Hexahydrofuro[2,3-b]furan-3-yl-n-{3-[(1,3-benzodioxol-5- yl- sulfonyl)(isobu tyl)amino]-1-benzyl-2-hydroxypropyl}carbamate, pharmaceutical composition based on thereof, methods for inhibition and method for treatment

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new bis-tetrahydrofuranbenzodioxolyl sulfonamide compounds of the formula (I): , its salts, stereoisomers and racemates that are effective inhibitors of protease activity. Also, invention relates to pharmaceutical preparations, methods for inhibition of retrovirus proteases, in particular, to resistant retrovirus proteases, to many drugs, methods for treatment and prophylaxis of infection or disease associated with retrovirus infection in mammals and to methods for inhibition of retrovirus replication. Invention provides preparing new derivatives of bis-tetrahydrofuranbenzodioxalyl sulfonamides eliciting the valuable pharmaceutical properties.

EFFECT: valuable medicinal properties of compound and composition, improved treatment method.

16 cl, 2 dwg, 3 tbl

 

This application claims priority in accordance with the provisional application for U.S. patent No. 60/157850, filed October 6, 1999, which is specifically incorporated here by reference.

The present invention relates to new bis-tetrahydro-parabenzoquinone compounds containing compositions and methods for their preparation. The invention relates to the use of these compounds as pharmaceutically active compounds for the treatment and prophylaxis of retroviral infections, particularly HIV infections, and particularly resistant to many drugs HIV infections mammals.

Resistance to HIV inhibitors is the most important cause of unsuccessful therapy. Half of the patients receiving combination therapy against HIV are not fully responsive to treatment mainly because of registertest virus to one or more of the prescribed drugs. Moreover, it was shown that the resistant virus is transferred newly infected individuals, leading to a strong restriction on the choice of therapy and for data-naïve drugs patients. There is therefore a need in the field of production of new compounds for the treatment of retroviral infections, in particular for the treatment of AIDS. The need in this area is one the Xia particularly acute regarding connections, which are active not only against wild-type virus, but also against the increasing number of resistant viruses. In addition, the protease inhibitors are usually entered with AIDS in combination with other agents active against HIV, such as NRTIs and/or NNRTIs. This fact is the cause of high drug load for the patient. One way to reduce this drug load is the search for drugs active against HIV, such as protease inhibitors with high bioavailability, i.e. favorable pharmacokinetic and metabolic profile, so that the daily dose could be minimal. Another important characteristic of a good protease inhibitor and, in General, drugs that are active against HIV, is the minimal binding of protease inhibitor plasma proteins or even complete absence of influence on its effectiveness.

Several published applications for the grant of a patent related to HIV protease inhibitors. For example, WO 95/06030 belongs to the protease inhibitor with a structure containing hydroxyethanesulfonic the core. Also Ghosh et al. (Bioorganic & Medicinal Chemistry Letters, 8, 1998, 687-690) reveals hydroxyethanesulfonic inhibitors of HIV protease.

Compounds according to the present invention are unexpectedly effective in what ibitoye HIV in relation to their activity against a broad spectrum of mutants of HIV in relation to their bioavailability. Additional objects and advantages will be set forth in part in the following description, and will be partially understood from the description or can be learned in the practical application of the invention. The objects and advantages of the invention will be realized and attained by the elements and combinations of detail specified in the claims.

BRIEF DESCRIPTION of DRAWINGS

Figure 1 shows the concentration of compound 13 in serum after a single oral dose as a function of time.

Figure 2 shows a comparison of the activity of compounds 13 and 14 according to the invention and several commercially available antiviral compounds against a small panel of viral strains.

DETAILED description of the INVENTION

For a more complete understanding of the invention described here provides the following detailed description.

The present invention relates to compounds represented by the formula

and its N-oxides, salts, esters, stereoisomeric forms, racemic mixtures, prodrugs and metabolites. The molecular structure shown above is called hexahydrofuro[2,3-b]furan-3-yl-N-{3-[(1,3-benzodioxol-5-ylsulphonyl)(isobutyl)amino]-1-benzyl-2-hydroxypropyl}- carbamate.

This invention also envisions the quaternization of the atom is in the nitrogen in these compounds. The basic nitrogen atom can be quaternity with any agent known to the person skilled in the art, including, for example, the lowest alkylhalogenide, diallylsulfide, long chain halides and aralkylated. Using such quaternization can be obtained water - or fat-soluble or dispersible products.

The term "prodrug", as used in this text means the pharmacologically acceptable derivatives such as esters, amides and phosphates, such that the resulting product in the biotransformation of a derivative is the active drug substance, as represented by formula (I). In the present description includes a link Goodman and Gilman (The Pharmacological Basis of Therapeutics, 8thed, McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs", p 13-15), which describes prodrugs in a General sense. Typical examples of prodrugs are described, for example, in WO 99/33795, WO 99/33815, WO 99/33793 and WO 99/33792 included here as a reference.

Prodrugs are characterized by excellent solubility, increased bioavailability and easily metabolized into the active inhibitors in vivo.

For use in therapy acceptable such salts of compounds of formula (I), in which the counterion is pharmaceutically or physiologically acceptable. However, it can also be used salts containing pharmaceutically unacceptable in Aion, for example, when receiving or purification of pharmaceutically acceptable compounds represented by formula (I). All salts, pharmaceutically acceptable, or unacceptable, are included in the scope of the present invention.

Pharmaceutically acceptable or physiologically tolerated salt additive, which is able to form compounds according to the present invention can be easily obtained using the appropriate acids, such as, for example, inorganic acids such as halogenation acid, for example hydrochloric or Hydrobromic acid, sulfuric, nitric, phosphoric or 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-toluensulfonate, reklamowa, salicylic, p-aminosalicylic, AMOVA and the like acid.

Conversely, these salt forms can be converted into firm free base by treatment with a suitable base.

The term "salt" also includes a hydrate and a solvate, which may be formed by the compounds of the present invention. Examples of such forms are, for example, hydrates, alcoholate, and the like.

The N-oxide forms is in accordance with the present invention mean compounds represented by formula (I)where one or more atoms of nitrogen oxidized to the so-called N-oxide.

These compounds may also exist in tautomeric forms. Although this form is not explicitly stated in the above formula, it is understood that they are included in the scope of the present invention.

The term "stereochemical isomeric forms of the compounds according to the present invention"is used here previously, defines all possible compounds consisting of the same atoms connected in the same sequence of bonds but having different spatial patterns that are not interchangeable, which the compounds according to the present invention can take. If not marked or otherwise indicated, the chemical designation of compounds comprises a mixture of all possible stereochemical isomeric forms, which specified the connection can take. This mixture can include all diastereomers and/or enantiomers basic molecular structure of the compounds. All stereochemical isomeric forms of the compounds according to the present invention in pure form and in admixture with each other, included in the scope of the present invention.

Pure stereoisomeric forms of the compounds and intermediates, as mentioned here, is defined as isomers, essentially its adnie from other enantiomeric or diastereoisomeric forms of the same basic molecular structure of these compounds and intermediates. In particular, the term "stereoisomer pure" refers to compounds or intermediate products containing excess stereoisomer, at least 80% (i.e. at least 90% of one isomer and a maximum of 10% of the other possible isomers) to receive stereoisomer 100% (i.e. 100% of one isomer and no other), especially the compounds or intermediate products with excess stereoisomer from 90% to 100%, especially with excess stereoisomer from 94% to 100%, and most particularly with excess stereoisomer from 97% to 100%. The terms "enantiomerically pure" and "diastereomers clean" should be understood the same, and then, respectively, the enantiomer excess mean excess stereoisomer in the mixture.

Pure stereoisomeric forms of the compounds and intermediates according to the invention can be obtained by means known in the field of methods. For example, the enantiomers can be separated from each other by selective crystallization of their diastereomeric salts with optically active acids. Alternative enantiomers can be separated by chromatography using a chiral stationary phase. These pure stereochemical isomeric forms may also be derived from the corresponding pure stereochemical isomeric forms of the appropriate starting compounds, providing stereospecific the durability of the reaction. Preferably, if you want a specific stereoisomer, the specified connection will be synthesized using stereospecific methods of obtaining. In these methods are mainly applied enantiomerically pure source materials.

The person skilled in the art it is clear that the compounds represented by formula (I)contain 5 chiral centers and therefore exist in stereoisomeric forms. Data 5 centers of chirality are indicated by numbers with asterisks(*1, *2, *3, *4 and *5) in the figure below.

The absolute configuration of each center of asymmetry can be specified using stereochemical designations R and S, this R and S configuration follows the rules described in Pure Appl. Chem. 1976, 45, 11-30. The preferred configuration bis-tertrahydrofuran ring ring is one in which the carbon atom *1 is R-configuration, the carbon atom and *2 is in S-configuration and the carbon atom *3 is R-configuration, in which the carbon atom *1 is in S-configuration, the carbon atom and *2 is the R-configuration and the carbon atom *3 is in S-configuration. The carbon atom *4 preferably is in the S-configuration and the carbon atom *5 is R-configuration.

To connect, presents the basic structure (I), the following 32 enantio Ernie form, specified in table A. Chiral carbon atoms are marked as indicated in the figure above.

Table a
Connection.*1*2*3*4*5.Connection.*1*2*3*4*5
andRRRRRqRRSSS
bRRRRSrRSRSS
RRRSRSSRRSS
dRRSRRtRSSRS
eRSRRRuSRSRS
f SRRRRvRSSSR
gRRRSSwSRSSR
hRRSRSxSSSRR
iRSRRSSSRSR
jSRRRSzSSRRS
kRRSSRaaSSSSR
1RSRSRbbSSSRS
mSR SRccSSRSS
nRSSRRddSRSSS
aboutSRSRRitRSSSS
pSSRRRffSSSSS

Connections l and w are the preferred enantiomerically pure forms, especially the connection 1.

Used the term "compounds of formula (I)" or "the present compounds" or similar term include the connection above, its N-oxides, salts, esters, stereoisomeric forms, racemic mixtures, prodrugs and metabolites, as well as his quaternion nitrogen derivatives.

These compounds, therefore, can be used in animals, preferably mammals and especially humans as a drug separately, in smesa the one with the other or in the form of pharmaceutical preparations.

In addition, the present invention relates to pharmaceutical preparations which contain as active ingredients an effective dose of at least one of the compounds of formula (I) and/or their physiologically tolerable salt in addition to customary pharmaceutically safe fillers and excipients. The pharmaceutical preparations generally contain from 0.1% to 90% by weight of compounds of formula (I) and/or its physiologically tolerable salt. The pharmaceutical preparations can be obtained by methods known to experts in this field. For this purpose, at least one of the compounds of formula (I) and/or its physiologically tolerated salts together with one or more solid or liquid pharmaceutical excipients and/or auxiliaries and, if necessary, in combination with other pharmaceutically active compounds is introduced into a suitable for administration form or dosage form which can then be used as a pharmaceutical in human or veterinary medicine.

Pharmaceutical preparations containing the compound according to the invention and/or its physiologically tolerated salt, may be administered orally, parenterally, for example intravenously, rectally, by inhalation or topically, the preferred route of administration will depend who know the case, for example, features of the flow being treated with disease. It is preferable to oral administration.

The person skilled in the art will easily determine based on the experience of excipients suitable for the desired pharmaceutical preparation. In addition to solvents, gel-forming agents, bases for suppositories, excipients for tablets and other carriers of active compounds are also used antioxidants, dispersing agents, emulsifiers, protivovspenivayushchie agents, flavorings, preservatives, soljubilizatory, substances to create a depot, buffer substances or dyes.

Compounds according to the present invention due to their antiretroviral properties, particularly anti-HIV activity, especially activity against HIV-1 that are applicable for the treatment of HIV-infected individuals and for preventive measures for these persons In General, the compounds according to the present invention may be suitable for the treatment of warm-blooded animals infected with viruses, the existence of which is indirect and depends on the enzyme protease. The condition, prevention or treatment which is performed by the compounds according to the present invention, particularly conditions associated with HIV and other pathogenic retroviruses, include AIDS, AIDS-associated complex (RC), progressive generalized lymphadenopathy (PGL), as well as chronic CNS diseases caused by retroviruses, such as HIV - mediated dementia and multiple sclerosis.

Compounds according to the present invention or any subgroup, therefore, can be used as a drug for the above conditions. Specified use as a medicine or method of treatment involves the systematic introduction of HIV-infected patients in an effective amount for correction of conditions associated with HIV and other pathogenic retroviruses, particularly HIV-1. Therefore, the compounds according to the present invention can be applied to obtain drugs suitable for treatment of conditions associated with HIV and other pathogenic retroviruses, in particular medicinal drugs with inhibitory activity against the retroviral protease.

The combination, including the connection with antiretroviral activity, and the connection according to the present invention can be used as a drug. Thus, the present invention also relates to a product containing (a) compound according to the present invention and (b) another connection with antiretroviral asset is awn, in the form of a combined preparation for simultaneous, separate or sequential use in the treatment of retroviral infections, especially retroviruses, are resistant to many drugs. Thus, to combat or treat HIV infections or infection or disease associated with HIV infections, such as acquired immunodeficiency syndrome (AIDS) or AIDS-associated complex (ARC), compounds according to this invention can sachetana be administered in combination, for example, the binding inhibitors, such as, for example, extrasolar, suramin, polyanion, soluble CD4; hybrid inhibitors, such as, for example, T20, T, SHC-C; inhibitors, coreceptor binding, such as, for example, AMD 3100 (Bicyclams), SO 779; reverse transcriptase inhibitors, such as, for example, foscarnet and prodrugs; nucleoside inhibitors of reverse transcriptase, such as AZT, 3TC, DDC, DDI, D4T, Abacavir, FTC, DAPD, the dOTC; a nucleotide Yod, such as, for example, RMEA, RMR; NNRTIs, such as nevirapine, delavirdine, efavirenz, 8 and 9-C1 TIBO (teveren), lowered, TMC-125, TMC-120, MKC-442, UC 781, capravirine, DPC 961, DPC963, DPC082, DPC083, calanolide A, SJ-3366, TSAO, 4"-diaminononane TSAO; inhibitors of RNA-ASE N, such as, for example, SP1093V, PD126338; inhibitors tyrosinekinase, such as, for example, RO-5-3335, K12, kastrofylakas k37; Inga is itonami integrase, such as, for example, L 708906, L 731988; protease inhibitors, such as, for example, APV, ritonavir, nelfinavir, saquinavir, indinavir, lopinavir, BMS 232632, DPC 681, DPC 684, tipranavir, AG1776, DMP 450, L 756425, PD178390; inhibitors of glycosylation, such as, for example, castanospermine, deoxynojirimycin.

The combination can provide a synergistic effect, whereby the infectivity of the virus and its associated symptoms can be prevented, significantly reduced or completely eliminated. Compounds according to the present invention can also be administered in combination with immunomodulators (e.g., bropirimine, antibodies against human alpha-interferon, IL-2, mentionedearlier, alpha-interferon and naltrexone) or antibiotics (for example, pentanedinitrile) to mitigate, control or destruction of HIV infection and its symptoms.

Upon receipt forms for oral administration of the compounds according to the present invention or their salts are mixed with suitable additives, such as excipients, stabilizers or inert diluents, and attach using conventional methods, the desired form of administration, such as tablets, coated tablet, hard capsules, aqueous, alcoholic or oily solutions. Examples of suitable inert carriers are Arabian gum, magnesium oxide, magnesium carbonate potassium phosphate, lactose, glucose or starch, in particular corn starch. In this case, the drug can be obtained in the form of dry or moist granules. Suitable oily excipients or solvents are vegetable or animal oils, such as vegetable oil or fish oil. Suitable solvents for aqueous or alcohol solutions are water, ethanol, sugar syrup, or a mixture thereof. The glycols and polypropylenglycol are also suitable as additional auxiliary substances for other forms of injection.

For percutaneous or intravenous administration of the active compounds, if necessary together with accepted for this substances such as soljubilizatory, emulsifiers or further auxiliaries, is administered in the form of a solution, suspension or emulsion. Compounds represented by formula (I)and their physiologically tolerated salts can also be liofilizovane and received lyophilizate can be used, for example, for injection or infusion preparations. Suitable solvents are, for example, water, physiological saline solution or alcohols, for example ethanol, propanol, glycerin, in addition, solutions of sugars, such as glucose or mannitol, or alternatively a mixture of the above solvents.

the right pharmaceutical forms for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the compounds represented by formula (I)or their physiologically-tolerated salts in a pharmaceutically acceptable solvent such as ethanol or water or a mixture of such solvents. If necessary, the drug can additionally contain other pharmaceutical excipients such as surfactants, emulsifiers and stabilizers, as the propellant. Such preparation usually contains the active compound in concentrations of from about 0.1 to 50%, in particular from about 0.3 to 3% by mass.

To increase the solubility and/or stability of the compounds represented by formula (I), the pharmaceutical preparations may be desirable to use α-, βor γ-cyclodextrins or their derivatives. The co-solvents, such as alcohols, can increase the solubility and/or stability of the compounds represented by formula (I)in pharmaceutical preparations. Upon receipt of an aqueous compositions of the addition salts of the considered compounds is undoubtedly more suitable due to their higher water solubility.

Appropriate cyclodextrins are α-, βor γ-cyclodextrins (CDS) or ethers and mixed ethers in which one or more hydroxy groups anhydroglucose OST the Cove cyclodextrin substituted by such groups, as C1-6-alkyl, especially methyl, ethyl or isopropyl, e.g. randomly methylated βCD; hydroxy-C1-6-alkyl, particularly hydroxyethyl, hydroxypropyl or hydroxybutyl; carboxy-C1-6-alkyl, particularly carboxymethyl or carboxyethyl; C1-6-alkylsulphonyl, especially acetyl; C1-6-allyloxycarbonyl-C1-6-alkyl or carboxy-C1-6-alkyloxy-C1-6-alkyl, especially carboxyphenoxypropane or carboxitherapy; C1-6-alkyl - carbonyloxy-C1-6-alkyl, especially 2-acetyloxybenzoic. Especially noteworthy as complexing agents and/or solubilization β-CD, statistically methylated β-CD, 2,6-dimethyl-β-CD, 2-hydroxyethyl-β-CD, 2-hydroxyethyl-γ-CD, 2-hydroxypropyl-γ-CD and (2-carboxymethoxy)propyl-β-CD and 2-hydroxypropyl-β-CD (2-SE-βCD).

The term "mixed ether" refers to derivatives of cyclodextrins, in which at least two of the hydroxy-group of the cyclodextrin tarifitsirovana different groups, such as, for example, hydroxypropyl and hydroxyethyl.

Interesting way of making combinations of the compounds of the present invention with cyclodextrin or its derivatives described in EP-A - 721, 331. Although described there praparatestevia compounds with antifungal activity they are equally interesting for receiving the antiretroviral compounds according to the present invention. The preparations described therein are particularly suitable for oral administration and contain as an active ingredient a compound with antifungal activity, a significant amount of cyclodextrin or its derivative as a solubilizer, the aqueous acid medium as a liquid carrier phase and an alcohol co-solvent, which greatly simplifies the obtaining of the drug. The taste of these drugs can also be improved by using pharmaceutically acceptable sweeteners and/or flavorings.

Other suitable methods of increasing the solubility of the compounds according to the present invention in the pharmaceutical preparations described in WO-94/05263, PCT - application PCT/EP 98/01773, EP-A-499299 and WO 97/44014, incorporated herein by reference.

In more detail, the compounds of the present invention can be applied to obtain a pharmaceutical preparation containing a therapeutically effective amount of particles consisting of a solid dispersion system comprising (a) compound of formula (I) and (b) one or more pharmaceutically acceptable water-soluble polymers.

The term "solid dispersion system" means a system in the solid phase (in contrast to liquid and gaseous phases), lucaus, at least two components, where one component dispersed more or less uniformly with respect to another component or components. When this dispersion component system is a system that is chemically and physically uniform or completely homogeneous or single-phase, as defined in thermodynamics, such a solid dispersion system referred to as "solid solution". Solid solutions are preferred physical systems, because their components are usually readily bioavailable to organisms in which they are inserted.

The term "solid dispersion system also includes a disperse system, which are less homogeneous compared with solid solutions. Such dispersed systems are not chemically and physically homogeneous or contain more than one phase.

Water-soluble polymer included in the particles, is simply a polymer that has an apparent viscosity of 1 to 100 MPa·when dissolved in 2% aqueous solution at 20°With solution.

Preferred water-soluble polymers are hydroxypropylmethylcellulose or GPMC. HPMC having a degree of substitution by methoxypropane from about 0.8 to 2.5 molar substitution hydroxypropionate groups from about 0.05 to 3.0, usually are water-soluble. The degree for which edenia methoxypropane refers to the average number mutilating groups on the glucose residue of a molecule of cellulose. Molar substitution hydroxypropionate groups refers to the average number of moles of propylene oxide, reacted with each anhydroglucose the remainder of the molecule of cellulose.

The particles described herein above, can be obtained using the initial receipt of solid dispersion system connections and then an optional grinding or crunching this dispersed system. There are various ways to obtain a solid dispersion systems, including extrusion melt, dry spray, evaporation of the solution, it is preferable to extrusion from the melt.

In addition, it may be convenient to convert antiretroviral compounds of the present invention in the form of nanoparticles having on its surface adsorbed modifier surface in sufficient quantity to maintain an effective average particle size less than 1000 nm. It is assumed that the applied surface modifiers include those that are associated physically with the surface of antiretroviral compounds, but does not have a chemical connection with antiretroviral connection.

Suitable surface modifiers preferably can be selected from known organic and inorganic pharmaceutical excipients. Such fillers include various polim the market, low molecular weight oligomers, natural compounds and surfactants. Preferred surface modifiers include nonionic and anionic surfactants.

Another interesting way of converting compounds of the present invention includes obtaining a pharmaceutical preparation in which antiretroviral compound incorporated in hydrophilic polymers, and put this mixture as a film coating on a lot of small balls, thereby obtaining the compound with good bioavailability, which can be easily obtained and which is suitable for pharmaceutical dosage forms for oral administration.

These balls include (a) a Central, rounded or spherical core, (b) covering the film of the hydrophilic polymer and antiretroviral agent, and (C) water polymer layer.

Substances suitable as cores balls, numerous, provided that these substances are pharmaceutically acceptable and have the appropriate size and stability. Examples of such substances are polymers, inorganic substances, organic substances and sugars and their derivatives.

Injected dose of the compounds according to the present invention or their physiologically tolerable with the and (salts) depends on the specific case and, as usual, adapted in each case to achieve the optimal effect. Thus, it depends, of course, on the frequency of administration and the effectiveness and duration of action of the compounds used in each case for treatment or prevention, but also on the type and severity of infection and symptoms, sex, age, weight and individual reactions in need of treatment of the human or animal and is therapy for acute situations or is preventive. Usually, the daily dose of the compounds of formula (I) in the case of the introduction of patient weighing approximately 75 kg is from 1 mg to 1 g, preferably 3 mg to 0.5 g

The dose can be administered in a single dose or can be divided into several, for example two, three or four separate doses.

Organic synthesis hexahydrofuro [2,3-b]furan-3-yl-N-{3-[(1,3-benzodioxol-5-ylsulphonyl)(isobutyl)amino]-1-benzyl-2-hydroxypropyl}carbamate

Synthesis hexahydrofuro[2,3-b]furan-3-yl-N-{3-[(1,3-benzo - dioxol-5-ylsulphonyl)(isobutyl)amino]-1-benzyl-2-hydroxy - propyl}carbamate carried out through the interaction of bis-tertrahydrofuran ring rings and the corresponding benzodioxathiepin, as set forth below.

1) Synthesis hexahydrofuro[2,3-b]furan-3-ol 5

Racemic synthesis of bis - tetrahydrofuran (bis-THF) 5 conduct as is provided in figure 1, according to the process according to Ghosh et al., J. Med. Chem. 39: 3278-3290 (1996). Conduct commercial reaction of 2,3-dihydrofuran N-yogakriya and propargilovyh alcohol in methylene chloride at 0-25°C for 2 hours to obtain jadefire 2 (yield 88%). Radical cyclization of jadefire 2 tributyltinhydride in toluene at 80°in the presence of catalytic amount of 2,2'-azobisisobutyronitrile (AIBN) allows to obtain the bicyclic acetate 3. Sonalities cleavage results in the formation of ketone 4. Recovery of the resulting ketone with sodium borohydride in ethanol at -15°With results in racemic endosperma 5 (see scheme 1).

Scheme 1

2) Synthesis of amerosport 8 N-{3-[(1,3-benzodioxol-5 - ylsulphonyl)(isobutyl)amino]-1-benzyl-2-hydroxypropyl}-amine

Restoring acylchlorides 9 using NaBH4in a mixture of methanol: tetrahydrofuran 1:1 (stage a, scheme 2 below) results racemate 10A and 10b, which divide and organize the interaction of the enantiomers with KOH in ethanol (stages B, C) to obtain the epoxide 11 according to published methods (Getman et al., J Med. Chem. 36: 288-291 (1993), Luly et al., J Org. Chem. 52(8): 1487-1492 (1987)). The epoxide was treated with an excess of isoamylamine in 2-propanol at boiling in a flask with reflux condenser (stage d) to obtain amerosport 12. Minisport 12 next is srabatyvayut 1,3-benzodioxol-5-ylsulphanilamide (stage e) obtaining amerosport 8 with carbobenzoxy (Cbz)-protected amine. Hydrogenation Cbz-group using 10% Pd/C and H2in methanol (stage f) results of the free amerosport 8. Data stage is conducted according to widely known published methods (Vazquez et al., J. Med. Chem. 38: 581-584 (1995), scheme 2).

Scheme 2

3) Synthesis hexahydrofuro[2,3-b]furan-3-yl-N-{3-[(1,3 - benzodioxol-5-ylsulphonyl)(isobutyl)amino]-1-benzyl-2-hydroxypropyl}carbamate

Spend the interaction of bis-tertrahydrofuran ring ligand 5 with disuccinimidylsulfite 6 and triethylamine in methylene chloride to obtain carbonate 7, which is mixed in situ with the amine 8. This connection leads to the final compound 13 (scheme 3). The connection 13 is a mixture of 2 diastereomers, in stereoisomeric forms defined for compounds 1 and w in table A. This mixture may be separated using well-known in the field of methods of separation.

Alternative pure enantiomeric forms, corresponding to connection 1 and w, hereinafter referred to as compounds 14 and 15 can be obtained by separation of racemic bis-THF 5 stage through enzymatic cleavage, as described in Tetrahedron Letters, 36, 4, (1995), 505-508, incorporated herein by reference. Enantiomerically pure intermediates bis-THF can be further subjected to reactions similar to those outlined in the output above, obtaining enantiomerically pure compounds 14 and 15.

Scheme 3

Experimental part

To a stirred solution of 500 mg of 3.84 mmol) (3R,3aS,6aR)-3-hydroxyhexanoate[2,3-b]-furan 5 (scheme 1) in CH2CL2(50 ml) at 25°C. add disuccinimidyl 6 (1.08 g, to 4.23 mmol) and triethylamine (0,77 g of 7.68 mmol). The resulting mixture was stirred for 6 h at 25°and add the amine 8 (scheme 2, 2,42 g, USD 5.76 mmol). The resulting solution was washed with water and dried over anhydrous Na2SO4. Evaporation of the solvent under reduced pressure yields a residue which is purified using chromatography (CH2Cl2/MeOH: 98/2) to obtain 1,36 g (62%) of inhibitor 13 (scheme 3) according to the present invention in the form of a white solid.

Range1H-NMR in CDCl3connection 13 consisted of the following: 7,4-7,1 (user. m, 7H), 6,9 (d, J=8,1 Hz, 1H), 6,1 (s, 2H), 5,7 (d, J=5,1 Hz, 1H), 5 (d, J=6,7 Hz, 1H), 5,1-4,8 (user. m, 1H), 4-3,4 (user. m, 7H), 3.25 to 2,6 (user. m, 6N), 2,35-1,2 (user. m, 4H), 1,17-0,7 (user. m, 6N). Also range of13C-NMR in Dl3consisted of the following: 151 (CO), 148-138 (C-O), 132-129,4-129,34-128,55-126,67-126,59-123,1 (AG-), 109,16-108,36-107,52-102,36 (SN-O), 73,43-72,58-70,73-69,47-58,87-53,78-45,04-36-35-27, 27-25,76-20,1-19,85. The mass spectrum showed the expected ion (m/z 577, corresponding to M++ N.

The obtained compound 13 and compound 14 was then tested for biological is practical and antiviral activity in several tests, as is described below. Suddenly discovered that these compounds are more effective and more active as a protease inhibitor in comparison with the previously known compounds.

Antiviral test:

Compound 13 and compound 14 was then tested for antiviral activity in cell test. The test showed that these compounds show considerable activity against HIV compared to the wild type laboratory strain of HIV. Cell test was performed according to the following method.

Experimental cell test:

HIV - or false-infected MT4 cells were incubated for 5 days in the presence of various concentrations of inhibitor. At the end of the incubation period for all HIV - infected cells are killed by virus replication in the control cultures in the absence of inhibitor. Cell viability was assessed by measuring the concentration of MTT, a yellow water-soluble tetrazole dye, preobrazovyvayutsya in purple the water-insoluble formazan in mitochondria only living cells. After dissolving the obtained crystals formazan using isopropanol was performed measuring the absorbance of a solution at 540 nm. Value is directly correlated with the number of live cells remaining in culture after five days of incubation. Inhibitory asset is ity compounds were monitored with the help of virus - infected cells and was expressed as IC 50and IC90. These values represent the number of connections required to protect 50% and 90%, respectively, of cells from cytopathogenic effect of the virus. The toxicity of the compounds was evaluated using a false - infected cells and was expressed as CC50representing the concentration required for inhibition of cell growth by 50%. Index selectivity (SI) (ratio CC50/IC50) reflects the selectivity of activity inhibitor against HIV.

Results cell test:

Compound 13 showed IC50equal to 1.1 nm, and IC902.4 nm (representing average values for 12 definitions), in relation to the HIV-1 strain LAI. CC50for compound 13 was 15.3 μm and SI are equal 13900. Compound 14 showed IC50equal to 0.8 nm, with respect to the HIV-1 strain LAI. CC50to connect 14 amounted to more than 100 microns.

Test binding proteins;

It is known that proteins of human serum, such as albumin (HSA) and acid glycoprotein alpha-1 (AAG), are associated with many drugs, leading to a possible decrease in the effectiveness of these compounds. To determine whether the undesirable effect of this binding compound 13 was evaluated for anti-HIV activity of the compounds in the presence of physiological concentrations of HSA or AAG, this mod is a way to measure the effect of the binding of the inhibitor protein data.

The results:

In a normal experiment HAS at a concentration of 45 mg/ml had no effect on the efficiency of the connection 13. AAG at a concentration of 2 mg/ml reduced the efficiency of the connection 13 in two to four times.

Antiviral spectrum:

Due to the increased emergence of HIV strains that are resistant to drugs, compound 13 and compound 14 was evaluated for their effectiveness against HIV strains carrying different mutations. These mutations are associated with resistance to protease inhibitors and are expressed by the viruses of various degrees of phenotypic cross-resistance to five available commercially available drugs (saquinavir, ritonavir, nelfinavir, indinavir and APV).

The results:

Table 1 presents the results of this testing as values IC50in microns. Compounds 13 and 14 are effective inhibitors even data of resistant viruses at low concentrations, which is lower than the achieved levels in the plasma. Figure 2 represents a comparison of the fold resistance of different strains of the virus to commercially available protease inhibitors and compounds 13. Strains unexpectedly showed an increased sensitivity to compound 13 in comparison with drugs saquinavir (SAQ), ritonavir (RIT), indinavir (IND), nelfinavir (NEL) and am is renauer (DFID).

Table 1

The activity of compounds 13 and 14 and 5

commercial protease inhibitors against strains

HIV resistant to protease inhibitors
StrainMutations associated with resistanceSaquinavirRitonavirIndinavirNelfinavirAPVThe connection 14Connection 13
LAI 0,00790,03040,02760,03310,03590,00080,0014
r13020L10I, K20R, M361, 154V, A71V, V82T, I84V3,519.28 are1,383,750,1070,00080,0014
r13021L01I, K20R, L24I, M36I, 154V, L63P, A71V, V82T, I84V1,54>101,754,100,2120,00150,0055

Table 1 (continued)
StrainMutations associated with resistanceSaquinavirRitonavirIndinavirNelfinavirAeronav the p The connection 14Connection 13
r13022K20R, M36I, M46I/M, 154V, L63P, A71V/I, V82T, L90M0,665>101,704,030,1810,00110,0017
r13023L10I, M36I/M, I54V/I, L63P, A71V, G73S, I84V, L90M0,7833,820,6801,020,2170,00280,0068
r13024L10I, M36I, L63P, A71V, G73S, I84V, L90M2,092,851,073,260,1800,00550,0081
r13025L10I, M46I, L63P, A71V, I84Vof) 0.1572,241,259,130,6610,03280,0454
r13026L10I, M46I, I54V, L63P, A71V, V82T, I84V1,99>102,721,220,1360,00080,0014
r13027L10M/I, K20R, M36I, L63P, A71V, G73S, V77I, I84V, L90M2,923,140,7143,20to 0.6450,00730,0074
r13029L10I/L, M36I, M46L, L63P, A71V, I84V, N88D, L90M2,613,600,9223,790,2140,00520,007
r13030L10V/I, M36I, I54V, L63P, A71V, V82T, L90M0,1732,990,5740,9950,0491is 0.00020,0004
r13031G48V, I54V, V77I, V82A, L90M/I0,6730,8560,15420,4970,03410,00030,0005

2,83
Table 1 (continued)
StrainMutations associated with resistanceSaquinavirRitonavirIndinavirNelfinavirAPVThe connection 14Connection 13
r13033L10I, M46L, I54V, L63P, A71V, V82A, L90M0,05213,470,8481,190,1940,00110,0017
r13034L10I, M36I, I54V, L63P, A71V, I84V1,01>100,6381,990,6770,00550,0080
r13035D30N, L63P, V77I, N88D0,00530,03110,00740,3610,0105is 0.00020,0003
r13036l10I, L63P, A71V, G73S, L90M0,5140,6383,250,4450,00290,0054
r13037L10I, M64I, I54V, L63P, A71T, V77I, V82A, L90M0,02742,270,1960,6560,1650,00050,0003

Bioavailability:

Next, we measured the absorbance of compound 13 when administered orally to rats to determine bioavailability. The compound was administered via gastric tube (by gavage) to rats at a single dose of 20 mg/kg in PEG 400. Animals were scored at different time points after injection, took whole blood and received the serum in the normal way. The concentration in serum was determined by titration of the activity of the sample in relation to HIV according to the method described above.

Of the definition of bioavailability:

The results are presented in table 2 and graphically illustrated by means of figure 1. The concentration of compound 13 in the serum reaches 1 μm, 1 h after oral administration and even exceeds the IC50compounds that are active against strains resistant to protease inhibitors, up to 3 hours after administration. Therefore, the connection 13 has a significant advantage, as expressed in therapeutic advantage. This unexpectedly high bioavailability in PLA the IU is particularly important in relation to drug-resistant viruses.

Table 2

The concentration of compound in serum after oral administration
Time after injection

(minutes)
The concentration of compound 13 in

serum (µm)
00,0000
600,9858
1800,6869
3000,2159

The present invention may be embodied in other specific forms without deviating from the essence or essential characteristics. The described embodiments are considered in all respects only as illustrative, but not restrictive. Scope of the present invention, therefore, is defined by the attached claims and not the foregoing description. All changes that fall within the meaning and scope of equivalence of the claims are included in the scope of the claims.

The following are the data of NMR spectra of enantiomeric compounds 14:

1H-NMR (Dl3): 7.35-7.2 (m, 6H), 7.17 (d, J=1.7Hz, 1H), 6.85 (d, J= 8.1Hz, 1H), 6.1 (s, 2H), 5.65 (d, J=4.96Hz, 1H), 5 (d, J=6.7Hz, 1H), 4.9-5 (m, 1H), 3.9 (dd, J=9.5 Hz and J=6.6Hz, 1H), 3.8-3.6 (m, 5H), 3.6 (dd, J=9.5Hz, and J=6.6Hz, 1H), 3.1 (dd, J=15.1 and J=8.6Hz, 1H), 3.1-2.85 (m, 4H), 2.8 (d, J=13.4Hz, J=6.7Hz, 1H), 2 (br.s, 1H), 1.85-1.8 (m, 1H), 1.65-1.55 (br.s, 2H), 0.9 (d, J=6.6Hz, 3H), 0.85 (d, J=6.6Hz, 3H).

13C-NMR (who Dl 3): 155.6 (CO), 151.6-148.4 (C-O), 137.5-131.5-129.4128.6-126.7-123.1 (Ar-C), 109.2 (CH-O)-108.4-107.5 (CH-Ar), 102.4 (O-CH2-O), 73.4-72.6-70.7-69.5-58.8-55.3-53.7-45-35.3-27.3-25.9-20.1-19 .8.

Mass spectroscopy gave an unexpected ion (m/z 577, corresponding to M++N.

1. The compound represented by the formula

his salt, stereoisomeric form, racemic mixture.

2. Connection on p. 1 in enantiomerically pure form.

3. Connection under item 1 or 2, representing

his salt.

4. The compound according to any one of paragraphs. 1-3 in the form of a pharmaceutically tolerable salt.

5. Pharmaceutical composition having the effect of retroviral protease inhibitor containing an effective amount of at least one compound according to any one of paragraphs. 1-4 and a pharmaceutically tolerable excipient.

6. A method of inhibiting retroviral protease in a mammal infected with the indicated retrovirus, comprising introducing the compound according to any one of paragraphs. 1-4 in number, the inhibitory protease specified needy in mammals.

7. A method of treating or combating infection or disease associated with retroviral infection in a mammal, comprising introducing an effective amount of at least one compound according to any one of paragraphs. 1-4 specified mammal.

8. SPO is about on p. 6 or 7, characterized in that said mammal is a human.

9. Method of inhibiting replication of a retrovirus, including the impact on retrovirus effective amount of at least one compound according to any one of paragraphs. 1-4.

10. The method according to p. 6, or 7, or 9, wherein the retrovirus is a human immunodeficiency virus (HIV).

11. The method according to p. 10, characterized in that the HIV virus is a strain that is resistant to many drugs.

12. The compound according to any one of paragraphs. 1-4, is used as active ingredient in the manufacture of a medicinal product for treating or combating infection or disease associated with retroviral infection, in mammals.

13. The compound according to any one of paragraphs. 1-4, is used as active ingredient in the manufacture of a drug for inhibiting retroviral protease in a mammal infected with the indicated retrovirus.

14. The compound according to any one of paragraphs. 1-4, is used as active ingredient in the manufacture of a drug for inhibiting replication of a retrovirus.

15. The compound according to any one of paragraphs. 12-14, where the retrovirus is a human immunodeficiency virus (HIV).

16. The compound according to any one of paragraphs. 12-14, where the HIV virus is a strain resistant to many drugs.



 

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FIELD: organic chemistry, biochemistry, medicine.

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4 dwg, 1 tbl, 5 ex

and tnf-" target="_blank">

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EFFECT: improved and valuable pharmaceutical properties of composition.

23 cl, 2 tbl, 3 dwg, 11 ex

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