Isoquinoline carboxamides and medicinal agent based on thereof for using as inhibitors of hiv protease

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of isoquinoline carboxamide of the formula (I):

and to their pharmaceutically acceptable salts wherein R1 means hydrogen atom, hydroxy-group or -NHR2 wherein R2 means alkyl, arylalkyl, heterocyclylalkyl that comprises one or some heteroatoms taken among nitrogen, oxygen and sulfur atoms, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl that comprises one or some heteroatoms taken among nitrogen, oxygen and sulfur atoms, arylalkylcarbonyl, heterocyclylalkylcarbonyl that comprises one or some heteroatoms taken among nitrogen and oxygen atoms, alkyloxycarbonyl, arylalkyloxycarbonyl, heterocyclylalkyloxycarbonyl that comprises one or some heteroatoms taken among nitrogen atom, heterocyclyl that comprises one or some heteroatoms taken among nitrogen and sulfur atoms, alkylsulfonyl, arylsulfonyl or the group of the formula:

R3 and R4 mean alkyl independently of one another; R5 means alkyl; or R4 and R5 in common with carbon and sulfur atoms to which they are bound form a heterocycle; R6 means alkyl; R13 means hydrogen atom or the group of the formula:

R15 means aryl under condition that if R3, R4 and R5 form methyl, R6 forms tert.-butyl then R13 means hydrogen atom, and if R15 means phenyl then R2 doesn't mean benzyloxycarbonyl and 2-quinoline carbonyl (other values of radicals are given in cl. 1 of the invention claim). Also, invention relates to a medicinal agent based on these compounds used in treatment of HIV-mediated diseases. Invention provides preparing new compounds and a medicinal agent based on thereof in aims for treatment of HIV-mediated diseases.

EFFECT: valuable medicinal properties of compounds and medicinal agent.

14 cl, 11 tbl, 173 ex

 

This invention relates to new inhibitors of HIV protease or depot forms, method of production thereof, pharmaceutical compositions and the use of such compounds in medicine. In particular, the compounds are imitators of hydroxyethylaminophenol, which act as inhibitors of aspirinplease HIV enzyme, which plays a significant role in the replicative life cycle of HIV. Therefore, the compounds of this invention can be usefully applied in treatment caused by HIV infection, or alone, or in combination with other inhibitors of viral replication, HIV, or with pharmacological modifiers, such as cytochrome P450 inhibitors.

Human immunodeficiency virus HIV is the causative agent of acquired immunodeficiency syndrome (AIDS), a disease characterized by the destruction of the immune system, especially CD4+T, with attendant susceptibility to opportunistic infections. The infection caused by HIV, is associated with the precursor to AIDS related complex (ARC)syndrome, which is characterized by symptoms such as persistent generalized lymphadenopathy, fever and weight loss.

As in the case of other retroviruses, the HIV genome encodes protein precursors, known as gag and gag-pol, which when the processing of the viral protease tautphoeus, reverse transcriptase (RT), endonuclease/integrase and Mature structural proteins of the virus bark. Termination of this processing prevents normal infectious virus. Considerable efforts have been made to control HIV by inhibiting encoded by the virus enzymes. In particular, much effort has been focused on the inhibition of HIV protease, HIV protease inhibitors (Pis) saquinavir, ritonavir, nelfinavir, indinavir, APV and LPV were adopted for the treatment of infections caused by HIV. Because when alone there is a steady virus, currently in clinical practice using these protease inhibitors in combination therapy usually with RT inhibitors.

The emergence of resistant virus can be explained by the errors introduced by the reverse transcriptase of HIV, combined with a high rate of viral replication. Obviously, the mutations that lead to sustainable virus, occur spontaneously, but remain netdetective up until the stimulation therapy will not lead to a selective effect on the appearance of the virus replicative advantage over the wild type. In the context of inhibition of HIV protease, the accumulation of mutations, which cause a decrease in the binding of the inhibitor while maintaining a sufficient turnover of the substrate, which may lead to drug resistance. And although the beginning of drug resistance may be somewhat delayed by the use of combinations of drugs, there remains a need for more effective HIV protease inhibitors that are active against viruses with simple and multiple resistance to protease inhibitors.

Therefore, the purpose of the invention is to provide novel compounds that are potent inhibitors aspirinplease HIV and who, consequently, have the ability to effective treatment of HIV-related diseases. Therefore, the compounds according to the invention may also have the ability to suppress viral replication, which is resistant to the usually used protease inhibitors.

This goal could be achieved by using new compounds of General formula I

where

R1means hydrogen, hydroxy or other2,

R2means hydrogen, alkyl, alkenyl, quinil, arylalkyl, geterotsiklicheskikh, cycloalkylcarbonyl, cycloalkylcarbonyl, arylcarbamoyl, heterocalixarenes, geterotsiklicheskikh, arylalkylamines, allyloxycarbonyl, arylalkylamines, geterotsiklicheskikh, allheterocoupless, alkylsulfonyl, arylsulfonyl, heterocyclisation or a group of the formula

where

X denotes oxygen or sulfur, and

R7and R8mean independently from each other hydrogen, alkyl, aryl, heterocyclyl, arylalkyl, geterotsiklicheskikh, or

R7and R8form together with the nitrogen atom to which they are attached, a saturated cycle, optionally containing an additional heteroatom or group

where

n means 0,

Y represents oxygen or sulfur, and

R10means hydrogen, alkyl, arylalkyl, geterotsiklicheskikh, aryl, heterocyclyl or

where

n means 1

Y represents nitrogen,

R9means hydrogen or alkyl, and

R10means hydrogen, alkyl, arylalkyl, geterotsiklicheskikh, aryl, heterocyclyl, or

R9and R10form together with the heteroatom to which they are bound, a heterocycle,

R11and R12mean independently from each other hydrogen or alkyl, or

R11and R12form together with the carbon atom to which they are linked, a cycle

R3, R4mean independently from each other alkyl or form together with the carbon atom to which they relate, carbocycle,

R5means alkyl, arylalkyl, geterotsiklicheskikh, or

R4and R5form together with the carbon atom or sulfur to which they are bound, a heterocycle,

R6means alkyl, arylalkyl, Goethe is acyclically, alkyloxyalkyl, hydroxyalkyl, aminoalkyl, foralkyl,

R13means hydrogen or an inorganic or organic residue of ester,

R15means aryl,

and their pharmaceutically acceptable salt,

provided that if R3, R4and R5means methyl, R6means tert-butyl, R13means hydrogen, and when R15means phenyl, R2does not mean benzyloxycarbonyl and does not imply 2-hinolincarbonova.

The term "alkyl" defines optionally substituted linear or branched alkyl chain containing 1-6 carbon atoms, preferably 1-4 carbon atoms.

The term "alkenyl" defines optionally substituted linear or branched alkenylphenol chain containing 2 to 6 carbon atoms, preferably 2-4 carbon atoms.

The term "quinil" defines optionally substituted linear or branched alkylamino chain containing 2 to 6 carbon atoms, preferably 2-4 carbon atoms.

Accordingly, the alkyl preferably denotes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl.

Accordingly, alkenyl means preferably vinyl, 1-propenyl, 2-propenyl, Isopropenyl and butenyl and its isomers.

Accordingly quinil preferably means ethinyl, PROPYNYL and its isomers and butenyl and its isomers.

With testwuide one or more substituents of alkyl, alkenyl or quinil can be selected from aryl, heterocyclyl, carboxy, cyano, alkoxy, cycloalkane, aryloxy, heterocyclic, hydroxy, alkylcarboxylic, cycloalkylcarbonyl, arylcarbamoyl, geterotsiklicheskikh, alkoxycarbonyl, cycloalkylcarbonyl, aryloxyalkyl, heterocalixarenes, aminocarbonyl, alkylaminocarbonyl, dialkylaminoalkyl, cycloalkylcarbonyl, arylenecarborane, heterocyclization, amino, alkylamino, dialkylamino, alkenylamine, alkynylamino, cyclooctylamine, arylamino, heterocyclisation, alkylcarboxylic, dialkylacrylamide, cycloalkylcarbonyl, arylcarboxamide, geterotsiklicheskikh, alkoxycarbonyl, cycloalkylcarbonyl, aryloxypropanolamine, heterocalixarenes, alkylaminocarbonyl, dialkylaminomethyl, cycloalkylcarbonyl, arylenecarborane, generallyunmemorable, alkylsulfonyl, cycloalkylcarbonyl arylsulfonamides, heterocyclization, nitro, alkylsulfonyl, cycloalkylcarbonyl, arylsulfonyl, heterocyclization, thio, alkylthio, cycloalkyl, aaltio, heterocyclic or halogen.

In all the cases mentioned above, where there is a group NH, hydrogen can also be substituted, preferably (ness.)Alki the om.

Cycloalkyl means optionally substituted cycloalkyl group containing 3-8 carbon atoms, preferably 3-6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl or substituted, which may also be bestonlinecasinos with optionally substituted saturated, partially unsaturated or aromatic monocyclic, bicyclic or tricyclic heterocycle or carbocycle, such as phenyl.

The term "aryl" means an optionally substituted phenyl or naphthyl, both optionally benzodizzepine with optionally substituted saturated, partially unsaturated or aromatic monocyclic, bicyclic or tricyclic heterocycle or carbocycle, such as cyclohexyl or cyclopentyl.

The term "heterocyclyl" means optionally substituted saturated, partially unsaturated or aromatic monocyclic, bicyclic or tricyclic a heterocycle that contains one or more heteroatoms selected from nitrogen, oxygen and sulfur, which may also be beskondensatornye with optionally substituted, saturated, partially unsaturated or aromatic monocyclic, bicyclic or tricyclic carbocycle or heterocycle.

Examples of relevant heterocy the crystals are oxazolyl, isoxazolyl, furyl, tetrahydrofuryl, 1,3-DIOXOLANYL, dihydropyran, thienyl, pyrazinyl, isothiazolin, ethenolysis, indolyl, indazoles, chinoline, dihydrooxazolo, pyrimidinyl, benzofuranyl, tetrazolyl, pyrrolidinyl, (N-oxide)pyridinyl, pyrrolyl, triazolyl, for example 1,2,4-triazolyl, pyrazolyl, benzotriazolyl, piperidinyl, morpholinyl, thiazolyl, pyridinyl, dihydrothiazolo, imidazolidinyl, pyrazolyl, benzothiazyl, piperazinil, imidazolyl, thiadiazolyl, for example 1,2,3-thiadiazolyl and benzothiazolyl.

Appropriate substituents for cycloalkyl, aryl, heterocyclyl can be selected from those mentioned for alkyl, however, in addition to selected should be added alkyl, alkeline and alkyline deputies.

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

The term "residue of an ester of an inorganic acid" means a sulfate of the formula-SO2OH or a phosphate of the formula RO(OH)2.

The term "residue of ester organic acid" means an acyl group, such as that described in the application for the European patent EP A1 0594540 for group R1.

The corresponding residues of esters of organic acids defined in R13as a group of the formula

where

R14means alkyl, alkenyl, cycloalkyl, aryl, arylalkylamines, GRU is PU-CH 2(CH2CH2O)mCH3in which m denotes an integer of 0-10, or linked carbonyl group of the radical of amino acids.

Except that the alkyl and Alchemilla chain can contain up to 20 carbon atoms, the meaning of the terms "alkyl", "alkenyl", "cycloalkyl", "aryl", "heterocyclyl" such as described above.

The term "associated carbonyl group of the radical amino" means a radical of a natural or unnatural amino acids, selected from, for example, glycine, alanine, leucine, isoleucine, phenylalanine, lysine, methionine, threonine, tryptophan, valine, serine, glutamine, etc. that is associated with the carbonyl group

Any functional (i.e. reactive) group present in the side chain can be protected using the actually well-known protective groups, for example, as described in "Protective Groups in Organic Synthesis", 2ndEd., T.W.Greene and P.G.M.Wuts, John Wiley & Sons, New York, NY, 1991. For example, the amino group may be protected by tert-butoxycarbonyl (VOS), formyl, trailvoy, benzyloxycarbonyl (Z), 9-fluorenylmethoxycarbonyl (FMOC), trifluoracetyl, 2-(biphenylyl)isopropoxycarbonyl or isobutylacetophenone group or in the form phthalimido group; or a hydroxyl group may be protected by tert-butyldimethylsilyl is Noah, tetrahydropyranyl, 4-methoxybenzyl or benzyl or acetyl group; or a carboxyl group can be protected in the form of ester, such as methyl, benzyl or tert-butyl ester. The protective group may be stored in the destination connection or optionally be removed using known in the field of methods.

The compounds of this invention differ in the structure of the nucleus with a fixed stereochemistry as shown in the General formula.

The remains of R1-R15in the compounds of this invention can contain one or more asymmetric carbon atoms and can therefore exist as single enantiomers, racemates and racemic mixtures, individual diastereomers and diastereomeric mixtures. In addition, if the connection according to the invention contains olefinic double bond, it may be (E)- or (Z)-configuration. In addition, each chiral center may be R - or S-configuration. All such isomeric forms of these compounds covered by this invention.

The compounds of formula I, which have acidic properties, can form pharmaceutically acceptable salts with bases, such as hydroxides of alkali metals such as sodium hydroxide, potassium hydroxide and the like; hydroxides of alkaline-earth metals such as calcium hydroxide, the barium hydroxide, magnesium hydroxide and the like; organic bases, for example N-ethylpiperidine, dibenzylamine and the like. Those compounds of formula I which are basic can form pharmaceutically acceptable salts with inorganic acids, for example kaleidotrope acids such as hydrochloric acid and Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; and organic acids such as acetic acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malic acid, salicylic acid, citric acid, methanesulfonic acid, n-toluensulfonate acid and the like. Education and the provision of such salts may be carried out in accordance with methods known to experts.

Preferred compounds of formula (I) are compounds having the formula

where R2, R3, R4, R5, R6, R13and R15have the above values.

In an additional preferred variant of embodiment of the invention R3, R4and R5means methyl, R6means tert-butyl or hydroxy-tert-butyl, and R15means phenyl.

In additional preferred variations is the embodiment R 2means alkylsulphonyl, cycloalkylcarbonyl, arylcarbamoyl, heterocalixarenes, geterotsiklicheskikh or a group of the formula

where, if

n means 0,

Y represents oxygen or sulfur, and

R10means alkyl, arylalkyl, geterotsiklicheskikh, aryl, heterocyclyl, or

if

n means 1

Y represents nitrogen,

R9means hydrogen and

R10means alkyl, arylalkyl, geterotsiklicheskikh, aryl, heterocyclyl, and

where

R11and R12means independently hydrogen.

Moreover, preferred are compounds in which R3, R4, R5means methyl, R6means tert-butyl, R15means phenyl and R2means alkylsulphonyl, cycloalkylcarbonyl, arylcarbamoyl, heterocalixarenes, geterotsiklicheskikh or a group of the formula

where, if

n means 0,

Y represents oxygen or sulfur, and

R10means alkyl, arylalkyl, geterotsiklicheskikh, aryl, heterocyclyl, or

if

n means 1

Y represents nitrogen,

R9means hydrogen and

R10means alkyl, arylalkyl, geterotsiklicheskikh, aryl, heterocyclyl, and

where

R11and R12means independently hydrogen.

Moreover, preferred are compounds in which the R s 3, R4, R5means methyl, R6means tert-butyl, R15means phenyl and R2means arylcarbamoyl, heterocalixarenes or a group of the formula

where

Y represents oxygen, NH, S, CH2and

R10means aryl, heterocyclyl.

In an even more preferred variant of embodiment R13means hydrogen.

Examples of compounds of the formula I or II where R13, meaning the hydrogen below in table A.

In another preferred variant of embodiment R13means-SO2OH, RHO(OH)2or group

where

R14means alkyl, alkenyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, a group-CH2(CH2CH2O)min which m denotes an integer of 0-10, or linked carbonyl group of the radical of amino acids.

Examples of compounds of the formula I or II with R13not meaning hydrogen below in table B.

Additional preferred compounds of formula I are compounds having the formula

where R3, R4, R5, R6, R13and R15have the meanings described above, and R20means heterocyclyl.

More predpochtite lname compounds of the formula (X) are such where R3, R4and R5means methyl, R6means tert-butyl, R13means hydrogen and R15means phenyl.

Examples of such preferred compounds of the formula (X) below.

- N-tert-Butyl-1,2,3,4,4A(S),5,6,7,8A(S)-decahydro-2-[2(R)-hydroxy-3(S)-[[3-(methanesulfonyl)-N-[2-(3-pyridyloxy)acetyl]-L-valil]amino]-4-phenylbutyl]-3(S)-ethanolinduced

- N-tert-Butyl-1,2,3,4,4A(S),5,6,7,8,8A(S)-decahydro-2-[2(R)-hydroxy-3(S)-[[3-(methanesulfonyl)-N-[2-(2-pyridyloxy)acetyl]-L-valil]amino]-4-phenylbutyl]-3(S)-ethanolinduced

- N-tert-Butyl-1,2,3,4,4A(S),5,6,7,8,8A(S)-decahydro-2-[2(R)-hydroxy-3(S)-[[3-(methanesulfonyl)-N-[2-(6-methyl-3-pyridyloxy)acetyl]-L-valil]amino]-4-phenylbutyl]-3(S)-ethanolinduced

- N-tert-Butyl-1,2,3,4,4a(S),5,6,7,8,8a(S)-decahydro-2-[2(R)-hydroxy-3(S)-[[3-(methanesulfonyl)-N-[2-(3-pyrazinone)acetyl]-L-valil]amino]-4-phenylbutyl]-3(S)-ethanolinduced

- tert-Butylamide 2-(2-hydroxy-3-{3-methanesulfonyl-3-methyl-2-[2-(pyrimidine-2-yloxy)acetylamino]bucillamine}-4-phenylbutyl)decahydroquinoline-3-carboxylic acid.

The most preferred compound is N-tert-butyl-1,2,3,4,4A(S),5,6,7,8A(S)-decahydro-2-[2(R)-hydroxy-3(S)-[[3-(methanesulfonyl)-N-[2-(3-pyridyloxy)acetyl]-L-valil]amino]-4-phenylbutyl]-3(S)-ethanolinduced, its pharmaceutically acceptable salts and esters.

Derivatives hydroxyethylamine, PR is haunted by the present invention, are powerful inhibitors or depot forms inhibitors aspirinplease HIV enzyme, which plays a significant role in the replicative cycle of HIV. Accordingly, they are therapeutically active substances in the treatment of mediated HIV disease and can therefore be used as medicines, or alone, or in combination with other therapeutically active agents.

Derivatives hydroxyethylamine provided by the present invention are particularly useful in combating painful conditions caused by HIV, such as acquired immunodeficiency syndrome.

Compounds according to the invention of formula I, where R1means other2can be obtained from compounds of formula III

where R3, R4, R5, R6and R15have the above values.

(a) In the case of the compounds of formula I, where R1means a group with other2in which R2means alkylsulphonyl, cycloalkylcarbonyl, arylcarbamoyl, heterocalixarenes, geterotsiklicheskikh, arylalkylamines, allyloxycarbonyl, arylalkylamines, geterotsiklicheskikh, sulfonyl, alkylsulfonyl, arylsulfonyl, heterocyclisation or a group of the formula

where R9, R10, R11and R 12have the above values, the compound of formula III is reacted with the corresponding acid derivative such as acid chloride, mixed anhydride, etc. Alternatively, when n is 1, Y represents a nitrogen, R9means hydrogen and R10means alkyl, arylalkyl, geterotsiklicheskikh, compound III is reacted with N-protected glycine, is released and reacts with the aldehyde or ketone in reducing conditions, as described in the variant embodiment (b) of the method.

(b) In the case of the compounds of formula I, where R1means a group with other2in which R2means alkyl, alkenyl, quinil, arylalkyl, geterotsiklicheskikh, cycloalkyl, the compound of formula III is reacted with an aldehyde or ketone under the reduction conditions.

(C) In the case of the compounds of formula I, where R1means other2where R2means a group of the formula

in which X, R7and R8have the same meanings as previously described, the compound of formula III interacts with the reagents described in this region for the formation of ureas and thioureas.

(g) In the case of the compounds of formula I, where R1means a group with other2in which R2means a heterocycle, the compound of formula III reacts in accordance with the methods described in this region for the formation of heterocycles. E.g. the measures in the case where R7means thiazole, using the synthesis of Ceramic according to the scheme 1, by transformation of compounds of formula III in the thiourea IV, followed by reaction of the compound IV with the required α-haloalkene or α-guidalberto.

Scheme 1

In the above scheme, R2, R3, R4, R5, R6and R15have the previously described meanings; R16means hydrogen, alkyl, alkoxycarbonyl, aryl, heterocyclyl; R17means hydrogen, alkyl, aryl, heterocyclyl; R18means the same as R16and R19means the same as R19. Hal means a halogen atom selected from chlorine, bromine and iodine.

(d) In the case of the compounds of formula I, where R1means a group with other2in which R2means aryl, the compound of formula III reacts with arylhalides in terms of catalysis by transition metals known in the field. Alternative derived amino acids obtained by releasing the connection V (scheme 3), may react with arylhalides in such conditions before condensation with compounds of formula VI (scheme 3).

(e) In the case of the compounds of formula I in which R6means alkyl, arylalkyl, geterotsiklicheskikh, alkyloxyalkyl, hydroxyalkyl, aminoalkyl, foralkyl, the compound of formula IVa (scheme 2) is reacted with the appropriate amine is m in conditions of catalysis by a Lewis acid.

Scheme 2

In the above scheme, R1, R3, R4, R5, R6and R15have the above values.

(g) In the case of the compounds of formula I, in which R means-SO2OH, RHO(OH)2or group

where R14has the previous value, the compound of formula I, in which R13means hydrogen, reacts with an appropriate activated acid derivative or amino acids with her aminosidine form according to the procedures described in this area for the formation of esters.

In accordance with a variant embodiment (a) of the method suitable reagents which form alkylsulphonyl, cycloalkylcarbonyl, arylcarbamoyl, heterocalixarenes, arylalkylamines, geterotsiklicheskikh, allyloxycarbonyl, arylalkylamines, geterotsiklicheskikh, sulfonyl, alkylsulfonyl, arylsulfonyl, heterocyclisation or a group of the formula

where R9, R10, R11and R12have previously described the values are the corresponding acids or their reactive derivative such as the corresponding galoidoproizvodnykh acids (for example, the anhydrides of the acids, acid anhydrides, mixed anhydrides, intense activity is consistent esters, etc. The reaction of compound III with the above reagents is carried out in accordance with the techniques described in this area, for example, in organic chemistry, such as J. March (1992) Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4thed. John Wiley & Sons. So, when using the acid, the reaction is preferably carried out in the presence of condensing agents, such as hydrochloride, N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide (EDAC·HCl), in the presence of hydroxybenzotriazole (NOVT). This reaction is conveniently carried out in an inert organic solvent, such as tetrahydrofuran (THF), dichloromethane or dimethylformamide at temperatures between -10°C to +25°C. When using the reactive derivative, the reaction can be carried out in an inert solvent such as dichloromethane or tetrahydrofuran in the presence of organic bases (for example, N-ethylmorpholine, triethylamine, etc. at temperatures between -10°C to +25°C.

In accordance with a variant embodiment (b) of the method is the reaction of compounds of formula III with an aldehyde or ketone can be performed according to the procedures described in this area for recovery amination of aldehydes or ketones. For example, you can consult the manual for organic chemistry, such as J. March (1992) Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4thed. John Wiley & Sons. So,for example, the reaction is conveniently carried out with triacetoxyborohydride sodium in an inert haloesters a solvent such as dichloromethane, in the presence of acetic acid according to the method described .F. Abdel-Magid and others; Tetrahedron Letters 1990, 31, 5595.

In accordance with a variant embodiment () method, the reaction can be performed according to methods known in this field, for example in organic chemistry, such as J. March (1992) Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4thed. John Wiley & Sons. For example, for compounds in which X is oxygen, the reaction may be carried out by the interaction of the compounds of formula III with n-nitrophenylphosphate in the presence of inorganic bases such as sodium bicarbonate, followed by reaction with the amine R7R8NH, where R7and R8have the above meanings, in the presence of an organic base such as triethylamine (see, for example, N.Choy and other Org. Prep. Proced. Int. 1996, 28(2), 173-7). The reaction is conveniently carried out in an inert solvent, such as acetonitrile, at a temperature of 0-25°C. If X is oxygen or sulfur, and one of R7or R8means hydrogen, the reaction may conveniently be performed by interaction of the compounds of formula III with an isocyanate (R7N=C=O or R8N=C=O) or isothiocyanates (R7N=C=S or R8N=C=S) according to the procedures described in this region the tee.

In accordance with a variant embodiment (g) of the method, the reaction can be hold according to the procedures described in manuals on heterocyclic chemistry such as T.L.Gilchrist (1992) "Heterocyclic Chemistry", 2nded. John Wiley and Sons. For example, when R2means thiazole, the reaction may be performed by heating a mixture of compounds IV and α-haloalkaliphilic compounds in an appropriate solvent, such as alkanol (e.g., ethanol). Compound IV can be easily obtained from compound III in accordance with known methods, for example by reaction with benzoylisothiocyanate in acetone at boiling, followed by hydrolysis with an inorganic base such as potassium carbonate, in a mixture of polar organic solvent and water (see, for example, N.M.Oiken and others, J.Med. Chem. 1992, 35, 1137).

In accordance with a variant embodiment (d) of the method, the reaction of amino acids (obtained by releasing compounds of the formula (V) with arylhalides, such as brombenzene, can be carried out in the presence of copper salts such as copper iodide in dimethylacetamide. See, for example, D. MA and others, J.Amer. Chem. Soc. 1998, 120, 12467.

In accordance with a variant embodiment (e) of the method is the reaction of compounds of formula IVa with amines R6NH2carried out using the techniques described in this area, for example using a reagent derived from the amine and acid Lewis on the basis of production is one of aluminum, for example trimethylaluminum, at ambient temperature in an inert solvent such as dichloromethane or toluene (see, for example, S.M.Weinreb and others, Tetrahedron Letters 1977, 4171).

In accordance with a variant embodiment (g) of the method, the reaction can be carried out according to methods known in this field, for the formation of esters, see, for example, of the manual of organic chemistry, such as J.March (1992) "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4thed. John Wiley & Sons. For example, the reaction is conveniently carried out at ambient temperature using a carboxylic acid derivative and a condensing reagent for peptides, such as EDAC·HCl, in an inert solvent, such as dichloromethane, in the presence as catalyst 4-dimethylaminopyridine. Alternative acid chloride of the acid can be used in an inert solvent in the presence of pyridine and 4-dimethylaminopyridine as a catalyst at a temperature of 0-25°C.

The compounds of formula III used as starting materials in embodiment variants (a)-(e), or known, or can be obtained in accordance with scheme 3. Thus, the reaction of the compound of formula V with the compound of the formula VI can be carried out according to methods known in the chemistry of peptides, with the formation of the compounds of formula VII (see J. Jones (1994), "The Chemical Synthesis of Peptides", Oxord University Press). The term "aminosidine group (Prot), used in context, refers to used in the chemistry of peptides groups such as tert-butoxycarbonyl group (BOC) or 9-fluorenylmethoxycarbonyl group (FMOC). Preferred aminosidine group (Prot) for this reaction is a 9-fluorenylmethoxycarbonyl group. This reaction is preferably carried out by the interaction of the compounds of formula V with chloroformiate (for example, isobutylparaben) in the presence of an organic base, such as N-ethylmorpholine to cause the formation of a mixed anhydride, which subsequently reacts with the compound of the formula VI. The reaction is conveniently carried out in an inert solvent, such as a simple ether (e.g. diethyl ether, tetrahydrofuran, etc. or in a halogenated aliphatic solvent (e.g. dichloromethane) at a low temperature, conveniently at about-10-5°C. the Conversion of compounds of formula VII into compounds of the formula III is carried out using known methods used in peptide chemistry, for the release of amino groups in amino acids. For example, if aminosidine group is FMOC, the reaction is conveniently carried out by interaction of the compounds of formula VII with piperidine in dimethylformamide or dichloromethane at room temperature.

Scheme 3

In the above scheme, R3, R4, R5, R6and R15have the previously described meanings. The compounds of formula V, where R3and R4means methyl, can be obtained from penitsillamin according to the scheme 4.

Scheme 4

In the above scheme, R5has the previously described meaning.

Thus, the reaction of L-penitsillamin with alkylhalides R5X, where R5has the value, and X means a halogen (e.g. bromine)in the presence of inorganic bases such as potassium carbonate, followed by interaction with a reagent for introducing an amino acid protective group [for example, FMOCONSu (N-9-fluorenylmethoxycarbonyl)succinimide) or VOS2About] gives the compounds of formula VIII. The reaction can be conducted at room temperature in a solvent mixture consisting of water and an organic solvent, preferably dioxane. The compounds of formula VIII are oxidized in the compounds of formula Va according to known methods, preferably by reaction with axonom (for K.S. Webb, Tetrahedron Lett. 1994, 35(21), 3457-60).

Other compounds of formula V can be obtained in a similar ways of analogues of penitsillamin described in this field.

The compounds of formula VI can be obtained according to known methods described in this field, for example in EP 432695 A2.

The compounds of formula I, to the ora R 1means a hydroxy-group, can be obtained according to the procedures described in this area, for example A.N.Cook and others; J.Chem. Soc. 1949, 1022. For example, the release of amino acids V, followed by diazotization, by hydrolysis and combined with the compounds of the formula VI according to the procedures described above, gives the compounds of formula I in which R is a hydroxy-group.

The compounds of formula I in which R is hydrogen, can be obtained from compounds of formula VI and compounds of formula IX (scheme 5) in the manner similar to that already described.

The compounds of formula IX can be obtained from the corresponding acrylic acid and thiol according to the procedures described in this area and presented in figure 5 (see, for example, G. Pattenden, etc., J. Chem. Soc., Perkin TranS. 1, 1992, (10), 1215-21).

Scheme 5

In the above scheme, R3, R4and R5have previously described values.

Educt of formula V, VI, IX and their reactive derivatives, because they are unknown compounds or analogues of known compounds, can be obtained similarly to known compounds, or as described below in the examples or in analogy with this. Moreover, the reagents used in variants of the embodiments (a)-(g)are generally known compounds. The reagents required for the introduction of groups of the formula

where R9, R10, R11and R12such as previously described, are the corresponding carboxylic acids or their activated derivatives, which are known compounds or can be easily obtained by analogy with known compounds. For example, when n is 0, Y represents oxygen or sulfur, and R10means aryl or heterocyclyl, the reagent is produced by interaction of the corresponding alcohol (e.g., 3-hydroxypyridine) with tert-butylbromide in basic conditions (e.g. sodium hydride in dimethylformamide or potassium carbonate in acetone) with the subsequent release catalyzed by acid (e.g. hydrochloric acid in ether, Hydrobromic acid in acetic acid or triperoxonane acid in dichloromethane). Also, when n is 1, Y represents nitrogen, the reagent can be obtained by similar methods, using Amin R9R10NH instead of alcohol and without addition of base.

Alternative tert-butyl ester of glycine may be subjected to reductive aminating with aldehyde or ketone under conditions similar to those described in the variant embodiment (b) of the method, with the subsequent release of the carboxylic acid group, acid catalyzed; preferably with HBr in acetic acid.

is Attiki analysis

Analysis of the inhibition of HIV protease

Inhibitory activity against HIV protease was evaluated using adaptation techniques Matayoshi and others [E.D. Matayoshi and others (1990). Science. 247. 954-958].

Crude HIV-1 protease was obtained from E. coli RRTΔN. the Cultures were grown at 30°in M9 medium with addition of 0.2% Kazimirovich acids, 100 μg/ml ampicillin and 25 μg/ml of thiamine to OD600=0,5-0,6 and raised the temperature to 42°to induce the expression of the protease. After 1.5 h, the cells were collected and kept precipitation at -70°s to use.

The protease was obtained by lysis of cells in the high-pressure cell French with subsequent precipitation of the enzyme with ammonium sulfate at 30% saturation.

The analysis is based on intramolecular energy transfer fluorescence using fluorogenic substrate DABCYL quenching-[4-(4-dimethylaminophenyl)benzoyl]-Ser-Gln-Asn-Tyr-Pro-Ile-Val-Gln-EDANS[5-(2-aminoethylamino)-1-naphtalenesulfonic acid], a peptide sequence which is received from one of the natural polypeptide processing sites of the protease of HIV-1.

The peptide substrate was dissolved in dimethyl sulfoxide (DMSO) for spectroscopy with the aim of obtaining 500 microns of the original solution. Inhibitors were dissolved in a mixture of DMSO is 0.1% aqueous tween-20 (1:9)to give a concentration of ihibitor 20 times the desired final concentration. The buffer was 0.1 M azeta the sodium with a pH of 4.7, 8 mm EDTA (ethylenediaminetetraacetic acid), 0.2 M sodium chloride.

Diluted 1:1 10 ál protease of HIV-1 in a mixture of 0.1% tween-buffer for analysis (the concentration was adjusted to give approximately 20% of the turnover of substrate) was added to a mixture containing 455 μl of buffer for analysis, 25 μl of inhibitor solution, 10 μl of the substrate solution.

The tubes were incubated for 2 h at 37°C, the reaction was stopped by adding 500 μl of a mixture of DMSO-50 mm tricin (2:1), pH 8.5. Fluorescence was measured on a fluorescence spectrophotometer, excitation at λ=340 nm, emission at λ=492 nm.

Methodology antiviral analysis

Antiviral activity against HIV was assessed using adaptation techniques Pauwels and others [Pauwels and others, 1988, J.Virol. Methods 20: 309-321]. The method is based on the ability of compounds to protect T-lymphoblastic cells (MT4 cells)infected with HIV from cell death, mediated infection. End-point analysis was calculated as the concentration at which cell viability in the culture was maintained at 50% (50% inhibitory concentration (IC50). The viability of cells in culture was determined by the absorption of the soluble yellow dye MTT [bromide 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium] and its recovery in a purple insoluble salt formazan. After the dissolution of use is built by spectrophotometric method for measuring the amount of a derivative formazan.

The MT4 cells were prepared in the logarithmic growth phase, and the number of 2×106cells were infected or clones of wild-type virus, or site-directed mutant clones of HIV-NHV when a plurality of approximately 0.0001 of infectious units of virus per cell in the total volume of 200-500 ál. Cells were incubated with virus for 1 h at 37°C, then washed in 0.01 M SR, pH 7.2 and again suspended in culture medium for incubation in culture with serial dilutions of tested compound. Used culture medium was RPMI 1640 without phenol red and with the addition of penicillin, streptomycin, L-glutamine and 10% fetal bovine serum (GM10).

The compounds were prepared as 2 mm solutions in dimethylsulfoxide (DMSO). Then received four duplicate serial 2-fold dilution in GM10 and quantity components of 50 μl, were placed in 96-well tablets at a range of final concentrations 625-1,22 nm. Then in each cell was added 50 μl GM10 and 3.75×104infected cells. Were prepared with control cultures containing no cells (blind experience), uninfected cells (100% viability; 4 repeats) and infected cells without compounds (total cell death, mediated by the virus). Then the cultures were incubated at 37°C in humidified atmosphere WITH 5 2on the air for 5 days.

Preparing a fresh solution of 5 mg/ml MTT in 0.01 M SR, pH 7.2 and each culture was added to 20 μl. Cultures were incubated additionally, as described above, for 2 hours Then they were mixed by a fence with a pipette and descent from her, was added 170 µl of Triton X-100 in acidified isopropanol (10% vol./about. Triton X-100 in a mixture of concentrated hydrochloric acid and isopropanol, 1:250), and the culture was again mixed by pipetting. When the deposition of formazan completely dissolved with additional mixing, measured the absorbance (OD) of the cultures at wavelengths of 540 nm and 690 nm (measured at 690 nm was used as controls for artifacts between wells). The percentage of protection for each treated culture was then calculated by the equation

The values of the IC50then received from the graphs of the dependence of the percentage of protection against log10the concentration of the drug.

The values of the IC50compounds of the present invention, typically are in the range of 1-10000 nm, preferably in the range of 1-60 nm.

Some representative data activity are summarized below in table 9.

Table 9
Example No.Inhibiting the enzyme concentration IC50(h is) Antiviral concentration IC50(nM)
30,617
42,814
72,321
161,012
281,021
401,419
924,033
930,58
9561,0250
10610,760
1127,594
1387,865
1521,217
1540,516
1680,516
1701,013

Inhibiting the enzyme concentration IC50rounded off after the decimal point before the tenth, antiviral concentration IC50rounded to the nearest whole number.

Compounds of the present invention, and their pharmaceutically acceptable acid salt additive can be used as medicines, for example in the form of pharmaceutical preparations. Pharmaceuticals mo the ut to be administered orally, for example, in the form of tablets, pills, coated, coated tablets, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, the introduction can also be carried out rectally, for example in the form of suppositories, or parenterally, e.g. in the form of injection solutions.

Compounds of the present invention and their pharmaceutically acceptable acid additive salts can be processed with pharmaceutically inert inorganic or organic fillers to obtain tablets, tablets coated, coated tablets and hard gelatin capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc can be used as such excipients, for example, tablets, coated tablets and hard gelatin capsules.

Appropriate excipients for soft gelatin capsules are vegetable oils, waxes, fats, semi-solid and liquid polyols etc

Appropriate fillers to obtain solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose, etc.

Appropriate excipients for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils etc.

Appropriate excipients for suppositories are, for example, natural or is confirmed oil, waxes, fats, semi-liquid or liquid polyols etc

Moreover, the pharmaceutical preparations can contain preservatives, substances that contribute to the dissolution, stabilizers, moistening agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for modifying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain other therapeutically valuable substances.

The dose can vary within wide limits and will, of course, be adjusted to the individual requirements in each particular case. Usually in the case of oral administration a daily dose of about 10-2500 mg of the compounds of formula I to the patient should be appropriate, although mentioned upper limit can also be exceeded if necessary.

The daily dose can be administered as a single dose or in divided doses. The treatment may be conducted in conjunction with the introduction of one or more additional therapeutically active substances, and such introduction can be competitive or sequential with respect to the introduction of compounds of formula I. Thus, a competitive introduction, as it is used in a context that includes the introduction of agents in combination or combinations, together either before or after each other.

Examples

Mass spectra were recorded under conditions of ionization elektrorazpredelenie on one of the following when the Directors: (a) THERMOQUEST SSQ 7000 [solvent of 0.085% TFA (triperoxonane acid) in a mixture of 90% acetonitrile/water; the flow rate of 100 μl/min; capillary temperature 250°C; voltage spray 5 KB; carrier gas 80 pounds/inch2] or (b) system LC-MS (liquid chromatograph connected to a mass spectrometer) THERMOQUEST 7000 ELECTROSPRAY or MICROMASS PLATFORM ELECTROSPRAY (gradient of 0.1% TFA in water to of 0.085% TFA in acetonitrile).

As for the original substances, which are known compounds, some of them can be purchased from trade suppliers. Other known source substances and their analogues can be obtained by methods known in this field. Examples of the compounds are available from commercial suppliers, and links to the synthesis of other compounds and their analogs are provided in the future.

The following examples illustrate the present invention.

Example 1

2-[3(S)-[[N-Benzoyl-3-(methanesulfonyl)-L-valil]amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert-butyl-1,2,3,4,4a(S),5,6,7,8,8A(S)-decahydro-3(S)-ethanolinduced

Mix a solution of 105 mg (0,13 mmole) of N-tert-butyl-2-[3(S)-[[N-[(9-fluorenyl)methoxycarbonyl]-3-(methanesulfonyl)-L-valil]amino]-2(R)-hydroxy-4-phenylbutyl]-1,2,3,4,4A(S),5,6,7,8,8A(S)-decahydro-3(S)-ethanolinduced in 4 ml of anhydrous dimethylformamide at room temperature was treated with 0.4 ml (4 mmole) of piperidine. After 2.5 h the volatiles were evaporated, the residue was treated with hexane, obtaining N tre the-butyl-1,2,3,4,4A(S),5,5,6,7,8,8A(S)-decahydro-2-[2(R)-hydroxy-3(S)-[[3-(methanesulfonyl)-L-valil]amino]-4-phenylbutyl]-3(S)-ethanolinduced resin, which was dissolved in 3 ml dichloromethane and cooled to 0°C. was Added a 0.035 ml (0,26 mmole) N-ethylmorpholine (NEM), then 0,016 ml of 0.13 mmole) of benzoyl chloride (Aldrich 24,054-0). After 2 h, the solution was diluted with 20 ml dichloromethane and washed sequentially with 10% aqueous citric acid solution, saturated sodium bicarbonate solution and saturated saline solution. The solution was dried over magnesium sulfate and evaporated under reduced pressure, obtaining a solid substance, which was chromatographically on silica gel, elwira a mixture of dichloromethane/methanol (37:3)to give 60 mg (67%) of product as a white solid, tPL212-18°C, (M+H)+683,2.

Starting material was prepared as follows.

N-tert-Butyl-2-[3(S)-[[N-[(9-fluorenyl)methoxycarbonyl]-3-(methanesulfonyl)-L-valil]amino]-2(R)-hydroxy-4-phenylbutyl]-1,2,3,4,4A(S),5,6,7,8,8A(S)-decahydro-3(S)-ethanolinduced

(A) Mix a solution of 596 mg (4 mmole) of L-penitsillamin (Aldrich 19,631-2) in 40 ml of a mixture of water/dioxane (1:1) was treated at room temperature 11,04 g (80 mmol) of potassium carbonate followed by treatment of 710 mg (5 mmol) of iodomethane and after 1 h of 5.39 g (20 mmol) of N-(9-fluorenylmethoxycarbonyl)-oxysuccinimide (Advanced Chemtech RC8015). After an additional 2 h the volatiles were evaporated, the residue was distributed between water and ether. The solution was acidified using 2 N. x is olistostromes acid, was extracted with ether and the combined organic phase was dried over magnesium sulfate. Evaporation to dryness gave a yellow foam, which was chromatographically on silica gel, was suirable a mixture of dichloromethane/methanol (9:1)to give 4.8 g (78%) of N-[(9-fluorenyl)methoxycarbonyl]-3-(methylthio)-L-valine in the form of a white foam, (M+H)+385,9.

(B) Vigorously stirred solution of 4.8 g (12.4 mmole) of N-[(9-fluorenyl)methoxycarbonyl]-3-(methylthio)-L-valine obtained above in section (A), 36 ml of water containing 600 mg (15 mmol) of sodium hydroxide, treated 8,43 g (99 mmol) of sodium bicarbonate and 12 ml of acetone. Was added dropwise 10,26 g (16.88 in mmole) OXONE® (peroxymonosulfate potassium) (Aldrich 22,803-6) in 36 ml of 0.0004 M EDTA solution, and the solution was vigorously stirred for 2 h and Then was added a solution of 6.3 g of sodium metabisulfite in 12.6 ml of water, and the solution was stirred for the next 15 minutes were Added ethyl acetate, the aqueous phase is acidified to pH 2 with 6 N. hydrochloric acid, saturated sodium chloride, and was extracted with ethyl acetate. The combined organic phase was washed successively with water, saturated salt solution, dried over magnesium sulfate and evaporated under reduced pressure, obtaining a yellow resin. Rubbing with a mixture of petroleum ether (tKip40-60°C)/ether gave a solid cream color, which was additionally washed with ether, is the learn 3,18 g (61%) of N-[(9-fluorenyl)methoxycarbonyl]-3-(methanesulfonyl)-L-valine in the form of a white solid, tPL189-92°C, (M+H)+417,8.

(C) the Solution to 8.34 g (20 mmol) N-[(9-fluorenyl)methoxycarbonyl]-3-(methanesulfonyl)-L-valine obtained above in section (B), in anhydrous tetrahydrofuran was cooled to -10°and was added to 2.8 ml (20 mmol) of triethylamine, then a 2.6 ml (20 mmol) of isobutylphthalate (Aldrich 17,798-9). Then added 8,02 g (20 mmol) of 2-(3(S)-amino-2(R)-hydroxy-4-phenylbutyl)-N-tert-butyl-1,2,3,4,4a(S),4,5,6,7,8,8A(S)-decahydro-3(S)-ethanolinduced (obtained according to known methods, for example, Martin, Joseph Armstrong; Redshaw, Sally; EP 432695 A2), and the mixture was stirred at -10°C for additional 2 h, then was allowed to warm to room temperature during the night. Volatiles were evaporated, the residue was distributed between 100 ml of dichloromethane and 100 ml of 10% citric acid solution. The aqueous phase was extracted with dichloromethane, the combined organic phase was washed with saturated sodium bicarbonate solution and saturated saline solution, dried over magnesium sulfate and evaporated under reduced pressure, obtaining a solid, which is triturated with ether, then with a mixture of ether/ethyl acetate (10:1), receiving 10,84 g (68%) of N-tert-butyl-2-[3(S)-[[N-[(9-fluorenyl)methoxycarbonyl]-3-(methanesulfonyl)-L-valil]amino]-2(R)-hydroxy-4-phenylbutyl]-1,2,3,4,4a(S),5,6,7,8,8A(S)-decahydro-3(S)-ethanolinduced in the form of a white solid, (M+H)+801,4.

the example 2

N-tert-Butyl-2-[3(S)-[[N-methylethylamine-3-(methanesulfonyl)-L-valil]amino]-2(S)-hydroxy-4-phenylmethyl]-1,2,3,4,4A(S),5,6,7,8,8A(S)-decahydro-3(S)-ethanolinduced

A solution of 38 mg (0.2 mmole) of the hydrobromide of N-ethyl-N-methylglycine and 116 mg (0.2 mmole) of N-tert-butyl-1,2,3,4,4A(S),5,5,6,7,8,8A(S)-decahydro-2-[2(R)-hydroxy-3(S)-[[3-(methanesulfonyl)-L-valil]amino]-4-phenylmethyl]-3(S)-ethanolinduced in 5 ml of dichloromethane was treated with 28 mg (0.2 mmole) of 1-hydroxy-7-sebestianova (NEAT), 0.05 ml (0.4 mmole) of N-ethylmorpholine (NEM) and 38 mg (0.2 mmole) of the hydrochloride of N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide (EDAC·HCl) at 0°and allowed to warm to room temperature over night. The reaction mixture was diluted with dichloromethane, washed with saturated sodium bicarbonate solution and saturated saline solution, dried over magnesium sulfate and evaporated under reduced pressure, obtaining a resin, which was chromatographically on silica gel, was suirable a mixture of chloroform/methanol (19:1)to give 65 mg of N-tert-butyl-2-[3(S)-[[N-(N-ethyl-N-methylglycyl)-3-(methanesulfonyl)-L-valil]amino]-2(R)-hydroxy-4-phenylbutyl]-1,2,3,4,4A(S),5,6,7,8,8A(S)-decahydro-3(S)-ethanolinduced in the form of a white foam, (M+N)+to 678.4.

The original substance of the hydrobromide of N-ethyl-N-methylglycine (1:1) was prepared as follows.

(A) a Mixed solution of 0.6 ml (7 mmol) of N-ethylmethylamine è0,97 ml (7 mmol) of triethylamine in 7 ml of dichloromethane was treated with 1 ml (7 mmol) of tert-butylbromide (Aldrich 12,423-0) and was stirred over night. Volatiles were evaporated, the residue triturated with ethyl acetate, and the solid was removed by filtration. The solvent was evaporated, getting 459 mg of yellow oil, which was treated at room temperature with 2 ml of 45% Hydrobromic acid in acetic acid and was stirred for 6 hours Volatiles were removed under reduced pressure, the residue is thoroughly triturated with ethyl acetate, getting 413 mg hydrobromide N-ethyl-N-methylglycine in the form of a white solid.

Example 3

N-tert-Butyl-1,2,3,4,4a(S),5,6,7,8A(S)-decahydro-2-[2(R)-hydroxy-3(S)-[[3-(methanesulfonyl)-N-[2-(3-pyridyloxy)acetyl]-L-valil]amino]-4-phenylbutyl]-3(S)-ethanolinduced

Was obtained in a manner analogous to that described in example 2, but from trifenatate 2-(3-pyridyloxy)acetic acid. (M+N)+714,4.

The original substance triptorelin 2-(3-pyridyloxy)acetic acid was prepared as follows.

(A) a Solution of 9.5 g (0.1 mol) 3-hydroxypyridine in 50 ml of anhydrous dimethylformamide at 0°processed portions of a suspension of sodium hydride in hexane (obtained by washing with hexane 4 g of 60% dispersion of sodium hydride in mineral oil). After 30 min was added dropwise to 19.4 g (0.1 mol) of tert-butylbromide, and the solution was stirred over night. Volatiles were evaporated, the residue was distributed IU what do dichloromethane and water. The organic phase is washed with water, dried over magnesium sulfate and evaporated under reduced pressure, obtaining oil, which was chromatographically on silica gel, was suirable dichloromethane, getting a 8.9 g of green-brown oil. The oil was dissolved in dichloromethane, cooled to 0°C, was treated with 18 ml triperoxonane acid and allowed to warm to room temperature over night. Volatiles were evaporated, the residue triturated with ether, receiving 9.2 grams of triptoreline 2-(3-pyridyloxy)acetic acid as light brown solid.

Example 4

N-tert-Butyl-1,2,3,4,4a(S),5,6,7,8,8A(S)-decahydro-2-[2(R)-hydroxy-3(S)-[[3-(methanesulfonyl)-N-(methoxycarbonyl)-L-valil]amino]-4-phenylbutyl]-3(S)-ethanolinduced

Mix a solution of 200 mg (0.25 mmole) of N-tert-butyl-2-[3(S)-[[N-[(9-fluorenyl)methoxycarbonyl]-3-(methanesulfonyl)-L-valil]amino]-2(R)-hydroxy-4-phenylbutyl]-1,2,3,4,4A(S),5,6,7,8,8A(S)-decahydro-3(S)-ethanolinduced in 5 ml of anhydrous dimethylformamide at room temperature was treated with 0.63 ml (6.3 mmole) of piperidine. After 2.5 h the volatiles were evaporated, the residue triturated with hexane, obtaining N-tert-butyl-1,2,3,4,4A(S),5,5,6,7,8,8A(S)-decahydro-2-[2(R)-hydroxy-3(S)-[[3-(methanesulfonyl)-L-valil]amino]-4-phenylbutyl]-3(S)-ethanolinduced resin which was dissolved in 5 ml of dichloromethane and the processing is Tivoli 0.2 ml (1.5 mmole) of N-ethylmorpholine (NEM) and 0.02 ml (0.25 mmole) of methylchloroform (Aldrich, M3, 530-4) and stirred over night. Added additional 0,02 ml (0.25 mmole) of methylchloroform and stirred the reaction mixture for a further 3 hours the Solution was diluted with dichloromethane and washed with 10% citric acid solution, saturated sodium bicarbonate solution and saturated saline solution. Citrate solution were transferred into basic by adding solid sodium bicarbonate and was extracted with dichloromethane. The combined organic phase was dried over magnesium sulfate and evaporated under reduced pressure, obtaining the remainder, which was chromatographically on silica gel, elwira a mixture of dichloromethane/methanol (19:1), triturated with ether, receiving 75 mg of N-tert-butyl-1,2,3,4,4a(S),5,6,7,8,8a(S)-decahydro-2-[2(R)-hydroxy-3(S)-[[3-(methanesulfonyl)-N-(methoxycarbonyl)-L-valil]amino]-4-phenylbutyl]-3(S)-ethanolinduced in the form of a white solid, tPL190-194° (M+H)+637,4.

Example 5

2-[3(S)-[[N,3-Bis(methanesulfonyl)-L-valil]amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert-butyl-1,2,3,4,4A(S),5,6,7,8A(S)-decahydro-3(S)-ethanolinduced

Mix a solution of 200 mg (0.25 mmole) of N-tert-butyl-2-[3(S)-[[N-[(9-fluorenyl)methoxycarbonyl]-3-(methanesulfonyl)-L-valil]amino]-2(R)-hydroxy-4-phenylbutyl]-1,2,3,4,4A(S),5,6,7,8,8A(S)-decahydro-3(S)-ethanolinduced in 5 ml of anhydrous dimethylformamide at on the th temperature was treated with 0.63 ml (6.3 mmole) of piperidine. After 2.5 h the volatiles were evaporated, and the residue triturated with hexane, obtaining N-tert-butyl-1,2,3,4,4A(S),5,5,6,7,8,8A(S)-decahydro-2-[2(R)-hydroxy-3(S)-[[3-(methanesulfonyl)-L-valil]amino]-4-phenylbutyl]-3(S)-ethanolinduced resin which was dissolved in 5 ml dichloromethane and treated to 0.12 ml (1.5 mmole) of pyridine, after which 0,02 ml (0.25 mmole) of methanesulfonamide. After 2 h, the solution was diluted with dichloromethane, washed with saturated sodium bicarbonate solution and saturated saline solution, dried over magnesium sulfate and evaporated under reduced pressure, obtaining a resin, which was washed with ether and then was chromatographically on silica gel, elwira a mixture of dichloromethane/methanol (19:1) and getting 105 mg of 2-[3(S)-[[N,3-bis(methanesulfonyl)-L-valil]amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert-butyl-1,2,3,4,4A(S),5,6,7,8A(S)-decahydro-3(S)-ethanolinduced in the form of a white solid, tPL135-160°C (foams), 230-235°With (again melts, decomp.), (M+N)+657,2.

In a manner analogous to that described in example 1, the obtained compounds are shown in table 1. The compounds of examples 6, 7, 8, 9, 10 obtained from N-tert-butyl-2-[3(S)-[[N-[(9-fluorenyl)methoxycarbonyl]-3-(methanesulfonyl)-L-valil]amino]-2(R)-hydroxy-4-phenylbutyl]-1,2,3,4,4A(S),5,6,7,8,8A(S)-decahydro-3(S)-ethanolinduced, the compounds of examples 11 and 12 obtained by analogy with example 1, but with IP is the use of iodata instead of iodomethane in section (A). All the anhydrides of the acids used as starting substances purchased from commercial sources such as Aldrich and Lancaster.

In a manner analogous to that described in examples 2 and 3 were obtained compounds of table 2, based on N-tert-butyl-2-[3(S)-[[N-[(9-fluorenyl)methoxycarbonyl]-3-(methanesulfonyl)-L-valil]amino]-2(R)-hydroxy-4-phenylbutyl]-1,2,3,4,4A(S),5,6,7,8,8A(S)-decahydro-3(S)-ethanolinduced.

Other reagents used in the synthesis of compounds of table 2 were obtained from commercial sources such as Aldrich, Lancaster and Maybridge Int., or synthesized by the methods described in this field or similar to those described.

For example, venexiana acid (example 14), 3-francebuy acid (example 28), 2-ethyl-2-hydroxipropionic acid (example 23) and 5-bromo-2-francebuy acid (example 32) was purchased from Aldrich company (catalog numbers 15,851-8; 16,339-2; 13843-6; B6,740-6), 4,5-dimethyl-2-francebuy acid (example 33) and 5-(trifluoromethyl)-2-francebuy acid (example 34) was purchased from a company Maybridge Int. (catalog numbers BTB 08890; R), thiophene-3-carboxylic acid (example 68) and 5-chlorothiophene-2-carboxylic acid (example 36) was purchased from a company Lancaster (catalog numbers 1089; 5453).

The thiazole-5-carboxylic acid (example 69) was obtained according to the methods of the e, described in WO 97/14687, and 5-methylthiazole-2-carboxylic acid (example 61) was obtained in the same way. 2-Methylthiazole-4-carboxylic acid (example 74) was obtained by analogy with the method W.R.Tully and others, J.Med. Chem; 1991, 34, 2060. 2-Isopropoxyethanol acid (example 72) was obtained according to the method described in J.Chem. Soc., 1969, 2698. 2-Methyl-2-phenoxypropionic acid (example 80) was obtained according to the method described in the patent Romania RO 69-61256.

Other aryloxyalkyl acid was obtained by analogy with the method Mertes and others, J.Heterocycl. Chem., 1968, 5, 281 or according to the method described in example 3A to obtain trifenatate 2-(3-pyridyloxy)acetic acid. In a similar manner 2-(1-pyrrolyl)acetic acid (example 62), pyrazole-1-acetic acid (example 64), 1-pyrrolidinyloxy acid (example 66), etc. received by analogy with the method described in example 2A to obtain hydrobromide N-ethyl-N-methylglycine.

In a manner analogous to that described in example 4, the compounds of table 3 have been derived from N-tert-butyl-2-[3(S)-[[N-[(9-fluorenyl)methoxycarbonyl]-3-(methanesulfonyl)-L-valil]amino]-2(R)-hydroxy-4-phenylbutyl]-1,2,3,4,4A(S),5,6,7,8,8A(S)-decahydro-3(S)-ethanolinduced and commercially available chloroformate.

Example 92

N-tert-Butyl-1,2,3,4,4a(S),5,6,7,8,8a(S)-decahydro-2-[2(R)-hydroxy-3(S)-[[N-[2-(isopropylamino)acetyl]-3-(methanesulfonyl)-L-valil]amino]-4-phenylbutyl]-3(S)-ethanolinduced

The solution 0,123 g of 2-[3(S)-[[N - [N-(benzyloxycarbonyl)-N-isopropylphenyl]-3-(methanesulfonyl)-L-valil]amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert-butyl-1,2,3,4,4A(S),5,6,7,8,8A(S)-decahydro-3(S)-ethanolinduced in 30 ml ethanol in the presence of 10% palladium on coal was first made in an atmosphere of hydrogen overnight.

The catalyst was removed by filtration and the volatiles were evaporated under reduced pressure, obtaining a colorless glassy substance that chromatographia and on silica gel, elwira a mixture of dichloromethane/methanol (25:1) and receiving the oil. The oil is triturated with a mixture of petroleum ether (tKip40-60°C)/ether, receiving 29 mg of N-tert-butyl-1,2,3,4,4A(S),5,6,7,8,8A(S)-decahydro-2-[2(R)-hydroxy-3(S)-[[N-[2-(isopropylamino)acetyl]-3-(methanesulfonyl)-L-valil]amino]-4-phenylbutyl]-3(S)-ethanolinduced in the form of a white solid, (M+N)+678,5.

Starting material was prepared as follows.

The solution was 1.04 ml (7.6 mmole) of tert-butyl ester of glycine and 0.11 ml (scored 8.38 mmole) in acetone (30 ml ethanol in the presence of 10% palladium on coal (Fluka) was first made in an atmosphere of hydrogen overnight. The catalyst was removed by filtration, volatiles were evaporated under reduced pressure, getting 1,08 g (82%) opaque rolling oil, which was treated at 0°With 7 ml triperoxonane acid and allowed to warm to room temperature. After 5 h the volatiles were evaporated, receiving 2.65 g of pale yellow oil, 1.44 g of which was dissolved in 10 ml of 2 M sodium hydroxide solution at 0°and processed simultaneously to 0.89 ml (6,23 mmole) of benzylchloride and 10 ml of 2 M sodium hydroxide solution. The reaction mixture was allowed to warm to room temperature overnight and washed with ether. The solution was acidified and extracted with ethyl acetate, the combined organic phase was washed with water, dried over magnesium sulfate and evaporated in eigendom pressure, getting 0,338 g of N-(benzyloxycarbonyl)-N-isopropylaniline in the form of a colorless oil. Part of this oil, 0,043 g, was introduced into the reaction with 0.1 g (1,73 mmole) of N-tert-butyl-1,2,3,4,4A(S),5,5,6,7,8,8A(S)-decahydro-2-[2(R)-hydroxy-3(S)-[[3-(methanesulfonyl)-L-valil]amino]-4-phenylbutyl]-3(S)-ethanolinduced by the method similar to that described in example 2, receiving 0,123 g of 2-[3(S)-[[N-[N-(benzyloxycarbonyl)-N-isopropylphenyl]-3-(methanesulfonyl)-L-valil]amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert-butyl-1,2,3,4,4A(S),5,6,7,8,8A(S)-decahydro-3(S)-ethanolinduced as a yellow glassy substance.

Example 93

N-tert-Butyl-1,2,3,4,4a(S),5,6,7,8,8a(S)-decahydro-2-[2(R)-hydroxy-3(S)-[[3-(methanesulfonyl)-N-(N-phenylglycyl)-L-valil]amino]-4-phenylbutyl]-3(S)-ethanolinduced

Was obtained in a manner analogous to that described in example 92, from N-phenylglycine (Aldrich 33,046-9). (M+N)+712,5.

Example 94

N-tert-Butyl-1,2,3,4,4A(S),5,6,7,8,8a(S)-decahydro-2-[2(R)-hydroxy-3(S)-[[3-(methanesulfonyl)-N-(N-methylglycyl)-L-valil]amino-4-phenylbutyl]-3(S)-ethanolinduced

Was obtained in a manner analogous to that described for example 92, from N-(benzyloxycarbonyl)sarcosine (Bachem C-2570), excluding the stage of protection in obtaining the original substance. (M+N)+650,4.

Example 95

N-tert-Butyl-1,2,3,4,4A(S),5,6,7,8,8A(S)-decaid is about-1-[2(R)-hydroxy-3(S)-[3-(methanesulfonyl)-3-methylbutyrate]-4-phenylbutyl]-2(S)-piperazinecarboxamide

3-(Methanesulfonyl)-3-methylmalonyl acid was introduced into the reaction with 2-(3(S)-amino-2(R)-hydroxy-4-phenylbutyl)-N-tert-butyl-1,2,3,4,4A(S),4,5,6,7,8,8A(S)-decahydro-3(S)-ethanolammonium in a manner analogous to that described in example 2, obtaining the product as a white solid, tPL95-110° (foaming), (M+N)+made 564.3.

Starting material 3-(methanesulfonyl)-3-methylmalonyl acid was prepared as follows. Stir the solution 0,81 g (6 mmol) of 3-mercapto-3-butyric acid obtained from 3,3-dimethylacrylic acid (Aldrich D13,860-6) according to the method described by G. Pattenden, etc., Chem. Soc. Perkm Trans. 1, 1992, 10, 1215-21, 25 ml of a mixture of dioxane/water (3:2) were processed to 4.14 g (30 mmol) of potassium carbonate in 5 ml of water, after which 1,14 g (8 mmol) of iodomethane, was extracted with ether, the organic phase was dried over magnesium sulfate and evaporated under reduced pressure, getting 0,57 g (64%) of 3-methyl-3-(methylthio)butyric acid as a pale orange oil. The oil was dissolved in 12 ml of water containing 188 mg (4,63 mmole) of sodium hydroxide, and treated 2,59 g (31 mmol) of sodium bicarbonate and 4 ml of acetone, and then dropwise added to 3.16 g (5,13 mmole) OXONE® (Aldrich 17,798-9), dissolved in 12 ml of 0.0004 M solution of EDTA. After 2 h was added 2 g of sodium metabisulfite, and the solution was stirred for 15 minutes the Solution was acidified to pH 2 and extras is listed with ethyl acetate. The organic phase is washed with water, saturated salt solution, dried over magnesium sulfate and evaporated under reduced pressure, getting 585 mg colourless oil (M+N)+181 (chemical ionization with the formation of positive ions).

Example 96

2-[3(S)-[3-(Econsultancy)-3-methylbutyrate]-2(R)-hydroxy-4-phenylbutyl]-1,2,3,4,4A(S),5,6,7,8,8A(S)-decahydro-3(S)-ethanolinduced

Was obtained in a manner analogous to that described in example 2, the interaction of 3-(econsultancy)-3-methylmalonic acid with 2-(3(S)-amino-2(R)-hydroxy-4-phenylbutyl)-N-tert-butyl-1,2,3,4,4a(S),4,5,6,7,8,8A(S)-decahydro-3(S)-ethanolammonium (M+N)+578,2.

Starting material 3-(econsultancy)-3-methylmalonyl acid was obtained in a manner analogous to that described for the preparation of 3-(methanesulfonyl)-3-methylmalonic acid, the starting materials of example 95, using Iodate instead of iodomethane.

Example 97

2-[3(S)-[3-(Benzylmethyl)-3-methylbutyrate]-2(R)-hydroxy-4-phenylbutyl]-N-tert-butyl-1,2,3,4,4a(S),5,6,7,8,8A(S)-decahydro-3(S)-ethanolinduced

Was obtained in a manner analogous to that described in example 2, the interaction of 3-(benzylmethyl)-3-methylmalonic acid with 2-(3(S)-amino-2(R)-hydroxy-4-phenylbutyl)-N-tert-butyl-1,2,3,4,4A(S),4,5,6,7,8,8A(S)-decahydro-3(S)-athinaikos the Ministry of foreign Affairs. (M+N)+640.

Starting material 3-(benzylmethyl)-3-methylmalonyl acid was obtained from 3-(benzylthio)-3-methylmalonic acid (G.Pattenden and others, J.Chem. Soc., Perkin Trans. 1, 1992, 10, 1215-21) in a manner analogous to that described to obtain the original substance in example 95.

Example 98

N-tert-Butyl-1,2,3,4,4A(S),5,6,7,8,8A(S)-decahydro-2-[3(S)-[[N-[2-(tetrahydro-2(RS)-methyl-1,1-dioxo-2-thienyl)acetyl]amino]-2(R)-hydroxy-4-phenylbutyl]-3(S)-ethanolinduced (a mixture of diastereoisomers)

Was obtained in a manner analogous to that described in example 2, the interaction of S,S-dioxide, tetrahydro-2(RS)-methyl-2-tifemoxone acid with 2-(3(S)-amino-2(R)-hydroxy-4-phenylbutyl)-N-tert-butyl-1,2,3,4,4A(S),4,5,6,7,8,8A(S)-decahydro-3(S)-ethanolammonium. (M+N)+576,3.

The original substance S,S-dioxide, tetrahydro-2(RS)-methyl-2-tifemoxone acid was obtained from tetrahydro-2-methylthioadenosine acid (R.A.Bunce and others, J.Org. Chem. 1992, 57(6), 1727-33) in a manner analogous to that described to obtain the original substance in example 95.

Example 99

N-tert-Butyl-1,2,3,4,4A(S),5,6,7,8,8A(S)-decahydro-2-[2(R)-hydroxy-3(S)-[2(R)-hydroxy-3-(methanesulfonyl)-3-methylbutyrate]-4-phenylbutyl]-3(S)-ethanolinduced

Was obtained in a manner analogous to that described in example 2, the interaction of 2(R)-hydroxy-3-(methanal is of IMT-3-methylmalonic acid with 2-(3(S)-amino-2(R)-hydroxy-4-phenylbutyl)-N-tert-butyl-1,2,3,4,4A(S),4,5,6,7,8,8A(S)-decahydro-3(S)-ethanolammonium. (M+N)+580,4.

Starting material 2(R)-hydroxy-3-(methanesulfonyl)-3-methylmalonyl acid was prepared as follows.

Mix a solution of 2.25 g (5.3 mmole) of the protected amino acid of example 1 (part B) in 20 ml of anhydrous dimethylformamide was treated with 1.1 ml (11 mmol) of piperidine. After 1 h the volatiles were evaporated, and the residue was rubbed out with ether, then with ethyl acetate, receiving 1 g of resin which was dissolved in 8 ml of 10% vol./about. sulfuric acid and heated to 50°C. was Added dropwise a solution of 1.3 g of sodium nitrite in 3 ml of water and after 30 min was added additional 0.7 g of sodium nitrite in 2 ml of water. The reaction mixture was cooled and was extracted with ethyl acetate, the combined organic phase was washed with water and saturated saline solution, dried over magnesium sulfate and evaporated under reduced pressure, receiving 200 mg of 2(R)-hydroxy-3-(methanesulfonyl)-3-methylmalonyl acid resin.

Example 100

N-tert-Butyl-1,2,3,4,4A(S),5,6,7,8,8A(S)-decahydro-2-[2(R)-hydroxy-3(S)-[[N-(dimethylcarbamoyl-3-(methanesulfonyl)-L-valil]amino]-4-phenylbutyl]-3(S)-ethanolinduced

Mix a solution of 0.4 g (0.5 mmole) of N-tert-butyl-2-[3(S)-[[N-[(9-fluorenyl)methoxycarbonyl]-3-(methanesulfonyl)-L-valil]amino]-2(R)-hydroxy-4-phenylbutyl]-1,2,3,4,4A(S),5,6,7,8,8A(S)-decahydro-3(S)-ethanolinduced in 10 ml of anhydrous dimethyl rmaed at room temperature was treated with 1 ml (10 mmol) of piperidine. After 1 h the volatiles were evaporated, and the residue triturated with hexane, obtaining N-tert-butyl-1,2,3,4,4A(S),5,5,6,7,8,8A(S)-decahydro-2-[2(R)-hydroxy-3(S)-[[3-(methanesulfonyl)-L-valil]amino]-4-phenylbutyl]-3(S)-ethanolinduced resin which was dissolved in 5 ml of acetonitrile and treated with 100 mg (0.5 mmole) of n-nitrophenylphosphate (Aldrich 16,021-0), then 84 mg (1 mmol) of solid sodium bicarbonate. After 15 min was added 0.25 ml of 2 M solution of dimethylamine in tetrahydrofuran (Aldrich 39,195-6) and 0.14 ml of triethylamine, and the reaction mixture was stirred for 2 hours Volatiles were evaporated under reduced pressure, and the residue was distributed between water and dichloromethane, the aqueous phase was extracted with dichloromethane. The combined organic phase was washed with saturated saline, dried over magnesium sulfate and evaporated under reduced pressure, obtaining oil, which was chromatographically on silicagel, elwira a mixture of dichloromethane/methanol (19:1) and receiving 62 mg (20%) N-tert-butyl-1,2,3,4,4A(S),5,6,7,8,8A(S)-decahydro-2-[2(R)-hydroxy-3(S)-[[N-(dimethylcarbamoyl-3-(methanesulfonyl)-L-valil]amino]-4-phenylbutyl]-3(S)-ethanolinduced in the form of a white solid, (M+N)+650,4.

In a manner analogous to that described in example 100, on the basis of N-tert-butyl-2-[3(S)-[[N-[(9-fluorenyl)methoxycarbonyl]-3-(methanesulfonyl)-L-valil]amino]-2(R)-hydroxy-4-phenylbutyl]-1,2,3,4,4A(S), 5,6,7,8,8A(S)-decahydro-3(S)-ethanolinduced, received also compounds listed in table 4. Other reagents used in the synthesis of compounds of table 4 were obtained from commercial sources such as Aldrich and Lancaster.

Example 110

N-tert-Butyl-1,2,3,4,4,4A(S),5,6,7,8,8A(S)-decahydro-2-[2(R)-hydroxy-3(S)-[[N-isopropyl-3-(methanesulfonyl)-L-valil]amino]-4-phenylbutyl]-3(S)-ethanolinduced

Mix a solution of 0.4 g (0.5 mmole) of N-tert-butyl-2-[3(S)-[[N-[(9-fluorenyl)methoxycarbonyl]-3-(methanesulfonyl)-L-valil]amino]-2(R)-hydroxy-4-phenylbutyl]-1,2,3,4,4A(S),5,6,7,8,8A(S)-decahydro-3(S)-ethanolinduced in 10 ml of anhydrous dimethylformamide at room temperature was treated with 1 ml (10 mmol) of piperidine. After 1 h the volatiles were evaporated, and the residue triturated with hexane, obtaining N-tert-butyl-1,2,3,4,4A(S),5,5,6,7,8,8A(S)-decahydro-2-[2(R)-hydroxy-3(S)-[[3-(methanesulfonyl)-L-valil]amino]-4-phenylbutyl]-3(S)-ethanolinduced resin which was dissolved in 8 ml of dichloromethane and treated in nitrogen atmosphere 0.037 ml (0.5 mmole) of acetone, 0,028 ml (0.5 mmole) of glacial acetic acid and 160 mg (0.75 mmole) of triacetoxyborohydride sodium. The reaction mixture was stirred over night, then volatiles were evaporated. The residue was distributed between dichloromethane and vodoyi was extracted with dichloromethane. The combined organic phase was washed with saturated saline, dried over magnesium sulfate and evaporated under reduced pressure, obtaining a resin, which was chromatographically on silica gel, elwira a mixture of ethyl acetate/hexane (4:1), then triturated with hexane, getting 127 mg (41%) of N-tert-butyl-1,2,3,4,4,4a(S),5,6,7,8,8a(S)-decahydro-2-[2(R)-hydroxy-3(S)-[[N-isopropyl-3-(methanesulfonyl)-L-valil]amino]-4-phenylbutyl]-3(S)-ethanolinduced in the form of a white solid. (M+N)+621,3.

In a manner analogous to that described in example 110, on the basis of N-tert-butyl-2-[3(S)-[[N-[(9-fluorenyl)methoxycarbonyl]-3-(methanesulfonyl)-L-valil]amino]-2(R)-hydroxy-4-phenylbutyl]-1,2,3,4,4A(S),5,6,7,8,8a(S)-decahydro-3(S)-ethanolinduced were also obtained compounds are shown in table 5. Other reagents used in the synthesis of compounds of table 5 were obtained from commercial sources such as Aldrich, Lancaster and Maybridge Int., for example, furfural (example 114)and 2-forbindelse (example 116) was purchased from Aldrich, catalog numbers (b-0), (a-7), 4(5)-formyl-2-Mei (example 134) purchased from Maybridge Int. (SB 01361).

Example 137

N-tert-Butyl-1,2,3,4,4A(S),5,6,7,8,8A(S)-decahydro-2-[2(R)-hydroxy-3(S)-[[3-(methanesulfonyl)-N-(2-thiazolyl)-L-valil]amino]-4-phenylbutyl]-3(S)-ethanolinduced

Mix a solution of 255 mg (0.4 mmole) of N-tert-butyl-1,2,3,4,4a(S),5,6,7,8,8a(S)-decahydro-2-[2(R)-hydroxy-3(S)-[[3-(methanesulfonyl)-N-(thiocarbamoyl)-L-valil]amino]-4-phenylbutyl]-3(S)-ethanolinduced in 5 ml of ethanol was treated with 0.1 ml of chloroacetaldehyde (50% solution in water) and heated at boiling for 4 hours Flying the substance was evaporated, the residue was distributed between dichloromethane and saturated aqueous sodium bicarbonate. The aqueous phase was extracted with dichloromethane, and the combined organic phase was washed with saturated saline, dried over magnesium sulfate and evaporated under reduced pressure, obtaining a solid substance, which was chromatographically on silica gel, elwira a mixture of dichloromethane/methanol (19:1) and receiving 100 mg (38%) of N-tert-butyl-1,2,3,4,4A(S),5,6,7,8,8A(S)-decahydro-2-[2(R)-hydroxy-3(S)-[[3-(methanesulfonyl)-N-(2-thiazolyl)-L-valil]amino]-4-phenylbutyl]-3(S)-ethanolinduced in the form of a white solid, (M+N)+662,2.

Starting material N-tert-butyl-1,2,3,4,4A(S),5,6,7,8,8A(S)-decahydro-2-[2(R)-hydroxy-3(S)-[[3-(methanesulfonyl)-N-(thiocarbamoyl)-L-valil]amino]-4-phenylbutyl]-3(S)-ethanolinduced was prepared as follows.

(A) Mix of races is a thief 1.6 g (2 mmole) of N-tert-butyl-2-[3(S)-[[N-[(9-fluorenyl)methoxycarbonyl]-3-(methanesulfonyl)-L-valil]amino]-2(R)-hydroxy-4-phenylbutyl]-1,2,3,4,4a(S),5,6,7,8,8A(S)-decahydro-3(S)-ethanolinduced in 40 ml of anhydrous dimethylformamide at room the temperature was treated with 4 ml (40 mmol) of piperidine. After 1 h the volatiles were evaporated, and the residue triturated with hexane, obtaining N-tert-butyl-1,2,3;4,4A(S),5,5,6,7,8,8A(S)-decahydro-2-[2(R)-hydroxy-3(S)-[[3-(methanesulfonyl)-L-valil]amino]-4-phenylbutyl]-3(S)-ethanolinduced resin which was dissolved in 5 ml of acetone and treated, and 0.28 ml (2.1 mmole) benzoylisothiocyanate (Aldrich 26,165-3). Stir the reaction mixture was heated at boiling for 4 h and then cooled. Volatiles were evaporated under reduced pressure, and the residue triturated with hexane, obtaining a resin, which was then chromatographically on silica gel, elwira a mixture of ethyl acetate/hexane (2:1) and receiving 765 mg (52%) of 2-[3(S)-[[N-(benzoylthiourea)-3-(methanesulfonyl)-L-valil]amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert-butyl-1,2,3,4,4a(S), 5,6,7,8,8A(S)-decahydro-3(S)-ethanolinduced in the form of yellowish-brown foam, (M+N)+742,3, which was merged with another series of substances and used in the next step.

(B) Mix a solution of 850 mg (1.15 mmole) 2-[3(S)-[[N-(benzoylthiourea)-3-(methanesulfonyl)-L-valil]amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert-butyl-1,2,3,4,4A(S),5,6,7,8,8A(S)-decahydro-3(S)-ethanolinduced obtained above in section (A), in 6 ml of methanol/acetone (1:1) was treated with 115 mg (1.15 mmole) of potassium bicarbonate and 0.5 ml of water. After 5 h was added 1 ml of acetic acid, and the mixture p is remedial for an additional 10 minutes

Volatiles were evaporated under reduced pressure, the remaining water was removed by repeated sopariwala with ethanol, receiving resinous oil that was chromatographically on silica gel, elwira a mixture of chloroform/methanol (19:1)to give 710 mg (97%) of N-tert-butyl-1,2,3,4,4A(S),5,6,7,8,8A(S)-decahydro-2-[2(R)-hydroxy-3(S)-[[3-(methanesulfonyl)-N-(thiocarbamoyl)-L-valil]amino]-4-phenylbutyl]-3(S)-ethanolinduced in the form of a white foam, (M+N)+638.

In a manner analogous to that described in example 137, on the basis of N-tert-butyl-1,2,3,4,4A(S),5,6,7,8,8A(S)-decahydro-2-[2(R)-hydroxy-3(S)-[[3-(methanesulfonyl)-N-(thiocarbamoyl)-L-valil]amino]-4-phenylbutyl]-3(S)-ethanolinduced obtained compounds are presented in table 6. Other reagents obtained from commercial sources.

Example 143

N-tert-Butyl-1,2,3,4,4a(S),5,6,7,8,8a(S)-decahydro-2-[2(R)-hydroxy-3(S)-[[N-[4-(hydroxymethyl)-2-thiazolyl]-3-(methanesulfonyl)-L-valil]amino]-4-phenylbutyl]-3(S)-ethanolinduced

Mix a solution of 73 mg (0.1 mmole) 2-[3(S)-[[N-[4-(acetoxymethyl)-2-thiazolyl]-3-(methanesulfonyl)-L-valil]amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert-butyl-1,2,3,4,4A(S),5,6,7,8,8A(S)-decahydro-3(S)-ethanolinduced (example 141) in 7 ml of methanol/water (5:2) was treated with 700 mg of potassium carbonate. After 15 hours of flying the e substance was evaporated, and the residue was distributed between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate, the combined organic phase was washed with saturated saline, dried over magnesium sulfate and evaporated under reduced pressure, obtaining a resin, which was chromatographically on silica gel, elwira a mixture of dichloromethane/methanol (40:3) and receiving 32 mg (48%) of N-tert-butyl-1,2,3,4,4A(S),5,6,7,8,8A(S)-decahydro-2-[2(R)-hydroxy-3(S)-[[N-[4-(hydroxymethyl)-2-thiazolyl]-3-(methanesulfonyl)-L-valil]amino]-4-phenylbutyl]-3(S)-ethanolinduced in the form of solids, tPL126° (M+H)+692.

Example 144

N-tert-Butyl-1,2,3,4,4a(S),5,6,7,8,8a(S)-decahydro-2-[3(S)-[2(R)-(2,3-dihydro-2-oxo-1H-imidazol-3-yl)-3-(methanesulfonyl)-3-methylbutyrate]-2(R)-hydroxy-4-phenylbutyl]-3(S)-ethanolinduced

Stir the solution 0,578 g (1 mmol) N-tert-butyl-1,2,3,4,4A(S),5,5,6,7,8,8A(S)-decahydro-2-[2(R)-hydroxy-3(S)-[[3-(methanesulfonyl)-L-valil]amino]-4-phenylbutyl]-3(S)-ethanolinduced was dissolved in 20 ml of acetonitrile and treated 201 mg (1 mmol) of n-nitrophenylphosphate, then 168 mg (21 mmol) of sodium bicarbonate. After 15 min was added to 0.11 ml of dimethylacetal of aminoacetaldehyde (Lancaster 7520) and 0.28 ml (2 mmole) of triethylamine, and the reaction mixture was stirred for 2 hours Volatiles were evaporated under reduced pressure, and the residue was distributed is between water and dichloromethane. The aqueous phase was extracted with dichloromethane, the combined organic phase was washed with saturated saline, dried over magnesium sulfate and evaporated under reduced pressure, obtaining a yellow resin, which was washed with hexane, then ethyl acetate, getting 466 mg (66%) of a cream solid color, tPL228-30°C (M+N)+710. Dissolved 420 mg (0,59 mmole) of the solid in 20 ml of acetone and treated with 5 ml of 10% hydrochloric acid and was stirred overnight. The solution was treated with saturated sodium bicarbonate solution and partially evaporated. The solution was extracted with dichloromethane, and the combined organic phase was washed with saturated saline, dried over magnesium sulfate and evaporated, getting a solid cream color, which was chromatographically on silica gel, elwira a mixture of dichloromethane/methanol (38:1)to give 50 mg(13%) N-tert-butyl-1,2,3,4,4A(S),5,6,7,8,8A(S)-decahydro-2-[3(S)-[2(R)-(2,3-dihydro-2-oxo-1H-imidazol-2-yl)-3-(methanesulfonyl)-3-methylbutyrate]-2(R)-hydroxy-4-phenylbutyl]-3(S)-ethanolinduced in the form of a white solid, (M+N)+646.

Example 145

N-Benzyl-1,2,3,4,4A(S),5,6,7,8,8A(S)-decahydro-2-[2(R)-hydroxy-3(S)-[[3-(methanesulfonyl)-N-(methoxycarbonyl)-L-valil]amino]-4-phenylbutyl]-3(S)-ethanolinduced

A solution of 0.13 ml (1.2 mmole) be the of Salamina in 5 ml of dichloromethane was treated with 0.6 ml of trimethylaluminum (2m solution in toluene) and stirred at room temperature for 15 minutes Was added dropwise a solution of 68 mg of the lactone N1-[1(S)-(1,3,4,6,6a(S),7,8,9,10,10a(S),11,11a(S)-dodecahydro-1-oxo-1,4-oxazino[4,3-b]isoquinoline-3(R)-yl)-2-phenylethyl]-3-(methanesulfonyl)-N2-(methoxycarbonyl)-L-valinamide dissolved in 5 ml of dichloromethane, after which was added 5 ml of toluene, and the solution was stirred for night. Was added dropwise dilute hydrochloric acid, and the solution was extracted with dichloromethane. The combined organic phase was washed with diluted hydrochloric acid and saturated saline solution, dried over magnesium sulfate and evaporated under reduced pressure, obtaining the remainder, which was led from a mixture of dichloromethane/methanol education 15 mg of N-benzyl-1,2,3,4,4A(S),5,6,7,8,8A(S)-decahydro-2-[2(R)-hydroxy-3(S)-[[3-(methanesulfonyl)-N-(methoxycarbonyl)-L-valil]amino]-4-phenylbutyl]-3(S)-ethanolinduced in the form of a white solid, (M+N)+671.

The original substance of N1-[1(S)-(1,3,4,6,6a(S),7,8,9,10,10a(S),11,11a(S)-dodecahydro-1-oxo-1,4-oxazino[4,3-b]isoquinoline-3(R)-yl)-2-phenylethyl]-3-(methanesulfonyl)-N2-(methoxycarbonyl)-L-valinamide was prepared as follows.

(A) Suspended to 23.8 g (0.1 mol) of N-tert-butyl-1,2,3,4,4a(S),4,5,6,7,8,8A(S)-decahydro-3(S)-ethanolinduced obtained according to known methods, for example Martin, Joseph Armstrong; Redshaw, Sally, EP 432695 A2, 100 ml of 6 N. hydrochloric acid and stirred at boiling during the course the e 23 PM The reaction mixture was evaporated to dryness, obtaining 23.1 g of a white solid, which was dissolved in 200 ml of water and was treated with 30 ml of 4 n sodium hydroxide solution. The solution was cooled to 4°and vigorously stirred as simultaneously added to 15.5 ml of 0.11 mol) of benzylchloride and 4.4 g (of 0.11 mole) of sodium hydroxide in 15 ml of water. The reaction mixture was stirred for the next 1 h, bringing the pH to 9 by addition of 4 n sodium hydroxide solution, and then heated to room temperature. After 2 h, the solution was diluted with water and extracted with hexane. The aqueous phase was acidified with concentrated hydrochloric acid and was extracted with ethyl acetate. The combined organic phase was washed with water and saturated saline solution, dried over magnesium sulfate and evaporated under reduced pressure, obtaining of 29.6 g of resin which was dissolved in 300 ml of ethyl acetate and vigorously stirred, adding dropwise to 10.7 ml (0,093 mole) of cyclohexylamine. Added the following 200 ml of ethyl acetate, and the mixture was stirred overnight and then filtered, obtaining of 28.9 g of solid, which was combined with 10.4 g of the same substance from another series and distributed between 400 ml of ethyl acetate and 250 ml of 2 N. hydrochloric acid. The organic phase is washed with water and saturated saline solution, dried over sulfate magney was evaporated, receiving resin. Stir a solution of the resin in 50 ml of dichloromethane was treated with a solution 41,3 g (0,18 mmole) of tert-butyltrichlorosilane (Aldrich) in 400 ml of cyclohexane, and then 1.9 ml of titlefirst boron TRIFLUORIDE (Fluka). The mixture was stirred overnight, was added sodium bicarbonate, and after 30 min the solution was filtered. Volatiles were evaporated, obtaining a resin which was dissolved in 500 ml ethyl acetate and washed 2 N. solution of sodium carbonate, water and saturated saline solution, dried over magnesium sulfate and evaporated under reduced pressure, obtaining 28 g of resin. A solution of 18.8 g of resin in 500 ml of ethanol was first made in the presence of 1.9 g of 5% palladium on coal (Fluka). The catalyst was separated by filtration, volatiles were evaporated under reduced pressure, obtaining white solid, which was distributed between 300 ml of methyl tert-butyl ether and 250 ml of saturated sodium bicarbonate solution. The organic phase is washed with water and saturated saline solution, dried over magnesium sulfate and evaporated under reduced pressure to give 10 g (0,042 mole) of pale yellow resin which was dissolved in 200 ml of ethanol. Added 12,43 g (0,042 mole) 2(S)-[1(S)-(benzyloxycarbonyl)-2-phenylethyl]oxirane (obtained according to known methods (EP 346847 A2)), and the mixture was heated at boiling for 10 hours Volatiles were evaporated, and the residue chromatography which was referable on silica gel, elwira a mixture of ethyl acetate/hexane (1:2), and receiving 19.5 g cream solid colors from which 1,072 g (2.0 mmole) was dissolved in 5 ml of glacial acetic acid and treated with 10 ml of 45% hydrogen bromide in acetic acid was stirred for 1.5 hours Volatiles were evaporated almost to dryness, the solid was separated by filtration and washed with glacial acetic acid, after which the ether. The solid substance was distributed between ethyl acetate and aqueous sodium carbonate solution, the organic phase is washed with water and saturated saline solution, dried over magnesium sulfate and evaporated under reduced pressure, getting 493 mg hydrobromide 3(R)-(1(S)-amino-2-phenylethyl)-3,4,6A(S),7,8,9,10,10a(S),11,11a(S)-decahydro-1,4-oxazino[4,3-b]isoquinoline-1(6H)-it is in the form of a white foam, (M+N)+329,0.

(B) Stirring the suspension 417 mg (1 mmol) N-[(9-fluorenyl)methoxycarbonyl]-3-(methanesulfonyl)-L-valine obtained above in example 1(B), in 5 ml of tetrahydrofuran was treated with 115 mg (1 mmol) N-ethylmorpholine (NEM) and cooled to 0°C in nitrogen atmosphere. Was added to 0.13 ml (1 mmol) isobutylphthalate, and the reaction mixture was stirred for 15 minutes was Added a solution of 295 mg (0.9 mmole) of hydrobromide 3(R)-(1(S)-amino-2-phenylethyl)-3,4,6A(S),7,8,9,10,10A(S),11,11a(S)-decahydro-1,4-oxazino[4,3-b]isoquinoline-1(6H)-she obtained above in section (A), in 5 ml of tetrahydrofuran and gave the solution to the retsa to room temperature over night. The solution was distributed between ethyl acetate and water and the organic phase was washed with 10% citric acid solution, aqueous sodium bicarbonate solution and saturated saline solution, dried over magnesium sulfate and evaporated under reduced pressure, obtaining a yellow resin. The resin was chromatographically on silica gel, elwira a mixture of ethyl acetate/hexane (1:1) and getting 281 mg of the product (M+N)+729, which was dissolved in 5 ml dichloromethane and treated with 1 ml of piperidine was stirred at room temperature for 2 hours the Solution was diluted with hexane and filtered, the filtrate was evaporated under reduced pressure. The residue was chromatographically on silica gel, elwira a mixture of dichloromethane/methanol (19:1) and then was led from a mixture of ether/hexane, receiving 120 mg (0.24 mmole) of white solid, (M+N)+506, which was dissolved in 4 ml of a mixture of dioxane/water (1:1) and was treated with 66 mg of potassium carbonate and 0,19 ml methylcarbamate. The solution was stirred overnight and then was distributed between ethyl acetate and water. The organic phase was washed with an aqueous solution of sodium bicarbonate and saturated saline, dried over magnesium sulfate and evaporated under reduced pressure, receiving 68 mg of N1-[1(S)-(1,3,4,6,6a(S),7,8,9,10,10a(S),11,11a(S)-dodecahydro-1-oxo-1,4-oxazino[4,3-b]isoquinoline-3(R)-yl)-2-phenylethyl]-3-(methanesulfonyl)-N2-(methoxycarbonyl)-L-valinamide in form b the logo solids, (M+N)+564.

Example 146

N-tert-Butyl-1,2,3,4,4A(S),5,6,7,8,8A(S)-decahydro-2-[2(R)-(isobutyryloxy)-3(S)-[[3-(methanesulfonyl)-N-[(3-pyridyl)carbonyl]-L-valil]amino]-4-phenylbutyl]-3(S)-ethanolinduced

A solution of 0.15 g (of 0.21 mmole) of N-tert-butyl-1,2,3,4,4a(S),5,6,7,8,8a(S)-decahydro-2-[2(R)-hydroxy-3(S)-[[3-(methanesulfonyl)-N-[(3-pyridyl)carbonyl]-L-valil]amino]-4-phenylbutyl]-3(S)-ethanolinduced (example 7) in 1 ml of pyridine was treated 0,092 ml of 0.21 mmole) of Isobutyraldehyde at 0°and during the night was allowed to reach room temperature. Volatiles were evaporated, and the residue was distributed between dichloromethane and a saturated solution of sodium bicarbonate. The organic phase was dried over sodium sulfate and evaporated under reduced pressure, obtaining a resin, which was chromatographically on silica gel, elwira a mixture of dichloromethane/methanol (25:1), and triturated with a mixture of ether/petroleum ether with tKip40-60°getting 83 mg of N-tert-butyl-1,2,3,4,4A(S),5,6,7,8,8A(S)-decahydro-2-[2(R)-(isobutyryloxy)-3(S)-[[3-(methanesulfonyl)-N-[(3-pyridyl)carbonyl]-L-valil]amino]-4-phenylbutyl]-3(S)-ethanolinduced in the form of a white solid, (M+N)+754,5.

Example 147

N-tert-Butyl-1,2,3,4,4A(S),5,6,7,8,8A(S)-decahydro-2-[2(R)-(isobutyryloxy)-3(S)-[[3-(methanesulfonyl)-N-[2-(3-pyridyloxy)acetyl]-L-valil]amino]-4-phenylbutyl]-3(S)-ethanolinduced

Mix a solution of 190 mg (2,66 mmole) of N-tert-butyl-1,2,3,4,4A(S),5,6,7,8A(S)-decahydro-2-[2(R)-hydroxy-3(S)-[[3-(methanesulfonyl)-N-[2-(3-pyridyloxy)acetyl]-L-valil]amino]-4-phenylbutyl]-3(S)-ethanolinduced (example 3) and 26 mg (2,66 mmole) somaclonal acid in 3 ml of dichloromethane was treated with 36 mg (2,92 mmole) of 4-(dimethylamino)pyridine (DMAP) and 56 mg (2,92 mmole) of EDAC·HCl and left at room temperature over night. Added a new portion 26 mg somaclonal acid, 36 mg of DMAP and 56 mg EDAC·HCl, and the reaction mixture was stirred an additional 2 hours the Solution was diluted with dichloromethane, and the organic phase is washed with saturated sodium bicarbonate solution and saturated saline solution, dried over magnesium sulfate and evaporated under reduced pressure, obtaining a colorless glassy substance, which was chromatographically on silica gel, elwira a mixture of dichloromethane/methanol (97:3)to give 153 g of N-tert-butyl-1,2,3,4,4A(S),5,6,7,8,8A(S)-decahydro-2-[2(R)-(isobutyryloxy)-3(S)-[[3-(methanesulfonyl)-N-[2-(3-pyridyloxy)acetyl]-L-valil]amino]-4-phenylbutyl]-3(S)-ethanolinduced in the form of a white foam, (M+N)+784,6.

Example 148

N-tert-Butyl-1,2,3,4,4A(a),4,5,6,8,8(S)-decahydro-2-[3(S)-[[3-(methanesulfonyl)-N-[(3-pyridyl)carbonyl]-L-valil]amino]-4-phenyl-2(R)-(L-Wallace)butyl]-3(S)-ethanolinduced

Mix a solution of 150 mg (2,19 IMO is I) N-tert-butyl-1,2,3,4,4A(S),5,6,7,8,8A(S)-decahydro-2-[2(R)-hydroxy-3(S)-[[3-(methanesulfonyl)-N-[(3-pyridyl)carbonyl]-L-valil]amino]-4-phenylbutyl]-3(S)-ethanolinduced (example 7), 61 mg (2,41 mmole) carbobenzoxy-L-valine (VASHEM WITH-2805) and 33 mg (2,41 mmole) of 1-hydroxybenzotriazole (NOVT) in 2 ml of dichloromethane was treated was 0.026 ml (2.1 mmole) of NEM and 46 mg (2,41 mmole) of EDAC·HCl. Additional equivalent portions of carbobenzoxy-L-valine, NOWT and EDAC·HCl was added daily for 11 days. The solution was diluted with dichloromethane and washed with saturated sodium bicarbonate solution and saturated saline solution, dried over magnesium sulfate and evaporated under reduced pressure, getting orange resin, which was chromatographically on silica gel, elwira a mixture of dichloromethane/methanol (97:3)to give 137 mg of a white foam. The foam was dissolved in 20 ml of ethanol and was first made with 10% palladium on coal in an atmosphere of hydrogen for 1 h, the Catalyst was removed by filtration, volatiles were evaporated under reduced pressure, obtaining white solid, which was chromatographically on silica gel, elwira a mixture of dichloromethane/methanol (47:2), triturated with a mixture of ether/petroleum ether with tKip40-60°receiving 14 mg of N-tert-butyl-1,2,3,4,4A(a),4,5,6,8,8(a

)-decahydro-2-[3(S)-[[3-(methanesulfonyl)-N-[(3-pyridyl)carbonyl]-L-valil]amino]-4-phenyl-2(R)-(L-Wallace)butyl]-3(S)-ethanolinduced in the form of a white solid, (M+N)+783,5.

Example 149

N-tert-Butyl-1,2,3,4,4A(S),5,6,7,8,8A(S)-decahydro-2-[3(S)-[[N-[(2-indolyl)carbonyl]-3-(methanesulfonyl)-L-valil]am is but]-2(R)-[4-(morpholinomethyl)benzoyloxy]-4-phenylbutyl]-3(S)-ethanolinduced

Was obtained in a manner analogous to that described for example 157, proceeding from N-tert-butyl-1,2,3,4,4A(S),5,6,7,8,8A(S)-decahydro-2-[2(R)-hydroxy-N-[(2-indolyl)carbonyl]-3(S)-[[3-(methanesulfonyl)-L-valil]amino]-4-phenylbutyl]-3(S)-ethanolinduced (example 86) and 4-(morpholinomethyl)benzoic acid, which was obtained according to the method described .Bundgaard and others, J.Med. Chem. 1989, 32, 2503. (M+N)+925,6.

Example 150

N-tert-Butyl-2-[3(S)-[[N-(3-cyanobenzoyl)-3-(methanesulfonyl)-L-valil]amino]-2(R)-[2-[2-(2-methoxyethoxy)ethoxy]acetoxy]-4-phenylbutyl]-1,2,3,4,4A(S),5,6,7,8,8A(S)-decahydro-3(S)-ethanolinduced

Got a way similar to that described in example 147, proceeding from N-tert-butyl-2-[3(S)-[[N-(3-cyanobenzoyl)-3-(methanesulfonyl)-L-valil]amino]-2(R)-hydroxy-4-phenylbutyl]-1,2,3,4,4A(S),5,6,7,8,8A(S)-decahydro-3(S)-ethanolinduced (example 39) and 2-[2-(2-methoxyethoxy)ethoxy]acetic acid (Aldrich 40,7000-3). (M+N)+868,5.

Example 151

N-tert-Butyl-2-[2(R)-(3-carboxyphenoxy)-3(S)-[[3-(methanesulfonyl)-N-[(3-pyridyl)carbonyl]-L-valil]amino]-4-phenylbutyl]-1,2,3,4,4A(S),5,6,7,8,8A(S)-decahydro-3(S)-ethanolinduced

A solution of 68 mg (0.1 mmole) of N-tert-butyl-1,2,3,4,4A(S),5,6,7,8,8A(S)-decahydro-2-[2(R)-hydroxy-3(S)-[[3-(methanesulfonyl)-N-[(3-pyridyl)carbonyl]-L-valil]amino]-4-phenylbutyl]-3(S)-ethanolinduced is (example 7) in 10 ml of tetrahydrofuran was treated with 10 mg (1 mmol) of succinic acid anhydride (Aldrich 23,960-0) and was heated at boiling during the night. Volatiles were evaporated under reduced pressure, and the residue was chromatographically on silica gel, elwira a mixture of dichloromethane/methanol (19:1) and receiving 53 mg of N-tert-butyl-2-[2(R)-(3-carboxyphenoxy)-3(S)-[[3-(methanesulfonyl)-N-[(3-pyridyl)carbonyl]-L-valil]amino]-4-phenylbutyl]-1,2,3,4,4A(S),5,6,7,8,8A(S)-decahydro-3(S)-ethanolinduced in the form of a foam, (M+N)+784,5.

Example 152

N-tert-Butyl-1,2,3,4,4A(S),5,6,7,8,8A(S)-decahydro-2-[2(R)-hydroxy-3(S)-[[3-(methanesulfonyl)-N-[2-(2-pyridyloxy)acetyl]-L-valil]amino]-4-phenylbutyl]-3(S)-ethanolinduced

Was obtained in a manner analogous to that described in example 2, but from 2-(2-pyridyloxy)acetic acid. (M+N)+714.

Starting material 2-(2-pyridyloxy)acetic acid was obtained according to the procedures described in this area. For example, following the methods of Hill and MC Graw, J. Org.Chem., 1949, 14, 783-787 and Maas and others, Rec. Trav. Chim. Pays-Bas, 1955,74, 175-179.

Example 153

N-tert-Butyl-1,2,3,4,4A(S),5,6,7,8,8A(S)-decahydro-2-[2(R)-hydroxy-3(S)-[[3-(methanesulfonyl)-N-[2-(6-methyl-3-pyridyloxy)acetyl]-L-valil]amino]-4-phenylbutyl]-3(S)-ethanolinduced

Was obtained in a manner analogous to that described in example 2, but from the hydrobromide of 2-(6-methyl-3-pyridyloxy)acetic acid.

The original substance of the hydrobromide of 2-(6-methyl-3-pyridyloxy)acetic acid the floor of the Ali as follows.

Added 1,09 g (0,01 mol) of 3-hydroxy-6-methylpyridine to a stirred suspension of 440 mg of sodium hydride (60% dispersion in mineral oil) in 20 ml of anhydrous dimethylformamide at 0°C in nitrogen atmosphere. After the liberation of gas bubbles weakened, was added dropwise 1,94 g (0,01 mol) tert-butylbromide, and the solution was stirred over night. Volatiles were evaporated, and the residue was distributed between dichloromethane and 10% citric acid solution. The organic phase was washed with saturated sodium bicarbonate solution and saturated saline solution. The combined organic phase was dried over magnesium sulfate and evaporated under reduced pressure, obtaining 1.8 g of resin (M+N)+224, which was treated with 3 ml of 45% Hydrobromic acid in acetic acid at 0°C. was Added 5 ml of acetic acid, and the suspension was stirred over night. Volatiles were evaporated, and the residue triturated with petroleum ether with tKip40-60°receiving the hydrobromide of 2-(6-methyl-3-pyridyloxy)acetic acid as a yellowish brown solid.

Example 154

N-tert-Butyl-1,2,3,4,4A(S),5,6,7,8,8A(S)-decahydro-2-[2(R)-hydroxy-3(S)-[[3-(methanesulfonyl)-N-[2-(3-pyrazinone)acetyl]-L-valil]amino]-4-phenylbutyl]-3(S)-ethanolinduced

Was obtained in a manner analogous to that description is N. in example 2, but based on trifenatate 2-(3-pyrazinone)acetic acid.

The original substance triptorelin 2-(3-pyrazinone)acetic acid was prepared as follows.

Stir a suspension of 88 g (2.2 mmole) of sodium hydride (60% dispersion in mineral oil) in 5 ml of anhydrous dimethylformamide at -5°C in an atmosphere of nitrogen was treated with 264 mg (2 mmole) of tert-butylglycol. After 10 min was added 298 mg (2 mmole) of 3,6-dichloropyridazine (Aldrich D7, 320-0), the solution was allowed to warm to room temperature and was stirred overnight. Volatiles were evaporated under reduced pressure, and the residue was chromatographically on silica gel, elwira a mixture of ethyl acetate/hexane (1:2), and receiving 210 mg of resin, which was dissolved in 20 ml of ethanol and was first made in an atmosphere of hydrogen with 10% palladium on coal (Fluka) during the night. The catalyst was removed by filtration, volatiles were evaporated under reduced pressure, obtaining a resin, which was chromatographically on silica gel, elwira a mixture of ethyl acetate/hexane (1:2), then with ethyl acetate, receiving 50 mg of resin (M+H+MeCN)+252. The resin was dissolved in 2 ml dichloromethane and treated with 1 ml triperoxonane acid. After 10 min, the volatiles were evaporated, and the residue triturated with toluene and again evaporated, obtaining a resin, which was further washed with petroleum ether with tKip40-60°receiving Triforce the t 2-(3-pyrazinone)acetic acid.

Example 155

N-tert-Butyl-1,2,3,4,4a(S),5,6,7,8,8A(S)-decahydro-2-[2(R)-hydroxy-3(S)-[[3-(methanesulfonyl)-N-[2-(2-pyrimidinone)acetyl]-L-valil]amino]-4-phenylbutyl]-3(S)-ethanolinduced

Was obtained in a manner analogous to that described in example 2, but from trifenatate 2-(pyrimidine-2-yloxy)acetic acid. (M+N)+715.

The original substance triptorelin 2-(pyrimidine-2-yloxy)acetic acid was prepared as follows.

Stir a suspension of 88 mg (2.2 mmole) of sodium hydride (60% dispersion in mineral oil) in 5 ml of dimethylformamide at -5°C in an atmosphere of nitrogen was treated with 264 mg (2 mmole) of tert-butylglycol. After 30 min was added 318 mg (2 mmole) of 2-bromopyridine, the solution was allowed to warm to room temperature and was stirred overnight. Volatiles were evaporated, and the residue was distributed between dichloromethane and 10% citric acid solution. The organic phase was washed with saturated sodium bicarbonate solution and saturated salt solution. The combined organic phase was dried over magnesium sulfate and evaporated under reduced pressure, getting 360 mg of resin. The resin was chromatographically on silica gel, elwira a mixture of ethyl acetate/hexane (1:1) and getting 105 mg of resin, which was dissolved in 3 ml dichloromethane and treated with 1.5 ml triperoxonane acid. After 1.5 hours flying the f substance was evaporated, and the residue triturated with toluene and again evaporated, obtaining a resin, which was further washed with petroleum ether with tKip40-60°receiving 60 mg of triptoreline 2-(pyrimidine-2-yloxy)acetic acid as a white solid.

Example 156

N-tert-Butyl-2-[3(S)-[[N-[2-(3-pertenece)acetyl]-3-(methanesulfonyl)-L-valil]amino]-2(R)-hydroxy-4-phenylbutyl]-1,2,3,4,4A(S),5,6,7,8,8a(S)-decahydro-3(S)-ethanolinduced

Was obtained in a manner analogous to that described in example 3, but based on 3-terfenol instead of 3-hydroxypyridine. (M+N)+731,6, tPL197-199°C.

Example 157

N-tert-Butyl-2-[3(S)-[[N-[2-(4-pertenece)acetyl]-3-(methanesulfonyl)-L-valil]amino]-2(R)-hydroxy-4-phenylbutyl]-1,2,3,4,4a(S),5,6,7,8,8a(S)-decahydro-3(S)-ethanolinduced

Was obtained in a manner analogous to that described in example 3, but from 4-terfenol instead of 3-hydroxypyridine. (M+N)+731.

In a manner analogous to that described in examples 2 and 3 were obtained compounds of table 7, on the basis of N-tert-butyl-2-[3(S)-[[N-[(9-fluorenyl)methoxycarbonyl]-3-(methanesulfonyl)-L-valil]amino]-2(R)-hydroxy-4-phenylbutyl]-1,2,3,4,4A(S),5,6,7,8,8A(S)-decahydro-3(S)-ethanolinduced.

Other reagents used in the synthesis of compounds of table 7, were obtained from a commercial source is, such as Aldrich, Lancaster and Maybridge Int., or synthesized using the techniques described in this field or similar to those described.

In a manner analogous to that described in example 100 was also compounds of table 8, on the basis of N-tert-butyl-2-[3(S)-[[N-[(9-fluorenyl)methoxycarbonyl]-3-(methanesulfonyl)-L-valil]amino]-2(R)-hydroxy-4-phenylbutyl]-1,2,3,4,4a(S),5,6,7,8,8A(S)-decahydro-3(S)-ethanolinduced. Other reagents used in the synthesis of compounds of table 8, were obtained from commercial sources such as Aldrich and Lancaster, or synthesized using the techniques described in this field or similar to those described.

Example 172

N-tert-Butyl-2-[3(S)-[[N-[2-(4-forbindelsen)acetyl]-3-(methanesulfonyl)-L-valil]amino]-2(R)-hydroxy-4-phenylbutyl]-1,2,3,4,4A(S),5,6,7,8,8A(S)-decahydro-3(S)-ethanolinduced

Was obtained in a manner analogous to that described in example 121, based on 4-forventelige and N-tert-butyl-2-[3(S)-[[N-glycyl(methanesulfonyl)-L-valil]amino]-2(R)-hydroxy-4-phenylbutyl]-1,2,3,4,4A(S),5,6,7,8,8A(S)-decahydro-3(S)-ethanolinduced. (M+N)+744.

Starting material N-tert-butyl-2-[3(S)-[[N-g is ITIL(methanesulfonyl)-L-valil]amino]-2(R)-hydroxy-4-phenylbutyl]-1,2,3,4,4a(S),5,6,7,8,8A(S)-decahydro-3(S)-ethanolinduced received by way similar to that described in example 94, proceeding from N-(benzyloxycarbonyl)glycine.

Example 173

2-[3(S)-[[N-[2-(Benzylamino)acetyl]-3-(methanesulfonyl)-L-valil]amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert-butyl-1,2,3,4,4A(S),5,6,7,8,8a(S)-decahydro-3(S)-ethanolinduced

Was obtained in a manner analogous to that described in example 172, based on the benzaldehyde instead of 4-forventelige. (M+N)+726.

APPLICATION

The composition of the tablets (wet granulation)
ComponentIngredients mg/tablet
5 mg25 mg100 mg500 mg
1. The compound of the formula I525100500
2. Lactose anhydrous DTG12510530150
3. Sta-Rx 150066630
4. Microcrystalline cellulose303030150
5. Magnesium stearate1111
Only167167 167831

Method of delivery:

1. Components 1, 2, 3 and 4 are mixed and granularit with purified water.

2. Drying the granules at a temperature of 50°C.

3. Grinding granules using a suitable grinding equipment.

4. Add the component 5 and stirred for 5 minutes; pressing using the right equipment.

The capsules composition

ComponentIngredients mg/tablet
5 mg25 mg100 mg500 mg
1. The compound of the formula I525100500
2. Lactose anhydrous159123148-
3. Corn starch25354070
4. Talc10151025
5. Magnesium stearate1225
Only200200300600

The methods of production.

1. Mix components 1, 2 and 3 in a suitable mixer for 30 minutes.

2. Add recipients who have components 4 and 5 and mix for 3 minutes.

3. Fill capsules.

1. Ethanolinduced formula

and their pharmaceutically acceptable salt,

where R1means hydrogen, hydroxy or other2,

R2means alkyl, arylalkyl, geterotsiklicheskikh, which contains one or more heteroatoms selected from nitrogen, oxygen and sulfur, cycloalkyl, alkylaryl, cycloalkylcarbonyl, arylcarbamoyl, heterocalixarenes, which contains one or more heteroatoms selected from nitrogen, oxygen and sulfur, arylalkylamines, geterotsiklicheskikh, which contains one or more heteroatoms selected from nitrogen and oxygen, allyloxycarbonyl, arylalkylamines, geterotsiklicheskikh, which contains one or more heteroatoms selected from nitrogen, heterocyclyl, which contains one or more heteroatoms selected from nitrogen and sulfur, alkylsulfonyl, arylsulfonyl, or a group of the formula

where X means oxygen and

R7and R8mean independently from each other hydrogen, alkyl, aryl, heterocyclyl, which contains one or more heteroatoms selected from nitrogen or oxygen, aralkyl, or

R7and R8form together with the nitrogen atom to which they shall prisoedinneny, a saturated cycle, optionally containing an additional heteroatom selected from nitrogen, oxygen and sulfur, or a group

where n means 0;

Y represents oxygen or sulfur, and

R10means alkyl, aryl, arylalkyl, heterocyclyl, geterotsiklicheskikh where heterocyclyl contains one or two heteroatoms, represents nitrogen, or

where n is 1;

Y represents nitrogen;

R9means hydrogen or alkyl, and

R10means hydrogen, alkyl, aryl, arylalkyl, heterocyclyl, geterotsiklicheskikh where heterocyclyl contains one or two heteroatoms, represents nitrogen, or

R9and R10form together with the heteroatom to which they relate, heterocyclyl, optionally containing an additional heteroatom selected from nitrogen or oxygen;

R11and R12mean independently from each other hydrogen or alkyl, or

R11and R12form together with the carbon atom to which they relate, cycloalkyl;

R3, R4mean independently from each other alkyl;

R5means alkyl, or

R4and R5form together with the carbon atom and sulfur, to which they are bound, a heterocycle, and

R6means alkyl, arylalkyl and

where R14means alkyl, aryl, a group-CH2(CH2CH2O)mCH3in which m denotes an integer of 0-10, or linked carbonyl group of the radical of the amino acids, and

R15means aryl,

provided that if R3, R4and R5means methyl, R6means tert.-butyl, R13means hydrogen, and when R15means phenyl, R2does not mean benzyloxycarbonyl and does not imply 2-hinolincarbonova.

2. Compounds according to claim 1, having the formula

where R2, R3, R4, R5, R6, R13and R15have the above values.

3. Compounds according to claim 1 or 2, where R3, R4and R5means methyl, R6means tert.-butyl and R15means phenyl.

4. Compounds according to claims 1-3, where R2means alkylsulphonyl, cycloalkylcarbonyl, arylcarbamoyl, heterocalixarenes, which contains one or more heteroatoms selected from nitrogen, oxygen and sulfur, geterotsiklicheskikh, which contains one or more heteroatoms selected by their nitrogen and oxygen, or a group of the formula

where n means 0;

Y represents oxygen Il is sulfur and

R10means alkyl, aryl, arylalkyl, heterocyclyl, geterotsiklicheskikh where heterocyclyl contains one or two heteroatoms, represents nitrogen, or

where n is 1;

Y represents nitrogen;

R9means hydrogen and

R10means alkyl, aryl, arylalkyl, heterocyclyl, geterotsiklicheskikh where heterocyclyl contains one or two heteroatoms, represents nitrogen, and where R11and R12means independently hydrogen.

5. Compounds according to claims 1-4, where R3, R4and R5means methyl, R6means tert.-butyl, R15means phenyl and R2means alkylsulphonyl, cycloalkylcarbonyl, arylcarbamoyl, heterocalixarenes, geterotsiklicheskikh or a group of the formula

where n means 0;

Y represents oxygen or sulfur, and

R10means alkyl, aryl, arylalkyl, heterocyclyl, geterotsiklicheskikh where heterocyclyl contains one or two heteroatoms, represents nitrogen, or

where n is 1;

Y represents nitrogen;

R9means hydrogen and

R10means alkyl, aryl, arylalkyl, heterocyclyl geterotsiklicheskikh where heterocyclyl contains one or two heteroatoms, represents nitrogen, and

where R11and R12oz achut independently hydrogen.

6. Compounds according to claims 1-5, where R3, R4, R5means methyl, R6means tert.-butyl, R15means phenyl, and R2means arylcarbamoyl, heterocalixarenes or a group of the formula

where Y represents oxygen, NH, S, and

R10means aryl, heterocyclyl, which contains one or two heteroatoms, represents nitrogen.

7. Compounds according to claims 1-6, where R13means hydrogen.

8. Compounds according to claims 1-7, selected from table A.

10. Compounds according to claim 1 of the formula

where R3, R4, R5, R6, R13and R15have the meanings described above, and R20means heterocyclyl, which contains one or two heteroatoms, represents nitrogen.

11. Connection of claim 10, where R3, R4and R5means methyl, R6means tert.-butyl, R13means hydrogen and R15means phenyl.

12. Compounds according to claims 1 to 11 for use as therapeutically active substances.

13. Compounds according to claims 1 to 11 for use in the treatment of diseases mediated HIV.

14. Drug containing the compound according to claims 1-11, along with a therapeutically inert carrier, for use in the treatment of diseases mediated HIV.



 

Same patents:

FIELD: organic chemistry, herbicides, agriculture.

SUBSTANCE: invention elates to novel derivatives of uracil of the formula [I] possessing herbicide activity, a herbicide composition based on thereof and to a method for control of weeds. In derivatives of uracil of the formula [I] the group Q-R3 represents a substituted group taken among:

wherein a heterocyclic ring can be substituted with at least a substitute of a single species taken among the group involving halogen atom, (C1-C6)-alkyl-(C1-C6)-alkoxy; Y represents oxygen, sulfur atom, imino-group or (C1-C3)-alkylimino-group; R1 represents (C1-C3)-halogenalkyl; R2 represents (C1-C3)-alkyl; R3 represents OR7, SR8 or N(R9)R10; X1 represents halogen atom, cyano-group, thiocarbamoyl or nitro-group; X2 represents hydrogen or halogen atom wherein each among R7, R8 and R10 represents independently carboxy-(C1-C6)-alkyl and other substitutes given in the invention claim; R9 represents hydrogen atom or (C1-C6)-alkyl. Also, invention relates to intermediate compounds used in preparing uracil derivatives.

EFFECT: improved preparing method, valuable properties of compounds.

40 cl, 16 sch, 12 tbl, 65 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to substituted pyridines and pyridazines with angiogenesis inhibition activity of general formula I

(I)1, wherein ring containing A, B, D, E, and L represents phenyl or nitrogen-containing heterocycle; X and Y are various linkage groups; R1 and R2 are identical or different and represent specific substituents or together form linkage ring; ring J represents aryl, pyridyl or cycloalkyl; and G's represent various specific substituents. Also disclosed are pharmaceutical composition containing claimed compounds, as well as method for treating of mammalian with abnormal angiogenesis or treating of increased penetrability using the same.

EFFECT: new pyridine and pyridazine derivatives with angiogenesis inhibition activity.

26 cl, 6 tbl, 114 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a method for preparing derivatives of indole of the general formula (I):

wherein R1 represents hydroxy-group; R2 represents hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C2-C6)-alkoxyalkyl or 4-methoxybenzyl; R3 represents hydrogen atom or (C1-C6)-alkyl; each among R4 and R represents independently hydrogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group; D represents an ordinary bond, (C1-C6)-alkylene, (C2-C6)-alkenylene or (C1-C6)-oxyalkylene; in the group-G-R6 wherein G represents an ordinary bond, (C1-C6)-alkylene; R represents saturated or unsaturated carbocyclic ring (C3-C15) or 4-15-membered heterocyclic ring comprising 1-5 atoms of nitrogen, sulfur and/or oxygen wherein this ring can be substituted. Also, invention describes a method for preparing derivatives of indole and DP-receptor antagonist comprising derivative of the formula (I) as an active component. As far as compounds of the formula (I) bind with DP-receptors and they are antagonists of DP-receptors then they can be useful for prophylaxis and/or treatment of diseases, for example, allergic diseases.

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

11 cl, 7 tbl, 353 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to biologically active compounds, in particular, to substituted 5R1,6R2-thiadiazine-2-amines and pharmaceutical compositions comprising thereof that can be used in medicine as potential pharmacologically active substances eliciting the unique combination of properties: expressed anticoagulant activity in combination with capacity to inhibit aggregation of platelets. Effect of these substances differ from preparations used in medicinal practice and they can be used therefore in treatment of such diseases as myocardium infarction, disturbance in cerebral circulation, rejection of transplanted organs and tissues and so on. Indicated compounds correspond to the formula (I):

wherein values of radicals R1, R2 and R3 are given in the invention claim.

EFFECT: valuable medicinal properties of compounds.

4 cl, 2 tbl, 7 dwg, 33 ex

FIELD: organic chemistry, pesticides, agriculture.

SUBSTANCE: invention relates to compounds that elicit high pesticide activity and can be used in control of pests of domestic and agricultural animals. Indicated compounds show the formula (I):

wherein R1 means halogen atom, (C1-C6)-halogenalkyl; R2 means hydrogen atom (H), (C1-C6)-alkyl, (C1-C6)-alkylene-phenyl; X1 means nitrogen atom (N); X2 means group C(CN); X3 means oxygen atom (O); Q means CH; R3 and R4 mean independently of one another hydrogen atom (H) or in common with carbon atom with which they are bound form (C3-C7)-cycloalkyl ring; R5 means a substitute taken among group including (C1-C6)-halogenalkyl, halogen atom being if m above 1 then substitutes R5 can be similar or different; m = 1, 2 or 3; n = 0 or 1. Also, invention describes a method for their preparing and method for control of pests.

EFFECT: valuable pesticide properties of compounds.

7 cl, 3 tbl, 14 ex

FIELD: organic chemistry, chemical technology, agriculture.

SUBSTANCE: invention describes substituted azadioxocycloalkenes of the general formula (I): wherein A means unsubstituted or methyl-substituted dimethylene; Ar means unsubstituted or fluorine-substituted ortho-phenylene, thiophendiyl or pyridindiyl; E means group of the formula: wherein G means oxygen atom, groups -O-CH2-, -CH2-O- or -C(CH3)=N-O-CH2-; Z means unsubstituted or substituted phenyl, pyrimidinyl or thiadiazolyl, or naphthyl. Invention describes 4 methods for preparing compounds of the formula (I), 5 species of intermediate compounds used for preparing compounds of the formula (I), fungicide agents comprising compound of the formula (I) as an active substance, a method for preparing fungicide agents, method for control of harmful fungi using compound of the formula (I). Compounds of the formula (I) show fungicide properties and therefore they can be used in agriculture.

EFFECT: improved preparing methods, valuable properties of compounds.

13 cl, 5 tbl, 18 ex

FIELD: organic chemistry.

SUBSTANCE: method relates to new method for production of 5-chloro-4-[(2-imidazoline-2-yl)amino]-2,1,3-benzothiadiazole hydrochloride of formula I . Claimed compound is high effective drug and is used in medicine as myorelaxant of central action. Claimed method includes condensation of N,N-dimethyldichloromethyleneammonium chloride with 5-chloro-4-amino-1,1,3-benzothiadiazole in organic solvent followed by treatment of formed alpha-chloroformamidine of formula R-N=C(Cl)N(CH3)2, wherein R is 5-chloro-2,1,3-benzothiazol-4-yl, with ethylenediamine. Formed intermediate of formula R-N=C(NH-CH2-CH2-NH2)N(CH3)2 is treated with hydrochloric acid, heated in organic solvent and 5-chloro-4-[(2-imidazoline-2-yl)amino]-2,1,3-benzothiadiazole hydrochloride of formula I is isolated.

EFFECT: simplified method for preparation of target compound directly in hydrochloride form.

FIELD: pharmaceutical industry, medicine.

SUBSTANCE: invention relates to 5-membered N-heterocyclic compounds and salts thereof having hypoglycemic and hypolipidemic activity of general formula I , wherein R1 is optionally substituted C1-C8-alkyl, optionally substituted C6-C14-aryl or optionally substituted 5-7-membered heterocyclic group, containing in ring 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; or condensed heterocyclic group obtained by condensation of 5-7-membered monoheterocyclic group with 6-membered ring containing 1-2 nitrogen atoms, benzene ring, or 5-membered ring containing one sulfur atom; { is direct bond or -NR6-, wherein R6 is hydrogen atom or C1-C6-alkyl; m = 0-3, integer; Y is oxygen, -SO-, -SO2- or -NHCO-; A ring is benzene ring, condensed C9-C14-aromatic hydrocarbon ring or 5-6-membered aromatic heterocyclic ring containing 1-3 heteroatoms selected from oxygen and nitrogen, each is optionally substituted with 1-3 substituents selected from C7-C10-aralkyloxy; hydroxyl and C1-C4-alkoxy; n = 1-8, integer; B ring is nitrogen-containing 5-membered heterocycle optionally substituted with C1-C4-alkyl; X1 is bond, oxygen or -O-SO2-; R2 is hydrogen atom, C1-C8-alkyl, C7-C13-aralkyl or C6-C14-aryl or 5-6-membered heterocyclic group containing in ring 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with 1-3 substituents; W is bond, C1-C20-alkylene or C1-C20-alkenylene; R3 is -OR8 (R8 is hydrogen or C1-C4-alkyl) or -NR9R10 (R9 and R10 are independently hydrogen or C1-C4-alkyl). Compounds of present invention are useful in treatment of diabetes mellitus, hyperlipidemia, reduced glucose tolerance, and controlling of retinoid-associated receptor.

EFFECT: new medicines for treatment of diabetes mellitus, hyperlipidemia, etc.

26 cl, 518 ex, 3 tbl

FIELD: organic chemistry, pharmaceutical composition.

SUBSTANCE: new isoindoline-1-on-glucokinase activators of general formula I , as well as pharmaceutically acceptable salts or N-oxide thereof are disclosed. In formula A is phenyl optionally substituted with one or two halogen or one (law alkyl)sulfonyl group, or nitro group; R1 is C3-C9cycloalkyl; R2 is optionally monosubstituted five- or six-membered heterocyclic ring bonded via carbon atom in cycle to amino group, wherein five- or six-membered heteroaromatic ring contains one or two heteroatoms selected form sulfur, oxygen or nitrogen, one of which is nitrogen atom adjacent to carbon atom bonded to said amino group; said cycle is monocyclic or condensed with phenyl via two carbon atoms in cycle; said monosubstituted with halogen or law alkyl heteroaromatic ring has monosubstituted carbon atom in cycle which in not adjacent to carbon atom bonded to amino group; * is asymmetric carbon atom. Claimed compounds have glucokinase inhibitor activity and useful in pharmaceutical composition for treatment of type II diabetes.

EFFECT: new isoindoline-1-on-glucokinase activators useful in treatment of type II diabetes.

23 cl, 3 dwg, 43 ex

FIELD: organic chemistry, heterocyclic compounds, medicine, pharmacy.

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

wherein m = 1, 2 or 3; q means NH or oxygen atom (O); R1, R2, R3, R4 and R5 are taken independently among the group including hydrogen atom, (C1-C15)-alkyl, OR20 wherein R20 represents hydrogen atom; R6, R7 and R8 represent hydrogen atom; R9, R10, R11, R12, R13, R14, R15 and R16 are taken independently among the group including hydrogen atom, (C1-C4)-alkyl; or R9 and R10 in common with carbon atom to which they are joined form carbonyl group; R17 means heteroaryl that is taken among the group including indolyl, benzoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, pyridyl, benzopyrazinyl substituted optionally with 1-2 substitutes taken among the group including hydrogen atom, CF3 group, (C1-C8)-alkyl, phenyl, CON(R20)2. Compounds elicit property as a partial inhibitor of oxidation of fatty acids and can be used in therapy for protection of skeletal muscles against results of muscular or systemic diseases. Also, invention describes a pharmaceutical composition based on the claimed compounds.

EFFECT: valuable medicinal properties of compounds.

39 cl, 3 tbl, 25 ex

FIELD: organic chemistry, medicine, pharmacy.

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

wherein Ag represents (1) group of the formula:

; (2) group represented by the formula:

or ; (3) group represented by the formula:

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

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

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

40 cl, 51 tbl, 741 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: present invention relates to new heterocyclic derivatives having calpain inhibition activity or oxygen reactive form recovering entrapping activity of formula I

1, wherein Het represent monocyclic 5-6-membered hetericyclic radical containing 1-2 heteroatoms selected from O or N; A represents A1

2, A'1 3, A2 4, A3 5 and A4 6; X represent -(CH2)n-, -(CH2)n-CO-, -N(R45)-CO-(CH2)n-CO, -CO-N(R45)-D-CO-, -N(R45)-(CH2)n-CO-, -N(R45)-CO-C(R46R47)-CO-, -O-(CH2)n-CO-, -N(R45)-CO-NH-C(R46R47)-CO-, -CO-N(R45)-C(R46R47)-CO- or -Z-CO Y represents -(CH2)p-, C(R53R54)-(CH2)p-, C(R53R54)-CO-; R1 represents hydrogen, group CR3 or oxo; R3 represents hydrogen, monocyclic saturated 6-membered heterocycloalkylcarbonyl, wherein heterocycle contains two heteroatoms selected from nitrogen or oxygen, C1-C6-alkylcarbonyl, phenylcarbonyl or phenyl(C1-C6)-alkylcarbonyl optionally substituted with NR4R5, or R4 and R5 independently represent C1-C6-alkyl; R2 represents hydrogen, and pharmaceutical compositions containing the same.

EFFECT: new heterocyclic drugs.

18 cl, 37 ex

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention relates to new amide derivatives of general formula I

1, as well as to pharmaceutical acceptable salts or cleaving in vivo esters thereof. Claimed compounds are capable to inhibit cytokine production due to inhibition of p38 kinase action and are useful in treatment of various diseases such as inflammation or allergic disorders. Also are disclosed methods for production the same, pharmaceutical composition and method for inhibition of TNFα cytokine production. In formula I X is -NHCO- or -CONH-; m = 0-3; R1 is halogen, C1-C6-alkoxy, N-(C1-C6)-alkyl-di{(C1-C6)-alkyl]-amino-(C2-C6)-alkylamino, or heterocyclyl, heterocyclyl-(C1-C6)-alkyl, heterocyclyloxy, heterocyclyl-(C1-C6)-alkoxy, heterocyclylamino, N-(C1-C6)-alkylheterocyclylamino, heterocyclyl-(C1-C6)-alkylamino, N-(C1-C6)-alkylheterocyclyl-(C1-C6)-alkylamino, heterocyclylcarbonylamino, heterocyclylsulfonylamino, N-heterocyclylsulfamoyl, heterocyclyl-(C2-C6)-alkanoylamino, heterocyclyl-(C1-C6)-alkoxy-(C1-C6)-alkyl, heterocyclyl-(C1-C6)-alkylamino-(C1-C6)-alkyl, or N-(C1-C6)-alkylheterocyclyl-(C1-C6)-alkylamino-(C1-C6)-alkyl, wherein any of heterocylyl in R1 optionally may contain 1 or 2 substituents selected from oxo- or thioxogroup; n = 0-2; R2 is hydrogen or C1-C6-alkyl; R2 is hydrogen, C1-C6-alkyl or C1-C6-alkoxy; q = 0-4; Q is aryl, aryloxy, etc.

EFFECT: new inhibitors of cytokine production.

13 cl, 8 tbl, 20 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a method for preparing derivatives of indole of the general formula (I):

wherein R1 represents hydroxy-group; R2 represents hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C2-C6)-alkoxyalkyl or 4-methoxybenzyl; R3 represents hydrogen atom or (C1-C6)-alkyl; each among R4 and R represents independently hydrogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group; D represents an ordinary bond, (C1-C6)-alkylene, (C2-C6)-alkenylene or (C1-C6)-oxyalkylene; in the group-G-R6 wherein G represents an ordinary bond, (C1-C6)-alkylene; R represents saturated or unsaturated carbocyclic ring (C3-C15) or 4-15-membered heterocyclic ring comprising 1-5 atoms of nitrogen, sulfur and/or oxygen wherein this ring can be substituted. Also, invention describes a method for preparing derivatives of indole and DP-receptor antagonist comprising derivative of the formula (I) as an active component. As far as compounds of the formula (I) bind with DP-receptors and they are antagonists of DP-receptors then they can be useful for prophylaxis and/or treatment of diseases, for example, allergic diseases.

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

11 cl, 7 tbl, 353 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivative of aroylpiperazine of the formula (I):

wherein Y means lower alkylene; R1 means phenyl with 1 or 2 substitutes taken among group consisting of trihalogen-(lower)-alkyl, halogen atom, lower alkylamino-, di-(lower)-alkylamino- and nitro-group; R2 means phenyl or indolyl and each comprises 1 or 2 substitutes taken among group consisting of lower alkyl, trihalogen-(lower)-alkyl, lower alkylene dioxy-, hydroxy-group, hydroxy-(lower)-alkyl, lower alkoxy- lower alkylamino- and di-(lower)-alkylamino-group; R3 means hydrogen atom; R4 means morpholinyl-(lower)-alkyl comprising 1 or 2 substitutes taken among group consisting of ethyl, hydroxy-(lower)-alkyl, halogen-(lower)-alkyl and lower alkoxy-(lower)-alkyl, or morpholinyl-(lower)-alkynyl that can comprise 1 or 2 substitutes taken among group consisting of ethyl, propyl, isopropyl, isobutyl, spirocyclo-(lower)-alkyl, lower alkoxy-(lower)-alkyl, hydroxy-(lower)-alkyl, carboxy-(lower)-alkyl, di-(lower)-alkyl-carbamoyl, lower alkoxycarbonyl and halogen-(lower)-alkyl. Also, invention relates to a method for preparing, pharmaceutical composition based on these compounds and a method for treatment of tachykinine-mediated diseases, such as respiratory diseases, ophthalmic, cutaneous, inflammatory diseases, and as analgetic agents. Describes compounds are antagonists of tachykinine.

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

8 cl, 94 ex

FIELD: organic chemistry, chemical technology, agriculture.

SUBSTANCE: invention describes substituted azadioxocycloalkenes of the general formula (I): wherein A means unsubstituted or methyl-substituted dimethylene; Ar means unsubstituted or fluorine-substituted ortho-phenylene, thiophendiyl or pyridindiyl; E means group of the formula: wherein G means oxygen atom, groups -O-CH2-, -CH2-O- or -C(CH3)=N-O-CH2-; Z means unsubstituted or substituted phenyl, pyrimidinyl or thiadiazolyl, or naphthyl. Invention describes 4 methods for preparing compounds of the formula (I), 5 species of intermediate compounds used for preparing compounds of the formula (I), fungicide agents comprising compound of the formula (I) as an active substance, a method for preparing fungicide agents, method for control of harmful fungi using compound of the formula (I). Compounds of the formula (I) show fungicide properties and therefore they can be used in agriculture.

EFFECT: improved preparing methods, valuable properties of compounds.

13 cl, 5 tbl, 18 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of tetrahydroisoquinoline of the formula [I] wherein R1 represents hydrogen atom or lower alkyl; R2 represents alkyl having optionally a substitute taken among alkoxycarbonyl and carboxy-group, cycloalkyl, cycloalkylalkyl, aryl having optionally a substitute taken among lower alkyl, arylalkyl having optionally a substitute taken among lower alkyl, lower alkoxy-group, halogen atom and acyl, alkenyl, alkynyl, or monocyclic heterocyclylalkyl wherein indicated heterocycle comprises 5- or 6-membered ring comprising nitrogen atom and having optionally a substitute taken among lower alkyl; R3 represents hydrogen atom or lower alkoxy-group; A represents a direct bond or >N-R5 wherein R5 represents lower alkyl; B represents lower alkylene; Y represents aryl or monocyclic or condensed heterocyclyl comprising at least one heteroatom taken among oxygen atom and nitrogen atom and having optionally a substitute taken among lower alkyl, carboxy-group, aryl, alkenyl, cycloalkyl and thienyl, or to its pharmaceutically acceptable salt. Also, invention relates to pharmaceutical composition eliciting hypoglycaemic and hypolipidemic effect based on these derivatives. Invention provides preparing new compounds and pharmaceutical agents based on thereof, namely, hypoglycaemic agent, hypolipidemic agent, an agent enhancing resistance to insulin, therapeutic agent used for treatment of diabetes mellitus, therapeutic agent against diabetic complication, agent enhancing the tolerance to glucose, agent against atherosclerosis, agent against obesity, an anti-inflammatory agent, agent for prophylaxis and treatment of PPAR-mediated diseases and agent used for prophylaxis and treatment of X-syndrome.

EFFECT: valuable medicinal properties of compounds and composition.

13 cl, 7 tbl, 75 ex

FIELD: organic chemistry, heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to new heterocyclic compounds corresponding to general formulas: (I) , (II) , (Ia) and (Ib) wherein substitutes have values given in the description. Such compounds are reversible inhibitors of cathepsins S, K, F, L and B. Also, invention relates to a method for preparing these compounds, pharmaceutical composition eliciting inhibitory activity with respect to cysteine proteases and to a method for modulation of autoimmune diseases, treatment of Alzheimer's disease and osteoporosis.

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

42 cl, 106 ex

FIELD: pharmaceutical industry, medicine.

SUBSTANCE: invention relates to 5-membered N-heterocyclic compounds and salts thereof having hypoglycemic and hypolipidemic activity of general formula I , wherein R1 is optionally substituted C1-C8-alkyl, optionally substituted C6-C14-aryl or optionally substituted 5-7-membered heterocyclic group, containing in ring 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; or condensed heterocyclic group obtained by condensation of 5-7-membered monoheterocyclic group with 6-membered ring containing 1-2 nitrogen atoms, benzene ring, or 5-membered ring containing one sulfur atom; { is direct bond or -NR6-, wherein R6 is hydrogen atom or C1-C6-alkyl; m = 0-3, integer; Y is oxygen, -SO-, -SO2- or -NHCO-; A ring is benzene ring, condensed C9-C14-aromatic hydrocarbon ring or 5-6-membered aromatic heterocyclic ring containing 1-3 heteroatoms selected from oxygen and nitrogen, each is optionally substituted with 1-3 substituents selected from C7-C10-aralkyloxy; hydroxyl and C1-C4-alkoxy; n = 1-8, integer; B ring is nitrogen-containing 5-membered heterocycle optionally substituted with C1-C4-alkyl; X1 is bond, oxygen or -O-SO2-; R2 is hydrogen atom, C1-C8-alkyl, C7-C13-aralkyl or C6-C14-aryl or 5-6-membered heterocyclic group containing in ring 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with 1-3 substituents; W is bond, C1-C20-alkylene or C1-C20-alkenylene; R3 is -OR8 (R8 is hydrogen or C1-C4-alkyl) or -NR9R10 (R9 and R10 are independently hydrogen or C1-C4-alkyl). Compounds of present invention are useful in treatment of diabetes mellitus, hyperlipidemia, reduced glucose tolerance, and controlling of retinoid-associated receptor.

EFFECT: new medicines for treatment of diabetes mellitus, hyperlipidemia, etc.

26 cl, 518 ex, 3 tbl

FIELD: organic chemistry, pharmacology.

SUBSTANCE: invention relates to new flavone, xanthone and coumarone derivatives of formula I

[R and R1 each are independently lower C1-C6-alkyl or together with nitrogen atom attached thereto form 4-8-membered heterocycle, optionally containing one or more heteroatoms, selected from group comprising N or O, wherein said heterocycle is optionally substituted with benzyl; Z has formula (A) , wherein R3 and R4 each are independently hydrogen, optionally substituted aromatic group containing in cyclic structure from 5 to 10 carbon atoms, wherein substituents are the same or different and represent lower C1-C4-alkyl, OR10 (OR10 is hydrogen, saturated or unsaturated lower C1-C6-alkyl or formula ) or linear or branched C1-C6-hydrocarbon; or R2 and R3 together with carbon atom attached thereto form 5-6-membered carbocycle; and R4 represents hydrogen or attaching site of group –OCH2-C≡CCH2NRR1; or formula (B) , wherein R5 is hydrogen, linear or branched lower C1-C6-hydrocarbon, with the proviso, that when Z represents R and R1 both are not methyl or R and R1 together with nitrogen atom attached thereto cannot form groups , or ]. Also disclosed are drug component with proliferative activity for prophylaxis or treatment of neoplasm and pharmaceutical composition with proliferative activity based on the same. Derivatives of present invention have antyproliferative properties and are useful as modulators of drug resistance in cancer chemotherapy; as well as in pharmaceuticals for prophylaxis or treatment of neoplasm, climacteric disorders or osteoporosis.

EFFECT: new compounds with value bioactive effect.

31 cl, 2 tbl, 32 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

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

wherein R2 means acyloxy-group; R7 means hydroxy-group; R9 means keto-group; R10 means carbonate; R14 means hydrogen atom; X3 means (C2-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl, phenyl substituted optionally with nitro-group or 5-6-membered heteroaromatic group comprising heteroatoms taken among oxygen (O), nitrogen (N) or sulfur (S) atoms; X5 means -C(O)X10, -C(O)OX10 or -CONHX10 wherein X10 means (C2-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl, phenyl, furyl, pyridyl or thienyl; Ac means acetyl. Also, invention describes a pharmaceutical composition based on taxanes and a method for inhibition of a tumor growth.

EFFECT: improved inhibiting method, valuable medicinal properties of compounds.

98 cl, 6 ex

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