Synthesis of protease inhibitor precursor

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I) or stereoisomer thereof, or salt thereof, as well as synthesis method thereof and intermediate compounds of formulae (II) and (III) used in this method.

EFFECT: novel compound which can be used to produce HIV protease inhibitors.

23 cl, 2 tbl, 1 ex

The technical FIELD TO WHICH the INVENTION RELATES

The present invention relates to compounds and methods for their preparation, which are used for receiving protease inhibitors, in particular inhibitors of HIV protease wide range.

The LEVEL of TECHNOLOGY

HIV infection remains an important medical problem. Currently available drugs for the treatment of HIV include nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, as well as peptidomimetics - protease inhibitors. Each of these drugs can only temporarily suppress viral replication, if used by itself. The lack of medicines, lack of coordination, limited penetration into the tissue and the limited specificity of drugs within certain types of cells may explain the incomplete suppression of sensitive viruses.

In addition, HIV is highly heterogeneous virus. The clinical significance indicated heterogeneity is evident from the ability of the virus to avoid immune effects, transfer the selective action of drugs and to adapt to different cell types and growth conditions. Therefore, diversity is the main clause is hepatities for pharmacological or immunological control of infection with human immunodeficiency virus.

One of the crucial stages in the life cycle of a retrovirus is the processing of protein precursors using aspartic protease. For example, in the case of HIV protein gag-pol is subjected to processing by the HIV protease. Correct processing of protein precursors using aspartic protease required for Assembly of infectious virion, thus making aspartic protease attractive target for antiviral therapy. In particular, for the treatment of HIV HIV protease is an attractive target.

HIV protease inhibitors (PIS) are usually entered in AIDS patients in combination with other compounds against HIV, such as, for example, nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), nucleotide reverse transcriptase inhibitors (Ntot), or other protease inhibitors. Despite the fact that these funds against retroviruses are very useful, they have a common limitation, namely, enzymes target of the HIV virus is able to mutate in such a way that known drugs become less effective or even ineffective against these modified viruses HIV. Or, in other words, the HIV virus becomes even greater resistance against the public is karstenii funds.

In search of compounds that are able to meet the needs of medicine in the treatment of HIV, were obtained sulfa derivative of General formula (a) and it was found that they possess a wide virological range with insignificant variation in the degree of resistance, i.e. the difference in the activity of viral inhibition in the case of HIV wild-type and mutant strains of HIV (WO 2004003817, WO 2003106461, WO 2003097616, WO 2003090691, WO 2003090690, WO 2003078438, WO 2003076413, WO 2003070976, WO 2003064406, WO 2003057173, WO 2003053435, WO 2003049746, EP 1265073, WO 2002092595, WO 2002083657, WO 2002081478, WO 2001025240, WO 9967417, WO 9967254, Ohtaka et al. Protein Science (2002), 11(8), 1908-1916, Gatanaga et al. Journal of Biological Chemistry (2002), 277(8), 952-5961, Ghosh et al. Antiviral Research (2002), 54(1), 29-36, Yoshimura et al. Journal of Virology (2002), 76(3), 1349-1358, Ghosh et al. Farmaco (2001), 56(1-2), 29-32; Ghosh et al. Bioorganic & Medicinal Chemistry Letters (1998), 8(6), 687-690).

Despite the results obtained in the prior art, there is a continuous need for improvement of HIV protease inhibitors. Such improved HIV protease inhibitors can be created if the advances in medical chemistry make it possible to obtain chemical options. Compounds of General formula (A) receive in the prior art by the reaction of a combination of using hexahydrofuro[2,3-b]furan-3-ol as an intermediate. Further research pharmacophore hexahydrofuro[2,3-b]furan as the connection-basis for new and improved inhib the tori HIV protease has so far been limited, because there is not enough knowledge of how to obtain replacement options hexahydrofuro[2,3-b]furan-3-ol.

The INVENTION

In accordance with the first aspect of the present invention relates to the compound of structure (I)including stereoisomers and salts.

In accordance with the second aspect of the present invention relates to the compound of formula (II), including stereoisomers and salts,

where

X and Y independently are selected from Si and s, and

R¹, R², R³and R⁴independently selected from the group consisting of-H and monovalent hydrocarbon radicals.

In accordance with a third aspect of the present invention relates to the compound of formula (III), including stereoisomers and salts,

where

X and Y independently are selected from Si and s, and

R¹, R², R³and R⁴independently selected from the group consisting of-H and monovalent hydrocarbon radicals.

In accordance with the fourth aspect of the present invention relates to the compound of formula (IV), including stereoisomers and salts,

where

X and Y independently are selected from Si and s, and

R¹, R², R³and R⁴independently selected from the group consisting of-H and monovalent hydrocarbon radicals.

ACC is accordance with the fifth aspect of the present invention relates to a method for obtaining compounds of structure (I), including the introduction of the compounds of formula (II) in terms of removing the protection from the alcohol, and thus obtained intermediate compound with the corresponding protective group undergoes intramolecular cyclization.

In accordance with the sixth aspect of the present invention relates to a method for obtaining compounds of formula (II), including the oxidation of compounds of formula (III).

In accordance with the seventh aspect, the present invention relates to a method for obtaining compounds of formula (III), including hydroporinae the compounds of formula (IV) and subsequent oxidation of the thus obtained hydroborating intermediate connection.

In accordance with the eighth aspect of the present invention relates to a method for obtaining compounds of formula (IV), including the interaction of the compounds of formula (V) or its stereoisomer or salt,

where

X and Y independently are selected from Si and s, and

R¹, R², R³and R⁴independently selected from the group consisting of-H and monovalent hydrocarbon radicals; with the reagent of the Wittig type.

In the above-mentioned compounds of the formula (II), (III), (IV) and (V) R¹and R²may also be taken together to form divalent hydrocarbon radical, denoted-R¹-R²-. Similarly, R³and R⁴can the e can be taken together to form divalent hydrocarbon radical, denoted-R³-R⁴-.

DISCLOSURE of the INVENTION

The term "stereoisomer" refers to a representative group of compounds that have the same molecular formula (the same number and type of atoms) and the same connectivity, but differ in the arrangement of atoms in space. Stereoisomers include enantiomers and diastereomers.

Used herein, the term "monovalent hydrocarbon radical" refers to any monovalent cyclic, heterocyclic, a linear, branched, saturated or unsaturated radical having the main carbon chain containing one or more hydrogen atoms, optionally with one or more heteroatoms in the main carbon chain. The term "monovalent hydrocarbon radical" is intended to encompass the terms "alkyl", "alkenyl", "quinil", "cycloalkyl", "cycloalkenyl", "cycloalkenyl", "alkoxyalkyl", "alkoxyaryl", "(cycloalkyl)alkyl", "(cycloalkenyl)alkyl", "(cycloalkenyl)alkyl", "geterotsiklicheskikh", "alkylglycerol", "heterocyclyl", "alkylaryl", "arylalkyl" and "aryl"as defined below.

Used herein, the term "alkyl" as a group or part of a group refers to a linear or branched saturated monovalent hydrocarbon radical having the specified number of carbon atoms of neobythites is but substituted with halogen. For example, With_1-3alkyl as a group or part of a group means a saturated hydrocarbon radical with a linear or branched chain having 1-3 carbon atoms, such as methyl, deformity, ethyl, 1-chloroethyl, propyl, 1-methylethyl etc.; C_1-4alkyl as a group or part of a group means a saturated hydrocarbon radical with a linear or branched chain having 1-4 carbon atoms such as the group described for C_1-3of alkyl, butyl, 2-bromobutyl etc.; C_2-4alkyl as a group or part of a group means a saturated hydrocarbon radical with a linear or branched chain having 2-4 carbon atoms, such as ethyl, propyl, 2-chloropropyl, 1-methylethyl, butyl and the like; (C_1-6alkyl as a group or part of a group means a saturated hydrocarbon radical with a linear or branched chain having 1-6 carbon atoms such as the groups described for C_1-4of alkyl, and pentyl, hexyl, 2-methylbutyl, 2-chloro-1-methylbutyl etc.; C_1-9alkyl as a group or part of a group means a saturated hydrocarbon radical with a linear or branched chain, having 1-9 carbon atoms such as the groups described for C_1-6of alkyl, and heptyl, 3-forgetter, octyl, nonyl, 2-etylhexyl, 2-methylheptan, decyl and the like; (C_1-10alkyl as a group or part of a group means a saturated hydrocarbon radical with a linear or osvetleni chain having 1-10 carbon atoms such as the groups described for C_1-9of alkyl, and decyl, 2-methylnon, 4-brondell etc.; C_1-20alkyl as a group or part of a group means a hydrocarbon radical with a linear or branched chain having 1-20 carbon atoms such as the groups described for C_1-10of alkyl, and undecyl, dodecyl, 2-ethyl-3-hardtail etc.

Used herein, the term "alkenyl" as a group or part of a group refers to a linear or branched unsaturated monovalent hydrocarbon radical having the specified number of carbon atoms and a characteristic feature of the double carbon-carbon linkages. For example, the term "C_2-3alkenyl" as a group or part of a group means a hydrocarbon radicals with 2 to 3 carbon atoms, containing at least one double bond, for example ethynyl, propenyl and the like; the term "C_2-5alkenyl" as a group or part of a group means a hydrocarbon radicals of from 2-5 carbon atoms, containing at least one double bond such as the groups described for C_2-3alkenyl, butenyl, pentenyl and the like; the term "C_2-6alkenyl" as a group or part of a group means a hydrocarbon radical with a linear or branched chain having 2-5 carbon atoms, containing at least one double bond such as the groups described for C_2-5alkenyl, hexene, the La and the like; "C_2-20alkenyl" represents a hydrocarbon radical with a linear or branched chain having 2 to 20 carbon atoms and at least one double carbon-carbon bond.

Used herein, the term "quinil" as a group or part of a group refers to a linear or branched unsaturated or partially unsaturated monovalent hydrocarbon radical having the specified number of carbon atoms and a characteristic feature of the triple carbon-carbon linkages. For example, the term "C_2-3quinil" as a group or part of a group means a hydrocarbon radicals with 2 to 3 carbon atoms, containing at least one triple bond, such as, for example, ethinyl, PROPYNYL and the like; the term "C_2-5quinil" as a group or part of a group means a hydrocarbon radical with a linear or branched chain having 2-5 carbon atoms, containing at least one triple bond such as the groups described for C_2-3the quinil, butenyl, pentenyl and the like; the term "C_2-6quinil" as a group or part of a group means a hydrocarbon radical with a linear or branched chain having 2 to 6 carbon atoms containing at least one triple bond such as the groups described for C_2-5the quinil, hexenyl etc.; "C_2-20quinil" represents a hydrocarbon radical with a linear eliasville chain having 2-20 carbon atoms and at least one triple carbon-carbon bond.

Used herein, the term "cycloalkyl" as a group or part of a group refers to a cyclic saturated monovalent hydrocarbon radical having the specified number of carbon atoms. For example, the term "C_3-6cycloalkyl" as a group or part of a group is typical for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; the term "C_3-7cycloalkyl" as a group or part of a group is typical for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl; "C_3-30cycloalkyl" represents a cyclic saturated monovalent hydrocarbon radical with 3 to 30 carbon atoms.

Used herein, the terms "cycloalkenyl and cycloalkenyl" as a group or part of a group refers to a cyclic, unsaturated or partially unsaturated monovalent hydrocarbon radicals. Cycloalkenyl characterized by at least one carbon-carbon double bond, and cycloalkenyl characterized by at least one carbon-carbon triple bond. For example, "C_3-30cycloalkenyl" represents a cyclic unsaturated monovalent hydrocarbon radical with 3 to 30 carbon atoms and at least one carbon-carbon double bond. In addition, for example, "C_8-30 cycloalkenyl" represents a cyclic unsaturated or partially unsaturated monovalent hydrocarbon radical with 8 to 30 carbon atoms and at least one carbon-carbon triple bond.

Used herein, the term "aryl" as a group or part of a group refers to a cyclic aromatic monovalent hydrocarbon radical, such as phenyl and naphthyl, optionally substituted by one or more substituents, such as, for example, an alkyl group, CNS group or albandeira group. A typical example of aryl, substituted alkadienes group, the latter is defined as a divalent alkyl group, represents indan. Where the aryl group contains more than one ring, the rings may be condensed, bicyclic or substituted phenyl, for example, biphenyl is also intended for inclusion in the definition of aryl. Based on the above definition should clarify that the aromatic group as a whole need not be aromatic, but it contains at least one aromatic group, such as, for example, indan. Also, for example, "C_6-30aryl" represents a cyclic aromatic hydrocarbon radical with 6-30 carbon atoms.

Used herein, the term "heterocyclyl" as a group or part of a group refers to C is likesome saturated, partially saturated or aromatic monovalent hydrocarbon radical having at least one heteroatom in the main chain of such cyclic hydrocarbon, optionally substituted by one or more substituents, such as, for example, an alkyl group or alkyloxy. Examples of heterocycles include, but are not limited to, dihydroisoxazole, furanyl, pyridyl, phthalimido, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolin, oxazolyl, pyrrolidinyl, pyrrolyl, imidazolidinyl, imidazolyl, pyrazolidine, tetrahydrofuranyl, pyranyl, pyranyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinil, morpholinyl, Tinetti, benzofuranyl, isobenzofuranyl, indolyl, oxyindole, isoindolyl, indazoles, indolinyl, 7-isoindolyl, isoindolyl, benzopyranyl, coumarinyl, isocoumarins, hinely, ethanolic, naphthyridine, cinnoline, hintline, iridoviridae, benzoxazines pinoxaden, bromanil, bromanil, isopropanol, carbonyl, etc. as Well as example, "C_5-30heterocyclyl" represents a cyclic aromatic or not aromatic hydrocarbon radical having at least one heteroatom in the main chain of the specified cyclic hydrocarbon and has 5 to 30 carbon atoms in the cyclic hydrocarbon.

As stated in the definitions, terms, op the sled above, can be used as part of a larger group.

For example, when used herein, the term "(cycloalkyl)alkyl" refers to alkyl group with cycloalkyl Deputy. Connection is through the alkyl group. Such groups have the specified number of carbon atoms. For example, "C_4-30(cycloalkyl)alkyl" refers to alkyl group with cycloalkyl Deputy, where the total number of carbon atoms in (cycloalkyl)alkyl group varies between 4 and 30. Another example includes a_5-11cycloalkyl_1-6alkyl and a is a C_1-6alkyl group With_5-11cycloalkenyl Deputy.

Used herein, the term "(cycloalkenyl)alkyl" refers to alkyl group with cycloalkenyl Deputy. Connection is through the alkyl group. Such groups have the specified number of carbon atoms. For example, "C_4-30(cycloalkenyl)alkyl" refers to alkyl group with cycloalkenyl Deputy, where the total number of carbon atoms in (cycloalkenyl)alkyl group varies between 4 and 30. Another example includes a_5-11cycloalkenyl_1-6alkyl and a is a C_1-6alkyl group With_5-11cycloalkenyl Deputy.

Used herein, the term "(cycloalkyl)alkyl" refers to alkyl group with cycloalkenyl Deputy. Connection is produced which goes through the alkyl group. Such groups have the specified number of carbon atoms. For example, "C_9-30(cycloalkenyl)alkyl" refers to alkyl group with cycloalkenyl Deputy, where the total number of carbon atoms in (cycloalkenyl)alkyl group varies between 9 and 30. Another example includes a_8-11cycloalkenyl_1-6alkyl and a is a C_1-6alkyl group With_8-11cycloalkenyl Deputy.

Used herein, the term "alkoxyalkyl" refers to an alkyl group having alkoxy (also called alkyloxy) Deputy. Connection is through the alkyl group. An alkyl group and/or alkoxy-group have the specified number of carbon atoms. For example, "C_2-20alkoxyalkyl" refers to an alkyl group, alkoxy Deputy, where the total number of carbon atoms in alkyloxyalkyl group varies between 2 and 20. Another example includes a_1-6alkoxyl_1-6alkyl and a is a C_1-6alkyl group With_1-6alkoxy Deputy.

Used herein, the term "alkoxyaryl" refers to an aryl group having alkoxy Deputy. The attachment comes through aryl group. Aryl group and/or alkoxy-group have the specified number of carbon atoms. For example, "C_7-20alkoxyaryl" refers to aryl group, alkoxy Deputy, where the total number at the MOU carbon alkyloxyaryl group varies between 7 and 20. Another example includes a_1-6alkoxyl_5-10aryl and belongs to the_5-10aryl group_1-6alkoxy Deputy.

Used herein, the term "alkylaryl" refers to an alkyl group, aryl Deputy. The attachment comes through aryl group. Such groups have the specified number of carbon atoms. For example, "C_7-30alkylaryl" refers to an aryl group with an alkyl Deputy, where the total number of carbon atoms in alcylaryl group varies between 7 and 30. Another example includes a_1-6alkyls_5-11aryl and belongs to the_5-11aryl group_1-6alkyl Deputy.

Used herein, the term "arylalkyl" refers to an aryl group with an alkyl substituent. Connection is through the alkyl group. Such groups have the specified number of carbon atoms. For example, "C_7-30arylalkyl" refers to an alkyl group, aryl Deputy, where the total number of carbon atoms in arylalkyl group varies between 7 and 30. Another example includes a_5-11arils_1-6alkyl and a is a C_1-6alkyl group With_5-11aryl Deputy.

Used herein, the term "alkylglycerol" refers to an alkyl group with Deputy heterocycle. The attachment comes through a group of the heterocycle. Did the group have a specified number of carbon atoms. For example, "C_2-30alkylglycerol" refers to a heterocycle group with alkyl Deputy, where the total number of carbon atoms in the group alkylglycerols varies between 2 and 30. Another example includes a_1-6alkyls_1-11the heterocycle and belongs to the group With_1-11a heterocycle with C_1-6alkyl Deputy.

Used herein, the term "geterotsiklicheskikh" refers to a heterocycle group with an alkyl substituent. Connection is through the alkyl group. Such groups have the specified number of carbon atoms. For example, "C_2-30geterotsiklicheskikh" refers to an alkyl group with Deputy heterocycle, where the total number of carbon atoms in heterocyclisation group varies between 2 and 30. Another example includes a_1-11heterocyclic_1-6alkyl and a is a C_1-6alkyl group with Deputy_1-11the heterocycle.

Used herein, the term "divalent hydrocarbon radical" refers to a divalent cyclic, heterocyclic, a linear chain, branched chain, saturated or unsaturated radicals, which contain the main carbon chain having one or more hydrogen atoms, optionally with one or more heteroatoms in the main carbon chain. The term "divalent hydrocarbon radical" is intended coverage of what it terms "alcander", "alcander", "alcindor", "cycloalkenyl", "cycloalkenyl" and "cycloalkenyl".

The term "alcander" is defined identically specified for "alkyl", but is a divalent instead monovalent. The term "alcander" is defined identically specified for alkenyl", but is a divalent instead monovalent. The term "alcindor" is defined identically specified for "quinil", but is a divalent instead monovalent. The term "cycloalkenyl" is defined identically specified for "cycloalkyl", but is a divalent instead monovalent. The term "cycloalkenyl" is defined identically specified for alkenyl", but is a divalent instead monovalent. The term "cycloalkenyl" is defined identically specified for "quinil", but is a divalent instead monovalent.

Used herein, the term "substituted" provides for the inclusion of all acceptable substituents of organic compounds. In a broad aspect, acceptable substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Acceptable substituents can be one or more and same or different for the respective organic compounds the deposits. For the purposes of the present invention, the heteroatoms such as nitrogen may have substituents hydrogens and/or any acceptable substituents of organic compounds described herein which satisfy the valences of the heteroatoms. It is not intended that the present invention be limited in any way by means of suitable substituents of organic compounds.

Used herein, the term "heteroatom" includes N, O, and S.

Compounds and their intermediates in accordance with the present invention may exist in their basic form or in salt form. All salts, whether or not pharmaceutically acceptable, included in the scope of the present invention.

Salt forms which the compounds and their intermediates in accordance with the present invention are capable of forming, can appropriately be obtained using the appropriate acids, such as, for example, inorganic acid, such as halogen acids, for example chloromethane or Hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids, such as, for example, acetic, propanoic, hydroxyestra, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methansulfonate, econsultancy, benzolsulfonat, p-tol is alsultany, reklamowa, salicylic, p-aminosalicylic, AMOVA and the like acids; or organic or inorganic bases, in order to obtain salts with bases, such as, for example, ammonium salts, Quaternary ammonium salts, salts with alkali and alkaline earth metals, for example, salts with lithium, sodium, potassium, magnesium, calcium and the like, salts with organic bases, for example, salt, benzathine, N-methyl-D-glucamine, geranamine, and salts with amino acids such as, for example, arginine, lysine, etc.

These forms of salts of the adducts with acid, can be converted in the processing of a suitable base in the form of a free base. Conversely, the salt form adducts with the base, can be converted in the processing of the appropriate acid in the form of the free acid.

X and Y are preferably the same. X and Y preferably represent C.

R¹, R², R³and R⁴preferably independently selected from the group consisting of-H, C_1-20of alkyl, C_2-20alkenyl,_2-20alkoxyalkyl,_7-20alkoxyaryl,_2-20the quinil,_3-30cycloalkyl,_4-30(cycloalkyl)alkyl, C_4-30(cycloalkenyl)alkyl, C_9-30(cycloalkenyl)alkyl, C_3-30cycloalkenyl,_4-30cycloalkenyl,_7-30arylalkyl,_7-30alkylaryl,_6-30aryl, sub> 6-30geterotsiklicheskikh,_6-30Alkylglucoside and C_5-30heterocyclyl.

R¹, R², R³and R⁴preferably independently selected from the group consisting of-H, C_1-16of alkyl, C_2-16alkenyl,_2-16alkoxyalkyl,_7-16alkoxyaryl,_2-16the quinil,_3-20cycloalkyl,_4-20(cycloalkyl)alkyl, C_4-20(cycloalkenyl)alkyl, C_9-20(cycloalkenyl)alkyl, C_3-20cycloalkenyl,_4-20cycloalkenyl,_7-20arylalkyl,_7-20alkylaryl,_6-20aryl, C_6-20geterotsiklicheskikh,_6-20Alkylglucoside and C_5-20heterocyclyl.

R¹, R², R³and R⁴preferably independently selected from the group consisting of-H, primary or secondary_1-6of alkyl, C_2-6alkenyl,_1-6alkoxyl_1-6of alkyl, C_1-6alkoxyl_5-10aryl, C_5-7cycloalkyl,_5-11cycloalkyl_1-6of alkyl, C_4-11cycloalkenyl_1-6of alkyl, C_8-12cycloalkenyl_1-6of alkyl, C_5-7cycloalkenyl,_5-7cycloalkenyl,_6-11arils_1-6of alkyl, C_1-6alkyls_6-11aryl, C_6-11aryl, C_5-12heterocyclic_1-6of alkyl, C_1-6alkyls_5-12heterocyclyl and C_5-12heterocyclyl.

Preferably, R¹, R², R³and R⁴anlaufstelle from N.

Preferably, R¹, R², R³and R⁴independently selected from the group consisting of-H, methyl, ethyl, propyl, butyl, hexyl, cyclohexyl, Attila, Manila, dodecyl, eicosyl, norbornyl, adamantyl, vinyl, propenyl, cyclohexenyl, phenylethyl, phenylpropyl, methoxyphenyl, ethoxyphenyl, phenyl, talila, dimetilfenil, trimetilfenil, ethylphenyl, propylphenyl, biphenyl, naphthyl, matildaville, Anttila, feniletil, benzylphenol, pyrenyl, tetrahydropyranyl, acenaphthyl, phenalenyl, aceanthrylene, tetrahydronaphthyl, indlela, methoxypropyl, ethoxyethyl, methoxyethyl, amyl, trityl, methoxytrityl, dimethoxytrityl, trimethoxytrityl, allyl, trimethylsilyl, (tert-butyl)dimethylsilane and benzyl, including their isomers.

Preferably, R¹, R², R³and R⁴independently selected from the group consisting of methyl, ethyl, n-propyl, sec-propyl, n-butyl, sec-butyl, tert-butyl, benzyl, phenyl and methoxyphenyl.

Preferably, R¹and R²are the same. Preferably, R³and R⁴are the same.

Preferably, R¹, R², R³and R⁴are the same and are selected from the group consisting of methyl, ethyl, n-propyl, sec-propyl and tert-butyl.

Preferably, R¹, R², R³and R⁴sepratist an ethyl.

Preferably, R¹and R²taken together, form a-R¹-R²and R³and R⁴taken together, form a-R³-R⁴-.

Preferably, R¹and R²taken together, form a-R¹-R²and R³and R⁴taken together, form a-R³-R⁴-, and-R¹-R²and R³-R⁴each independently represents a C_1-20alcander,_2-20alcander,_4-20alcinder,_3-20cycloalkenyl,_4-20cycloalkenyl and C_8-20cycloalkenyl.

Preferably, R¹and R²taken together, form a-R¹-R²and R³and R⁴taken together, form a-R³-R⁴-, and-R¹-R²and R³-R⁴- are the same and are selected from the group consisting of C_1-20Alcantara,_2-20Alcantara,_4-20alcindoro,_3-20cycloalkenyl,_4-20cycloalkenyl and C_8-20cycloalkenyl.

Preferably, X and Y are the same, and R¹, R², R³and R⁴are the same.

Preferably, X and Y are C, and R¹, R², R³and R⁴are the same.

Preferably, X and Y are C, and R¹, R², R³and R⁴are the same and are selected from the group consisting of C_1-20of alkyl, C_2-20alkenyl, With_2-20alkoxyalkyl,_7-20alkoxyaryl,_2-20the quinil,_3-30cycloalkyl,_4-30(cycloalkyl)alkyl, C_3-30cycloalkenyl,_4-30cycloalkenyl,_7-30arylalkyl,_7-30alkylaryl,_6-30aryl, C_6-30geterotsiklicheskikh,_6-30Alkylglucoside and C_5-30heterocyclyl.

Preferably, X and Y are C, and R¹, R², R³and R⁴are the same and are selected from the group consisting of C_1-16of alkyl, C_2-16alkenyl,_2-16alkoxyalkyl,_7-16alkoxyaryl,_2-16the quinil,_3-20cycloalkyl,_4-20(cycloalkyl)alkyl, C_3-20cycloalkenyl,_4-20cycloalkenyl,_7-20arylalkyl,_7-20alkylaryl,_6-20aryl, C_6-20geterotsiklicheskikh,_6-20Alkylglucoside and C_5-20heterocyclyl.

Preferably, X and Y are C, and R¹, R², R³and R⁴are the same and are selected from the group consisting of primary or secondary_1-6of alkyl, C_2-6alkenyl,_1-6alkoxyl_1-6of alkyl, C_1-6alkoxyl_5-10aryl, C_5-7cycloalkyl,_5-11cycloalkyl_1-6of alkyl, C_5-7cycloalkenyl,_5-7cycloalkenyl,_6-11arils_1-6of alkyl, C_1-6alkyls_6-11aryl, C_6-11aryl, With heterocyclic_1-6of alkyl, C_1-6alkyls_5-12heterocyclyl and C_5-12heterocyclyl.

Preferably, X and Y are C, and R¹, R², R³and R⁴are the same and are selected from the group consisting of methyl, ethyl, propyl, butyl, hexyl, cyclohexyl, Attila, Manila, dodecyl, eicosyl, norbornyl, adamantyl, vinyl, propenyl, cyclohexenyl, phenylethyl, phenylpropyl, methoxyphenyl, ethoxyphenyl, phenyl, talila, dimetilfenil, trimetilfenil, ethylphenyl, propylphenyl, biphenyl, naphthyl, matildaville, Anttila, financila, benzylphenol, pyrenyl, tetrahydropyranyl, acenaphthyl, phenalenyl, aceanthrylene, tetrahydronaphthyl, indlela, methoxypropyl, ethoxyethyl, methoxyethyl, amyl, trityl, methoxytrityl, dimethoxytrityl, trimethoxytrityl, allyl, trimethylsilyl, (tert-butyl)dimethylsilane and benzyl, including their isomers.

Preferably, X and Y are C, and R¹, R², R³and R⁴are the same and are selected from the group consisting of methyl, ethyl, n-propyl, sec-propyl, n-butyl, sec-butyl, tert-butyl, benzyl, phenyl and methoxyphenyl.

Preferably, X and Y are C, and R¹, R², R³and R⁴are the same and are selected from the group consisting of methyl, ethyl, n-propyl, sec-ol the saw and tert-butyl.

Preferably, R¹, R², R³and R⁴represent ethyl.

Preferably, X and Y are C, and R¹and R²taken together, form a-R¹-R²and R³and R⁴taken together, form a-R³-R⁴-, and-R¹-R²and R³-R⁴- are the same and are selected from the group consisting of C_1-20Alcantara,_2-20Alcantara,_4-20alcindoro,_3-20cycloalkenyl,_4-20cycloalkenyl and C_8-20cycloalkenyl.

When X and Y are Si, R¹, R², R³and R⁴preferably represent From_1-20alkyl, more preferably_1-6alkyl, even more preferably tert-butyl.

To indicate the stereochemistry of the compounds of formula (I) throughout the text use the following numbering bicyclic ring system.

It is envisaged that the compound (I) encompasses all its preferred thermodynamically stable stereoisomers. Stereoisomers with CIS-configuration are all stereoisomers, which have a hydrogen atom at the carbon in position 5 and the hydrogen atom at the carbon in position 1 on the same side of the ring system formed by two tetrahydrofuranyl rings. Stereoisomers with TRANS-configuration is predstavlyaet all stereoisomers, which have a hydrogen atom at the carbon in position 5 and the hydrogen atom at the carbon in position 1 on opposite sides of the ring system formed by two tetrahydrofuranyl rings. Preferred are stereoisomers that have the CIS-configuration. On the basis of obtaining compounds of formula (I) in thermodynamic reaction conditions and their investigation by x-ray structure analysis, it was found that the stereoisomers having the TRANS configuration, are thermodynamically less stable than CIS-stereoisomers. In particular, the stereoisomers (Ia), (Ib), (Ic) and (Id) are preferred.

The compounds of formula (Ia) and (Ib) are enantiomers. The compounds of formula (Ic) and (Id) are diastereoisomers. The compounds of formula (Ic) and (Ia) are diastereoisomers. The compounds of formula (Ic) and (Ib) are diastereoisomers. The compounds of formula (Ia) and (Id) are diastereoisomers. The compounds of formula (Ib) and (Id) are diastereoisomers.

Provided that the compound of formula (II) covering all of its stereoisomers. Depending on the nature of X, Y, R¹, R², R³and R⁴stereognostic Central carbon atom bearing aldehyde group may be different. In particular, preferred are the stereoisomers, the use of which has been created upon receipt of the compounds of formula (Ia), (Ib), (Ic) and (Id), i.e. the compound of formula (Ia) is produced from compound (IIa), the compound (IIb) is necessary to obtain compound (Ib), a mixture of the compound (IIc) (IId) will lead to a mixture of compounds (Ic) and (Id), where the compound (IIc) can lead to the formation of compounds (Ic) and compound (Id) and the compound (IId) can lead to the formation of compounds (Ic) and compound (Id).

Provided that the compound of formula (III) covers all of its stereoisomers. Depending on the nature of X, Y, R¹, R², R³and R⁴stereognostic Central carbon atom carrying a hydroxyalkyl group may be different. In particular, preferred are stereoisomers used in the preparation of compounds of formula (Ia), (Ib), (Ic) and (Id), i.e. the compound of formula (Ia) is ultimately derived from the compounds (IIIa), the compound (IIIb) is necessary to obtain the end compound (Ib), and the mixture of the compound (IIIc) and the compound (IIId) will eventually lead to a mixture of compounds (Ic) and (Id)in which the compound (IIIc) ultimately leads to the formation of compounds (Ic) and compound (IIId) ultimately leads to the formation of compounds (Id).

Provided that the compound of formula (IV) covering all of its stereoisomers. Particularly preferred which are stereoisomers, used in the preparation of compounds of formula (Ia), (Ib), (Ic) and (Id), i.e. the compound of formula (Ia) is ultimately derived from the compounds (IVa), compound (IVb) is necessary to obtain the end compound (Ib), and the mixture of compound (IVc) and the compound (IVd) will eventually lead to a mixture of compounds (Ic) and (Id).

Attracting the attention of the compounds of the formula (II) are the compounds of formula (II), where XR¹R²YR³R⁴are identical. Also attracting the attention of the compounds of the formula (II) are the compounds of formula (II), where X and Y are C and R¹, R², R³and R⁴are identical. Other interesting compounds of the formula (II) are the compounds of formula (II), where X and Y are C and R¹, R², R³and R⁴represent_1-20alkyl. Other interesting compounds of the formula (II) are the compounds of formula (II), where X and Y are C and R¹, R², R³and R⁴represent ethyl.

Attracting the attention of the compounds of the formula (III) are compounds of the formula (III), where XR¹R²YR³R⁴are identical. Also attracting the attention of the compounds of the formula (III) are compounds of the formula (III), where X and Y are C and R , R², R³and R⁴are identical. Other interesting compounds of the formula (III) are compounds of the formula (III), where X and Y are C and R¹, R², R³and R⁴represent_1-20alkyl. Other interesting compounds of the formula (III) are compounds of the formula (III), where X and Y are C and R¹, R², R³and R⁴represent ethyl.

Attracting the attention of the compounds of the formula (IV) are compounds of the formula (IV), where XR¹R²YR³R⁴are identical. Also attracting the attention of the compounds of the formula (IV) are compounds of the formula (IV), where X and Y are C and R¹, R², R³and R⁴are identical. Other interesting compounds of the formula (IV) are compounds of the formula (IV), where X and Y are C and R¹, R², R³and R⁴represent_1-20alkyl. Other interesting compounds of the formula (IV) are compounds of the formula (IV), where X and Y are C and R¹, R², R³and R⁴represent ethyl.

Suitable removing protection agents used in the removal of the protective group and subsequent intramolecular cyclization of compounds fo the formula (II) into compounds of formula (I), choose from reagents hydrogenolysis, fluoride containing reagents, acids and bases, preferably, inorganic and organic acids, most preferably, sulfonic acids or carboxylic acids.

Suitable acid selected from the group consisting of chloroethanol acid, Hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, triperoxonane acid, gluconic acid, citric acid, maleic acid, fumaric acid, pyruvic acid, phenylacetic acid, benzoic acid, 4-aminobenzoic acid, Anthranilic acid, 4-hydroxybenzoic acid, salicylic acid, 4-aminosalicylic acid, pambou acid, nicotinic acid, methanesulfonic acid, econsultancy acid, hydroxyethanesulfonic acid, benzosulfimide acid, p-toluensulfonate acid, naphtalenesulfonic acid, sulfanilic acid, cyclohexylsulfamic acid, camphorsulfonic acid, chlorosulfonic acid, pyridine pair-toluensulfonate acid and ascorbic acid.

Removing the protective groups, and subsequent intramolecular cyclization of compounds of formula (II) predpochtite is) takes place in aqueous solution. Preferably, the aqueous solution contains one or more organic solvents. The preferred organic solvent is a dichloromethane. Other suitable organic solvents may be selected from the group consisting of alcohols, preferably₁-C₁₀the alcohols. Preferred alcohols are selected from the group consisting of methanol, ethanol, propanol, butanol, pentanol, hexanol and their isomers. Can be used mixtures of one or more solvents.

Removing the protective groups, and subsequent intramolecular cyclization preferably occurs at a temperature of 0°-100°C., preferably at 10°-50°C., preferably at approximately 25°C.

Removing the protective groups, and subsequent intramolecular cyclization is usually done within 10 minutes - 4 hours depending on the reaction conditions. When following the preferred conditions described above, removing the protective group and subsequent intramolecular cyclization proceeds essentially completely within about 15 minutes.

Oxidizing agents used in the oxidation of compounds of formula (III) in a compound of the formula (II)include oxidizing agents capable of converting the primary alcohol to the aldehyde.

Preferred methods of oxidation is used to oxidize the compounds of formula (II) in the compound of formula (II), include dimethyl sulfoxide mediated oxidation method. Dimethyl sulfoxide (DMSO) can be activated by reaction with a variety of electrophilic reagents including oxalicacid, dicyclohexylcarbodiimide, sulfuric anhydride, acetic anhydride and N-chlorosuccinimide. There are a number of reviews devoted to the sulfoxide mediated oxidation (Lee,Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I, Eds., Pergamon Press: New York, 1991, Vol. 7, p. 291-303.Tidwell, T. T.Synthesis 1990, 857-870.Tidwell, T. T.Organic Reactions 1990, 39, 297-557).

Oxidation of compounds of formula (III) in the compounds of formula (II) preferably proceeds with the use of the terms Swarna (Swern), Pfitzner-Moffat (Pfitzner-Moffatt) or the Parikh-Doering (Parikh-Doering), it is most preferable conditions of the Parikh-Doering.

The reaction of the Parikh-Doering involves activation of dimethyl sulfoxide complex of sulfuric anhydride-pyridine and described by Parikh J.P., W.E. DoeringJ. Am. Chem. Soc., 1967, 89, 5505-5507.

Oxidation in Turn provides for the activation of dimethyl sulfoxide using oxalicacid or triperoxonane anhydride. Oxidation in Turn described by Mancuso A.J., Swern D.Synthesis, 1981, 165-185.

The oxidation Pfitzner-Moffat provides for the activation of dimethyl sulfoxide with dialkylacrylamide reagent such as DICYCLOHEXYL, aminobutiramida; and described by Pfitzner K.E., J.G. MoffattJ. Am. Chem. Soc., 85, 3027 (1963).

Di is ethylsulfonyl mediated oxidation method allows you to easily control the reaction and to oxidize alcohols to the corresponding aldehydes in high yields, because it prevents further oxidation of the resulting aldehyde to the corresponding carboxylic acid.

Oxidation of compounds of formula (III) to compounds of formula (II) preferably takes place in an organic solvent, preferably in an inert reaction solvent. Suitable solvents are selected from the group consisting of hydrocarbons, chlorinated hydrocarbons, ketones, polar aprotic solvents, aromatic hydrocarbons and mixtures thereof.

Preferred inert reaction solvents are selected from the group consisting of pentane, hexane, heptane, cyclohexane, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachlorethane, acetone, methyl ethyl ketone, acetonitrile, propionitrile, benzene, toluene, chlorobenzene, xylene, simple ether, 1,4-dioxane, tetrahydrofuran and mixtures thereof.

Oxidation of compounds of formula (III) to compounds of formula (II) preferably takes place at a temperature in the range -50°C-50°C, preferably below 25°C., most preferably in the range of -10°C.-5°C.

Oxidation of compounds of formula (III) to compounds of formula (II) is preferably carried out for 10 minutes-2 hours depending on the reaction conditions. When following the preferred conditions outlined above, the oxidation reaction proceeds essentially completely within about 4 hours. When is the incorrect the most preferred conditions, mentioned above, the oxidation reaction proceeds essentially completely within about 1.5 hours.

Hydroporinae and subsequent oxidation of compounds of formula (IV) can occur under any conditions conducive to the conversion of the alkene to the primary alcohol (III).

Preferred conditions include reaction of compounds of formula (IV) with a suitable boron-containing reagent and subsequent reaction using an oxidizing agent.

Suitable boron-containing reagents for hydroporinae compounds of the formula (IV) are selected from the group consisting of BH₃With₁-C₆mono - or dialkylamino,₆-C₁₈bicycloalkanes,₆-C₁₈arylboronic and mixtures thereof. Preferred reagents hydroporinae selected from the group consisting of BH₃Dimethylbutane, vetiveria, dipropylamine, 9-borabicyclo[3.3.1]nonane [9-BBN], catecholborane, phenylboron, borolane and mixtures thereof.

Preferred boron-containing reagent includes Diatessaron, which can be obtainedin situwhen mixing BH₃and triethylborane.

The reaction of compounds of formula (IV) with boron reagents preferably proceeds in the presence of a solvent. Suitable solvents are selected from the group consisting of benzene, toluene, xylene, simple ether, 1,4-dioxane, tetrahydrofuran and mixtures thereof. is the most preferred is tetrahydrofuran.

The reaction of compounds of formula (IV) with boron reagents preferably occurs at a temperature in the range of 0°C-50°C, preferably about 25°C.

The reaction of compounds of formula (IV) with boron reagents preferably carried out for 5 minutes to 1 day, depending on the reaction conditions. When following the preferred conditions outlined above, the reaction is essentially completely runs for approximately 1 hour.

Followed by reaction of compounds of formula (IV) with boron reagents, reaction products usually turn into alcohol in the presence of an oxidizing agent. Suitable oxidizing agents include peroxides, particularly hydrogen peroxide. The oxidation preferably takes place in aqueous alkaline solution. Suitable substances with basic properties include carbonates of alkali metals and hydroxides of alkali metals. The most preferred base is sodium hydroxide.

The phase oxidation reaction of hydroporinae preferably occurs at a temperature in the range from -20°C to 30°C, preferably about 0°C.

The phase oxidation reaction of hydroporinae preferably occurs within 5 minutes to 1 day, depending on the reaction conditions. When following the preferred conditions outlined above, the oxidation reaction on su is estu completely runs for approximately 2 hours.

Obtaining compounds of formula (IV) based on the compounds of the formula (V)held by type Wittig reaction may be carried out using classical Wittig reaction or a modified Wittig reaction, such as reaction Horner-Emmons (Horner-Emmons) or the reaction of the Wittig-Horner (Wittig-Horner).

Preferred reagents classical Wittig reaction include the ylides of phosphonium, which can be obtained by the reaction of salt and phosphonium bases. Phosphonium salts of can be obtained, for example, from triarylphosphine and halogenmethyl. Tris₆-C₂₀arylphosphine are preferred, in particular triphenylphosphine. The preferred halogenation is bromatan or Harmattan. The preferred base is containing alkali metal ORGANOMETALLIC reagent, such as hexamethyldisilazane sodium or lithium.

Obtaining compounds of formula (IV) based on the compounds of the formula (V)held by type Wittig reaction preferably is carried out in an organic solvent, preferably the reaction-inert solvent. Suitable solvents are selected from the group consisting of hydrocarbons, chlorinated hydrocarbons, ethers, polar aprotic solvents, aromatic hydrocarbons and mixtures thereof. The preferred solvent is tetrahed furan.

Obtaining compounds of formula (IV) based on the compounds of the formula (V)held by type Wittig reaction preferably occurs at a temperature in the range from -50°C to 20°C, preferably below 25°C., most preferably in the range from -10°C to 5°C.

Other types of Wittig reagents instead of the reaction of the phosphonium include derivatives of phosphinic acid, reagent Tebbe (Tebbe) or reagent Pete (Petais) and can be used in accordance with the reaction conditions known from the prior art.

The compounds of formula (IV) can be obtained using the method that is identical or similar to the method described in Maleczkaet al.,Org Lett., 2002, 4(17), 2841-2844.

All the above methods can be implemented separately or as a sequence of reactions.

Referred to here as the "pure stereoisomeric forms of the compounds are defined as isomers essentially free from other enantiomeric and diastereoisomeric forms of the same General molecular structure of these compounds. In particular, the term "stereoisomer pure" refers to compounds with the contents of the enantiomer of at least 80% (i.e. at least 90% of one isomer and a maximum of 10% of the other possible isomers), until the content stereoisomer 100% (i.e. 100% of one isomer and the absence of other isomers), more specifically, compounds containing stereozoom the RA 90%, up to 100%, even more specifically, with stereoisomer content of 94%up to 100% and, most specifically, with stereoisomer content of 97%up to 100%. The terms "enantiomerically pure" and "diastereomers clean" should be understood in a similar way, but should take into account the content of the enantiomer, respectively, the contents of the diastereoisomer mixture in question.

As it turned out, the methodology for conducting the reaction leads to a mixture of enantiomers, the enantiomers can be separated from each other by the selective crystallization of their diastereomeric salts with optically active acids or bases. Examples of this are tartaric acid, dibenzoyltartaric acid, ditawarkannya acid and camphorsulfacid. Alternatively, the enantiomers can be separated by chromatographic methods using chiral stationary phases. Pure diastereoisomers mixture of diastereomers can be obtained by conventional methods. Suitable physical separation methods that can be successfully applied are, for example, selective crystallization and chromatography, such as column chromatography.

Pure stereochemical isomeric forms of the compounds of formula (I) can also be derived from the corresponding pure stereochemical isomeric forms of the appropriate starting compounds, in which slowie that the reaction proceeds in a stereospecific.

For example, the compound of formula (Ia) can be obtained from pure L-Arabica as a parent compound that is presented in scheme C. the Compound of formula (Ib) can be obtained from the pure D-Arabia as the source connection. The use of xylitol or Ribica (or adonica) as the source of the substance will result in a mixture of diastereoisomers of formula (Ic) and (Id), a mixture which can be separated using separation techniques well known in the prior art.

The compounds of formula (I) can be used for synthesis of new inhibitors of HIV protease candidates for the medicinal product in accordance with known prior art methods of synthesis. Thus, the present invention also relates to the use of compounds of formula (I) upon receipt of HIV protease inhibitors and the invention also relates to inhibitors of HIV protease, obtained using the compounds of formula (I) in the chemical receiving the specified HIV protease inhibitors that exhibit antiviral activity against HIV wild-type and/or mutant strains of HIV that are resistant to currently available drugs.

The following examples illustrate obtaining typical connection the developments of the present invention.

EXAMPLES

Preferably, the synthesis of compound (I) provides for sequential synthesis, one of the synthetic routes which in General is presented below. The first two stages are described in detail Linclauet al.(J. Org. Chem., 2003, 68, 1821-1826). Accordingly, the first two stages are presented below only as a reference. Synthesis, appropriately begins with regioselective protection of Arabica, xylitol or ribita, preferably Arabica. Arabic has a pseudo-C2 symmetry (Central carbon atom is not a stereogenic), and this symmetry is preserved in 1. While Arabic is chiral, xylitol and ribitol are meso-forms. In the second step, oxidation of the protected Arabica leads to C2-symmetric (2S,4S)-1,2:4,5-bis(3,3-intelligentiae)-3-pentanone. Preferably, the low temperature used at this stage because it minimizes the epimerization of (2S,4R)-1,2:4,5-bis(3,3-intelligentiae)-3-pentanone.

Next, the following terms are used:

DCM is dichloromethane;

THF - tetrahydrofuran;

Ph is phenyl;

Py - pyridine;

DMSO - dimethyl sulfoxide;

min - minute;

h - hour;

D. day;

IU - methyl;

Et is ethyl;

CSA - chlorosulphuric acid;

PPTS - pyridine pair-toluensulfonate acid;

NaHMDS - Na, hexamethyldisilazane.

Synthesis of CIS-(4R,6R)-2,8-dioxa-4,6-dihydroxybutyl[3.3.0]Oct is on

Step 1. Synthesis of (2S,4S)-1,2:4,5-di-O-(3,3-pentylidene)Arabica

Boiling a suspension of L-Arabica (20,00 g, 131, 5mm mmol) and 3,3-dimethoxyethane (76,46 g, 578,4 mmol) in THF (200 ml) is stirred for 15 minutes Add CSA (9,16 g, to 39.4 mmol) and the reaction mixture is stirred at the boil for exactly 5 minutes the Reaction is completed by addition of NaOH (aq., 2M, 40 ml) at boiling. Add diethyl ether (50 ml) and water (20 ml) and separate the layers. The aqueous phase is extracted with diethyl ether (3×50 ml). The combined organic layers dried over anhydrous Na₂SO₄, filtered and the solvent is removed in vacuum, obtaining a pale yellow oil. The crude product was dissolved in CH₂Cl₂(200 ml) and add triethylamine (20 ml). The mixture is heated to boiling and add succinic anhydride (3,40 mg, 34,0 mmol). The reaction mixture is heated at boiling for 1.5 h and then quenched with NaHCO₃(aq., the feast upon., 200 ml) at the boiling point. After cooling, the layers separated and the aqueous layer was extracted with CH₂Cl₂(2×100 ml). The combined organic phases are washed with saturated salt solution (100 ml), dried over anhydrous Na₂SO₄, filtered and evaporated to obtain a pale yellow oil. Purification using column chromatography (hexane/acetone 80:20) to give (2S,4S)-1,2:4,5-di-O-(3,3-pentylidene)Arabic in the form of a pale yellow oil (as opposed to 28.18 per g, 74%). [α]_{D -5,8 (with 2.5, HCl3, 25°C). Spectra¹H and¹³With the NMR data are as described in B. Linclauet al.,J. Org. Chem., 2003, 68, 1821.}

Stage 2.Synthesis of (2S,4S)-1,2:4,5-bis(3,3-inteligencije)-3-pentanone

In dvuhholos round bottom flask (500 ml stirred solution of 1,2:4,5-di-O-isobutylidene acetal (10,00 g, to 34.7 mmol) in CH₂Cl₂(100 ml) and DMSO (50 ml) at 0°C. In dvuhholos round bottom flask (In), 250 ml stirred solution of the complex SO₃·pyridine (16.56 g, 104,0 mmol) and triethylamine (17,9 ml, 128,3 mmol) in CH₂Cl₂(50 ml) and DMSO (50 ml) at 0°C for 10 minutes the Contents of the flask (B) then transferred via cannula to the flask (A) within 10 minutes Then the reaction mixture was stirred at 0°C for 5 hours. The reaction mixture was then poured into a mixture of saturated aqueous solution of NH₄Cl:water:diethyl ether:pentane(1:1:1:1, 600 ml). The layers are separated and the aqueous layer was extracted with a mixture of diethyl ether:pentane (1:1, 2×150 ml). The combined organic phases are dried over anhydrous Na₂SO₄, filtered and evaporated to obtain the crude product as a pale yellow oil. Purification using column chromatography (hexane/ethyl acetate 90:10) to give (2S,4S)-1,2:4,5-bis(3,3-intelligentiae)-3-pentanone in the form of a colorless oil (9,20 g, 93%). [α]_D68,8 (with0,31, HCl₃, 25°C). Spectra¹N 13With the NMR data are as described in B. Linclauet al.,J. Org. Chem., 2003, 68, 1821.

Step 3.Synthesis of (2R,4R)-di-O-(3,3-pentylidene)-3-deoxy-3-Methylenebis

To a stirred suspension of bromide methyltriphenylphosphonium (21,20 g, 59,36 mmol) in THF (100 ml) at 0°C is added NaHMDS (of 56.4 ml of 56.4 mmol, 1.0m in THF). The obtained yellow suspension is stirred for 10 minutes a Solution of C2-symmetric ketone (8.5 g, 29.7 mmol)dissolved in THF (20 ml), then added dropwise and the mixture is stirred at 0°C for 4 h Then the reaction mixture was poured into water (150 ml) and extracted with CH₂Cl₂(3×100 ml). The combined organic phases are dried over anhydrous Na₂SO₄, filtered and evaporated. Purification using column chromatography (hexane/ethyl acetate 90:10) to give (2S,4S)-di-About-(3,3-pentylidene)-3-deoxy-3-Methylenebis in the form of a colorless oil (8,30 mg, 98%) (Maleczkaet al.,Organic Letters, 2002, 4(17), 2841-2844). R_fof 0.16 (hexane/ethyl acetate 95:5). [α]_D-86,9 (with1,33, HCl₃, 25°C).¹H NMR (400 MHz, CDCl₃) and 5.30 (2H, d, J=1.0 Hz), to 4.52 (2H, m), 4,19 (2H, DD, J=8.0 a, 6,0 Hz), of 3.56 (2H, t, J=8.0 Hz), 1,74 is 1.60 (8H, m)to 0.92 (6H, t, J=7.5 Hz) and 0.90 (6H, t, J=7.5 Hz).

Step 4.Synthesis of (2R,4R)-di-O-(3,3-pentylidene)-3-deoxy-3-hydroxymethylamino

The solution triethylborohydride (10,2 ml, 1.0m in THF) and borohydride (1.7 ml, 1.0m in THF) paramesh what happens at room temperature for 1 h Add a solution of C2-symmetrical alkene (968 mg, 3,40 mmol) in THF (7 ml) and the reaction mixture stirred for 2 days the Reaction mixture was then cautiously added dropwise to a stirred mixture of NaOH (aq., 3M):H₂O₂(aq., 27 wt.%):CH₂Cl₂(1:1:1, 90 ml) at 0°C and stirred for 2 hours, the Layers separated and the aqueous layer was extracted with CH₂Cl₂(3×30 ml). The combined organic phases are dried over anhydrous Na₂SO₄, filtered and evaporated to obtain the crude product as a colourless oil. Purification using column chromatography (hexane/acetone 85:15) to give (2R,4R)-di-About-(3,3-pentylidene)-3-deoxy-3-hydroxymethyluracil in the form of a colorless oil (950 mg, 92%). R_fof 0.28 (hexane/acetone 80:20). [α]_D-9,7 (with1,06, HCl₃, 25°C).¹H NMR (300 MHz, CDCl₃) δ 4,24-4,11 (2H, m), of 4.12 (1H, DD, J=8,1, 5,9 Hz), of 3.96 (1H, TD, J=8,8, 5,9 Hz), 3,74-3,66 (3H, m), 3,61 (1H, DD, J=8,8, 8.1 Hz), 2,63 (1H, Sirs), of 1.84 (1H, m), 1,67-and 1.54 (8H, m), 0,897 (3H, t, J=7,35 Hz), 0,890 (3H, t, J=7,35 Hz)of 0.87 (3H, t, J=7,35 Hz) and 0,86 (3H, t, J=7,35 Hz).

Step 5.Synthesis of (2R,4R)-di-O-(3,3-pentylidene)-3-deoxy-3-fimilarity

In dvuhholos round bottom flask (A) in a 250 ml stirred solution of pseudo-C2-symmetric primary alcohol from step 4 (1.90 g, 6,28 mmol) in CH₂Cl₂(30 ml) and DMSO (15 ml) at 0°C. In dvuhholos round bottom flask (In) per 100 ml of mixed races is a thief at SO ₃·pyridine (3.00 g, to 18.9 mmol) and triethylamine (3.2 ml, 23.2 mmol) in CH₂Cl₂(30 ml) and DMSO (15 ml) at 0°C for 10 minutes the Contents of the flask (B) then transferred via cannula to the flask (A) within 10 minutes Then the reaction mixture was stirred at 0°C for 1.5 hours. The reaction mixture was then poured into a mixture of saturated aqueous solution of NH₄Cl:water:diethyl ether:pentane(1:1:1:1, 100 ml). The layers are separated and the aqueous layer was extracted with a mixture of diethyl ether:pentane (1:1, 2×100 ml). The combined organic phases are dried over anhydrous Na₂SO₄, filtered and evaporated to obtain the crude product as a colourless oil. Purification using column chromatography (hexane/acetone 95:5) to give (2R,4R)-di-About-(3,3-pentylidene)-3-deoxy-3-formularium in the form of a colorless oil (is 1,809 g, 96%). R_fof 0.52 (hexane/acetone 80:20). [α]_D+39,5 (with0,40, HCl₃, 23°C).¹H NMR (300 MHz, CDCl₃) δ 9,83 (1H, d, J=1.5 Hz), 4,37 (1H, TD, J=7,7, 5,9 Hz), 4,28-4,18 (3H, m), 3,82 (1H, m), of 3.54 (1H, m)2,60 (1H, m), 1,69 of 1.50 (8H, m), 0,90-of 0.82 (12H, m).

Step 6.Synthesis of CIS-(4R,6R)-2,8-dioxa-4,6-dihydroxybutyl[3.3.0]octane

To a stirred solution of pseudo-C2-symmetric aldehyde (6,9 g, 22,97 mmol) in 70 ml of dichloromethane at room temperature add to 7.7 ml of a mixture of triperoxonane acid and water (9:1; V/V). After 15 minutes the solvent is removed in Vacu the IU and the crude product together evaporated with toluene. Purification using column chromatography (dichloromethane/methanol 9:1) gives CIS-(4R,6R)-2,8-dioxa-4,6-dihydroxybutyl[3.3.0]octane in the form of a white precipitate (2,844 g, 85%). R_f0,24 (CH₂Cl₂/MeOH 90:10). [α]_D+45,8 (withTo 0.61, MeOH, 24°C).¹H NMR (400 MHz, DMSO-d₆) δ 5,62 (1H, d, J=5.5 Hz), with 5.22 (1H, d, J=4.5 Hz), is 4.85 (1H, d, J=4.5 Hz), 4,43 (1H, t, J=4.0 Hz), the 4.29 (1H, m), with 3.79 (1H, d, J=9.5 Hz), of 3.78 (1H, DD, J=9,0,2,5 Hz), 3,68 (1H, d, J=9.5 Hz), or 3.28 (1H, m) and to 2.57 (1H, DD, J=9,0, 5.0 Hz).

Next steps 7-10 (represented in figure 1 as steps g-j) describe the synthesis of CIS-(4R,6R)-4-benzyloxy-2,8-dioxa-6-hydroxybenzyl[3.3.0]octane (10), starting from CIS-(4R,6R)-2,8-dioxa-4,6-dihydroxybutyl[3.3.0]octane (6).

Scheme 1. Synthesis of (3R,3R,4R,6S)-3-benzylpenicillin[2,3-b]furan-4-ol (10)

a. i. CSA (30% mole.), DMP (4.4 equiv.) THF, boiling, 5 min; ii. Succinic anhydride, CH₂Cl₂Et₃N, boiling, 1.5 h, 68%; b. SO₃.py (3 equiv.) DMSO, Et₃N, CH₂Cl₂, 0°C, 5 h, 96%; Ph₃PCH₃Br (2 equiv.) NaHMDS (1.9 equiv.) THF, 0°C, 4 h, 95%; d. Et₃B (3 equiv.) BH₃(0.5 equiv.) THF, room temperature, 2 d, 81%; e. SO₃.py (3 equiv.) DMSO, Et₃N, CH₂Cl₂, 0°C, 1.5 h, 93% ; f. TFA, CH₂Cl₂H₂O 85%; g. TBDPSO (4 equiv.) DMAP (0.8 equiv.) the imidazole (8 equiv.) DMF. room temperature, 79%; h. NH₄Cl (4 equiv.) CH₃OH, room temperature, 40%; i. BnBr (3 equiv.) NaH (3 equiv.) TBAI (0.2 equiv.) THF, 0°C, 65%; j. TBAF (1.5 equiv.) THF, room temperature is a, 73%.

List of abbreviations

BnBr - benzylbromide

CSA - camphorsulfacid

d - doublet

DD - doublet of doublets

dt - doublet of triplets

DMAP - 4-dimethylaminopyridine

DMF - dimethylformamide

DMP - dimethoxyethan

DMSO - dimethyl sulfoxide

EtOAC - ethyl acetate

m - multiplet

NaHMDS - hexamethyldisilazane sodium

T_rooms- room temperature

s - singlet

t - triplet

TBAF is tetrabutylammonium fluoride

TBAI - tetrabutylammonium iodide

TBDPSCl - tert-butyldiphenylsilyl chloride

TFA - triperoxonane acid

THF - tetrahydrofuran

Step 7.Synthesis of CIS-(4R,6R)-2,8-dioxa-4,6-bis(tert-butyldiphenylsilyl)bicyclo[3.3.0]octane

To a solution of diol6(100 mg, of 0.68 mmol), imidazole (372 mg, of 5.48 mmol) and DMAP (66 mg, 0.54 mmol) in DMF (10 ml) is added tert-butyldiphenylsilyl (to 0.72 ml, is 2.74 mmol) and stirred at room temperature during the day. The solvent is removed in a vacuum rotary evaporator at 40°C and the residue purified by column chromatography (hexane/acetone 95/5). Subsequent purification by the method of preparative HPLC (hexane/acetone 95/5) to give CIS-(4R,6R)-2,8-dioxa-4,6-bis(tert-butyldiphenylsilyl)bicyclo[3.3.0]octane as a colourless oil (337 mg, 79%). R_fof 0.24 (hexane/acetone 95/5). [α]_Dsituated 10.5 (with4,24, CHCl₃, 24°C).¹H NMR (400 MHz, CCl ₃) δ 7,73-of 7.70 (4H, m), EUR 7.57-7,52 (4H, m), 7,49-7,33 (N, m)of 5.89 (1H, d, J=5.0 Hz), 4,96 (1H, d, J=2.5 Hz), 4,36 (1H, dt, J=9,5, 6,8 Hz)to 4.01 (1H, DD, J=9,5, 1.0 Hz), 3,93 (1H, DD, J=9,5, 3.0 Hz), 3,40 (1H, DD, J=9,5, 6,5 Hz)to 3.34 (1H, DD, J=9,5, 7,0 Hz)to 2.94 (1H, DD, J=9,0, 5.0 Hz), 1,12 (N, C)0,91 (N, s) ppm

Step 8.Synthesis of CIS-(4R,6R)-2,8-dioxa-4-hydroxy-6-(tert-butyldiphenylsilyl)bicyclo[3.3.0]octane

Method And

To a stirred solution of compound7(47 mg, of 0.075 mmol) in methanol (1.5 ml) at room temperature add NH₄F (22 mg, 0.6 mmol). Four days later, the solvent is removed in vacuum and purified by the method of column chromatography (hexane/EtOAc 85:15) to give CIS-(4R,6R)-2,8-dioxa-4-hydroxy-6-(tert-butyldiphenylsilyl)bicyclo[3.3.0]octane (8) as a colourless oil (13 mg, 45 %). R_f0,76 (hexane/acetone 5:5). [α]_D+18 (with0,25, CHCl₃, 27°C).¹H NMR (400 MHz, CDCl₃) δ 7,71 to 7.62 (4H, m), 7,49-7,39 (6N, m), 5,71 (1H, d, J=5.0 Hz), a 4.83 (1H, d, J=3.5 Hz), 4,48 (1H, dt, J=7,0, 9.0 Hz), of 4.12 (1H, DD, J=4,0, 10,0 Hz), of 3.97 (1H, d, J=10.0 Hz), of 3.69 (1H, DD, J=7,0, 9.0 Hz), 3,48 (1H, t, J=8.5 Hz), 2,61 (1H, DD, J=5.0 and 9.0 Hz), 1,92 (1H, s), 1,11 (N, s) ppm

Method In

To a solution of diol6(8,633 g, 0,059 mol), imidazole (32,174 g, 0,472 mol), DMAP (5,773 g 0,047 mol) in DMF (200 ml) is added tert-butyldiphenylsilyl (66,18 ml, 0,236 mol) and stirred at room temperature during the day. Once the reaction is the head of the would close, add 200 ml Et₂O and 500 ml of water. The layers are separated and the organic layer was washed with 300 ml of water and 300 ml of saturated salt solution, dried over anhydrous Na₂SO₄, filtered and the solvent is removed in vacuo to obtain the crude product as a colourless oil. The crude product is dissolved in 400 ml of methanol and add NH₄F (8,752 g, 0,236 mol). The reaction is stirred at the boiling temperature for 2.5 h, then the solvent is removed in vacuum. Purification of the crude product using column chromatography (hexane/acetone 90:10, 85:15 and then 100% acetone) to obtain one after another secure connection7(net not allocated), CIS-(4R,6R)-2,8-dioxa-4-hydroxy-6-(tert-butyldiphenylsilyl)bicyclo[3.3.0]octane (8) as a colourless oil (there is a 10.03 g, 44%) and unprotected connection6(1,59 g, 18%).

Step 9.Synthesis of CIS-(4R,6R)-4-benzyloxy-2,8-dioxa-6-(tert-butyldiphenylsilyl)bicyclo[3.3.0]octane

To a stirred suspension of NaH (268 mg, 7 mmol, 60% in oil) in 3 ml THF at s add a solution of alcohol 8 (900 mg, 2.34 mmol) in 9 ml THF. After 10 minutes add benzylbromide (from 0.84 ml, 7 mmol) and TBAI (177 mg, 0.47 mmol) and the reaction stirred at s. Upon completion of the reaction after 4 hours is added dropwise 2 ml of water, to quench excess NaH and solvent is removed in vacuum. Purification of the crude product is that using column chromatography (hexane/AcOEt 95:5) leads to CIS-(4R,6R)-4-benzyloxy-2,8-dioxa-6-(tert-butyldiphenylsilyl)bicyclo[3.3.0]octane as a colourless oil (725 mg, 65%). R_fof 0.62 (hexane/AcOEt 7:3). [α]_D-10,6 (with0,7, CHCl₃, 25°C).

¹H NMR (400 MHz, CDCl₃) δ 7,58 is 7.50 (4H, m), 7,39-7,18 (11N, m), 5,64 (1H, d, J=5.3 Hz), 4,56 (1H, d, J=3,4 Hz), and 4.40 (1H, d, J=12.0 Hz), 4,37 (1H, m), 4,32 (1H, d, J=11.7 Hz), 4,11 (1H, J=10.0 Hz), 3,98 (1H, DD, J=9,8, 10,2 Hz), 3,55 (1H, DD, J=8,7, 6,8 Hz)to 3.36 (1H, t, J=8.7 Hz), was 2.76 (1H, DD, J=5,3, 9,0 Hz), and 0.98 (N, s) ppm

Stage 10.Synthesis of CIS-(4R,6R)-4-benzyloxy-2,8-dioxa-6-hydroxybenzyl[3.3.0]octane

To a stirred solution of compound9(532 mg, 1.12 mmol) in 20 ml of THF at room temperature add TBAF (1,68 ml, 1,68 mmol, 1M in THF). After 10 minutes the solvent is removed in vacuo and purify "the crude product using column chromatography (hexane/AcOEt 80:20) to give CIS-(4R,6R)-4-benzyloxy-2,8-dioxa-6-hydroxybenzyl[3.3.0]octane (10) as a white solid (194 mg, 73%). R_fof 0.58 (hexane/acetone 5:5). [α]_D+74 (with0,15, CHCl₃, 27°C).¹H NMR (400 MHz, CDCl₃) 7,34-7,28 (5H, m), of 5.83 (1H, d, J=5.0 Hz), 4,55 (3H, m), 4,48 (1H, d, J=3.8 Hz), 4,13 (1H, d, J=10.0 Hz), 4,00 (2H, m), 3,62 (1H, DD, J=7,0, 9.0 Hz), with 2.93 (1H, DD, J=5.0 and 8.0 Hz), 1,79 (1H, Sirs) ppm

In addition to receiving the connection (10), described above, also received additional compounds of General formula

where R=OBn (=compound 10), OPh, OCH₂CN, or

orrespectively.

This is item 11. Synthesis of 4-benzyloxyacetophenone[2,3-b]furan-3-silt ether {3-[(4-aminobenzenesulphonyl)isobutylamino]-1-benzyl-2-hydroxypropyl}carbamino acid (13)

To a stirred solution of triethylamine (43 mg, 423 μmol) and bis-(2,5-dioxopiperidin-1-yl)new ester of carbonic acid (11) (58 mg, 226 μmol) in CH₂Cl₂(5 ml) add (10) (50 mg, 212 μmol). The mixture is stirred at room temperature for 4 hours. Add 4-amino-N-(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutylacetophenone (12) (83 mg, 212 μmol) at one time. The mixture is stirred over night at room temperature. The mixture was then separated using column chromatography using CH₂Cl₂→CH₂Cl₂/MeOH (NH₃) 97-3 as eluent. After evaporation receive (13) (53 mg, 81 μmol, 38%) as a white solid.

LC-MS (M+N)⁺: 654;¹H NMR (400 MHz, CDCl₃) δ rate of 7.54 (2H, d, J=8,68 Hz), 7,39-7,14 (10H, m), to 6.67 (2H, d, J=8,61 Hz), and 5.8 (1H, d, J=5,18 Hz), 5,12 (1H, DDD, J =11.87 per Hz, J=6,06 Hz, J=5,81 Hz), of 4.95 (1H, d, J=8.54 in Hz), 4,37 (1H, d, 7=11.8 Hz), 4.26 deaths (1H, d, J=11.8 Hz), is 4.15 (2H, Sirs), 4,08 (1H, d, J=10.1 Hz) 3,98 (1H, DD, J=10,0, J=6,1 Hz), 3,91-of 3.80 (3H, m), 3.75 to a 3.50 (3H, m), of 3.12 (1H, DD, J=15,07, J=8,43), 3,05 and 2.9 (4H, m), 2,84-to 2.74 (2H, m), is 1.81 (1H, septet, J=6,62), of 0.87 (3H, d, J=6,58), OF 0.45 (3H, d, J =6,58 Hz).

Thus obtained compounds were tested in the biological test antivirus is current activity.

As an example, the following is the result of the test compounds (13): 4-benzyloxyacetophenone[2,3-b]furan-3-silt ether {3-[(4-aminobenzenesulphonyl)isobutylamino]-1-benzyl-2-hydroxypropyl}carbamino acid, while the reference drug used connection, called the TMC 114 or darunavir, the following chemical structure, a new protease inhibitor in clinical studies for the treatment of HIV infection.

Darunavir has the following chemical name: (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl-N-[(1S,2R)-1-benzyl-2-hydroxy-3-(N-1 isobutyronitrile)propyl]carbamate

Compounds were tested on cells using cells MT4-LTR-EGFP to determine antiviral activity. Studies show that compounds exhibit potential anti-HIV activity against laboratory strains of HIV wild-type (WT IIIB-2-001) and several mutant strains of HIV known as the mutants 1, 2, 3 and 4 in tables 1 and 2 respectively.

Research on the cells was carried out in accordance with the following method.

HIV - or false-infected cells MT4-LTR-EGFP were incubated for three days in the presence of the above-mentioned compounds in different concentrations. During infection with the viral tat protein activates the reporter GFP. At the end of the incubation period was measured signal GF. In the control samples with the virus (in the absence of any inhibitor) received the maximum fluorescence signal. Inhibitory activity of compounds was investigated using virus-infected cells and to calculate the value of the EU₅₀. These values represent the number of connections required to protect 50% of the cells from viral infection. The data presented in table 1, contain the values ofpEU₅₀that represents the negative logarithm of the values of the EU₅₀.

Viral mutant strains 1-4, which were used for testing contained mutations presented in table 2

Table 2

1. The compound of formula (I) or a stereoisomer

or its salt form.

2. The compound according to claim 1, where the connection is one of the following stereoisomers

3. A method of obtaining a compound according to claim 1 or 2, including the effects of the compounds of formula (II)

where X and Y are carbon atoms; and
R¹, R², R³and R⁴represent₁-C₂₀alkyl;
conditions unprotect alcohol and exposure of the thus obtained intermediate compound with the corresponding protective groups intramolecular cyclization to obtain the compounds of formula (I).

4. The method according to claim 3, further comprising the oxidation of compounds of formula (III)

where X and Y are carbon atoms; and
R¹, R², R³and R⁴represents a C₁-C₂₀alkyl;
obtaining the compounds of formula (II).

5. The method according to claim 4, additionally comprising hydroporinae the compounds of formula (IV)

where X and Y are carbon atoms; and
R¹, R², R³and R⁴represents a C₁-C₂₀alkyl;
and subsequent oxidation obtained in this about what atom hydroborating intermediate connection with obtaining the compounds of formula (III).

6. The compound of formula (II) or a stereoisomer

where X and Y are carbon atoms; and
R¹, R², R³and R⁴represents a C₁-C₂₀alkyl;
or its salt form.

7. The connection according to claim 6, where the connection is one of the following stereoisomers

8. A method of obtaining a compound according to claim 6 or 7, comprising the oxidation of compounds of formula (III)

where X and Y are carbon atoms; and
R¹, R², R³and R⁴represents a C₁-C₂₀alkyl;
obtaining the compounds of formula (II).

9. The compound of formula (III) or a stereoisomer

where X and Y are carbon atoms; and
R¹, R², R³and R⁴represents a C₁-C₂₀alkyl;
or its salt form.

10. The connection according to claim 9, where the compound is one of the following stereoisomers

11. A method of obtaining a compound according to claim 9 or 10, including hydroporinae the compounds of formula (IV)

where X and Y are carbon atoms; and
R¹, R², R³and R⁴represents a C₁-C₂₀alkyl;
and then Oka is of thus obtained hydroborating intermediate connection with obtaining the compounds of formula (III).

12. The compound according to any one of p, 7, 9, or 10, where R¹, R², R³and R⁴independently selected from the group consisting of C_1-20the alkyl.

13. The compound according to any one of p, 7, 9, or 10, where R¹, R², R³and R⁴independently selected from the group consisting of primary or secondary C_1-6the alkyl.

14. The compound according to any one of p, 7, 9, or 10, where R¹, R², R³and R⁴are the same.

15. The compound according to any one of p, 7, 9, or 10, where X and Y are carbon atoms, and R¹, R², R³and R⁴are the same and are selected from the group consisting of methyl, ethyl, n-propyl, sec-propyl, n-butyl, sec-butyl, tert-butyl.

16. The method according to any of PP, 4, 5, 8 or 11, where R¹, R², R³and R⁴independently selected from the group consisting of C_1-20the alkyl.

17. The method according to any of PP, 4, 5, 8 or 11, where R¹, R², R³and R⁴independently selected from the group consisting of primary or secondary_1-6the alkyl.

18. The method according to any of PP, 4, 5, 8 or 11, where R¹, R², R³and R⁴are the same.

19. The method according to any of PP, 4, 5, 8 or 11, where X and Y are C, and R¹, R², R³and R⁴are the same and are selected from the group consisting of methyl, ethyl, n-propyl, sec-propyl, n-butyl, sec-butyl,tert-butyl.

20. The method according to claim 3, where removing the protecting agent selected from the group consisting of reagents hydrogenolysis, fluoride containing reagents, acids and bases, preferably inorganic and organic acids, most preferably sulfonic acids or carboxylic acids.

21. The method according to claim 3, where the removal of the protective groups takes place in aqueous solution, optionally containing one or more organic solvents.

22. The method according to claim 4 or 8, where the oxidation takes place in conditions of Swarna (Swern), Pfitzner-Moffat (Pfitzner-Moffatt) or the Parikh-Doering (Parikh-Doering).

23. The use of compounds according to claim 1 or 2 upon receipt of the inhibitor of HIV protease.