalent of acylhalides, alkylhalides, alkoxyalkyl, alkoxycarbonyl, benzolamide, diphenylcarbonate or phenylisocyanate, and purification on a chromatographic column from unwanted bis-alkyl derivatives and UP> represents H, include protection of nitrogen /if necessary/ and restore diol to monosperma, using known in the art methods (see, for example, Chem. Comm. 1971; J. Org. Chem., 1969, 3923/. The preferred method is the formation of ester cyclic diol and restore using hydride. Remove protection from nitrogen /if necessary/ results in the desired connection.

Methods for producing compounds in which R5is OH, and R6is F, include protection of nitrogen /if necessary/ followed by the formation of mono-protected diol, as described previously. As a result of reaction with a fluorinating agent, preferably, diethylaminosulfur /company is changing/ /Reagents for Organic Synthesis Vol. 13, p110, Wiley Interscience, NY, 1988/ get alkylphenyl. Remove protection from nitrogen /if necessary/ and hydroxyl results in the desired connection.

Methods for producing compounds in which R5- OH, and R6is = O, include protection of nitrogen /if necessary/, and standard conditions for oxidation of glycols to pinicola. The preferred oxidant is one equivalent of pyridinediamine in dichloromethane, or one equivalent of NaOCl in HOAc. After removing the protection from azote can oxidize to the ketone under standard conditions, preferably, the oxidation Swarna (Swern), using oxalicacid, DMSO and Et3N, with subsequent alpha-hydroxylation ketone /see Tet. Zett. 1981; 604; Tet. Zett. 1982, 2917/.

Methods for producing compounds in which R5is OH, and R6is ditoro-include protection of nitrogen /if necessary/ and hydroxyl obtained previously penacola, with subsequent interaction of the carbonyl with a fluorinating reagent, for example, DAST. After removing protection from hydroxyl and nitrogen /if necessary/ get the target connection

Methods for producing compounds in which R5and R6connected with the formation of the epoxide include protection of nitrogen /if necessary/ further standard conditions to obtain the epoxide of glycol /see for example, J. Org. Chem. 1981, 3361/. The preferred reaction of the glycol with more than two equivalents of base and one equivalent of an activating group, for example, methanesulfonamido. After removing /if necessary/ protection get the target connection.

Methods for producing compounds in which R5- OH, and R6- C1-C3-alkyl include protection of nitrogen /if necessary/ and liaising previously obtained epoxide with realvariable at low temperature /-78 to -40oC/ /cm Carruthers. Some Modern Methods in Organic Synthesis p. 64, Cambridge University Press, 1978/.

With appropriate choice of reagents specialist these manipulations can be done by obtaining the claimed combination of R5and R6.

Compounds of the present invention, where W is the N/R22/C/=Z/N/R23or N/R22/C/=O/C/=O/N/R23- and n=0;

can be obtained from diamines of the formula /V/.

< / BR>
which, in turn, can be obtained according to the method described in European patent application 402646 Al.

Protection /if necessary/, cyclization and manipulation of functional groups /when you wish/ carry out the previously described method to obtain compounds of the formula /VI/:

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Compounds of the present invention, in which W is-OC/=O/O - and n=1, (can be obtained from diols of the formula /VII/:

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which, in turn, can be obtained according to the method described in U.S. patent 5294720 (issued 15.03.1994).

Manipulation of functional groups /when you wish/ can be done in the way described earlier, followed by cyclization carbonate, using standard conditions, preferably phosgene or thiophosgene in the presence of 2 equivalents of such grounds as potassium hydride to obtain the compounds formuliert formula /VIII/

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which, in turn, can be obtained according to the method described in U.S. patent 5294720 (issued 15.03.1994) using one equivalent of azide in the reaction of the diol of formula /VII/ obtaining aspidosperma, with subsequent restoration by the method of U.S. patent 5294720 to education amerosport.

Protection /if necessary/ and manipulation of functional groups /when you wish/ carried out as described previously, followed by cyclization to obtain the carbamate using standard conditions, preferably phosgene or thiophosgene in the presence of 2 equivalents of base, such as potassium hydride, to obtain compounds of the formula /I/.

Compounds of the present invention, in which W is-OC/=Z/O-, and n=O, can be obtained from the diol of formula IX/:

< / BR>
which can, in turn, be obtained by reaction of R4CHO lithium anion of 1,3-dithiane, followed by reaction of R7CHO with anion product /see Carruthers, Some Modern Methods in Organic Synthesis, p. 45, Cambridge University Press, 1978/. Splitting dithiane ion mercury results in an acyclic alpha, alpha' dihydroxyacetone.

Manipulation of functional groups, if desired, is carried out in accordance with the above, with subsequent cyclization to carbonate, ispolzuet potassium hydride, to obtain the compounds of formula (I).

Compounds of the present invention, in which W is N/R22/C = Z/O-and n = 0; can be obtained from amerosport formula /X/

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which, in turn, can be obtained by the method described in published European patent application 402646 A1 for the synthesis of compounds of the formula /V/, previously, however, instead of azide in the disclosure of oxirane /below/ reacts oxygen nucleophile, such as acetate or hydroxide ion, in the presence of a polar aprotic solvent, for example DMSO.

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In another embodiment, oxiran treated with a catalytic amount of a strong acid in water and co-solvent, if necessary, with simultaneous removal of the BOC protective group.

Protection /if necessary/ and manipulation of functional groups /when needed/ carry out the method described above, followed by cyclization to the carbamate using standard conditions, preferably phosgene or thiophosgene, in the presence of 2 equivalents of base, such as potassium hydride, to obtain compounds of the formula /I/.

Compounds of the present invention, in which W is C/R25//R26/N/CH3//O/C/R27//R28/ - the sustained fashion benzyloxycarbonyloxy group; activation of the alcohol to the substitution preferably derived sulfonate, such as methylchloride; removing the protective group at the nitrogen, preferably with hydrogen in the presence of a catalyst such as palladium on charcoal, and heated in a dilute state in the presence of such a base as triethylamine to implement cyclization.

Then a secondary cyclic amine will was identified in preferably a mixture of formic acid and formaldehyde, and preferably oxidizes percolate, for example MSRWA, to obtain compounds of the formula I, where W is-C/R25//R26/N/CH3//O/C/R27//R28-. Secondary cyclic amine in another embodiment, directly oxidize to get the formula /I/, where W is-C/R25//R26/N/OR29/C/R27//R28/.

Compounds in which W is C/R25//R26/C/=Z/C/R27//R28/ - and n = 0, can be obtained by alkylation of the protected cyclohexandione /XI/ required R4-ZG and R7- ZG, and optional R4A- ZG and R7A- ZG groups, where ZG is tsepliaeva group, for example halogen or sulphonate ester.

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The recovery of the ketone to the alcohol, preferably using LiAlH4or manipulations, to each is Wiley, NV, 1981/. Protection of alcohol or other reactive groups, followed by alkylation of the ketone and removing protection, leads to the formation of compounds of the formula /1/, where W is-C/R25//R26/C/=Z/C/R27//R28/ - and n = 0.

Compounds in which W is C/R25//R26/= Z/C/R27//R28/ - and n = 1, can be obtained from the protected hydroxyketones described before, due to the expansion of the ring, for example, in the reaction Tiffeneau - Demyanov /March, Advanced Organic Chemistry, p 965, NV 1985/ or treatment dimethylsulfonium to obtain spiroepoxide, with subsequent expansion of the ring, acid catalyzed, to cycloheptanone /see above, pp 871, 966/.

The above methods have the advantage that they get a number of stereoisomers, which, after purification, can be estimated based on the best combination of performance, security and in vivo availability.

Compounds in which W is-C/R25//R26/C/F2/C/R27//R28/ - and n = 0 or 1, can be obtained from the above protected hydroxyketone processing fluorinating agent, preferably, DAST, as indicated previously.

Compounds in which W is N/R22/C/=Z/C/R27//R28/ - and n = 0, can be obtained by cyclization of compounds /XII/ to the lactam, use the /XII/ can, in turn, be obtained by a method described in the European patent publications 434365 A2, 386611 A2, 389127 A1 and CA 2005337, each of which is incorporated here by reference. OP formula /XII/ indicates a protected oxygen. The hydroxyl can be protected through the use of any of a number of groups, as indicated Greene, Protective Groups in Organic Synthesis, Chapter 2, Wiley, NV /1981/.

If desired, the resulting lactam /XIII/

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we can further functionalitywith, for example, in the following ways: the nitrogen of the lactam can be alkilirovanii R22- ZG group, preferably using sodium hydride in DMF); group R4A, R7or R7Ayou can add, remove protection and oxidizing the alcohol, followed by alkylation of enolate using R4A-ZG, R7-ZG or R7A-ZG; and recovering the ketone to hydroxyl, or otherwise functionalitya until the desired group R5as indicated previously.

Compounds where W is-N/R22/C/=Z/C/R27//R28/- and n = 1, you can get known in the art of ketones of the formula /I/, where W is the C/R25//R26/C/= Z/C/R27//R28/ - and n = 0, preferably by Beckmann rearrangement /March, Advanced Organic Chemistry, p 987, Wiley, NV, 1985/. In the manipulation group, R5when manual is UP>28
/ - and n = 1.

Compounds in which W is-C/R25//R26/C/=Z/O-and n = 0 or 1, can be obtained from compounds of formula (I), where W is-N/R22/C/= Z/C/R27//R28/-, n = 0 or 1, and R22- H, for example, by hydrolysis of the lactam with the subsequent substitution of the primary amine-hydroxyl and the circuit to the lactone /March, Advanced Organic Chemistry, p 348, Wiley, NV, 1985/.

Similarly, compounds in which W is-C/R25//R26/C/=Z/S - a n = 0 or 1, can be obtained from compounds of formula (I), where W = -N/R22/C/ = Z/C/R27//R28/ -, n = 0 or 1, and R22- H, for example, by hydrolysis of the lactam, followed by conversion of the primary amine in salt, page, substitution NaSH, and snapping to gliotactin /March, cm, previously, p 60/.

The compounds of formula (I) described earlier, in which Z=0, can be transformed into diprosone, where Z=S, using standard conditions /February, see above, p 792/; preferably using disulfide described in Bull. Soc, Chem. Belges, 1978, 223.

The compounds of formula I described earlier, where Z=0, can be transformed into imino-derivatives, where Z=NR24using standard conditions. If R24is OH or O-alkyl, you can get oximes, and if you want them to preaccelerated, as described in the March /cm, previously, pp 359, 805/. Similarly, it is p who should be obtained as depicted in figure 1 /next/. Intramolecular binding of the N-substituted or unsubstituted dialdehydes can be obtained at the expense of ORGANOMETALLIC reagents derived from vanadium, titanium, Samari, etc. Dialdehyde the original substance can be obtained from commercially available materials by methods known to experts in the field of organic synthesis, preferably, in accordance with the methods set forth in PCT application with publication number WO 92/14696. (date of publication 3.09.1992).

Compounds where W is-N/R22/C/=O/N/R23/ - and n=2, can be obtained in accordance with the following scheme 2. Eight-membered cyclic urea scheme 2 can be protected, if necessary, and processed as described previously to obtain the target compound.

Compounds in which W is N/R22/C/=O/N/R23/ - and n = 1, can likewise be obtained in accordance with the following schemes 3, 4, 6, 7 (see below). If necessary, the described intermediate compounds can be processed by renowned specialists of ways to produce compounds included in the scope of the present invention.

Compounds where W is-N/R22/C/=N OR/N/R23/ or N/R22/C/=S/N/R23- and n = 1, can be obtained in accordance with scheme 5 /and specialists of ways to produce compounds included in the scope of the present invention.

Compounds where W is-N/R22/C/=O/N/R23/ - and n = 0, can similarly be obtained in accordance with the following scheme 8. If necessary, the described intermediate compounds can be processed well-known specialists of ways to produce compounds within the scope of the present invention.

Obtaining the compounds of the present invention hereinafter described in more detail.

Method 1.

Obtaining di-N-CBZ-protected 1,4-diamino-2,3-diols /XIX/:

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Details of an experiment with the connection /XIX/ described in U.S. patent 5294720 (issued 15.03.1994)

Method 2.

Obtaining di-O-protected di-N-CBZ-1,4-diamentional /settle down under/ and /XXb/:

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(Settle down under) R = SEM

(XXb) R = MOM

A. Protection in the form of 2-trimethylsilyl)/ethoxymethylene /SAM/ ether /settle down under/:

Connection /XIX/ /60 g, 105 mmol/ dissolved in dry DMF /600 g/. Add diisopropylethylamine /75 ml/ and SEMCI /66,8 g, 400 mmol/ and the resulting mixture was stirred at room temperature for 16 h under nitrogen atmosphere. The resulting solution was diluted with water /1 l/ and extracted with 400 ml of hexane. The organic layer is isolated and washed with water /2 x 100 ml. The aqueous layers are combined and extracted with hexane /2 is evaporated. The remainder chromatographic on silicon dioxide and elute 10-30% mixture of ethyl acetate/hexane to yield a white solid product /91 g, 100%/.

NMR /CDCl3/: 7,0 - 7,4 /m, 2H, Ph/, 5,01 /Shir.S., 4H, PhCH2CO/, 4,5 - 4,95 /m, 6H, NH, OCH2O/, 3,6 - 4,25 /m, 4H, /, 3,5 /s, 4H, OCH2CH2/, was 2.76 /Shir. d, 4H, PhCH2/, 0,1 -1,0 /m, 4H, SiCH2/; MS: 846 /M + NH4, 100/, 695 /M - SEM, 40/.

B. Protection in the form of methoxymethanol /MOM/ ether /XXb/:

Connection /XIX/ /0.5 g, 0.88 mmol/ dissolved in dry DMF /10 ml/. Diisopropylethylamine /and 0.46 ml of 2.64 mmol/ and methoxyethylamine/ 0,165 ml, 2.02 mmol/ add, and the resulting solution was stirred at 40oC in nitrogen atmosphere for 4 hours. According to TLC /50/50 ethyl acetate/methylene chloride/ reaction is completed. The resulting mixture was separated by methylene chloride /50 ml/ 5% HCl /30 ml/. The organic layer emit, washed with water /5 x 20 ml/ brine /20 ml, dried over anhydrous magnesium sulfate and evaporated to obtain the oil is light yellow in color. After chromatographic processing on silica and elution 1-20% of a mixture of ethyl acetate/methylene chloride get /XXb/ in the form of a clear oil /0,29 g, 53%/.

NMR /CDCl3/: , 6,95 - 7,42 /m, 20H, Ph/, 5,1 - 3,8 /complex m/ 3,35 /s, 6H, OCH3/, 2,8 - 2,95 /m, 4H, PhCH2/. MS: 657 /13 M + 1/, 674/21, M + NH4
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(XXIa) R = SEM

(XXIb) R = MOM

A. hydrogenation of the SEM ester /settle down under/.

Connection /settle down under/ /90 g, 108,5 mmol/ dissolved in absolute ethanol /2.5 l/. Add 5% Pd/C /6.5 g/, and the resulting solution was stirred in an atmosphere of hydrogen for 1.5 hours prior to the cessation of hydrogen absorption. According to TLC /20/80 ethyl acetate/hexane/ reaction is completed. The resulting solution was filtered through Celite and evaporated in vacuo to obtain a colorless resin /60 g, 99%/.

NMR /CDCl3/: 7,1 - 7,35 /m, 10H, Ph/, 4,72 /Shir.D., 4H, OCH2O/, 3,5 - 3,9 /m, 6H, NH2, /, 3,15 /m, 2H, /, 2,55 - 2,95 /m, 4H, PhCH2/, 0,95 /m, 4H, SiCH2/.

B. Hydrogenation of IOM ether /XXb/

Connection /XXb/ /0,29 g, 0,441 mmol/ dissolved in 6 ml of ethyl acetate and 3 ml of methanol. Add 10% Pd/C /70 mg/, and the resulting solution was stirred in an atmosphere of hydrogen until it ceases to absorb. According to TLC /20/80 methanol-ethyl acetate/ reaction is completed. The resulting solution was filtered through Celite and evaporated in vacuo to obtain 3b in the form of a clear oil /0,132 g, 77.4 percent/.

NMR /CDCl3/: 7,1 - 7,35 /m, 10H, Ph/, 4,58 /s, 4H, OCH2O/, 3,75 /Shir. S. , 2H, /, 3,3 - 3,5 /m, 2H, /, 3,23 /s, 6H, OCH3/, 2,85 /Shir. d, 4H, PhCH2/. MS: 389/M+ 1, 100/, 345 /3,7/, 280 /1,8/120/ 6,1/.

Method 4.

Obtaining cyclic /XXIa/ /40 g from 71.3 mmol/ dissolved in methylene chloride /200 ml/. Carbonyldiimidazole /13,87 g, 85.6 mmol/ dissolved in methylene chloride /200 ml in a separate flask. Then, each solution was poured in dry methylene chloride /6 l/ with a speed of 90 ml/hour. The resulting mixture is stirred for 18 hours at room temperature in a nitrogen atmosphere. According to TLC /60/40 ethyl acetate/hexane/ reaction is completed. The solvent is removed in vacuo, and the residue is treated chromatography on silica and elute 1-50% of a mixture of ethyl acetate/hexane to obtain compound /XXIIa/ in the form of a white solid product /38,82 g, 93%/.

So pl. 75-76oC /NMR /CDCl3/: 7,05 - 7,4 /m, 10H, Ph/, 4,6 - 4,8 /DD, 4H, OCH2O/, 4,08 /s, 2H, /, 3,5 - 3,91 /m, 8H, NH, /, 2,86 /Shir.D., 4H, PhCH2/, 0,8 - 0,95 /m, 4H, SiCH2/. MS: 587 /M + 1, 100/.

B. Cyclization of IOM ether /XXIb/.

Connection /XXIb/ /0,53 g 1,364 mmol/ dissolved in dry methylene chloride /20 ml/. In a separate flask dissolve carbonyldiimidazole /0,265 g of 1.64 mmol/ 20 ml of methylene chloride. In a third flask, Saudargas pyridine /0,22 ml, 2,73 mmol/ methylene chloride /100 ml at room temperature in a nitrogen atmosphere add the first two solution through a syringe pump at a rate of 1.7 ml/hour. The resulting solution is stirred over night at room is 5% HCl /50 ml/ NaHCO3/50 ml/ brine /50 ml, dried over magnesium sulfate, filtered and evaporated. The resulting residue is treated on khromatograficheskoi column with SiO2and elute 50-75% mixture of ethyl acetate/methylene chloride to obtain /XXIIb/ in the form of a colourless resin /198 mg, 35%/. NMR /CDCl3/: 7,1 - 7,4 /m, 10H, Ph/, 4,65 /q, 4H, OCH2O/, 4,13 /s, 2H, NH/, 3,89 /t, 2H, /, 3,59 /s, 2H, /, 3,18 /s, 6H, OCH3/, 2,87 /m, 4H, PhCH2/. MS: 415 /M + 1, 100/, 102/11/. The intermediate connection Diem z (Dimem Diz):

DuZ diol 507 g /0.89 mol/ mix in 4 l of dichloromethane. To the resulting suspension is added N,N-diisopropylethylamine /780 g, 6.05 mol/ at once at room temperature, followed by precapitalism B-methoxyethoxymethyl /500 g, 4 mol/ /add 1 hour, exothermic/. Boil the solution under reflux for 12 hours. According to TLC /10:1:10 EtOAc: EtOH: hexane, Rf= 0,56/ reaction is completed. The resulting solution is treated with cooling with ice water /3 l/. Washed with dichloromethane extract with water /2 x 2 l/ and dried over magnesium sulfate. The obtained filtrate is dried to dryness. The obtained semi-solid substance is dissolved in chlorobutane (1 liter). The resulting solution was passed through a 4-inch ( 10 cm) layer of silica gel to remove most of the intensive crazeeeeee. The white solid product is washed with hexane /3 x 350 ml/. Dried at room temperature. Allocate the target intermediate connection Z Diem in the form of a white solid product with the release of 525 g /79% yield/.

So melting 52-54oC.

1H NMR /CDCl3/: 2,80 /m, 4H/ - CH2Ph/, 3,38 /6H/-OCH3, to 3.58 /m, 8H, -OCH2CH2O-, 3,80 /m, 2H/, 4,20 /m, 2H/, 4,6 - 5,2 /m, 10H, NH, H2CO2, -OCH2O-/, 7,25 /m, 20H, C6H5/.

The intermediate compounds of cyclic urea:

20 g Z Dimam /26.8 mmol/ dissolved in 200 ml of tetrahydrofuran. To this solution was added 2 g of 10% palladium on charcoal, and the resulting suspension is stirred for 7 hours in an atmosphere of hydrogen /1 ATM/. According to TLC /10: 1: 10 EtOAc:EtOH:Gex, Rf= 0,05/ reaction is completed. The resulting suspension is filtered through a layer of Celite to remove the catalyst. Layer Celite washed with 150 ml of tetrahydrofuran. The THF solution is transferred into a 500 ml round bottom flask. To a solution of THF added 5.5 g /33.3 mmol/ 1,1'-carbonyldiimidazole several portions in the form of a solid product. Stirred at room temperature for 12 hours. According to TLC /10:1:10 EtOAc:EtOH: Gex, Rf= 0,26/ reaction is completed. The resulting mixture is treated, ohlt water /2 x 100 ml and dried over magnesium sulfate. The obtained filtrate is dried to dryness. The residue is purified on silica gel /200 g; 1:1 EtOAc:EtOH:Gex, and then 10:1:10 EtOAc:EtOH:Gex/ to obtain 10.2 g /75.7% of output, after two stages of the target cyclic urea intermediate compound as a colourless oil.

1H NMR /CDCl3/: 2,90 /m, 4H, - CH2Ph/, 3,36 /s, 6H, -OCH3/, 3,40 /m, 8H, -OCH2CH2O-/, 3,60 /m, 2H/, 3,90 /t, 2H,/, 4,10 /s, 2H, NH/, 4,80 /q, 4H, -OCH2O/, 7,30 /m, 10H/C6H5/.

Method 5.

A common way alkylation/hydrolysis.

Connection /XXIIa/ /1 mmol/ dry DMF /5 ml/ add to flask containing sodium hydride /10 mmol, which was washed with hexane 3 x 20 ml)/ DMF /5 ml/. The resulting solution was stirred at room temperature under nitrogen atmosphere for 5 minutes. See the evolution of hydrogen. The corresponding allylbromide /5 mmol/ add, and the resulting solution was stirred at room temperature under nitrogen atmosphere for 1 hour. Interfering were synthesized necessary to heat at 40-70oC for up to 5 hours. To control for the absence of starting materials used TLC /40/60 ethyl acetate/hexane/. The resulting solution is cooled with methanol /1 ml, divided into ether layer /60 ml and the aqueous layer /50 ml/, and organically what SOLOM /30 ml/, dried over magnesium sulfate, filtered and evaporated. If allylbromide contains nitrogen, instead of water, use 1 N. NaOH.

The crude product is directly hydrolyzing in methanol /10 ml and 4 N. HCl /dioxane / /5 ml/ up to 16 hours at room temperature. The resulting solution is evaporated and process chromatography on silica to obtain balkrishna cyclic ureas. If nitrogen is present, the first solution is alkalinized 1 N. NaOH and extracted with ethyl acetate, dried over magnesium sulfate, filtered, evaporated and chromatographic.

As a result of hydrolysis /XXIIb/ in the same conditions receive a 67% yield of N, N-unsubstituted cyclic urea example 1A, so pl. 170-174oC.

Example 1G.

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Synthesis analogously to the synthesis of example 1F. Isomer /2R,3R,4R, 5R/-2,5-diamino-1,6-diphenyl-3,4-hexanediol, required for the synthesis, isolated from the reactions proceed with panditacharya, as described in U.S. patent 5294720 (issued 15.03.1994). /see method 1/.

Example 1G:

13C NMR /CDCl3/: /75,48 MHz/ 37,387; 51,51; 65,136; 72,779; 118,649; 126,540; 128,409; 129,714; 134,618; 137,757; 162,70.

Example 1F.

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Connection /XXIIb/ /0,85 g/ heated in a mixture of acetic acid /9,5 ml/ and water /0.5 second extract with saturated sodium bicarbonate and brine receive the mixture, which, after separation on a chromatographic column gives /XXIIb/ /TLC-1:10 ethyl acetate/hexane Rf= 0,4; 0,54 g/, target monospitovo intermediate /TLC 1:10 ethyl acetate/hexane Rf= 0,1; 0,13 g/ and pergidrolevaya diol /0.05 g/.

The above monospitovo intermediate connection /0.25 g, 0,455 mmol), triphenylphosphine /183 mg, 0.7 mmol/ diethylazodicarboxylate /of 0.11 ml, 0.7 mmol/ and Chloroacetic acid /0.7 mmol/ stirred in 5 ml of anhydrous tetrahydrofuran at 0oC for 15 minutes and then at room temperature for 18 hours. The excess reagent is cooled 0.5 ml of methanol, and the resulting mixture is left under stirring for 20 minutes. The resulting mixture was purified through column chromatography with silica gel to obtain the target intermediate chloracetate with reversed configuration.

13C NMR /CDCl3/: /75,48 MHz/ - 1,373; 14,413; 14,487; 18,253; 25,591; 33,851; 35,741; 40,505; 48,824; 49,962; 57,507; 58,234; 66,589; 67,885; 73,179; 77,423; 95,454; 117,296; 118,554; 126,588; 126,887; 128,518; 128,610; 129,117; 129,199; 129,479; 133,686; 134,168; 136,324; 138,285; 155,698; 166,323.

The above chloracetate intermediate connection 73 mg /0.12 mg/ DL in 2 ml of dry methanol is treated with 0.25 ml /0.5 M/ sodium methoxide and stirred for 30 minutes at room temperature. Noderole removal of the solvent is purified on a chromatographic column with silica gel to obtain compound of example 1F.

The compound of example 1F.

13C NMR /CDCl3/: /75,48 MHz/: 34,075; 37,672; 48,941; 48,985; 58,071; 60,640; 65,861; 73,212; 177,975; 118,669; 126,535; 126,858; 128,603; 128,915; 129,225; 133,605; 134,172; 137,637; 138,273; 155,497.

Getting monoacylglycerol urea.

The intermediate connection with the previous stage /2 g, 4 mmol/ dissolved in 25 ml of toluene and placed in a 100 ml round bottom flask. To this solution was added 85% KOH /0,82 g, 12 mmol/ glycol /MB = 1000/ 0,20, a trap Dean-stark resulting mixture is refluxed for 4 hours until until sobirat theoretical amount of water /0,20 ml/. Cooled to room temperature and add bromelicola /1.78 g, 13,2 mmol/. Stirred at 75oC for 17 hours. According to TLC /10:1:10 EtOAc: EtOH:Gex, Rf= 0,52/ reaction is completed. Treatment consists of cooling water ammoniacloridegas /50 ml and extraction with ethyl acetate /2 x 35 ml/. Washed the organic layer with water /2 x 35 ml and dried over magnesium sulfate. The obtained filtrate is dried to dryness. The residue is purified on silica gel /150 g, 2:3 EtOAc/Gex/ to obtain 1.55 g /70% out/ target monoacylglycerol urea as a colorless oil.

13C NMR /CDCl3/: 3,331; 4,000; 10,619; 32,877; 34,159; 55,677; 58,294; 58Z, 1AA-1AZ and 1BA-1BD.

The compounds listed in table 1a (see the end of the description, examples 1A-1Z, 1AA-1AZ and 1BA-1BD/ get the previously described ways.

The following lists the physical parameters of representative compounds of the present invention.

N example - MC /M+I/

1B - 327.9

1D - 406.5

1H - 407

1J - 531

1K - 463

1L - 604.5

1M - 619

1N - 607

1O - 467

1R - 473

1T - 604

1U - 793

1V - 411

1AE - 395

1AG - 355

1AS - 563

1AT - 435

1BD - 409

1AQ - 507.26

1AU - 559.29

Example, square,oC

1AR - 85-87

1C - 164-166

1A - 170-174

Using the above methods or their modifications, the specialists can obtain compounds of table I b (see the end of the description).

Obtaining a circular guanidino (see diagram at the end of the description).

Connection cyclic guanidines of the present invention, in which W= NH/C= N - CN/NH differ from compounds of cyclic ureas of the present invention, in which W=NH/C=O/NH (see representative methods for producing cyclic compounds guanidines of the present invention).

Structure the following examples are presented in table 1 (see end of description).

Example IBS /08239/. Getting between the keys 175 mg /1,2 mmol/ Dimethyl-N-cyanodithioiminocarbonate. All this is refluxed at 125oC in oil bath for 2 hours. /Warning: by-product is a mercaptan, and use a scrubber with Clorox/. According to TLC /1:2 EtOAc: hexane Rf = 0,4/ reaction is completed. The reaction mixture is diluted with 100 ml dichloromethane. The organic layer was washed with 1N. HCl /2 x 25 ml/, then saturated sodium bicarbonate solution /25 ml/. It is isolated and dried over magnesium sulfate, and the resulting filtrate is dried to dryness. The residue is purified on silica gel /55 g, using 1:3 then 1:2 EtOAc:Hexane to obtain 372 ml/ /60,9% output/ target intermediate compound As a colourless oil. The intermediate connection: Interim connection And 305 mg /0.5 mmol/ dissolved in 2 ml of dimethylformamide and to this solution was cooled to 0oC in a bath of ice, slowly add the NaH /60% in oil, 80 mg /2 mg/ DL. The contents stirred at room temperature for 30 minutes. The resulting mixture was cooled in an ice bath at 0oC and methyl bromide cyclopropane to 0.19 ml /2 mmol/ added by syringe and stirred at room temperature for 18 hours. According to TLC /1:4 EtOAc:Hexane Rf=0,31/ reaction is completed. The reaction mixture is treated, razbivochny the filtrate is dried to dryness. The residue is purified on silica gel /33 g, 1:5, then 1:4 EtOFc: hexane to obtain 243 mg /67.6% of output/ target intermediate compounds In the form of a colorless oil.

Example get IBS. The intermediate connection /10 mg, 0,153 mmol/ placed in a 10 ml round-bottom flask and cooled in a bath of ice at 0oC. To this flask was added 4M HCl in dioxane /1 ml, 4 mmol) and the resulting mixture was stirred at room temperature for 15 minutes. According to TLC /1: 1 EtOAc:hexane Rf=0,15/ reaction is completed. The resulting mixture is treated by cooling a saturated sodium bicarbonate /25 ml/ and extragere dichloromethane / 2 x 25 ml/. The organic extracts are dried over magnesium sulfate, and the resulting filtrate is evaporated to dryness. The residue is purified on silica gel /33 g, 1:1 EtOAc: hexane, then 10:1:10:EtoAc:EtOH:hexane to obtain 27 mg /output 38,5%/ target Q 8239 in the form of a white solid product. So pl. 211,2oC.

An example of IBT. The intermediate connection With.

The intermediate connection And 1,515 g / 2.48 mmol/ dissolved in 7.5 dimethylformamide and to this solution was cooled in an ice bath at 0oC, slowly add the NaH /60% in oil/ 397 mg/9,92 mmol/. All this was stirred at room temperature for 30 minutes. Polucen the form and the resulting mixture was stirred at room temperature for 18 hours. According to TLC /1:4 EtOAc:hexane Rf= 0,31/ reaction is completed. The reaction mixture is treated by adding water /100 ml, and extracted with a diethyl ether /2 x 50 ml/. The organic layer is dried over magnesium sulfate, and the resulting filtrate is evaporated to dryness. The residue is purified on silica gel /130 g, 1: 4, then 1:3 EtOAc:hexane to obtain 2,068 g /exit 83,1%/ target intermediate connection in the form of a colorless foam.

Obtaining compounds of example IBT. Intermediate connection, 1,928 g /1.92 mmol/ placed in a 100 ml round bottom flask and cooled at 0oC in an ice bath. To this flask was added 4M HCl in dioxane /15 ml, 60 mmol) and the resulting mixture was stirred at room temperature for 15 minutes. According to TLC /1: 1 EtOAc:hexane Rf=0,25/ reaction is completed. The resulting mixture was quenched with 0.5 n sodium hydroxide solution /100 ml and washed with a saturated solution of sodium bicarbonate /50 ml, extracted with dichloromethane /3 x 50 ml/. The organic extracts are dried over magnesium sulfate, and the resulting filtrate is evaporated to dryness. The residue is purified on silica gel /130 g, 1:1 EtOAc: Hexane to obtain 1,284 g /89,9% output/ target Q8241 in the form of a white solid product is of emer IBT /1,161 g, 1.56 mmol/ dissolved in 15 ml of ethanol. To this mixture is added 1.1 g of 5% palladium on charcoal, and the resulting suspension stirred for 18 hours in an atmosphere of hydrogen / 1 ATM/. According to TLC, the reaction is finished. The resulting mixture was treated with 1.1 g of 10% palladium hydroxide on charcoal, and stirred for 2 hours in an atmosphere of hydrogen /1 ATM/. TLC /10: 1:10 EtOAc:hexane Rf= 0,31/ indicates the completion of the reaction. The resulting suspension is filtered through a layer of celite, and the resulting filtrate is evaporated to dryness. The obtained residue is purified on silica gel /130 grams, 10:1:10, and then 10:2:10 EtOAc:EtOH:hexane to obtain 458 mg /output 52,2%/ target Q 8242 in the form of a white solid product. So pl. 103,3oC

The structure of the compounds of the following examples are presented in table. 1d and 1e

Example 7F. A solution of compound of example 1X /120 mg, 0.27 mmol/ in 25 ml of methylene chloride cooled in an ice bath at 0oC and treated with triethylamine /110 mg, 1.1 mol. Then was added dropwise a solution thionyl chloride /150 mg of 1.03 mmol in methylene chloride /10 ml/. The resulting mixture was stirred for 10 minutes and then washed with saturated aqueous NaHCO3brine and dried over magnesium sulfate. The resulting solution is filtered, and the solvent is removed in a rotary evaporator, and the floor of the treatment of 100 mg of a white foam.

WAS: calculated for C27H32N4O4S: 481,2161; found: 481,2152.

Example 7G. A solution of compound of example 1X /120 mg, 0.27 mmol/ in 25 ml of methylene chloride cooled in an ice bath at 0oC and treated with triethylamine /80 mg, 0.8 mmol/. Then was added dropwise a solution trichloro of chloroformate /Diphosgene/ /53 mg, 0.27 mmol/ 5 ml of methylene chloride. The resulting mixture is stirred for 60 minutes and then washed with saturated aqueous NaHCO3, brine and dried over magnesium sulfate. The resulting solution is filtered, and the solvent is removed in a rotary evaporator and the resulting residue is treated chromatography on silica gel /50% EtOAc/hexane/ to obtain 90 mg of a white foam. MC NH3/M+H/+= 461.

Example 7I. A solution of compound of example 1X /500 mg, 1.15 mmol/THF /15 ml is treated with thiocarbonyldiimidazole /410 mg, 2.3 mmol/ and refluxed for 1.5 hours. The solvent is removed in a rotary evaporator and the resulting residue is treated chromatography on silica gel /50% EtOAc /hexane/ to obtain 320 mg of a white solid, MC NH3/M+H/+= 477,3.

Examples 7H and 7U. A solution of the compound of example 71 /220 mg, 0.46 mmol/ dry toluene /25 ml/ heated to boiling with obratovalnem fridge for 2.5 hours. The solvent is removed in a rotary evaporator and the resulting residue is treated chromatography on silica gel /20% EtOAc/hexane/ to obtain 70 mg of compound 7H in the form of a solid white product. MC NH3/M+H/+= 447,2.

The last faction give 30 mg of the compound of example 7U in the form of a solid white product. MC /M+H/+= 419,2.

Example 7V. A solution of compound of example 1X /112 mg, 0.26 mmol/ 5 ml methylene chloride cooled in an ice bath at 0oC and treated with DAST /110 mg, 1.1 mmol/. The resulting mixture was stirred for 10 minutes and then washed with saturated aqueous sodium bicarbonate, brine and dried over magnesium sulfate. The resulting solution is filtered, and the solvent is removed on a rotary evaporator and the resulting residue is treated on silica gel in HPLC /65% EtOAc/hexane/ to obtain 40 mg of colorless residue. BPMC: calculated for C27H33N2O2F: 437,2604 found 437,2593.

Example 7O. A solution of compound of example 3U /600 mg, 1.9 mmol/ 10 ml of pyridine is treated with methanesulfonamide /170 mg, 1.5 mmol/ and stirred at room temperature for 3 hours. The resulting mixture was quenched with 5 ml of methanol. The solution was concentrated in a rotary evaporator, and the resulting mod. the received solution is filtered, and the solvent is removed in a rotary evaporator, and the residue is treated chromatography on silica gel /40% EtOAc/hexane/ to obtain the compound of example 7O /430 mg/ in the form of a white solid product. MC /M+H/+=685.

Example 7Y. A solution of compound 7O /100 mg, 0.15 mmol/ in 4 ml of DMF is treated with NaN3/100 mg, 1.5 mmol/ and heated at 80oC for 2 hours and then stirred overnight at 40oC. the resulting solution was diluted with water, and the remaining white solid is extracted with ethyl acetate. The organic extract was washed with water, brine and dried over magnesium sulfate. The resulting solution is filtered, and the solvent is removed in a rotary evaporator and the resulting residue is treated by HPLC on silica gel /50% EtOAc/hexane/ to obtain the compound of example 7Y /80 mg/ in the form of a white solid product. MC:/M+H/+=632. IR /CHCl3/ 2214 cm-1for N3.

Examples 7J and 7K. A solution of compound of example 3U /100 mg, 0,165 mol/ pyridine /3 ml/ treated with acetic anhydride /84 mg, 0,824 mmol/ and stirred at room temperature for 2 hours. The resulting mixture was quenched with 5 ml of methanol. The resulting solution was concentrated in a rotary evaporator, and the residue R is obtained, the solution is filtered, and the solvent is removed in a rotary evaporator, and the residue is treated by HPLC on silica gel /40% EtOAc/hexane/ to obtain the compound of example 7J /24 mg/ in the form of a white solid product. VRMS: /M+H/+calculated for C45H43N2O5: 691,3171198; found: 691,316252.

As the last faction receive connections 7K /27 mg/ in the form of a white solid product VRMS: /M+H/+calculated for C43H41N2O4: 649,306633; found 649,304918.

Example 7R. A solution of compound 3U /100 mg, 0,165 mmol/ 5 ml of methylene chloride is treated with 2,2-dimethoxypropane /174 mg, 1,65 mg/ DL, p-toluensulfonate /10 mg/ and stirred at room temperature overnight. The resulting mixture was diluted with methylene chloride and washed with saturated sodium bicarbonate solution, brine and dried over magnesium sulfate. The resulting solution is filtered, and the solvent is removed in a rotary evaporator and the resulting residue is treated HPLC on silica gel /50% EtOAc/hexane/ to obtain the product of example 7R /73 mg/ in the form of a white solid product. VRMS: /M+H/+calculated for C44H43N2O3: 647,327369; found: 647,327531.

Example 7P. A solution of compound of example 3U /200 mg, 0.33 mmol/ 5 ml METI the eyes. The solvent is removed in a rotary evaporator and the resulting residue is treated by HPLC on silica gel /50% EtOAc/hexane/ to obtain a solid product, a yellow-brown color. It crystallized from a mixture of CH2Cl2/hexane to obtain the product of example 7P /80 mg/ in the form of solid compounds in white. MC: /M+H/+of 661.4.

An example of 7S. A solution of compound of example 3U /100 mg, 0,165 mmol/ 5 ml of methylene chloride is treated with trimethylaminobutyric /244 mg, 1,65 mg/ DL, p-toluensulfonate /10 mg/ and stirred at room temperature for 30 minutes. The resulting mixture was diluted with methylene chloride and washed with saturated sodium bicarbonate solution, brine and dried over magnesium sulfate. The resulting solution is filtered, and the solvent is removed in a rotary evaporator and the resulting residue is treated by HPLC on silica gel /50% EtOAc/hexane/ to obtain the product of example 7S. MC: /M+H/+691,5.

Example 7B. A solution of Di-MEM-protected product of example 1C /550 mg, 0,94 mg/ DL in 11 ml of pyridine is treated with P2S5/420 mg, 0,94 mg/ DL and heated to boiling under reflux for 3 hours. The pyridine is evaporated in a rotary evaporator, and the residue is placed in methylene chloride and washed the solvent is removed in a rotary evaporator and the resulting residue is treated chromatography on silica gel /40% EtOAc/hexane/ to obtain the product of example 7B /120 mg/ in the form of a clear oil. BPMC: /M+H/+calculated for C27H33N2O3S: 465,221190; found 465,220899.

Example 7A. A solution of compound of example 1C /330 mg, 0.8 mmol/ 5 ml of pyridine is treated with acetic anhydride /160 mg, 1.6 mmol/ and stirred at room temperature for 4 hours. The resulting mixture was quenched with 5 ml of methanol. The solution was concentrated in a rotary evaporator, and the residue is dissolved in ethyl acetate, then washed with diluted HCl /water/ brine and dried over magnesium sulfate. The resulting solution is filtered, and the solvent is removed in a rotary evaporator and the resulting residue is treated chromatography on silica gel /50% EtOAc/Gex/ to obtain the product of example 7A /120 mg/ in the form of a white solid product. MC:/Cl, NH3/ /M+H/+= 449,1.

Example 7W. A solution of compound of example 1C /160 mg, 0,39 mmol/ 5 ml methylene chloride cooled in an ice bath at 0oC and treated with DAST /63 mg, 0.4 mmol/. The resulting mixture was stirred for 10 minutes and then washed with saturated aqueous sodium bicarbonate, brine and dried over the STATCOM process chromatography on silica gel /50% EtOAc/Gex/ to obtain 80 mg of colorless residue. BPMC: calculated for C25H30N2O2F: 409,2291; found: 409,2291.

Example 7X. Connection example 3U /100 mg, 0.16 mmol/ 5 ml of methylene chloride cooled in an ice bath at 0oC, and treated with DAST /26 mg, 0.16 mmol/. The resulting mixture was stirred for 10 minutes and then washed with saturated aqueous sodium bicarbonate, brine, and dried over magnesium sulfate. The resulting solution is filtered, and the solvent is removed in a rotary evaporator, and the residue is treated by HPLC on silica gel /50% EtOAc/Gex/ to obtain 35 mg of a white foam. VRMS calculated for C41H38N2O0F: 609,2917; found: 609,2911.

Example 8A. A solution of compound of example 1X /of 2.06 g, 4,74 mg/ DL in methylene chloride is treated with diisopropylethylamine /1,53 g, to 11.8 mmol/ MEM-Cl /0.71 g, 5.7 mmol/ and heated to boiling under reflux for 5 hours, and left under stirring overnight at room temperature. The resulting solution was concentrated on a rotary evaporator, and the residue is treated chromatographically by HPLC on silica gel /5% MeOH/CHCl3to obtain 1.3 g of mono - core mono-ol intermediate. MC: /Cl, NH3/ /M+H/+=about 523.4.

A solution of mono-core mono-Ola p is, what dietilazodikarboksilatom /DEAD/ /0.7 g, 4.0 mmol/ and Chloroacetic acid /0.4 g, 4.2 mmol/. The resulting solution is stirred over night at room temperature. The solvent is evaporated and the resulting residue is treated chromatography on silica gel /50% EtOAc/Gex/ to obtain 0,9 Chloroacetic intermediate. MC: /Cl, NH3/ /M+H/+= 599,3 /100%/; 600 /39%/.

Chloracetate intermediate /0.9 g, 1.5 mmol/ dissolved in MeOH /15 ml, treated with NaOH /aq/ /4 ml, 1N./ and stirred at room temperature for 15 minutes. The resulting solution is evaporated to dryness and the residue is divided between water and ethyl acetate. The organic layer was washed with water and brine, and then dried over magnesium sulfate. The resulting solution is filtered, concentrated, and the residue is treated by HPLC on silica gel /85% EtOAc/Gex/ to obtain 400 mg of the compound of example 8A. MC: /CI, NH3/ /M+H/+=about 523.4.

Example 7Z. A solution of the compound of example 8a /100 mg, 0.2 mmol/ MeOH and cooled in an ice bath and treated with HCl for 20 minutes, and then stirred for further 40 minutes at 0oC. the resulting solution is evaporated to dryness at room temperature and the residue is treated with HPLC on silica gel /80% EtOAc/Gex/ to obtain 48 mg of compound /160 mg, 0.3 mmol/ 10 ml of methylene chloride cooled to 0oC in an ice bath and treated with DAST /50 mg, 0.3 mmol/. The resulting solution was stirred at room temperature for 15 minutes, then quenched with water. The organic layer was washed with water and brine and dried over magnesium sulfate. The resulting solution is filtered, the solvent is evaporated, and the residue is treated chromatographically by HPLC on silica gel /50% EtOAc/Gex/ to obtain 100 mg of the compound of example 8C. MC: /CI, NH3/ /M+H/+= 525,4.

Example 8B. A solution of compound of example 8C /70 mg of 0.013 mmol/ MeOH and cooled in an ice bath and stirred for an additional 40 min at 0oC. the resulting solution is evaporated to dryness at room temperature and the residue is treated chromatographically by HPLC on silica gel /80%, EtOAc/hexane to obtain 40 mg of the compound of example 8B in the form of a white foam. MC: /CI, NH3/ /M+H/+= 437,3.

Example 7AA. To a stirred suspension of 750 mg /1,72 mmol/ diol /IX/ 35 ml of methylene chloride add 445 mg /3,45 mmol/ diisopropylethylamine and 322 mg (2,59 mmol) Memoria. After stirring for 5 days resulting solution was washed with diluted HCl, brine and dried over anhydrous magnesium sulfate. Solvent-delaystation in hexano obtain 430 mg (48% mono-protected ester (XXVa).

MS: 523 (M+1, 100), NMR (CDCl3): 7,20 (m, 10H), 4,96 (s, 2H), 4,08 (m, 1H), 3,90 (m, 2H), 3,61 (m, 7H), 3,42 (s, 3H), of 3.13 (m, 4H), of 1.99 (m, 2H), 0.88 to (m, 2H), and 0.40 (m, 4H), 0,06 (m, 4H).

To a stirred solution of 78 mg (0.15 mmol) of the compound (XXVa) in 3 ml of methylene chloride added 60 mg (0,74 mmol) of sodium acetate and 95 mg (0.44 mmol) of PCC. The resulting suspension is stirred for 3 days and diluted with ether, and filtered through Florisil. The solvent is removed under reduced pressure, and the residue is treated chromatography on silica gel. After elution with 2.5% methanol in methylene chloride obtain 68 mg (885) connection example 7AA.

MS: 521 (M+1, 100), NMR (CDCl3): 7,21 (m, 10H), of 4.90 (d, 1H), 4,70 (DD, 2H), 4,10 (t, 1H), 3,80-3,37 (m, 8H), to 3.36 (s, 3H), 3,26-2,82 (m, 4H), 2,22 (square, 1H), of 1.03 (m, 2H), 0,51 (m, 4H), 0,20 (m, 4H).

Oxidation monoamino diol: receive (XXVB):

To a stirred solution of 51 mg (0.10 mmol) of the compound of example 7AA in 4 ml of methanol was added 1 ml of concentrated HCl. The resulting solution was stirred for 5 hours, and the product precipitated by adding water. The resulting suspension is extracted with methylene chloride and the combined organic layers dried over anhydrous magnesium sulfate. The solvent is removed under reduced pressure to obtain and the rest chromatographic on silica gel. After elution, ,24 (t, 1H), 3,85 (m, 1H), 3,74 (d, 1H), 3,44 (m, 3H), 3,22 - by 2.73 (m, 4H), and 2.27 (square, 1H), 1,01 (m, 2H), 0,5 (m, 4H), 0,20 (m, 4H).

Example 7AC. To a stirred solution of 37 mg (0.09 mmol) of ketone (XXVb) in 4 ml ethanol and 2 ml of water is added 40 mg (0.48 mmol) of the hydrochloride of methoxylamine. The resulting solution is stirred overnight and the product precipitated by addition of water. The suspension is extracted with methylene chloride and the combined organic layers dried over anhydrous MgSO4. The solvent is removed under reduced pressure, receiving 40 mg (100%) of the compound of example 7AC.

MS: 462 (M+1, 100), NMR (CDCl3): 7,20 (m, 10H), and 5.30 (m, 2H), 4,80 (t, 1H), 4,24 (t, 1H), of 3.77 (m, 4H), 3,40 (m, 3H), 2,90 (m, 4H), of 2.25 (DD, 1H), of 1.03 (m, 2H), 0,48 (m, 4H), 0,23 (m, 2H), 0,12 (m, 2H).

Example 7AB. Using the method of example 7AC, replacing methoxylamine on gidroxinimesoulid with obtaining the target product:

MS: 448 (M+1, 100), NMR (CDCl3): 8,13 (s, 1H), 7,20 (m, 10H), 5,42 (t, 1H), a 4.83 (t, 1H, in), 3.75 (m, 2H), 3,40 (m, 3H), equal to 2.94 (m, 4H), 2,22 (DD, 1H), 1,17 (m, 1H), 0,90 (m, 1H), 0,47 (m, 4H), 0,23 (m, 2H), 0,11 (m, 2H).

Example 7AD. To a stirred solution of 98 mg (0.23 mmol) within (XXVb) in 5 ml of butanol added 57 mg (0.71 mmol) of formamidinesulfinic and 40 mg (0.75 mmol) of sodium methoxide. The resulting suspension is stirred for 30 minutes and refluxed over night. B and the combined organic layers dried over anhydrous magnesium sulfate. The solvent is removed under reduced pressure, and the residue is treated chromatography on silica gel. After elution of 25% ethyl acetate in hexano obtain 28 mg (28%) of the compound of example 7AD.

MS: 442 (M+1, 100), NMR (CDCl3): 7,58 (s, 1H), 7,20 (m, 10H), 4,55 (m, 2H), 3,51 (m, 2H), 3,24 (m, 2H), 3,05 (m, 2H), 2,53 (kV, 1H), and 2.27 (q, 1H), of 0.91 (m, 2H), 0,45 (m, 4H), 0,11 (m, 4H).

Examples 7AE and 7AF. To a mixed solution of 65 mg (0.15 mmol) of the diol (1X) in 1 ml DMF add to 5.5 mg (0.18 mmol) of 80% sodium hydride. The resulting suspension is stirred for 20 minutes, and added 68 mg (0.48 mmol) under the conditions. After stirring overnight the suspension is quenched with water, extracted with ethyl acetate, and the combined organic layers dried over anhydrous magnesium sulfate. The solvent is removed under reduced pressure, and the residue is treated chromatography on silica gel. After elution of 25% ethyl acetate in hexano obtain 19 mg (28%) of the compound of example 7AE along with 25 mg (37%) of the compound of example 7AF.

Example 7AE:

MS: 499 (M+1, 100), NMR (CDCl3): 7,26 (m, 10H), of 4.05 (DD, 1H), 3,84 (m, 1H), to 3.67 (m, 2H), 3,60 (s, 3H), 3,53 (m, 2H), 3,13 (m, 3H), 2,90 (m, 2H), was 1.94 (dt, 2H), 0,89 (m, 2H), 0,41 (m, 4H), 0,04 (m, 4H).

Example 7AE:

MS: 463 (M+1, 100), NMR (CDCl3): 7,21 (m, 10H), to 3.67 (m, 4H), 3,62 (s, 6H), to 3.58 (s, 2H), 3,10 (m, 4H), of 1.92 (DD, 2H), or 0.83 (m, 2H),Oded Hagai on benzyloxyethanol obtaining compounds of examples 7AG and 7AH.

Example 7AG:

MS: 615 (M+1, 100),1H NMR (CDCl3): 7,50 - 7,06 (m, 20H), 4,88 (AB, 4H), to 3.92 (s, 2H), of 3.56 (m, 2H), 3,47 (DD, 2H), 3,14 (M, 4H), of 1.88 (DD, 2H), and 0.62 (m, 2H), 0,34 (m, 4H), of 0.05 (m, 4H).

Example 7AH:

MS: 525 (M+1, 100),1H NMR (CDCl3): 7,45 - 7,10 (m, 15H), 4,74 (AB, 2H), 4,13 (DD, 1H), 3,82 - to 3.50 (m, 5H), to 3.09 (m, 4H), was 2.76 (s, 1H), 1,95 (dt, 2H), 0,92 (M, 2H), and 0.40 (m, 4H), 0,03 (m, 4H).

Examples of 7AI and 7AJ. Connection examples 7AI and 7AJ obtained by substitution allylbromide, as described in the above examples.

Example 7AI:

1H NMR (CDCl3) 7.26 (m, 10H), 6.05 (m, 2H), 5.30 (dd, 4H), 4.28 (m, 2H), 3.76 (s, 2H), 3.60 (m, 4H), 3.10 (m, 4H), 1.93 (dd, 2H), 0.86 (m, 2H), 0.40 (m, 4H), 0.01 (m, 4H).

Example 7AJ:

MS: 475 (m+1, 100);1H NMR (CDCl3) 7.27 (m, 10H), 6.01 (m, 1H), 5.32 (dd, 2H), 4.34 (dd, 1H), 4.18 (dd, 1H), 4.66 (m, 5H), 3.10 (m, 4H), 2.82 (s, 1H), 1.95 (m, 2H), 0.85 (m, 2H), 0.40 (m, 4H), 0.04 (m, 4H).

Example 8E. A solution of compound of example 5F /500 mg, 0.7 mmol/ 10 ml of methylene chloride cooled to 0oC in an ice bath and treated with DAST /112 mg, 0.7 mmol/. The resulting solution was stirred at 0oC for 15 min, then quenched with saturated NaHCO3. The organic layer was washed with water and brine and dried over magnesium sulfate. The resulting solution is filtered, the solvent is evaporated, and the residue is treated chromatographically by HPLC on silica gel /50% EtOAc/Gex/ to obtain 250 m the example 8E /200 mg, 0.28 mmol/ MeOH and cooled in an ice bath and treated with gaseous HCl for 20 min, and then stirred for further 40 min at 0oC. the resulting solution was then evaporated to dryness at room temperature and the residue is treated chromatographically by HPLC on silica gel /5% MeOH/CHCl3to obtain 120 mg of the compound of example 8F in the form of a white foam. MC: /Cl, NH3/ /M+H/+= 541.

Example 8G /via alkene intermediate XXIX/. A solution of compound of example 7Q /150 mg, 0.22 mmol/ DMF is treated with sodium iodide /160 mg, 1.1 mmol/ and heated at 90oC for 2 hours. The resulting mixture was cooled to room temperature, diluted with water, and the resulting residue extracted with CH2Cl2. The extract obtained was washed with water and brine, dried over magnesium sulfate and evaporated to dryness to obtain a yellow oil. It is treated chromatographically by HPLC on silica gel /50% EtOAc/Gex/ to obtain 50 mg alkinoos intermediate /XXIX/

< / BR>
in the form of a white solid. MC: /Cl, NH3/ /M+H/+= 589

The solution alkinoos intermediate /XXIX/ /40 mg, 0.07 mmol/ THF treated with 20 mg of 10% Pd/C, and hydronaut in a Parr apparatus at a pressure of 3.5 kg/cm2(50 psi) overnight. To graficheskiy on silica gel /70% EtOAc/Gex/, to obtain 10 mg of the compound of example 8G in the form of a white solid product. MC: /Cl, NH3/ /M+H/+= 591,5.

Example 8H.

Method 1.

A. Obtaining 6-membered cyclic urea /XXX/:

< / BR>
Getting six-membered cyclic urea /XXX/ carry out the scheme 8. A solution of N-Cbz-D-phenylalanine-N, O-dimethylhydroxylamine /33,5 g, 0,098 mole/ ether cooled to 0oC and treated with 300 ml of 1 M solution of vinylmania in THF. The resulting mixture was stirred for 30 minutes and then poured into ice a solution of 1H. HCl /500 ml/. The resulting mixture is extracted with ether and the extract is washed with water and brine. The organic layer is dried over magnesium sulfate, filtered and concentrated to obtain the target vinylketones in the form of a thick light yellow residue which is used without further purification. MC: /Cl, NH3/ /M+H/+= 310 /77%/; /M= NH4/+= 327,1 /100%/.

The crude ketone was dissolved in methanol /350/ ml and treated with heptahydrate of ceritacherita ,37,2 g, 0.1 mol/ and cooled in an ice bath. With vigorous stirring, slowly add sodium borohydride /of 3.78 g, 0.1 mol/, small portions each time for about 30 minutes. After added the tel removed under reduced pressure, and the remainder is divided between 1H. HCl and methylene chloride. The organic layer is washed with water, brine, and then dried over magnesium sulfate, filtered and concentrated to obtain the target allyl alcohol in the form of an off-white solid product, which is used without further purification.

A solution of the crude allyl alcohol and diisopropylethylamine /30 g, 0.23 mol/ methylene chloride cooled in an ice bath and treated, prokopeva methanesulfonanilide /28 g, 0.24 mol. The resulting solution was stirred for 30 minutes, then washed sequentially 1 N. HCl, water, brine and dried over anhydrous magnesium sulfate. The resulting solution was filtered and concentrated to obtain the crude nelfinavir in the form of a thick oil. In a flame-dried flask add cyanide copper /12 g, 0.144 mol and 10 ml THF. The flask was cooled to -78oC in nitrogen atmosphere. Add a solution of benzylmagnesium /360 ml, 2M in THF, to 0.72 mol/ via syringe, and the resulting thick solution was stirred at -60oC for 20 minutes and at 0oC for 30 minutes. Then the resulting solution was cooled to -78oC, and using a syringe add a solution of nelfinavir in 130 ml of THF. The resulting solution was stirred at -60oC for 45 minutes, and Thelen NH4Cl /aq. /, NH4OH, brine, dried over magnesium sulfate, filtered and concentrated. The resulting residue is treated chromatography on silica gel /hexane, then 10% EtOAc/Gex/ to obtain 11.7 g of the target alkene in the form of a white solid. MC: /Cl, NH3/ /M+H/+= 386,3 /98%/; /M+NH4/+= 403,2 /100%/.

The solution videolooking alkene /11,0 g 0,029 mol/ 75 ml of methylene chloride cooled to 0oC in an ice bath and treated with 60% m-chloroperbenzoic acid /14.0 g, 0,049 mol. The resulting solution was stirred at 0oC for 7 hours before until according to TLC remains the source material. During this time a precipitate. The resulting suspension is diluted with methylene chloride and washed successively 1 N. Na2S2O3, 1H. sodium hydroxide, water, brine, dried over magnesium sulfate, filter and concentrate to obtain the epoxide in the form of a thick oil, which was used without further purification.

To a solution of the crude epoxide in 80 ml of DMF added sodium azide /20 g, 0.3 mol/ amanifold /2.5 g, 0,047 mol and 20 l of water. The resulting mixture is heated at 90oC for 3 hours and then stirred at room temperature overnight. The solvent ski layer was washed with water and brine, dried over magnesium sulfate, filtered and concentrated to obtain a residue. Then it is treated chromatography on silica gel /20% EtOAc/Gex/ to obtain 7.4 g of aspidosperma in the form of a white solid. MC: /Cl, NH3/ /M+H/+= 445,0 /25%/; /M+NH4- BnOH/+= 462,2 /100%/.

The solution aspidosperma /7.2 g, to 0.016 mol/ methylene chloride is treated with diisopropylethylamine /4,2 g, to 0.032 mol/ and MEM - Cl /4.0 g, to 0.032 mol/ and heated to boiling under reflux over night /18 hours/. The resulting mixture was concentrated, and the residue is treated chromatography on silica gel /20% EtOAc/Gex = 35% EtOAc/Gex/ to obtain 7.7 g of the MEM protected aspidosperma in the form of a colorless oil, MS: /Cl, NH3/ /M+H/+= 533,2 /100%/.

To a solution of MEM-protected aspidosperma /5.7 g, 0,0107 mol/ ethyl acetate add 2 ml of acetic acid and 1 g of catalyst Reagan /10% Pd/OH/2coal/, and the resulting solution hydronaut with a 3.87 kg/cm2(55 psi) for 22 hours. The resulting solution was filtered through Celite, and the filtrate is extracted with 1N. HCl /organic layer becomes orange/. The acidic aqueous extract is alkalinized 50% NaOH /continuing cooling in an ice bath and the precipitate is extracted with ethyl acetate. The organization of the MEM-protected diaminopentane in the form of a colorless oil, MC: /Cl, NH3/ /M+H/+= 373,1 /100%/.

To a solution of MEM-protected diaminopurine /2.5 g, 0,0067 mol in THF added 1,1-carbonyldiimidazole /1.1 g, 0,0067 mol/ and stirred at room temperature overnight. The resulting solution was concentrated and the residue is divided between 1 N. HCl and CH2Cl2. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue is treated by HPLC on silica gel /5% MeOH/CHCl3to obtain 1.2 g MEM-protected 6-membered cyclic urea /XXX/ in the form of a white solid. MC: /Cl, NH3/ /M+H/+= 399,1 /100%/.

B. MEM-protected 6-membered cyclic urea /XXX/ /100 mg, 0.27 mmol/ alkylate cyclopropanemethylamine /250 mg, 1.8 mmol/, with subsequent removal of the MEM group, as described in General method 5, to obtain after chromatography treatment on silica gel /10% MeOH/CHCl3/ 20 mg of the compound of example 8H in the form of a clear viscous residue. MC: /Cl, NH3/ /M+H/+= 419,4 /100%/.

Method 2.

A solution of the compound of example 8A /160 mg, 0.3 mmol/ thiocarbonyldiimidazole /55 mg, 0.3 mmol/ THF heated to boiling under reflux for 4 hours. The resulting mixture is evaporated, and the residue obrabecim is THIOCARBAMATE dissolved in 2 ml of toluene and heated to boiling under reflux. To boiling under reflux solution add hydride presence of TBT /32 mg, 0.1 mmol/ and 2 mg of AIBN. The resulting mixture was refluxed for 1 hour, concentrated, and the residue is treated chromatography using HPLC /silica gel, 65% EtOAc/Gex/ to obtain 20 mg of a clear colorless oil. This oil is dissolved in MeOH, cooled in an ice bath and rinsed gaseous HCl through the solution for 30 minutes. The resulting solution was then stirred at room temperature, concentrated and the residue is treated chromatographically by HPLC on silica gel /10% MeOH/CHCl3to obtain 10 mg of the compound of example 8H in the form of a clear, viscous residue. MC: /Cl, NH3/ /M+H/+419,2 /100%/.

Using the above methods and known in the art and modifications, it is possible to obtain the compounds shown in tables 3-13 (see at the end of the description).

Application.

The compounds of formula (I) possess an inhibitory activity against protease retroviruses, and therefore can be used as antiviral agents for the treatment of viral diseases. More specifically, the compounds of formula I have activity on the inhibition of HIV protease and reveal the Oia is demonstrated in standard tests activity proetz, for example, using the following method for estimating activity inhibitors of HIV protease. The ability of the compounds of the present invention to inhibit the growth or infectionspokane demonstrated in standard growth analysis of viruses or infectionspokane, for example, using the following analysis.

A compound is considered active if it is IC50/IR50/ or Ki< 1 mm for the inhibition of HIV protease or growth of the HIV virus or infectionspokane.

Analysis of the inhibition of HIV protease - spectroscopic method

Materials:

Protease: inclusion Body of E. coli containing the plasmid containing HIV protease under the control of the inducible T7 promoter, get it on the way Cheng et.al /1990/ Gene 87:243. Body enable solubilizer in 8M urea, 50 mm Tris pH 8.0. Protease activity allocate twenty-fold dilution in buffer containing 50 mm sodium acetate pH 5.5, 1 mm EDTA, 10% glycerol and 5% ethylene glycol. The enzyme is used at a final concentration of 1.0 to 10.0 μg/ml.

Substrate: Peptide sequence Ala-Thr-His-Gln-Val-Tyr-Phe/NO2/-Val-Arg-Zys-Ala containing p-nitrovanillin /Phe/NO2/ get in solid-phase peptide synthesis.

Inhibiting compounds dissolved in the remaining amount of DMSO to obtain initial solutions of 2.5 or 25 mm. All further dilution is carried out in DMSO.

Reaction.

Connection /1-5 ál/ HIV-protease mixed in a buffer containing 50 mm MES, pH 6.5, 1M NaCl, 1 mm EDTA, 1 mm dithiothreitol, 10% glycerol. Reactions are initiated by adding the peptide substrate to a final concentration of 240 μm, and within 10 minutes control the absorption at 300 nm. Values of Kifor the binding of the inhibitor is defined as the percentage of activity measured in the presence or in the absence of a known concentration of inhibitor, using values of 0.07 mm for Kmsubstrate /Cheng et.al /1990/ Proc. Natl. Acad. Sci. USA 87:9660/.

The activity of inhibiting HIV-1 protease are presented compounds of the present invention is shown in the table. 1a-1e and 2A-2k.

Analysis of the inhibition of HIV protease - HPLC method.

Materials: inclusion Body of E. Coli containing the plasmid containing the plasmid T1718R with a synthetic gene coding for one circuit tetramer HIV protease, get it on the way /Cheng et.al, Proc. Natl. Acad. Sci. USA 87, 9660-9664, 1990/. Active protease receive as described, extragere 67% acetic acid, diluting 33 times with water, dialetheia. Protease store as the source of the drug in 10 µm in pampering buffer.

Substrate: Peptide with the sequence: aminobenzoyl-Ala-Thr-His-Gln-Val-Tyr-Phe /NO2/-Val-Arg-Zys-Ala containing p-nitrovanillin receive solid-phase synthesis, as described by Cheng et. al. The starting solutions of 2 mm substrate get in DMSO.

Inhibiting compounds are dissolved in sufficient quantity of DMSO to bring initial solution concentration to 3 mm. All further dilutions are prepared in "analytical buffer: 1M NaCl, 50 mm MES, pH 5.5, 1 mm EDTA, 1 mm DTT, 20% glycerol.

Reaction.

The enzyme reaction is: 2 ml vials centrifuge with a screw cap add 50 ál of protease /a final concentration of 0.25 nm/ and 0.1 ml of inhibitory connections /final concentration of 0.1 - 12500/. After 15 minutes pre-incubation at room temperature, the reaction start by adding 0.05 ml substrate /final concentration of 5 μm/. Incubation is carried out at 30oC for 1 hour. The reaction is stopped with 1 ml of ammonium hydroxide /0.1 M/.

Monitoring the formation of product by HPLC. Product /aminobenzoyl-Ala-Thr-His-Giu-Val-Tyr/ are separated from the substrate on anyoneeven mm Tris HCl, pH 9, with 0.02% sodium azide, 0.5 M of formatmoney, 10% acetonitrile/. Mobile phase was pumped at a rate of 1 ml/min, gradient from 0 to 30% B in 5 min, 100% B for 4 minutes to wash the column, and re-trim for 4 minutes. The retention time of the product is 3.6 minutes. Detection of the fluorescent monitor Shimadzu RF535 performed at 330 nm /excited/ and 430 nm /emission/. Kicalculated by the formula

Ki= J/[[/Km+ S - FAxS]/ /[FAxKm]] - 1/,

where J is inhibitory concentration:

S is the substrate concentration;

FA is the fractional activity = the peak height in cm when the inhibition of the peak height in cm without inhibition;

Km= 20 μm, the constant of Michaels.

Cellular analysis reducing the number of HIV.

Material: MT-2 cell line T-cells, which were cultured in RPM1 medium supplemented with 5% volume/volume/ thermoinactivation serum fetal calf /FCS/, Z - glutamine and gentamicin. The strain of the human immunodeficiency virus, HIV /SV/ HIV /RF/ multiply in H-9 cells in RPM1 with 5% FCS. Plates for cell culture, coated with poly-Z-lysine /σ/, prepared according to the method of Harada et. al /1985/ Science 229: 563-566. MTT, 3-or 4,5-dimethyl-thiazol-2-yl/-2,5-definite to a concentration of 5 mg/ml and serialno diluted in RPM1 medium in up to ten times the desired final concentration. MT-2 cells /5105/ ml 3.3 ml mixed with 0.3 ml of a solution of the appropriate test compound and left to stand for 30 minutes at room temperature. HIV /3B/ or HIV /RF/ about 5105plaque-forming units/ml in the 0.375 ml added to these cells and mixtures of compounds and incubated for one hour at 36oC. the resulting mixture is centrifuged at a speed of 1000 rpm for 10 minutes, and the supernatant containing unattached viruses, drained. The cell sediment is suspended in fresh RPM1 containing the appropriate concentration of test compound and placed in the 36oC, 4% CO2the incubator. The virus is allowed to proliferate for 3 days. The resulting culture is centrifuged for 10 minutes at a speed of 1000 rpm, and the supernatant containing cell-free viral progeny emit for analysis of plaques.

The titres of viral progeny obtained in the presence of test compounds or without them, determined in the analysis of the plaques. Suspension of viral progeny serialno diluted in RPM1 and 1.0 ml of each dilution is added to 9 ml of MT-2 cells in RPM1. Cells and viruses incubated for 3 hours at 36oC to ensure effective joined the Ural plates, coated with poly-Z-lysine, and incubated overnight at 36oC, 4% CO2. Liquid and non-aligned cells are removed before add 1.5 ml RPM1 0.75% /volume/weight/ Seaplaque agarose /FMC Corp/ 5% FCS. Plates are incubated for 3 days, and add the second RPM1 /agarose layer/ top. After standing for 3 days at 36oC, 4% CO2add the final layer of phosphate superyoung saline 0.75% Seaplague agarose and 1 mg MTT/ml Plates incubated overnight at 36oC. Clear plaques on a purple background is considered, and the number of forming plaques viral units calculated for each sample. Antiviral activity of test compounds is determined by the percentage reduction in viral titer relative to the titer of the virus grown in the absence of any inhibitor.

Analysis of the low reproduction of HIV.

Materials: MT-2, T cell-line person, which is grown in RPM1 medium supplemented with 5% volume/volume/ thermoinactivation serum fetal calf /FCS/, Z-glutamine and gentamicin/ GIBCO/. The human immunodeficiency virus strains HIV /3B/ HIV /RF/ multiply in H-9 cells in RPM1 with 5% FCS. Templ, benzosulfimide acid, 3,3'-/1-//phenyl-amino/cadinene dissolved in dimethyl sulfoxide to 5 mg/ml and diluted in sterile conditions in RPM1 medium up to ten times to the target final concentration. Cells MT-2 /5104/ 0.1 ml/ add to each cell culture plate with 96 cells, and 0.02 ml of the respective test compounds are added to cells so that each concentration was repeated in 2 cells. Of cells and connections leave at room temperature for 30 minutes. HIV /3B/ or RF /RF/ /about 5105plaque-forming units /ml diluted in medium and added to cells and the mixture of compounds to achieve a concentration of infection of 0.01 plaque-forming units/cell. The resulting mixture incubated for 7 days at 36oC, and during this time the virus replicates and causes the death of unprotected cells. The percentage of cells that are protected from the virus-caused death, determined by the extent of metabolism tetrazolium dye XTT. Living cells, XTT metabolift with the formation of colored product formazan that define quantified spectrophotometrically at 450 nm. The number painted formazan proportional to the number of cells protected from virus test connection. Determine the concentration of the compound that protects or 50% /IC50/, or 90% - /IC90/ compared to uninfected cell cultures.

Vlny cells, described above, are presented in table. 2.

Table 2

Example, N - IC90< / BR>
IC - +++

IX - +++

IZ - +++

IAC +++

IAF - +++

IAH - +++

IAQ - +++

The IC values in table 2 mean: +++ = < 10 μg/ml.

Listed in the table of values of Kidetermine, using the conditions of analysis specified in the analysis of the inhibition of HIV protease. These values of Kihave the values: +++ = < 10 nm; ++ = 10 nm to 1 μm; + = > 1 μm.

In the table of values IC90determine the conditions of the analysis described for the analysis of low reproduction of HIV. The values of the IC90indicate the following: +++ = < 10 μg/ml; ++ = 10 - 100 µg/ml; + = > 100 μg/ml.

Dose and composition.

Antiviral compounds of the present invention can be introduced for the treatment of viral infections by any means that ensures the contact of the active agent from the site of its action, with the viral protease in the body of a mammal. They can be administered by any conventional means available for use in conjunction with pharmaceutical carriers or as single therapeutic agent or combination of therapeutic agents. You can enter them separately, but they are usually administered in pharmaceutical socialassistance, vary depending on known factors such as the pharmacodynamic characteristics of the particular agent and the method and mode of administration; the age, health and weight of the recipient; the nature and character of symptoms, the type of the accompanying treatment; frequency of use; and the target effect. Daily dose of active ingredient may range from about 0.001 to 1000 mg/kg body weight, with the preferred dose in the range from 0.1 to about 30 mg/kg

Dosage forms /composition suitable for injection/ contain from about 1 mg to about 100 mg of the active ingredient on a single form. In these pharmaceutical compositions the active ingredient is typically present in an amount of from about 0.5 to 95 wt.% calculated on the total weight of the composition.

The active ingredient can be entered orally in solid forms, doses, such as capsules, tablets and powders, or in liquid forms, such as Alexiy, syrups and suspensions. They can also enter parenteral in sterile liquid dosage forms.

Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, etc., Similar diluents can Yves delayed release, to ensure continuous selection of drugs within hours. Molded tablets may be coated with sugar or film to mask the unpleasant taste and protect the tablet from the atmosphere, or you can apply a special coating to provide selective disintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration may contain coloring and flavoring agents to improve the receptivity of the patient.

In General, suitable carriers for parenteral solutions are water, suitable oil, saline, aqueous dextrose /glucose/ and related solutions of sugars and glycols such as propylene glycol or polyethylene glycol.

Solutions for parenteral administration, preferably contain a water-soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Suitable stabilizing agents are antioxidants such as sodium bisulfite, sodium sulfite, or ascorbic acid alone or in combination. Also use citric acid and its salts and sodium, EDTA. In addition, solutions for parenteral introduction>/P>Suitable pharmaceutical carriers are described in Remington''s Pharmaceutical Science, Mack Publishing Company, a standard reference text in this field.

Suitable pharmaceutical dosage forms for administration of the compounds of the present invention can be illustrated as follows:

The capsule.

A large number of unit capsules are prepared by filling standard hard gelatin capsules consisting of two parts, 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate in each capsule.

Soft gelatin capsules.

The mixture of active ingredient in the oil, which is well absorbed, such as soybean, cottonseed or olive oil is prepared and injected by using a distribution device in gelatin to obtain soft gelatin capsules containing 100 mg of active ingredient. These capsules are washed and dried.

Tablets.

Prepare a large number of tablets using conventional procedures so that a single dose was 100 mg of active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of crome the release of active ingredient.

In table. 3-16 presents the compounds covered by this invention.

In table. 3-12, relevant examples 1-5763, includes all stereoisomers of these structures.

Obtaining the compounds of the present invention, is presented in table 2d, described below:

Example 9A. To a solution of bis m-/HO-N= CH/-C6H4CH2cyclic urea /0,297 mg, 0,502 mmol/ 5 ml methanol add complex, borane-pyridine /0,464 g 5,02 mmol/ if -10oC, and the resulting mixture is stirred for 15 minutes. After processing 4M HCl in 5 ml of dioxane, the reaction mixture was stirred at room temperature for another 1.5 hours. The resulting solution was neutralized with saturated NaHCO3to pH 8, washed with water and dried over magnesium sulfate. After removal of solvent the residue is purified on silica gel, using as eluent a mixture of ethyl acetate:dichloromethane:methanol /50:50:2 to obtain 60 mg of solid product. So melting point 214-216oC.

1H NMR (CD3OD): 8.03 (s, 1H), 7.46 - 7.06 (m, 18H), 4.74 (d, J = 13.9 Hz, 1H), 4.73 (d, J = 13.9 Hz, 1H), 3.92 (s, 2H), 3.62 - 3.59 (bs, 4H), 3.07-2.91 (m, 6H),13C NMR (CD3OD): 163.88, 149.70, 141.26, 141.23, 139.92, 139.39, 138,73, 134.91, 131.50, 131.41, 130.64, 130.00, 129.72, 129.64, 129.57, 129.53, 128.47, 127.45, 127.42, 127.31, 71.96, 71.92, 67.42, 67.11, 58.65, 57.09, 57.03, 33.62, 33.57, MS: the 59th urea /257 mg, 0,434 mmol/, cyanoborohydride sodium /290 mg, 4.6 mmol/ and trace amounts of color indicators methyl orange in methanol /10 ml at room temperature was added dropwise 2n. HCl at a rate sufficient to maintain a pH of 3-4 for 3 hours. The methanol is removed in a rotary evaporator. Purification of the residue on TLC plate with reversed phase elution with 90% methanol in water gives the target product.

1H NMR /CDOD/ 7,33 - 7,09 /m, 18H/, 4,75 /d, J = a 13.9 Hz, 2H/, 3,93 /s, 4H/, 3,61 - 3,56 /m, 4H/, a 3.06 - 2,94 /m, 6H/;13C NMR /CD3OD/: 162,42; 139,72; 137,08; 137,79; 129,92; 128,31; 128,14; 128,06; 126,02; 70,36; 65,49; 57,40; 55,50; 32,09.

Example 9E. A solution of the compound of example 9C /30 mg/ in methanol is treated with 4M HCl in dioxane at room temperature. All the solvents removed in vacuo to obtain hydroxylaminopurine.

1H NMR /CD3OD/: 7,44 - of 7.23 (m, 4H/, 6,99 /d, J = 6.2 Hz, 4H/, 4,65 /d, J = 14,3 Hz, 2H/, 4,35 /s, 4H/, 3,70 - 3,66 /m, 4H/, 3,12 - 3,05 /m, 4H/, 2,89 - 2,85 /m, 2H/,13C NMR /CD3OD/: 163,68; 141,13; 140,39; 123,09; 132,03; 131,06; 130,59; 130,50; 129,50; 127,48; 71,82; 68,23; 57,40; 56,12; 33,70.

Example 9B. The crude sample of example 9C purified on TLC plate using a mixture of acetic acid:ethyl acetate:dichloromethane /5:50:45/ to obtain a salt of acetic acid.

1H NMR /CD3OD/: of 7.35-7.08 /m, 18H/, 4,73 /d, J = 10,6 Hz, 2H/, 3,97 /c, 4H/, 3,62-3,53 /m, 4H/, a 3.06 - 2,88 mmol/ O-benzylhydroxylamine hydrochloride /203 mg, of 1.27 mg/ DL in a mixture of pyridine/ethanol /6 ml, 1:1/ is refluxed for 3 hours. After removal of solvent the residue is purified on TLC plate with 15% ethyl acetate in dichloromethane to obtain 164 mg of solid product. So pl. 170-171oC.

1H NMR (CDCl3): 8.01 (s, 2H), 7.39 - 7.07 (m, 28H), 5.09 (s, 4H), 4.81 (d, J = 14.3 Hz, 2H), 3.59 (bs, 2H), 3.52 (d, J = 11.0 Hz, 2H), 3.07 - 2.88 (m, 8H);13C NMR (CDCl3): 162.14, 148,55, 139.40, 138.62, 137.39, 132.50, 130.50, 129.43, 128,87, 128.62, 128.35, 128.27, 128.87, 127.57, 126.56, 126.46, 76.34, 71.32, 64.55, 55.57, 32.70; MS 790 (M + NH4, 100%).

Example 9F. By way of the above example 9C solution of the compound of example 9D /60 mg, 0,078 mmol/, cyanoborohydride sodium /70 mg, 1.1 ml/, the trace amounts of color indicators methyl orange in methanol is treated with 1 N. HCl /approximately 0.5 ml/. After purification on TLC plate 40% solution of ethyl acetate in methylene chloride receive the product /30 mg/.

1H NMR (CDCl3): 8.05 (s, 1H), 7.43 - 7.06 (m, 28H), 5.13 (s, 24). 4.90 (d, J = 14.3 Hz, 1H), 4.87 (d, J = 14.3 Hz, 1H), 4.61 (s, 2H), 3.98 (s, 2H), 3.59 - 3.49 (m, 4H), 3.07 - 2.95 (m, 6H),13C NMR (CDCl3): 161.98, 148.59, 139.48, 138.86, 138.32, 138.05, 137.74, 137.48, 132.56, 130.61, 129.87, 129.51, 128.91, 128.67, 128.65, 128.44, 128.37, 128.11, 127.91, 127.86, 127.66, 126.59, 126.56, 126.40, 77.20, 76.41, 76.15, 71.52, 71.48, 64.33, 64.11, 56.26, 55.58, 55.57, 33.79, 32.47, MS: 792 (M+NH4, 40%) 775 (M+H, 100%).

Example 9G. To a solution of suspension of bis/m/HO/-C6H4CH2122,9 mg, 1.3 mmol/ and the resulting mixture was stirred at room temperature overnight. The resulting mixture was filtered through celite and concentrated to obtain residue, which was purified on TLC plate with 15% ethyl acetate in methylene chloride to obtain a product (220 mg/ in the form of a solid product. So pl. 146-147oC.

1H NMR (CD3OD): d 7.34 - 6.95 (m, 18m), 4.78 (d, J = 14.3 Hz, 2H), 3.78 (s, 6H), 3.68 (bs, 2H), 3.61 (d, J = 11.4 Hz, 2H), 3.10 - 2.83 (m, 6H).13C NMR (CD3OD): 162.22, 154,08, 151,28, 139.74, 129.28, 129.14, 128.11, 126.52, 125.99, 121.63, 119.85, 70.44, 66.14, 55.46, 54.51, 32.22; MS 655 (M+H, 100%).

Example 9I. To a solution of example 9S /100 mg/ 1 ml of tetrahydrofuran/ add methylamine /0.4 ml, 40% in water/ and the resulting solution stirred overnight. After concentration and purification of the plate, the product is obtained in good yield.

Examples 9J and 9K. The previously described method for producing the product of example 9D and replacing b-ethanolamine and trace amounts of molecular sieves /powder/ ethanol. The reaction mixture was filtered through celite and concentrated to obtain residue, which was purified on TLC plate with reversed-phase 90% methanol in water to obtain the target compound.

Example 9I

1H NMR (CD3OD): 8.31 (s, 2H), 7.67 (d, J=7.7 Hz, 2H), 7.59 (s, 2H), 7.43 - 7.03 (m, 14H), 4.74 (d, J=14 Hz, 2H), 3.81 - 9, 57.20, 33.68, MS: 649 (M+H, 100%).

Example 9K

1H NMR (CD3OD): 8.31 (s, 1H), 7.68 - 7.03 (m, 18H), 5.33 (s, 1H), 4.76 (d, J= 13.9 Hz, 1H), 4.75 (d, J=14.3 Hz, 1H), 3.81 - 3.55 (m, 10H), 3.12 - 2.7 (m, 8H);13C NMR (CD3OD): 164,97, 163,78, 141,29, 141,24, 140,18, 139,39, 137,63, 133,06, 130,67, 130,64, 130,53, 130,48, 130,05, 129,55, 129,50, 128,86, 128,49, 127,47, 127,45, 127,20, 104,35, 71,98, 67,90, 67,40, 64,25, 62,39, 57,22, 57,11, 53,23, 33,67, M. S: 649 (M+H, 100%).

Example 9L. To a solution of example 5J /0.7 g, 1.3 mmol/ triethylamine /to 0.263 g, 2.6 mmol/ THF /5 ml/ add benzylsuccinic /0,346 g, 2.6 mmol) and the resulting solution was stirred at room temperature overnight. After removal of all volatiles the residue is purified on TLC plate to obtain 0.7 g of a solid product. So melting 150oC /decomposition/.

1H NMR (CD3OD): 7.33 - 6.33 (m, 28H), 4.74 (d, J=13.9 Hz, 2H) 4.30 (s, 4H), 3.64 (bs, 2H), 3.59 (d, J=12.1 Hz, 2H), 3.13 - 2.91 (m, 6H);13C NMR (CD3OD): 162.54, 155.68, 151.33, 139.88, 139.30, 138.64, 129.29, 129.20, 128,24, 128.18, 127.02, 126.90, 126.13, 125.81, 122.44, 120.55, 70.44, 65.28, 55.20, 44.31, 32.28; M. S: 805 (M+H, 100%).

An example of 9M. To a solution of example 5J /100 mg, 0,186 mmol/ triethylamine /38 mg, 0,39 mmol/ THF /1 ml/ add methyl isocyanate /27 mg, 0.47 mmol/ at room temperature, and the resulting mixture is stirred over night. After removing all volatile reagent, the residue is purified on TLC plate with 40% ethyl acetate in dichloromethane to which, 18H/, 4,82 /d, J=14,2 Hz, 2H/, 3,69, - 3,65 /m, 4H/, 3,15 - 2,95 /m, 6H/, 2,84 /6H/,13C NMR /MD3OD/: 163,96; 157,56; 152,92; 141,31; 140; 83; 130,66; 130,55; 129,5; 127,46; 127,17; 123,70; 121,95; 71,88; 67,02; 56,67; 33,65; 27,57; MS: 670 /M+NH, 100%).

Example 9N. A solution of bis/m-bromobenzyl/cyclic urea /MEM-protected/ /0.84 g, 1 mmol/, propargilovyh alcohol /0,224 g, 4 mmol/, tetrakis /triphenylphosphine/ palladium /0,116 g, 0.1 mmol/, iodide copper /0,019 g, 0.1 mmol/ 5 ml of triethylamine is refluxed under nitrogen atmosphere overnight. After evaporation of all volatiles, the residue diluted with ether /20 ml and filtered through celite. The obtained filtrate is concentrated and purified on TLC plate to obtain 400 mg of MEM-protected-mono/attached product. After removing protection from 170 mg of the product of the merger using standard procedures, obtain 130 mg of the target product.

1H NMR (CD3OD): 7.50 - 7.09 (m, 18H), 4.72 (d, J=13.9 Hz, 1H), 4.69 (d, J=13.4 Hz, 1H), 4.46 (s, 2H), 3.75 - 3.68 (m, 4H), 3.18 - 2.86 (m, 6H).13C NMR (CD3OD): 163.61, 141.99, 141.07, 139.73, 133.64, 133.54, 131.91, 131.76, 131.47, 130.57, 130.50, 129.81, 129.59, 129.19, 127.51, 124.69, 123.46, 89.28, 85.09, 71.93, 71.91, 68.12, 67.75, 57.07, 57.03, 51.15, 33.60, 33.59; M. S.: 639/641 (M+H, 100%), 656/658 (M+NH4, 100%).

Example 9O and 9P. A solution of bis (m-Br-C6H4CH2cyclic urea /425 mg, 0.64 mmol/ 1 ethoxy-1-trimethylol is osphere nitrogen during the night. After cooling to room temperature the reaction mixture was diluted with ether /10 ml and filtered through silica gel to obtain two products. As a result of further purification on TLC plate with 20% ethyl acetate in methylene chloride receive the product of example 9O /107 mg, So pl. 190 - 191oC/ and the product of example 9P /225 mg, So melting 158 - 159oC/.

Example 9O

1H NMR (CDCl3): 7.78 (d, J=7.3 Hz, 1H), 7.71 (s, 1H), 7.42 - 7.02 (m, 16H), 4.81 (d, J=13.9 Hz, 1H), 4.77 (d, J=13.9 Hz, 1H), 3.71 (ds, 2H), 3.62 - 3.54 (m, 2H), 3.20 - 2.85 (m, 8H), 2.50 (s, 3H);13C NMR (CDCl3): 198.27, 161.86, 140.38, 139.29, 139.22, 138.81, 137.22, 133.99, 132.36, 130.65, 130.09, 129.36, 129.32, 128.99, 128.86, 128.66, 127.70, 127.55, 126.61, 122.53, 71.38, 65.24, 65.12, 55.83, 55.59, 32.77, 26.58, M. S.: 644/646 (M+NH4, 100%).

Example 9P:

1H NMR (CDCl3): 7.78 - 7.03 (m, 18H), 4.83 (d, J=14.3 Hz, 2H), 3.73 (ds, 2H), 3.60 (d, J=10.6 Hz, 2H), 3.17 - 3.08 (m, 4H), 2.92 - 2.89 (m, 2H), 2.49 (s, 6H);13C NMR (CDCl3): 198.03, 161.83, 139.40, 138.78, 137.12, 133.87, 129.29, 129.04, 128.74, 128.52, 127.36, 126.46, 71.25, 71.15, 65.32, 55.82, 30.73, 26.51; M. S.: 608 (M+NH4, 100%).

Example 9Q. A solution of example 9P /84 mg, 0,142 mmol/ and gidroxinimesoulid /59,4 mg, 0,854 mmol/ in a mixture of pyridine /ethanol /6 ml, 1:1/ refluxed over night. After evaporation of all solvent in vacuo get the remnant that purify by preparative TLC plates with a mixture of ethyl acetate: IU the SUB>3
ML/: to 7.67 - 7,07 /m, 18H/, 4,74 /d, J=a 13.9 Hz, 2H/, 3,64 - 3,62 (m, 4H), 3,09 - 2,89 (m, 6H), 2,17 (S, 6H);13C NMR (CD3OD): 163.94, 155.43, 141.23, 139.46, 138.97, 130.77, 130.65, 129.69, 129.37, 128.10, 127.47, 126.32, 72.02, 67.16, 57.08, 33.62, 11.96; M. S.: 621 (M+H, 100%).

Notes to table 2d.

/1/ Get the total by way of alkylation.

/2/ monoalkyl connections get in the way 5 synthesis monoacylglycerol urea.

/3/ is obtained by alkylation of the corresponding monoalkyl connection.

/4/ Produce as a by-product due to incompleteness of the reaction.

/5/ Gidroxinimesoulid /0.384 mmol/ add to relevant bis/N-m-benzaldehyde/cyclic urea /0,064 mmol/ mixed with 2 ml of pyridine and 2 ml of ethanol. The resulting mixture was refluxed for 4 hours, and the solvent is removed in a rotary evaporator. The residue is purified on silica gel /0,2:3:7/ methanol:ethyl acetate:methylene chloride/.

/6/ Getting monoalkyl connections facilitated by using one equivalent of alkylating agent.

/7/ the Solution bis/N-m-benzoic acid/cyclic urea /1.56 mmol/ in a mixture of 1:1 benzene:methylene chloride containing 1 drop of DMF, and pyridine /9,36 mmol/ process oxalylamino /2M in Meath is collected in a rotary evaporator, and the resulting residue is dried by pumping for 2 hours. To the residue is added 20 ml of methylene chloride, and then pyridine /9,36 mmol) and methylamine /8,03 M in ethanol, 9,36 mmol/. Stirred at room temperature overnight. The resulting mixture was extracted with Et, dried over magnesium sulfate and purified on silica gel /1:9 methanol:chloroform/.

/8/ the Solution bis/N-m-hydroxy-benzyl/cyclic urea /0,93 mg/ DL in methylene chloride is treated with triethylamine /1,67 mmol/ at -20oC. Then was added dropwise a solution of 1-adamantylidene /1 mmol/ 5 ml of methylene chloride. The resulting mixture was stirred at -20oC for 10 minutes, at 0oC for one hour at room temperature overnight and washed with chilled HCl, saturated sodium bicarbonate, water and dried over magnesium sulfate. The residue is purified on silica gel /2:8 ethyl acetate:methylene chloride/.

/9/ 2 drops OsO4/25% in tert-BuOH/ add to mixture bis/N-m-allyloxyphenyl/cyclic urea /0,19 mmol/ and N-methylmorpholine-N-oxide /0,57 mmol/ 5 ml acetone. The resulting mixture was stirred at room temperature overnight. The solvent is removed in a rotary evaporator and the residue is purified on silica gel /2:8 methanol:chloroform/.

/11/ To the corresponding complex of ethyl ether /0,21 mmol/ and hydroxylaminopurine /1,17 mmol/ /to the mixture in 10 ml of methanol/ added dropwise 5M /2.1 mmol/ solution of potassium hydroxide in methanol at room temperature. After stirring for 24 hours the methanol is evaporated and the solid residue is acidified with acetic acid and extracted with ethyl acetate, which was purified on silica gel /0,1:3:7 acetic acid:methanol:ethyl acetate/.

/12/ Through bis/-m-allyloxyphenyl/cyclic urea /0,16 mmol/ 10 ml of methanol purge ozone for 10 minutes at -78oC. After warming to room temperature, add sodium borohydride /1,16 mmol/ and stirred at room temperature overnight. The reaction mixture is treated, quenching with acetic acid, the solvent is removed in a rotary evaporator and purified on silica gel /0,3:9:7 methanol:ethyl acetate/.

/13/ Solution of bis-cyanocobalamine in absolute methanol saturated with hydrochloric acid and left at 0oC for 3 hours to complete the reaction /according to TLC/. After evaporation of the solvent the residue is dissolved in 2M ammonia in methanol. After a week of stirring at room temperature the solvent is removed under reduced pressure, the ukta.

/14/ To bis/N-hydroxybenzyl/cyclic urea /1.11 mmol/ ethanol was added dropwise NaOH /15,54 mmol/ 2 ml of water. The resulting mixture was heated to 80oC for 1 hour, then add 2 ml of chloroform, followed by heating at 80oC during the night. The reaction mixture is treated by neutralizing with 5% cold HCl, washed with saturated sodium bicarbonate, water and dried over magnesium sulfate. The residue is purified on silica gel /a 1.5 : 8.5 methanol : chloroform/. To this solid product add ethanol, and then the excess sodium borohydride. The resulting mixture is heated to boiling under reflux for 2 hours. The reaction mixture is treated, quenching with acetic acid, the solvent is removed in a rotary evaporator and purified on silica gel /2 : 8 methanol : chloroform/.

/15/ N-utility /1.6 M in hexane, 5 mmol/ added dropwise to bis/N-m-bromobenzyl/cyclic urea /1 mmol/ THF at -78oC. After stirring for 0.5 hours add trimethylboron /5 mmol/. The resulting mixture was slowly warmed to room temperature and left under stirring for 4 hours. The reaction mixture is decomposed by adding 5% HCl, diluted with ethyl acetate, washed twice with water and dried over magnesium sulfate. The residue cleaned what you get in three stages: 1/ Asymmetric cyclopropanation /D. A. Evans et. al., J. Am. Chem. Soc. 1991, 113, 726 - 728/. 2/ Recovery sociallyengaged. 3/ the Transformation of the bromide with CBr4Ph3P and imidazole.

The following list shows representative data for compounds listed in table 2d (see the end of the description).

Structure the following examples are presented in table 2e. Education Catala: Getting triacetone /XXVIa/:

Borohydride lithium /1.2 g, 56.2 mmol/ add four portions to a suspension of Z-Masonic-g-lactone /5 g, 28.1 mmol/ 250 ml of methanol at 0oC for 10 minutes. The ice bath removed and the reaction mixture stirred at room temperature for 30 minutes. The reaction is quenched at 0oC 2n HCl. The solvent is evaporated and the residue was placed in an acetone /75 ml/, to which is added in four portions 2,2-dimethoxypropane /20 ml, 168,6 mmol/ and camphorsulfonic acid /20 g of 84.3 mmol/. The reaction mixture becomes transparent after a few minutes, and then a precipitate. The reaction mixture was stirred at room temperature for 14 hours. The volume of solvent is reduced by 2/3 under reduced pressure, and then all poured into EtOAc, washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and concentrated. Solid on acetonide /XXVIa/ in the form of a yellowish solid product /7,1 g, 80%/. So melting 72-74oC. MC: /M+H, 100%/.

NMR /CDCl3, 300 MHz/: 4,25 /m, 2H/, 4,15 /m, 2H/, 4,05 /m, 4H/, 1,5 /s, 6H/, 1,45 /6H/, 1,4 /6H/.

Selective removal of protection from the acetonide: getting tetraol /XXVIb/

Connection /XXVIa/ /14 g/ 70% AcOH /200 ml stirred at 45oC for 2 hours. The solvent is removed under reduced pressure at a bath temperature of 45oC. the Residue is recrystallized from ether. The mother liquor is concentrated and process chromatographic /silica, 10% methanol in methylene chloride to obtain the target product as a white solid product /8,2 g, 80%/. So melting 91-93oC. = -26,40 /c=3, H20/; MC: 240 /M+NH4, 100%/.

NMR /CDCl3, 300 MHz/: 3,95 /m, 6H/, 3.75 per m, 4H/, 2,5 /Shir. with 2H/, 1,4 /6H/.

The formation of epoxide: getting diepoxide /XXVIc/:

A solution of compound /XXVIb/ /1 g, 4.5 mmol/ 5 ml of pyridine is cooled to -20oC and treated with paratoluenesulfonyl /1.89 g, 10 mmol/. Stirring is continued at -20oC for 20 minutes at 0oC for 20 minutes, and when the 23oC for 20 minutes. Then the reaction solution is diluted with methylene chloride and washed with 2n. HCl and sodium bicarbonate. The organic extract is dried over magnesium sulfate and concentrated. Then the crude about the mixture was stirred at room temperature for 30 minutes The methanol is distilled off /evaporated until dry but not as volatile epoxide/ and the crude product is washed with water, extracted with ether, dried over magnesium sulfate, filtered and concentrated. Connection purified on silica elwira 30-60% of a mixture of ether and petroleum ether to obtain diepoxide /0,63 g, 75%/ in the form of butter.

NMR /CDCl3, 300 MHz/: 3,81 /m, 2H/, 3,10 /m, 2H/, 2,80 /t, 2H,/, 2,68 /m, 2H/, 1,40 /s, 6H, CH3/.

Disclosure epoxide: Getting diol /XXVId/:

To a suspension of complex copper bromide-bimetallic /1.8 g, 8,7 mmol/ in anhydrous THF /5 ml/ -20oC add 8.5 ml of benzylacrylamide /2M IN THF, 17 mmol/. The reaction mixture was stirred at -20oC for 30 minutes and at 0oC for 1 hour. Then add the connection /XXVIc/ /0.54 g, 3 mmol/ THF /5 ml, and the reaction mixture was stirred at 0oC for 1 hour. The excess reagent is quenched with saturated NH4Cl solution and allowed to warm to room temperature. Then the contents washed with water and brine, extracted with ether, dried over magnesium sulfate, filtered and concentrated.

Then the crude material purified using chromatography with instant evaporation /30-60% ether-petroleum ether to obtain 0.84 g /78% oil/.


To a solution of compound /XXVId/ /of 0.48 g, 1.3 mmol) and triphenylphosphine /1.0 g, 3.9 mmol/ THF /5 ml/ at 0oC add diethylazodicarboxylate /and 0.61 ml, 3.9 mmol/ and diphenylphosphoryl /0,84 ml, 3.9 mmol/. The contents allowed to warm to room temperature in an ice bath for 1 hour. The excess reagent is quenched by adding methanol /0.2 ml, 5 mmol/ at 0oC. Then the resulting mixture was stirred at room temperature for 30 minutes and then concentrated to small volume. Then the product was then purified on silica using a 1:40 mixture of ethyl acetate/hexane, resulting in a gain 0,245 g /45%/ oil.

MC 438 /M+NH4, 8%/; NMR /CDCl3, 300 MHz/ 7,2-7,4 /m, 10H/, 4,18 /C, 2H/, 2,7-3,0 /m, 6H/, 2,0-2,3 /m, 4H/, 1,58 /6H/.

Recovery diazide /XXVIe/:

Connection /XXVIe/ /0,245 g of 0.58 mmol/ in 6 ml of ethanol in a nitrogen atmosphere, add 10% Pd/C /of 73.5 mg, 30 wt.%/. The reaction mixture was stirred in an atmosphere of H2at room temperature over night. The crude product is filtered through celite and concentrated. Collect 0.21 g /98%/ diamine in the form of oil and transferred to the next stage without further purification.

MC: 369 /M+H, 100%;/ NMR /CDCl3300 MHz/: 7,05-7,3 /m, 10H/, 3,9 /Shir. s, 2H/, 3,05 /Shir. s, 4H/, 2,8 /m, 2H/, 2,6 /m, 4H/, 1,7 /Shir. s, 4H/, 1.35m /s, 6m in methylene chloride /50 ml and add carbonyldiimidazole /is 0.102 g, to 0.63 mmol) and the reaction mixture was stirred at 23oC during the night. Then the resulting solution was concentrated and purified on silica using 75% ethyl acetate/hexane as eluent, resulting in a gain of 85 mg /38%/ /XXVIf/ foam.

MS: 395 /M+H, 100%;/ NMR /CDCl3, 300 MHz/: 7,0-7,2 /m, 10H/, 3,6-4,0 /m, 4H/, 3,6-2,7 /m, 4H/, 1,8-1,9 /m, 4H/, 1,3 /6H/.

Alkylation of cyclic urea /XXVIf/:

Connection /XXVIf/ /85 mg, 0.22 mmol/ dry DMF /3 ml/ added 60% NaH /0.07 g, 1.7 mmol/. The resulting solution was stirred for 5 minutes at room temperature. Then add benzylbromide /0.1 ml, 0.86 mmol) and the reaction mixture was stirred at 23oC during the night. Then the reaction mixture was quenched with methanol /several drops/, washed with H2O, extracted with ether, dried over magnesium sulfate and concentrated. Purify on silica gel using 1:1 hexane/ethyl acetate, resulting in a gain of 0.03 g /25%/ bis-alkilirovanny urea in the form of foam.

MS: 575 /M+H, 100%/ NMR /CDCl3, 300 MHz/: 7,1-7,4 /m, 20H/, 5,1 /d, 2H/, 4,0 /d, 2H/, 3,75 /Shir. s, 2H/, 3,6 /m, 2H/, 2,7 /m, 2H/, 2,6 /m, 2H/, 1,9-2,0 /m, 4H/, 1,25 /6H/.

Remove protection from acetonide: Obtaining compounds of example 16A:

To previously obtained bis-alkilirovanny cyclizes the HCl. The reaction mixture was stirred at room temperature for 2 hours. Then it was washed with 1 N. NaOH, extracted with ethyl acetate, dried over magnesium sulfate and concentrated. After chromatography was carried out /silica, 1-5% methanol in methylene chloride/ get 0,024 g /85%/ compound of example 16A in the form of foam.

MS: 535 /M+H, 100%/ NMR /CDCl3, 300 MHz/: 7,1-7,3 /m, 20H/, 5,15 /d, H/, 3,9 /d, 2H/, 3,5 /Shir. S., 2H/, 3,3-3,4 /m, 2H/, 2,7-2,8 /m, 2H/, 2,5-2,6 /m, 2H/, 2,0-2,1 /m, 6H/.

The formula of the compounds of the following examples are presented in tables 2f-h (see the end of the description).

Getting thiourea /XXVIIa/:

Deamination connection /XXIb/ /22,45 g of 47.1 mmol/ dissolved with 200 ml of tetrahydrofuran, and to this solution add 9,23 g /51,8 mmol/ thiocarbonyldiimidazole. After stirring the mixture for 18 hours at room temperature according to TLC /10:1:10 ethyl acetate/ethanol/hexane/ reaction is completed. The reaction mixture is dried to dryness, and the residue is purified on a chromatographic column with an instant evaporation/ silica gel, 250 g, 1:1 ethyl acetate: hexane to obtain a solid product, which was triturated with hexane to obtain 17.8 g /73% yield XXVIIa in the form of a solid white product.

Getting connection /XXVIIb/:

Pitch black/ via syringe, and stirred at room temperature for one hour. Contents are then dried to dryness. The residue is dissolved in 30 ml of dimethylformamide and to this solution was cooled in an ice bath at 0oC add NaOH /60% in oil/ 720 mg /18 mmol/ slow. /Gas/. The contents stirred at room temperature for 30 minutes. The resulting mixture was cooled in an ice bath at 0oC, and using a syringe add benzylbromide /2,052 g, 12 mmol/ within 18 hours. According to TLC /2:3 EtOAc:Hexane Rf= 0,25/ reaction is completed. The reaction mixture is treated by adding water /300 ml/ and extragere three times in diethyl ether, 50 ml Organic layer is dried over magnesium sulfate, and the resulting filtrate is brought to dryness. The residue is purified on silica gel /200 g, 2: 3 EtOAc:hexane to obtain of 2.93 g /78,2% output/ XXVIIb in the form of a colorless oil.

Getting connections /XXVIIc/ and /XXVIId/:

Connection /XXVIIb/ /2,90 g and 4.65 mmol/ dissolved in 25 ml of pyridine and to this solution add 742 mg /4,65 mmol/ benzylhydroxylamine. Content is boiled in an oil bath at 125oC for 18 hours. Warning: by-product is a mercaptan, and the exhaust gases should be given through the Scrubber Clorox. According to TLC/, and then saturated sodium bicarbonate solution /100 ml. It is isolated and dried over magnesium sulfate, and the resulting filtrate is dried to dryness. The residue is purified on silica gel /130 g, using 1:3 EtOAc: hexane to obtain 584 mg /18,0% output/ connections /XXVIIc/ in the form of a colorless oil, 1:2 EtOAc:hexane is used to produce 2,113 g of the solid product - thiourea /XXVIId/.

Getting oxime /XXVIIe/:

Connection /XXIIc/ /584 mg, 0.84 mmol/ dissolved in 5 ml of dimethylformamide and to this solution was cooled to 0oC in an ice bath, add NaH /60% in oil, 80 mg /2 mmol/ slowly /gas/. The contents stirred at room temperature for 30 minutes. The resulting mixture was cooled in an ice bath at 0oC, and add benzylbromide /of 0.24 ml, 2 mmol/ via syringe and stirred at room temperature for 18 hours. According to TLC /1:3 EtOAc:hexane Rf= 0,26/ reaction is completed. The reaction mixture is treated by adding water /50 ml/ and extragere diethyl ether /2 x 25 ml/. The organic layer is dried over magnesium sulfate, and the resulting filtrate is dried to dryness. The residue is purified on silica gel /33 g, 1:3 EtOAc: hexane to obtain 491 mg /74,2% output/ colorless oil.

Example 18A. Connection /XXVIId/ /450 is 4M HCl in dioxane /5 ml, 20 mmol/, and the resulting mixture was stirred at room temperature for 18 hours. According to TLC /2:3 EtOAc:hexane Rf= 0,29/ reaction is completed. The resulting mixture is treated, quenching with a saturated solution of sodium bicarbonate /50 ml/ and extragere dichloromethane /2 x 50 ml/. The organic extracts are dried over magnesium sulfate, and the resulting filtrate is dried to dryness. The residue is purified on silica gel /33 g, 2:3 EtOAc: hexane to obtain 246 mg /70,5% output/ connection example 18A in the form of a waxy solid.

Example 17A. The product of example 18A /160 mg, 0.26 mmol/ dissolved in 5 ml of ethanol. To this mixture is added 50 mg of 10% palladium hydroxide on charcoal, and the resulting suspension stirred for 18 hours in a hydrogen atmosphere. According to TLC /10: 1: 10 EtOAc:EtOH:hexane Rf= 0,3/ reaction is completed. The resulting suspension is filtered through a layer of celite, and the obtained filtrate is dried to dryness. The residue is purified on silica gel /33 g, 10:1:10 EtOAc:EtOH: hexane to obtain 97 mg of the product of example 17A /output 69,5%/ in the form of a white solid.

Example 19A. Connection /XXVIId/ /500 mg, 0.82 mmol/ placed in a 25 ml round bottom flask and cooled in an ice bath at 0oC. To this flask was added 4M HCl in dioxane /7.5 ml, 30 mmol) and poluceaetsea ends. The resulting mixture is treated, quenching in a saturated solution of sodium bicarbonate /50 ml) and extracted with dichloromethane /2 x 50 ml/. The organic extracts are dried over magnesium sulfate, and the resulting filtrate is evaporated to dryness. The residue is purified on silica gel /33 g, 1:2 EtOAc:hexane to obtain 182 mg /output 51,1%/ of the product of example 19A in the form of a white solid.

Structure the following examples are presented in table 2i:

Acetylation diol: connection /XXVIIIa/:

The product of example IX /3,517 g, 7,58 mmol/ dissolved in 25 ml of pyridine and to this solution was cooled in an ice bath at 0oC add 350 mg of 4-dimethylaminopyridine and 7,16 ml /75,85 mmol/ acetic anhydride. The contents stirred at room temperature for 18 hours. According to TLC /1: 4 EtOAc:hexane Rf= 0,3/ reaction is completed. The reaction solution was diluted with 250 ml dichloromethane. The organic layer was washed with 1 N. HCl /2 x 300 ml/, and then saturated sodium bicarbonate solution /100 ml. Separated and dried over magnesium sulfate, and the resulting filtrate is evaporated to dryness. The residue is purified on silica gel /200 g, 1:5 EtOAc:hexane to obtain 2,632 g /67,7%/ XXVIIIa in the form of a white solid product.

Nitration of benzyl groups: Connection /WMD -40oC in a bath consisting of a mixture of dry ice-acetone, added to 4.4 ml /2.2 mmol/ 0.5 M nitrosoanatabine in sulfolane. The contents stored at -40oC in the freezer for 18 hours. According to TLC, the reaction is finished. The reaction mixture is diluted with 100 ml ether and washed with water /2 x 50 ml/. The organic layer is dried over magnesium sulfate, and the resulting filtrate is evaporated to dryness. The residue is purified on silica gel /75 g, 1:3 EtOAc:hexane to XXVIIIb, EtOAc:hexane to XXVIIIc/ to obtain 106 mg /17,4% output/ XXVIIIb in the form of a white solid product and 159 mg / 26,2% output/ XXVIIIc in the form of a white solid.

Example 20A. Connection /XXVIIIb/ /106 mg, 0,174 mmol/ dissolved in 5 ml of methanol and to this solution add 0.5 ml of 0.5 M sodium methoxide in methanol with a syringe. The contents stirred at room temperature for 30 minutes. According to TLC, the reaction is finished. The resulting mixture was quenched by adding 500 mg AG50W - X8 acid resin and stir the resulting suspension at room temperature for 5 minutes. The obtained filtrate is dried to dryness and the residue is purified on silica gel /33 g, 1:2 EtOAc:hexane to obtain 43 mg/ 47,1% of example 20A in the form of a solid white product.

Example 20 B. Connection /XXVIIIc/ /159 mg, 0,261 mmol/ Rast is th stirred at room temperature for 30 minutes. A white precipitate begins to form after 15 minutes. According to TLC, the reaction is finished. The resulting mixture was quenched by adding 500 mg AG50W - X8 acid resin and the suspension is stirred at room temperature for 5 minutes. Add 10 ml of dichloromethane to dissolve the solids. The obtained filtrate is dried to dryness, and receive the remainder of 11 mg /81.1% of output/ example 20B in the form of a solid white product.

Example 20E. The product of example 20A /100 mg, 0,191 mmol/ dissolved in 5 ml of ethanol. To this mixture is added 50 mg of 5% Pd/C, and the resulting suspension stirred for 18 hours in an atmosphere of hydrogen /1 ATM/. According to TLC, the reaction is finished. The suspension is filtered through a layer of celite and the resulting filtrate is dried to dryness. The result is 47 mg /53,0% output/ product of example 20E in the form of a white solid.

Example 20F. The product of example 20B /100 mg, 0,191 mmol/ suspended in 5 ml of ethanol. To this mixture is added 50 mg of 5% Pd/C, and the resulting suspension stirred for 18 hours in an atmosphere of hydrogen /1 ATM/. The source material is introduced into the solution as the reaction. According to TLC, the reaction is finished. The suspension is filtered through a layer of celite, the obtained filtrate is dried to dryness. In the remainder receive 49 mg within 4-fermentaciones urea /XXXI/:

< / BR>
Getting 4-fermentaciones urea is conducted according to scheme 7. N-acetyl-D-4-pertanyaannya methyl ester /23,9 g, 0.1 mmol/ obtained by the method of M. J. Burk/ J. Am. Chem. Soc. 1991, 113, 8518/ dissolved in 40 ml acetic acid and treated with 100 ml of concentrated HCl, 40 ml of water and heated at boiling under reflux for 5 hours. The resulting solution was cooled to room temperature and then alkalinized /pH 10/ 50% NaOH while cooling in an ice bath. Benzylchloride /25 ml, 29 g, 0,17 mmol/ NaOH and add 4 portions, and the solution supports alkaline by adding NaOH. The resulting mixture was stirred at room temperature for 30 minutes. The alkaline solution is extracted with ether /2 x 500 ml) and the resulting solution was acidified with conc. HCl to pH 1. The precipitate is extracted with methylene chloride and dried over magnesium sulfate. The resulting solution was filtered and concentrated to obtain 20 g of N-Cbz-D-4-pertanyaannya in a solid white color, which is used without further purification.

A solution of N,O-dimethylhydroxylamine /8.0 g, 0,082 mg/ DL in DMF receive careful when heated. The resulting solution was left to cool slightly and treated with N-methylmorpholine /8,2 g, 0,082 mg/ DL and diluted mmol/ THF is treated with N-methylmorpholine /9.0 g, 0.09 mmol/ and cooled to 0oC in an ice bath. To a stirred cold solution add isobutylparaben /8.6 g, 0,063 mmol/ small portions over 10 minutes. Then add a solution of N, O-dimethylhydroxylamine in DMF, obtained previously, and the reaction mixture is stirred for 20 minutes. A large part of the solvent is removed on a rotary evaporator and the residue is divided between water and methylene chloride. The organic layer is successively washed with 1 N. HCl, 1 N. NaOH, water, brine, and then dried over magnesium sulfate. The resulting solution was filtered and concentrated, and the residue is treated chromatography on silica gel /50% EtOAc/Gex to obtain 16 g of the amide.

By the way J-A. Fehrentz and B. Castro/Synthesis, 1983, 676/, 11 g /0,031 mmol/ N-Cbz-D-4-forfinally-N,O-dimethylhydroxylamine turn in 9.0 g of N-Cbz-D-4-pertanyaannya obtained as a thick oil which is used without further purification.

N-CBz-D-4-pertanyaannya /9.0 g, 0,031 mmol/ turn, using method 1, /2R, 3S,4S,5R/-2,5-bis/N-Cbz-amino/-3,4-dihydroxy-1,6-di/4-forfinal/ hexane /4 d/ received in the form of a solid white color. MC: /Cl, NH3//M+H/+=605.

/2R, 3S, 4S, 5R/-2,5-bis/N-Cbz-amino/-3,4-dihydroxy-1,6-di/4-forfinal/hexane/ /4,0 g, 0,0066 mmol/ n MC/CJ, NH3/M+H/+= to 539.3.

B. 4-forbindelsessokkel urea /XXXI/ /270 mg, 0.5 mmol/ alkylate 3-benzoxazinoids /350 mg, 1.5 mmol/ method 5. The obtained intermediate compound is dissolved in THF and hydronaut for 12 hours /200 mg, 10% Pd/C, a 3.87 kg/cm2(55 psi) to remove benzyl protective groups. Then remove the MEM group method 5, to obtain after chromatography treatment on silica gel HPLC /10% MeOH//CHCl3/, 140 mg of the product of example 20G in the form of a white foam. MC: /Cl, NH3/ /M+H/+= 575,2 /100%/.

Structure the following examples are presented in table 2j.

Example 21A. A. Obtaining aziridination /XX 11a/:

A solution of the compound of example 1A /5.3g, to 0.016 mol/ pyridine is treated with acetic anhydride /3,3 g 0,033 mol/ and stirred at room temperature for 3 hours. Add 10 ml of MeOH, and the resulting mixture is evaporated to dryness. The residue is extracted with methylene chloride and washed successively with water, 1 N. HCl, brine and dried over magnesium sulfate. The resulting solution is filtered, concentrated, and the residue chromatographic on silica gel /5% MeOH/CHCl3to obtain 2.0 g of the corresponding monoacetate in a solid white color. The resulting product RA is via syringe, and the resulting solution was stirred for 10 minutes. The resulting mixture was quenched with saturated NaHCO3and the organic layer washed with water and brine. The resulting solution was dried over magnesium sulfate, and then filtered and concentrated to obtain 1.9 g of the acetate of aziridine /XXXIIa/, which is used without further purification.

B. the Acetate of aziridine /XXXIIa/ /100 mg, 0.29 mmol/ dissolved in MeOH /2 ml and treated with 1 N. NaOH /0.5 ml) and stirred at room temperature for 30 minutes. The resulting mixture was diluted with water /20 ml and extracted with CH2Cl2. The extract obtained was washed with water and brine, dried over magnesium sulfate, and then filtered and concentrated to obtain 30 mg of the product of example 21A in the form of a solid white product. MC /Cl, NH3/ /M+H/+= 309,0.

Examples 21B and 21C. Acetate of aziridine /XXXIIa/ /200 mg, or 0.57 mmol/ alkylate benzylbromide /120 mg, 0.69 mmol/ by way of 5 to obtain a mixture of products. This mixture is treated chromatographically by HPLC on silica gel /50% EtOAc/Gex/ to get the first 50 mg of the product of example 21B in the form of a solid white product. MC: /Cl, NH3/ /M+H/+= 309,0. Then get 30 mg of the product of example 21C in the form of a colorless oil. MC: /Cl, NH3/ / cyclic urea /XXXIIIa/:

< / BR>
A. Obtain 4-amino-2-/tert.-butoxycarbonylamino/-1,5-diphenyl-3-/2-methoxyethoxymethyl/ pentane.

The mixture 595 mg /1.50 mmol/ 4 azido-2-/tert-butoxycarbonylamino-1,5-diphenyl-3-hydroxypentanal /EP 0402646 A1/ 10 ml dioxane and 0.2 ml of 1.75 mmol/ MEM chloride and 0.32 ml /1,83 mmol/ diisopropylethylamine heated at 80oC for 16 hours. After evaporation of the solvent and purification of the residue by chromatography with instant evaporation on silica gel with a mixture of 85:15 hexane-ethyl acetate to obtain 0.64 g /88%/ oil. MC: /M+H/+= 485,2. After reduction with hydrogen using 100 mg of 10% Pd/C in 60 ml of ethyl acetate and 0.6 ml of acetic acid, receive specified in the title compound with a 49% yield.

B. Obtaining 2,4-diamino-1,5-diphenyl-3-hydroxypentanal.

The product of part A /218 mg/ dissolved in 2 ml of ice-cold mixture of 1:1 triperoxonane acid-dichloromethane. After 1 hour the solution was poured into a mixture of sodium bicarbonate and ethyl acetate. After extraction with ethyl acetate to obtain 163 mg of the target diaminododecane.

C. Cyclization of the diamine.

The product of part B /146 mg, 75 mg carbonyldiimidazole and 0.15 ml aminobutiramida ethylamine are dissolved in 2.5 ml of anhydrous THF, and stirred at room temperature in the Techa silica gel, a mixture of 90: 10 dichloromethane-methanol to obtain 108 mg /69%/ cyclic urea. MC /M+H/+=385,1.

N-alkylation of cyclic urea /XXXIIIa/:

D. the Product from part C /93 mg/ dissolved in 2.5 ml of anhydrous DMF and added 100 mg of 60% NaH in mineral oil. The resulting mixture is stirred for one hour. Add m-benzyloxybenzophenone /350 mg/, and the resulting mixture is stirred for 16 hours at room temperature. Add water and ethyl acetate. An ethyl acetate extract is washed with water, dried and evaporated. The residue is purified using preparative TLC on silica gel with a mixture of 60:40 hexane-ethyl acetate, to obtain 105 mg /54%/ target bis-alkylated product. MC /M+H/+= 777,5.

Removal of protective groups /example 22A/.

The product from part D /103 mg/ dissolved in 4 BC HCl /dioxane for 16 hours. The resulting solution was evaporated and purified using preparative TLC on silica gel with a mixture of 60:40 hexane-ethyl acetate MC /M+H/+= 689,4. The purified material hydronaut for 16 hours in the presence of 3 ml of ethanol, 0.2 ml of acetic acid and 35 mg of 10% Pd/C, to obtain the product of example 22A. MC /M+H/+= 509,25. Designed, 509,24.

1. Cyclic urea of General formula I

< / BR>
or their pharmaceutically SUB>-alkyl, substituted 0 - 3 R11C2- C8alkenyl, substituted with 0 to 3 R11C2- C8-quinil, substituted with 0 to 3 R11C3- C8-cycloalkyl, substituted with 0 to 3 R11C6- C10-bicycloalkyl, substituted with 0 to 3 R11, phenyl or naphthyl, substituted with 0 to 3 R12C6- C14-carbocyclic residue, represents a stable 5 - to 7-membered monocyclic or bicyclic or 7 - to 14-membered bicyclic, or tricyclic hydrocarbon ring, and any of them may be saturated, partially unsaturated or aromatic, and is substituted by 0 to 3 R12, heterocyclic system substituted with 0 2 R12and represents a stable 5 - to 7-membered monocyclic or bicyclic or 7 - to 10-membered bicyclic heterocyclic ring which may be saturated or unsaturated, and which consists of carbon atoms and 1 to 3 heteroatoms selected from nitrogen atoms, oxygen and sulfur;

R4Aand R7Aindependently selected from the following groups: hydrogen, C1- C4-alkyl substituted by halogen or C1- C2-alkoxy, benzyl, substituted by halogen or C1- C2-alkoxy;

R4and R4Acan be alternative is>and R7Acan be an alternative connected with formation of a 5 - to 7-membered carbocyclic ring, substituted with 0 2 R12;

n = 0 or 1;

R5selected from fluorine, Diptera, =O, C1- C3-alkyl or or20;

R6if n = 1, selected from the group: hydrogen, =O, fluorine, debtor, C1- C3-alkyl or or21;

R5and R6can be an alternative connected with the formation of the epoxy ring, -OCH2SCH2O-; -OS(= O)O-; -OC(=O)O-; -OCH2O-; -OC(=S)O-; -OC(=O(C)= O)O-; -OC(CH3)2O - or-OC(OCH3)(CH2CH2CH3)O-;

R20and R21independently selected from hydrogen, C1- C6of alkyl, substituted 0 - 3 R11C3- C6-alkoxyalkyl, substituted with 0 to 3 R11C1- C6-alkylsulphonyl, substituted with 0 to 3 R11C1- C6-alkoxycarbonyl, substituted with 0 to 3 R11, benzoyl, substituted with 0 to 3 R12, phenoxycarbonyl, substituted with 0 to 3 R12or phenylenecarbonyl, substituted with 0 to 3 R12;

R11choose from one or more of the following groups: keto, halogen, cyano, -CH2NR13R14, -NR13R14, -CO2R13, -OC(=O)R13, -OR13C2- C6-alkoxyalkyl, -S(O)mR13UP>14, -OC(=O)NR13R14, -NR13C(=O)NR13R14, -NR14SO2R13R14, -NR14SO2R13, -SO2NR13R14C1- C4-alkyl, C2- C4alkenyl, C3- C6-cycloalkyl, C3- C6-cyclooctylmethyl, 1 to 3 amino acids linked by an amide bonds, and linked with R4or R7via the amine or carboxylate end, C5- C14-carbocyclic residue substituted with 0 to 3 R12, phenyl or naphthyl, substituted with 0 to 3 R12or heterocyclic system substituted with 0 2 R12as described above and consisting of 5 to 10 atoms, containing at least one atom of nitrogen, oxygen, or sulfur;

R12when he is Deputy on carbon, selected from one or more of the following groups: phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1- C4-alkyl, C3- C6-cycloalkyl, C3- C6-cycloalkenyl, C7- C10-phenylalkyl, C1- C4-alkoxy, -CO2H, hydroxamic acid, hydrazide, oxime, boric acid, sulfonamide, formyl, C3- C6-cycloalkane, -OR13, -NR13R14C2- C6-alkoxyalkyl, C1- C1
- C4-alkoxycarbonyl, C1- C4-alkylcarboxylic, C1- C4-alkylsulphonyl, C1- C4-alkylcarboxylic, -S(O)mR13, -SO2NR13R14, -NHSO2R14, -OCH2CO2H, 2-(1-morpholino)ethoxy, C1- C4-alkyl, substituted-NR13R14or 5 - or 6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur, or R12can be 3 - or 4-membered carbon chain attached to adjacent carbons of the ring with the formation of condensed 5 - or 6-membered ring, with the specified 5 - or 6-membered ring optionally substituted on the aliphatic carbons with halogen, C1- C4-alkyl, C1- C4-alkoxy, hydroxy, or-NR13R14or, if R12attached to a saturated carbon atom, it may be carbonyl or thiocarbonyl; R12if he is a Deputy from nitrogen, are selected from one or more of the following groups: phenyl, benzyl, phenethyl, hydroxy, C1- C4-hydroxyalkyl, C1- C4-alkoxy, C1- C4-alkyl, C3- C6-cycloalkyl, C3- C6-cycloalkenyl, -CH2NR13R14, -NR13, CO2H, C1- C4-alkylcarboxylic, C1- C4-alkylsulphonyl;

R13Is H, phenyl, benzyl, C1- C6-alkyl or C3- C6-alkoxyalkyl;

R14- OH, H, C1- C4-alkyl or benzyl;

R13and R14can be an alternative connected with education -(CH2)4-, -(CH2)5-, -CH2CH2N(R15)CH2CH2- or-CH2CH2OCH2CH2-;

R15- H or CH3;

m = 0, 1, or 2;

w is selected from-N(R22(C)=Z(N)R23)-; -N(R22(S)=ONR23)-, where Z = O, S or NR24;

R22and R23independently selected from the following groups: hydrogen, C1- C8-alkyl, substituted 0 - 3 R31C2- C8alkenyl, substituted with 0 to 3 R31C2- C8-quinil, substituted with 0 to 3 R31C3- C8-cycloalkyl, substituted with 0 to 3 R31C6- C10-bicycloalkyl, substituted 0 - 3 OR31, aryl, substituted 0 - 3 R32C6- C14-carbocyclic residue as described above and is substituted by 0 to 3 R32, heterocyclic ring system, substituted with 0 to 3 R32as described above and consisting of 5 to 10 atoms including at least one nitrogen atom, laksi, C1- C4-aminoalkyl, cyano, nitro, benzyloxy;

or alternative R22can be connected with R4or R4Awith the formation of five - or six-membered condensed heterocyclic or carbocyclic ring, substituted with 0 2 R12where the heterocyclic ring are selected from pyrrolidine, research, thiomorpholine, piperidine or piperazine;

and alternative R23can be connected with R7or R7Awith the formation of five - or six-membered condensed heterocyclic or carbocyclic ring, substituted with 0 2 R12where the heterocyclic ring are selected from pyrrolidine, research, thiomorpholine, piperidine or piperazine;

and alternative R22and R23can connect with R5or R6with the formation of 0 - to 7-membered bridge with the formation of a carbocyclic or heterocyclic ring, with the specified bridge is substituted by 0 - 2 R12and a heterocyclic ring selected from the research, thiomorpholine, piperidine or piperazine;

R31choose from one or more of the following groups: keto, halogen, cyano, -CH2NR13>R14, -NR13>R14, -CO2R13, -OC(=O)R13, -OR13C214C(=O)R13, = NOR14, -NR14C(=O)OR14, -OC(=O)NR13>R14, -NR13C(=O)NR13>R14, -NR14SO2NR13>R14, -NR14SO2R13, -SO2NR13>R14C1- C4-alkyl, C2- C4alkenyl, C3- C6-cycloalkyl, C3- C6-cyclooctylmethyl, 1 to 3 amino acids, linked together by an amide bonds, and linked with R4or R7via the amine or carboxylate end, C5- C14-carbocyclic residue substituted with 0 to 3 R32, phenyl or naphthyl, substituted with 0 to 3 R32or heterocyclic system substituted with 0 2 R32as described above, and containing 5 to 10 atoms including at least one nitrogen atom, oxygen or sulfur;

R32if he is Deputy on carbon, selected from one or more of the following groups: phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1- C4-alkyl, C3- C6-cycloalkyl, C3- C6-cycloalkenyl, C7- C10-phenylalkyl, C1- C4-alkoxy, -CO2H, hydroxamic acid, hydrazide, oxime, baronova acid, sulfonamide, formyl, C3- C6-cycloalkane, -OR13, -NR13 and, C1- C4-haloalkyl, C1- C4-haloalkoxy, C1- C4-alkoxycarbonyl, C1- C4-alkylcarboxylic, C1- C4-alkylsulphonyl, C1- C4-alkylcarboxylic, -S(O)mR13, -SO2NR13>R14, -NHSO2R14, -OCH2CO2H, 2-(1-morpholino)ethoxy, -C(R14)=N(OR14), C1- C4-alkyl, substituted-NR13>R14or five - or six-membered heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur, or R32may be a chain of 3 or 4 carbon atoms, connected with the adjacent carbon ring with the formation of condensed five - or six-membered ring, with the specified five - or six-membered ring may be optionally substituted on the aliphatic carbons with halogen, C1- C4-alkyl, C1- C4-alkoxy, hydroxy, or-NR13>R14or, if R32attached to a saturated carbon atom, it may be carbonyl or thiocarbonyl; R32if he is a Deputy from nitrogen, are selected from one or more of the following groups: phenyl, benzyl, phenethyl, hydroxy, C1- C4-hydroxyalkyl, C1- C4-alkoxy, C14, -NR13>R14C2- C6-alkoxyalkyl, C1- C4-haloalkyl, C1- C4-alkoxycarbonyl, -CO2H, C1- C4-alkylcarboxylic, C1- C4-alkylaryl, -C(R14(=N)OR14), provided that R4, R4A, R7and R7Anot all are hydrogen if R4and R4Aboth hydrogen, at least one of R22and R23is not hydrogen.

2. The compound of formula I under item 1

< / BR>
or its pharmaceutically acceptable salt,

where R4and R7independently selected from hydrogen, C1- C4of alkyl, substituted 0 - 3 R11C3- C4-alkenyl, substituted with 0 to 3 R11C3- C4-quinil, substituted with 0 to 3 R11;

R4and R7Ais hydrogen;

n = 0 or 1;

R5selected from fluorine, Diptera, =O or-OR20;

R6selected from hydrogen, =O, fluorine, Diptera or21;

R5and R6can be an alternative connected with the formation of the epoxy ring, -OCH2SCH2O-, -OS(= O)O-, -OC(=O)O-, OCH2O-, -OC(=S)O-, -OC(=O)C(= O)O-, -OC(CH3)2O-, -OC(OCH3)(CH2CH2CH3)O-;

R20and R21independently selected from hydrogen, C2
NR13R14, -NR13R14, -CO2R13, -OC(=O)R13, -OR13C2- C4-alkoxyalkyl, -S(O)mR13C1- C4-alkyl, C2- C4alkenyl, C3- C6-cycloalkyl, C5- C14-carbocyclic residue substituted with 0 to 3 R12, phenyl or naphthyl, substituted with 0 to 3 R12or heterocyclic system substituted with 0 2 R12and characterized in p. 1, containing 5 to 10 atoms including at least one nitrogen atom, oxygen or sulfur;

R12if he is a Deputy at the carbon atom, selected from one or more of the following groups: phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1- C4-alkyl, C3- C6-cycloalkyl, C3- C6-cycloalkenyl, C7- C10-phenylalkyl, C1- C4-alkoxy, -CO2H, hydroxamic acid, hydrazide, oxime, baronova acid, sulfonamide, formyl, C3- C6-cycloalkane, -OR13, -NR13R14C2- C6-alkoxyalkyl, C1- C4-hydroxyalkyl, methylenedioxy, Ethylenedioxy, C1- C4-haloalkyl, C1- C4-haloalkoxy, C1- C4-alkoxycarbonyl, -S(O)mR13, -SO2NR13R14, -NHSO2R14C1- C4-alkyl, substituted-NR13R14or a five - or six-membered heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur; or R12may be a chain containing three or four carbon atoms attached to adjacent carbon ring with the formation of condensed 5 - or 6-membered ring, with the specified 5 - or 6-membered ring may be optionally substituted on the aliphatic carbons with halogen, C1- C4-alkyl, C1- C4-alkoxy, hydroxy, or-NR13R14or, if R12attached to a saturated carbon atom, it may be carbonyl or thiocarbonyl; R12if he is Deputy on the nitrogen are selected from one or more of the following groups: phenyl, benzyl, phenethyl, hydroxy, C1- C4-hydroxyalkyl, C1- C4-alkoxy, C1- C4-alkyl, C3- C6-cycloalkyl, C3- C6-cycloalkenyl, -CH2NR13R14, -NR13R14C2- C6-alkoxyalkyl, C1- C4-haloalkyl, C1- C4-alkoxycarbonyl, C1- C4-alkylcarboxylic, C1
R14- OH, H, C1- C4-alkyl or benzyl;

R13and R14can be an alternative connected with education -(CH2)4-, -(CH2)5, -CH2CH2(R15)CH2CH2or-CH2CH2OCH2CH2-;

R15- H or CH3;

m = 0, 1, or 2;

w is-N(R22(C)=Z(N)R23), Z = O, N-CN, N-OH, N-OCH3;

R22and R23independently selected from hydrogen, C1- C8of alkyl, substituted 0 - 3 R31C3- C8-alkenyl, substituted with 0 to 3 R31C3- C8-quinil, substituted with 0 to 3 R31C3- C6-cycloalkyl, substituted with 0 to 3 R31;

R31choose from one or more of the following groups: OR13, keto, halogen, cyano, -CH2NR13>R14, -NR13>R14, -CO2R13, -OC(=O)R13C2- C4-alkoxyalkyl, -S(O)mR13C1- C4-alkyl, C2- C4alkenyl, C3- C6-cycloalkyl, C5- C14-carbocyclic residue substituted with 0 to 3 R12and characterized in p. 1, phenyl, naphthyl, substituted with 0 to 3 R32or heterocyclic system substituted with 0 2 R32described in paragraph 1 and containing 5 to 10 atoms in which the carbon choose from one or more of the following groups: phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1- C4-alkyl, C3- C6-cycloalkyl, C3- C6-cycloalkenyl, C7- C10-phenylalkyl, C1- C4-alkoxy, -CO2H, hydroxamic acid, hydrazide, oxime, baronova acid, sulfonamide, formyl, C3- C6-cycloalkane, -OR13, -NR13>R14C2- C6-alkoxyalkyl, C1- C4-hydroxyalkyl, methylenedioxy, Ethylenedioxy, C1- C4-haloalkyl, C1- C4-haloalkoxy, C1- C4-alkoxycarbonyl, C1- C4-alkylcarboxylic, C1- C4-alkylsulphonyl, C1- C4-alkylcarboxylic, -S(O)mR13, -SO2NR13>R14, -NHSO2R14, -C(R14)= N(OR14), C1- C4-alkyl, substituted-NR13>R14or 5 - or 6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur; or R32may be a chain of 3 or 4 carbon atoms attached to adjacent carbon ring with the formation of condensed 5 - or 6-membered ring, with the specified 5 - or 6-membered, Calzolari, hydroxy or-NR13>R14or, if R32attached to a saturated carbon atom, it may be carbonyl or thiocarbonyl; R32if he is Deputy on the nitrogen are selected from one or more of the following groups: phenyl, benzyl, phenethyl, hydroxy, C1- C4-hydroxyalkyl, C1- C4-alkoxy, C1- C4-alkyl, C3- C6-cycloalkyl, C3- C6-cycloalkenyl, -CH2NR13>R14, -NR13>R14C2- C6-alkoxyalkyl, C1- C4-haloalkyl, C1- C4-alkoxycarbonyl, C1- C4-alkylcarboxylic, C1- C4-alkylsulphonyl, -CO2H, -C(R14)= N(OR14), provided that R4, R4A, R7and R7Anot all are hydrogen if R4and R4Aboth hydrogens, at least one of R22and R23is not hydrogen.

3. Connection on p. 1 of formula (II)

< / BR>
or its pharmaceutically acceptable salt,

where R4and R7independently selected from hydrogen, C1- C4of alkyl, substituted 0 - 3 R11C3- C4-alkenyl, substituted with 0 to 3 R11;

R5- -OR20;

R6- hydrogen or-OR21;
NR13R14, -NR13R14, -OR13C2- C4-alkoxyalkyl, C1- C4-alkyl, C2- C4alkenyl, C3- C6-cycloalkyl, phenyl or naphthyl, substituted with 0 to 3 R12or heterocyclic system substituted with 0 2 R12described in paragraph 1 and consisting of 5 to 10 atoms including at least one nitrogen atom, oxygen or sulfur;

R12if he is Deputy on carbon, selected from one or more of the following groups: phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, C1- C4-alkyl, C7- C10-phenylalkyl, C1- C4-alkoxy, -CO2H, hydroxamic acid, hydrazide, oxime, baronova acid, sulfonamide, formyl, C3- C6-cycloalkane, -OR13, -NR13R14methylendioxy, C1- C4-haloalkyl, C1- C4-alkylsulphonyl, C1- C4-alkylcarboxylic, hydroxy, hydroxymethyl, C1- C4-alkyl, substituted-NR13R14or 5 - or 6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur; R12if he is Deputy on nitrogen, is selected from benzyl or methyl;

R13- H, C1- C214an alternative can be connected with the formation of -(CH2)4-, -(CH2)5-, -CH2CH2N(R15)CH2CH2or-CH2CH2OCH2CH2-;

w is-N(R22(C)=Z(N)R23)-, where Z Is O, S or N-CN;

R22and R23independently selected from hydrogen, C1- C4of alkyl, substituted 0 - 3 R31C3- C4-alkenyl, substituted with 0 to 3 R31;

R31choose from one or more of the following groups: keto, halogen, -CH2NR13>R14, -NR13>R14, -OR13C2- C4-alkoxyalkyl, C1- C4-alkyl, C2- C4alkenyl, C3- C6-cycloalkyl, phenyl or naphthyl, substituted with 0 to 3 R32or heterocyclic system substituted with 0 2 R32described in paragraph 1 and containing 5 to 10 atoms including at least one nitrogen atom, oxygen or sulfur; R32if it is the Deputy of carbon, selected from one or more of the following groups: phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, C1- C4-alkyl, C7- C20-arylalkyl, C1- C4-alkoxy, -CO2H, hydroxamic acid, hydrazide, oxime, baronova acid, sulfonamide, formyl, C3- C6-alkylsulphonyl, C1- C4-alkylcarboxylic, hydroxy, hydroxymethyl, -C(R14)= N(OR14), C1- C4-alkyl, substituted-NR13>R14or 5 - or 6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur; R32if he is Deputy on nitrogen, is selected from benzyl or methyl, provided that if R4is hydrogen, R7is not hydrogen, and when R4is hydrogen, at least one of R22and R23is not hydrogen.

4. Connection on p. 3 in which R4and R7independently selected from the following groups: hydrogen, C1- C3-alkyl, substituted 0 - 1 R11;

R5- OR20;

R6- hydrogen or-OR21;

R20and R21is hydrogen;

R11choose from one or more of the following groups: halogen, -OR13C1- C4-alkyl, C3- C5-cycloalkyl; phenyl or naphthyl, substituted with 0 2 R12; or heterocyclic system is selected from pyridyl, pyrimidinyl, triazinyl, furanyl, teinila, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, indolyl, chinoline, izochinolina;

R12if the, 1- C4-alkoxy, CF3, 2-(1-morpholino)ethoxy, -CO2H, hydroxamic acid, hydrazide, oxime, cyano, baronova acid, sulfonamide, formyl, C3- C6-cycloalkane, C1- C4-alkyl, substituted-NR13>R14, -NR13>R14, hydroxy, hydroxymethyl; or R12if he is Deputy nitrogen, denotes methyl;

R13- H or methyl;

R14- OH, H or methyl;

R13and R14can be an alternative connected with education -(CH2)4-, -(CH2)5-, -CH2CH2N(R15)CH2CH2- or-CH2CH2OCH2CH2-; w is-N(R22(C)=O(N)R23)- or-N(R22(C)=N-CN(N)R23)-;

R22and R23independently selected from hydrogen, C1- C4of alkyl, substituted 0 - 1 R31C3- C4-alkenyl, substituted 0 - 1 R31;

R31choose from one or more of the following groups: halogen, -OR13C1- C4-alkyl, C3- C5-cycloalkyl; phenyl or naphthyl, substituted with 0 2 R32; or heterocyclic system is selected from pyridyl, pyrimidinyl, triazinyl, furanyl, teinila, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuro is Oh or more of the following groups: benzyloxy, halogen, methyl, C1- C4-alkoxy, CF3, 2-(1-morpholino)ethoxy, -CO2H, hydroxamic acid, hydrazide, oxime, cyano, baronova acid, sulfonamide, formyl, C3- C6-cycloalkane, C1- C4-alkyl, substituted-NR13>R14; -NR13>R14, hydroxy, hydroxymethyl, -C(R14)=N(OR14); or R32if he is a Deputy from nitrogen, is stands; provided that R4is hydrogen, R7is not hydrogen; if R4is hydrogen, at least one of R22and R23is not hydrogen.

5. Connection on p. 3 in which R4and R7- benzyl; R5- OH; R6- hydrogen or-OH; R13- H or methyl; R14- H or methyl; w is-N(R22(C)=O(N)R23or-N(R22(C)= N-CN(N)R23); R22and R23independently selected from hydrogen, C1- C4of alkyl, substituted 0 - 1 R31; R31choose from one or more of the following groups: C3- C5-cycloalkyl; phenyl or naphthyl, substituted with 0 2 R32; or heterocyclic system is selected from pyridyl, teinila, chinoline or izochinolina; R32if he is Deputy of carbon, selected from one or more from the Roxy, hydroxymethyl, -C(R14)=N(OR14); or R32if he is a Deputy from nitrogen, is stands.

6. Connection on p. 1 formula

< / BR>
where Z Is O, S or N-CN;

R22and R23independently selected from hydrogen, allyl, propyl, cyclopropylmethyl, n-butyl, isobutyl, CH2CH=CH(CH3)2, pyridylmethyl, Metallica, n-pentile, out-pentile, hexyl, benzyl, pyridylmethyl, isoprenyl, propargyl, picoline, methoxyethyl, cyclohexylmethyl, dimethyl-butyl, ethoxyethyl, naphthylmethyl, methyloxazolidine, vinyloxyethyl, pentafluorobenzyl, hyalinella, carboxybenzene, chloranil, picoline, benzyloxybenzyl, phenylbenzyl, adamantylamine, cyclopropylmethanol, ethoxybenzyl, hydroxybenzyl, hydroxymethylbenzene, aminobenzyl, formylmethyl, cyanobenzyl, cinnamyl, allyloxymethyl, tormentil, cyclobutylmethyl, formaldoxime, cyclopentylmethyl, nitrobenzyl, nitrosobenzene, carboxamidine, carbomethoxyamino, tetracarbonyl and dimethylallyl.

7. Connection on p. 1 of the formula IIa

< / BR>
in which R22and R23independently selected from hydrogen, allyl, propyl, cyclopropylmethyl, n-butyl, ISO-butyl, a is La, isoprenyl, propargyl, picoline, methoxyethyl, cyclohexylmethyl, dimethylbutyl, ethoxyethyl, methyloxazolidine, naphthylmethyl, methyloxazolidine, vinyloxyethyl, pentafluorobenzyl, hyalinella, carboxybenzene, chlorothene, picoline, benzyloxybenzyl, phenylbenzyl, adamantylamine, cyclopropylmethanol, ethoxybenzyl, hydroxybenzyl, hydroxymethylbenzene, aminobenzyl, formylmethyl, cyanobenzyl, cinnamyl, allyloxymethyl, tormentil, cyclobutylmethyl, formaldoxime, cyclopentylmethyl, nitrobenzyl, nitrosobenzene, carboxylatomethyl, carbomethoxyamino, tetracarbonyl, dimethylallyl, lidinopril and (Baranova acid) benzyl.

8. Connection on p. 1 of the formula IIa

< / BR>
which are selected from the group consisting of the compounds of formula IIa,

where R22and R23- allele;

R22and R23- propyl;

R22and R23- cyclopropylmethyl;

R22and R23are n-butyl;

R22and R23- CH2CH=CH(CH3)2;

R22and R23- isopentyl;

R22and R23- 4-pyridylmethyl;

R22and R23- 2-methallyl;

R22and R23- n-pentyl;

R2222- allyl, and R23- isoprenyl;

R22and R23- 3-propargyl;

R22and R23- 2-picoline;

R22and R23- 2-methoxyethyl;

R22and R23- cyclohexylmethyl;

R22and R23- 3,3-dimethyl-1-butyl;

R22and R23- 2-ethoxyethyl;

R22- 3-methyl-5-oxazolidinyl, and R23is hydrogen;

R22and R23- 1-naphthylmethyl;

R22and R23- 3-methyloxazolidine;

R22and R23- 2-vinyloxyethyl;

R22and R23- 2,3,4,5,6-pentafluorobenzyl;

R22is benzyl, and R23- 2-hyalinella;

R22and R23- 4-carboxybenzoyl;

R22and R23- 5-chloro-2-thienyl;

R22and R23- 2-hyalinella;

R22- 2-propyl, and R23- 2-picoline;

R22and R23- 3-benzyloxybenzyl;

R22- 4-phenylbenzyl, and R23- phenylbenzyl;

R22- 2-adamantylamine, and R23- 2-adamantylidene;

R22is hydrogen, and R23- cyclopropylmethyl;

R22- 2-picoline, and R23- 2-naphthylmethyl;

R22- 3-allyl, and R23is hydrogen;

R22- 3-allyl, and R23- 2-picoline;

R22- 3-allyl, and R23- 4-picoline;

R2223- 3-ethoxybenzyl;

R22and R23- 4-benzyloxybenzyl;

R22and R23- 3-hydroxybenzyl;

R22and R23- 4-hydroxybenzyl;

R22and R23- 3-hydroxymethylene;

R22and R23- 4-hydroxymethylbenzene;

R22and R23- 3-aminobenzyl;

R22and R23- 3-carboxybenzoyl;

R22and R23- 3-formylmethyl;

R22and R23- 3-cyanobenzyl;

R22and R23- 2-naphthylmethyl;

R22- n-butyl, and R23- benzyl;

R22- allyl, and R23- cyclopropylmethyl;

R22- n-butyl, and R23- cyclopropylmethyl;

R22- 3-methallyl, and R23- benzyl;

R22is benzyl, and R23- ethyl;

R22is benzyl, and R23- 4-picoline;

R22- cyclopropylmethyl, and R23- 4-picoline;

R22is benzyl, and R23- cyclopentylmethyl;

R22- cyclopropylmethyl, and R23- cyclopentylmethyl;

R22is benzyl, and R23- n-propyl;

R22- cyclopropylmethyl, and R23- cinnamic;

R22- cyclopropylmethyl, and R23- 2-naphthylmethyl;

R22- cyclopentylmethyl, and R23- 2-naphthylmethyl;

R22is benzyl, and R23- 2 the ZIL;

R22- 3-allyl, and R23- 2-naphthylmethyl;

R22- n-propyl, and R23- 2-naphthylmethyl;

R22- n-butyl, and R23- 2-naphthylmethyl;

R22- H, and R23- 2-naphthylmethyl;

R22- 4-picoline, and R23- 2-naphthylmethyl;

R22- 3-allyl, and R23- cyclopentylmethyl;

R22- 3-allyl, and R23- 2-hyalinella;

R22- 3-picoline, and R23- cyclopropylmethyl;

R22- 3-picoline, and R23- 2-naphthylmethyl;

R22- 3-allyloxymethyl and R23- 3-allyloxymethyl;

R22- 3-allyloxymethyl, and R23- 3-hydroxybenzyl;

R22- 3-picoline, and R23- 3-picoline;

R22- 2-naphthylmethyl, and R23- 4-terbisil;

R22and R23- 3-carbomethoxybiphenyl;

R22and R23- 4-formylmethyl;

R22and R23- 4-cyanobenzyl;

R22- 4-hydroxybenzyl, and R23- n-propyl;

R22- 3-hydroxybenzyl, and R23- n-propyl;

R22and R23- 3-carboxybenzoyl;

R22and R23- cyclobutylmethyl;

R22and R23- cyclopentylmethyl;

R22- n-butyl, and R23- 3-methallyl;

R22- n-butyl, and R23- cyclopentylmethyl;

RR22- cyclopropylmethyl, and R23- 4-hydroxybenzyl;

R22and R23- 3-(N-methylamino)benzyl;

R22and R23- 3-acetylbenzo;

R22and R23- 3-hydroxylamines;

R22- 2-naphthylmethyl, and R23- 3-hydroxybenzyl;

R22- 4-hydroxymethylbenzene, and R23- 3-hydroxybenzyl;

R22and R23- N-methyl-(3-amido)benzyl;

R22- N-methyl(3-amido)benzyl, and R23- 3-(amidino)benzyl;

R22- 3-(5-tetrazolyl)benzyl, and R23- cyclopropylmethyl;

R22and R23- 3-(5-tetrazolyl)benzyl;

R22and R23- phenylmethyl-3-baronova acid.

9. Connection on p. 1 of the formula IIa

< / BR>
which are selected from the group consisting of the compounds of formula IIa,

where R22and R23- allyl;

R22and R23- propyl;

R22and R23- cyclopropylmethyl;

R22and R23- n-butyl;

R22and R23- CH2CH=CH(CH3)2;

R22and R23- out-of pentyl;

R22and R23- 2-methallyl;

R22and R23- n-pentyl;

R22and R23- benzyl;

R22- allyl, and R23- isoprenyl;

R22and R23- 3-hydroxybenzyl;

RUP> - 4-hydroxymethylbenzene;

R22and R23- 3-aminobenzyl;

R22and R23- 3-carboxybenzoyl;

R22and R23- 3-formylmethyl;

R22and R23- 3-cyanobenzyl;

R22and R23- 2-naphthylmethyl;

R22- n-butyl, and R23- benzyl;

R22- allyl, and R23- cyclopropylmethyl;

R22- n-butyl, and R23- cyclopropylmethyl;

R22- 3-methallyl, and R23- benzyl;

R22is benzyl, and R23- ethyl;

R22is benzyl, and R23- 4-picoline;

R22- cyclopropylmethyl, and R23- 4-picoline;

R22is benzyl, and R23- cyclopentylmethyl;

R22- cyclopropylmethyl, and R23- cyclopentylmethyl;

R22is benzyl, and R23- n-propyl;

R22- cyclopropylmethyl, and R23- cinnamyl;

R22- cyclopropylmethyl, and R23- 2-naphthylmethyl;

R22- cyclopentylmethyl, and R23- 2-naphthylmethyl;

R22is benzyl, and R23- 2-naphthylmethyl;

R22- cyclopropylmethyl, and R23- 2-picoline;

R22- 3-cyanobenzyl and R23- 3-cyanobenzyl;

R22- 3-allyl, and R23- 2-naphthylmethyl;

R22- n-propyl, and R23- 2-naphthylmethyl;
23
- 2-naphthylmethyl;

R22- 3-allyl, and R23- cyclopentylmethyl;

R22- 3-allyl, and R23- 2-hyalinella;

R22- 3-picoline, and R23- cyclopropylmethyl;

R22- 3-picoline, and R23- 2-naphthylmethyl;

R22and R23- 3-allyloxymethyl;

R22- 3-allyloxymethyl, and R23- 3-hydroxybenzyl;

R22and R23- 3-picoline;

R22- 2-naphthylmethyl, and R23- 4-terbisil;

R22and R23- 3-carbomethoxybiphenyl;

R22and R23- 4-formylmethyl;

R22and R23- 4-cyanobenzyl;

R22- 4-hydroxybenzyl, and R23- n-propyl;

R22- 3-hydroxybenzyl, and R23- n-propyl;

R22and R23- 3-carboxybenzoyl;

R22and R23- cyclobutylmethyl;

R22and R23- cyclopentylmethyl;

R22- n-butyl, and R23- 3-methallyl;

R22- n-butyl, and R23- cyclopentylmethyl;

R22and R23- 3-formaldoxime;

R22- cyclopropylmethyl, and R23- 3-hydroxybenzyl;

R22- cyclopropylmethyl, and R23- 4-hydroxybenzyl;

R22and R23- 3-(N-methylamino)-benzyl;

R22and R23- 3-acetylbiphenyl;

R22- 4-hydroxymethylbenzene, and R23- 3-hydroxybenzyl;

R22and R23- N-methyl-(3-amido)-benzyl;

R22- N-methyl-(3-amido)benzyl, and R23- 3-(amidino)benzyl;

R22- 3-(5-tetrazolyl)-benzyl, and R23- cyclopropylmethyl;

R22and R23- 3-(5-tetrazolyl)benzyl;

R22and R23- phenylmethyl-3-baronova acid.

10. Connection on p. 1 of the formula IIa

< / BR>
which are selected from the group consisting of the compounds of formula IIa,

where R22and R23- allyl;

R22and R23- cyclopropylmethyl;

R22and R23- n-butyl;

R22and R23- CH2CH=CH(CH3)2;

R22and R23- propyl;

R22and R23- isopentyl;

R22and R23- benzyl;

R22and R23- 3-hydroxybenzyl;

R22and R23- 4-hydroxybenzyl;

R22and R23- 3-hydroxymethylene;

R22and R23- 4-hydroxymethylbenzene;

R22and R23- 3-aminobenzyl;

R22and R23- 3-carboxybenzoyl;

R22and R23- 3-formylmethyl;

R22and R23- 3-formaldoxime;

R22and R23- 3-(N-methylamino)benzyl;

R22and R23- 3-hydroxybenzyl;

R22is a 4-hydroxymethylbenzene, and R23is a 3-hydroxybenzyl;

R22and R23- N-methyl-(3-amido)-benzyl;

R22- N-methyl-(3-amido)benzyl, and R23- 3-(amidino)benzyl;

R22- 3-(5-tetrazolyl)-benzyl, and R23- cyclopropylmethyl;

R22and R23- 3-(5-tetrazolyl)benzyl;

R22and R23- phenylmethyl-3-baronova acid.

11. Connection on p. 1 of formula IIb

< / BR>
or its pharmaceutical acceptable salt,

in which R22and R23independently selected from the group consisting of hydrogen, cyclopropylmethyl, CH2(C6H4)-p-OCH2C6H5CH2(C6H4)-p-OH, cyclopentylmethyl, allyl, n-butyl, beta naphthylmethyl, benzyl, CH2(C6H4)-m-OCH2C6H5p-nitrobenzyl, m-nitrobenzyl, CH2(C6H4)-m-OH, CH2(C6H4)-m-(CH2OH), p-aminobenzoyl, m-aminobenzyl, p-nitrosobenzene, m-nitrosobenzene, dimethylallyl, cyclohexylmethyl, cyclobutylmethyl, propyl, 3-methyl-1-butyl, carboxamides and formaldoxime.

12. Connection on p. 1 of formula Ib

< / BR>
or its pharmaceutically acceptable Sol is a, CH2(C6H4)-p-OCH2C6H5CH2(C6H4)-p-OH, cyclopentylmethyl, allyl, n-butyl, beta naphthylmethyl, benzyl, CH2(C6H4)-m-OCH2C6H5p-nitrobenzyl, m-nitrobenzyl, CH2(C6H4)-m-OH, p-aminobenzoyl, m-aminobenzyl, p-nitrosobenzene, m-nitrosobenzene, dimethylallyl, cyclohexylmethyl, cyclobutylmethyl, propyl, 3-methyl-1-butyl, carboxamides and formaldoxime.

13. Connection on p. 1 formula

< / BR>
or its pharmaceutical acceptable salt,

where R4and R7independently selected from hydrogen, C1- C4of alkyl, substituted 0 - 3 R11; C3- C4-alkenyl, substituted with 0 to 3 R11;

R5is-OR20;

R11choose from one or more of the following groups: keto, halogen, -CH2NR13R14, -NR13R14, -OR13C2- C4-alkoxyalkyl, C1- C4-alkyl, C2- C4alkenyl, C3- C6-cycloalkyl, phenyl or naphthyl, substituted with 0 to 3 R12or heterocyclic system substituted with 0 2 R12described in paragraph (1 formulas and consisting of 5 to 10 atoms including at least one nitrogen atom, sour the group: phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, C1- C4-alkyl, C7- C10-phenylalkyl, C1- C4-alkoxy, -CO2H, hydroxamic acid, hydrazide, oxime, baronova acid, sulfonamide, formyl, C3- C6-cycloalkyl, -OR13, -NR13R14methylendioxy, C1- C4-haloalkyl, C1- C4-alkylsulphonyl, C1- C4-alkylcarboxylic, hydroxy, hydroxymethyl, C1- C4-alkyl, substituted-NR13R14or 5 - or 6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur; R12if he is Deputy on nitrogen, is selected from benzyl or methyl;

R13- H, C1- C2-alkyl or C3- C6-alkoxyalkyl;

R14- OH, H or C1- C2-alkyl;

R13and R14can be an alternative connected with education -(CH2)4-, -(CH2)5-, -CH2CH2N(R15)CH2CH2- or-CH2CH2OCH2CH2-;

R15- H or CH3;

w is-N(R22(C)=Z(N)R23)-, where Z Is O, S or N-CN;

R22and R23independently selected from hydrogen, C1- C4of alkyl, substituted 0 - the following groups: keto, halogen, -CH2NR13>R14, -NR13>R14, -OR13C2- C4-alkoxyalkyl, C1- C4-alkyl, C2- C4alkenyl, C3- C6-cycloalkyl, phenyl or naphthyl, substituted with 0 to 3 R32or heterocyclic system substituted with 0 2 R32described in paragraph 1 and containing 5 to 10 atoms including at least one nitrogen atom, oxygen or sulfur;

R32if he is Deputy on carbon, selected from one or more of the following groups: phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, C1- C4-alkyl, C7- C10-phenylalkyl, C1- C4-alkoxy, -CO2H, hydroxamic acid, hydrazide, oxime, baronova acid, sulfonamide, formyl, C3- C6-cycloalkane, -OR13, -NR13>R14methylendioxy, C1- C4-haloalkyl, C1- C4-alkylsulphonyl, C1- C4-alkylcarboxylic, hydroxy, hydroxymethyl, -C(R14)= N(OR14), C1- C4-alkyl, substituted-NR13>R14or 5 - or 6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur; R32if he is Deputy on nitrogen, is selected from benzyl sludge is carried out with hydrogen, at least one of R22, R23hydrogen is not.

14. The connection formulas

< / BR>
where R4and R7independently selected from hydrogen, C1- C3of alkyl, substituted 0 - 3 R11;

R20is hydrogen;

R11choose from one or more of the following groups: halogen, -OR13C1- C4-alkyl, C3- C5-cycloalkyl, phenyl or naphthyl, substituted with 0 2 R12or heterocyclic system is selected from pyridyl, pyrimidinyl, triazinyl, furanyl, teinila, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, indolyl, chinoline, izochinolina;

R12if he is Deputy on carbon, selected from one or more of the following groups: benzyloxy, halogen, methyl, C1- C4-alkoxy, CF3, 2-(1-morpholino)ethoxy, -CO2H, hydroxamic acid, hydrazide, oxime, cyano, baronova acid, sulfonamide, formyl, C3- C6-cycloalkane, -NR13R14, hydroxy, hydroxymethyl, C1- C4-alkyl, substituted-NR13R14; or R12if he is Deputy nitrogen, means methyl;

R13- H or methyl;

R14- OH, or methyl;

R13and R14can al the SUB>2CH2- or-CH2CH2OCH2CH2-;

R15is hydrogen or CH3;

Z IS O;

R22and R23independently selected from hydrogen, C1- C4of alkyl, substituted 0 - 1 R31C3- C4-alkenyl, substituted 0 - 1 R31;

R31choose from one or more of the following groups: halogen, -OR13C1- C4-alkyl, C3- C5-cycloalkyl, phenyl, naphthyl, substituted 0 - 2 R32or heterocyclic system is selected from pyridyl, pyrimidinyl, triazinyl, furanyl, teinila, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, indolyl, chinoline, izochinolina;

R32if he is Deputy on carbon, selected from one or more of the following groups: benzyloxy, halogen, methyl, C1- C4-alkoxy, CF3, 2-(1-morpholino)ethoxy, -CO2H, hydroxamic acid, hydrazide, oxime, cyano, baronova acid, sulfonamide, formyl, C3- C6-cycloalkane, -NR13>R14, hydroxy, hydroxymethyl, -C(R14)-N(OR14), C1- C4-alkyl, substituted-NR13>R14or R32if he is Deputy nitrogen, is stands, provided that if R4a Ki is UP> and R23hydrogen is not.

15. Connection on p. 1 formula

< / BR>
or its pharmaceutically acceptable salt,

where R33- OH, halogen, H, N3or (in another embodiment) taken together with R23, forms a simple link;

R22and R23independently selected from the group consisting of hydrogen, allyl, propyl, cyclopropylmethyl, n-butyl, isobutyl, CH2CH=CH(CH3)2, pyridylmethyl, Metallica, n-pentile, out-pentile, hexyl, benzyl, pyridylmethyl, isoprenyl, propargyl, picoline, methoxyethyl, cyclohexylmethyl, dimethylbutyl, ethoxyethyl, naphthylmethyl, methyloxazolidine, vinyloxyethyl, pentafluorobenzyl, hyalinella, carboxybenzene, chlorothene, picoline, benzyloxybenzyl, phenylbenzyl, adamantylamine, cyclopropylmethanol, ethoxybenzyl, hydroxybenzyl, hydroxymethylbenzene, aminobenzyl, formylmethyl, cyanobenzyl, cinnamyl, allyloxymethyl, tormentil, cyclobutylmethyl, formaldoxime, cyclopentylmethyl, nitrobenzyl, nitrosobenzene, carboxamidine, carbomethoxyamino and dimethylallyl.

16. The connection formulas

< / BR>
or its pharmaceutically acceptable salt.

17. FPIC characterized in that as active ingredient use an effective amount of a compound according to any one of paragraphs.1 - 16 or its pharmaceutically acceptable salt.

18. The method according to p. 17, characterized in that as the active ingredient using an effective amount of a compound according to p. 16 or its pharmaceutically acceptable salt.

19. The pharmaceutical composition inhibiting protease retroviruses, including an active ingredient and a pharmaceutically acceptable carrier, characterized in that as the active ingredient it contains an effective amount of a compound according to any one of paragraphs.1 - 16 or its pharmaceutically acceptable salt.

20. The composition according to p. 19, characterized in that as the active ingredient it contains a connection on p. 16 or its pharmaceutically acceptable salt.

Priority signs:

11.10.91 - all signs on PP.1 - 20 except: R5and R6can alternatively be connected with education-OCH2SCH2O-, OS(=O)O-, -OC(=O)O-, -OCH2O-OC(O=S)O-, -OC(=O)C(=O)O-, -OC(CH3)2O-, OC(OCH3)(CH2CH2CH3)O-; R11- -CH2NR13>R14; R12when attached to a carbon atom, chosen from-CO2H, residues guide is cycloalkanes, -OR13C1- C4-alkyl, substituted-NR13>R14; R12when attached to a nitrogen atom, represents a-CH2NR13>R14or-CO2H; R13- C3- C6-alkoxyalkyl group; R14- OH, or benzyl; R24- cyano - or nitro-group; R31- -CH2NR13>R14; R32when attached to a carbon atom, chosen from-CO2H, residues hydroxamic acid, hydrazide, oxime, Bronevoy acid, sulfonamida, formyl group, C3- C6-cycloalkanes, -OR13C1- C4-alkyl, substituted-NR13>R14; R32when attached to a nitrogen atom, represents a-CH2NR13>R14or-CO2H, provided that R4, R4A, R7and R7Aare not hydrogen atoms, and provided that when R4and R4Arepresent a hydrogen atom, at least one of the substituents R22, R23, R25- R28are not a hydrogen atom; these signs have priority 15.05.92,

29.09.92 - R24- benzyloxy and alternative w with R5or R6to form a three-semiline condensed heterocyclic Il the Il-(3-amido)benzyl, the compound of formula IIa, where R22- N-methyl-(3-amido)benzyl, R23- (3-amidino)benzyl; p. 15: R33can alternative together with the substituent R23to form a simple link.

 

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< / BR>
where

R1unbranched or branched alkyl with 1 to 20 carbon atoms, unbranched or branched halogenated, cianelli, oxyalkyl, alkoxyalkyl or alkoxycarbonyl with 1 to 8 carbon atoms in each alkyl part, unbranched or branched alkenyl with 2 to 12 carbon atoms, unbranched or branched quinil with 2 to 12 carbon atoms or unsubstituted or once to six times substituted by alkyl cyclohexyl or cyclohexylmethyl, unsubstituted or once to fivefold substituted in the phenyl part of the same or different substituents phenyl, phenylalkyl or phenylalkyl with 1 to 12 carbon atoms in each unbranched or branched alkyl or alkenylphenol part, moreover, as substituents of the phenyl can be called a halogen atom, hydroxyl, cyano, formylamino, unbranched or branched alkyl, alkoxygroup with 1 to 4 carbon atoms, unbranched or branched girsvetlana or branched, dialkylamino, alkylsulphonyl, alkylcarboxylic, alkoxycarbonyl, aminocarbonyl, N-alkylaminocarbonyl, N,N-dialkylaminoalkyl, formylamino, alifornian;

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R3, R4, R5and R6independently from each other mean a hydrogen atom, halogen atom, alkoxygroup with 1 to 6 carbon atoms

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