KR101327772B1 - Broadspectrum 2-amino-benzothiazole sulfonamide HIV protease inhibitors - Google Patents

Abstract

상기 식에서, R₁은 헥사하이드로푸로[2,3-b]푸라닐, 테트라하이드로푸라닐, 옥사졸릴, 티아졸릴, 피리디닐, 또는 C_{1 - 6}알킬, 하이드록시, 아미노, 할로겐, 아미노C_{1- 4}알킬 및 모노- 또는 디(C_1-4알킬)아미노로부터 독립적으로 선택되는 하나 이상의 치환체로 임의로 치환된 페닐이고; R₂는 수소 또는 C_{1 - 6}알킬이고; L은 직접 결합, -0-, C_{1 - 6}알칸디일-O- 또는 -O-C_{1 - 6}알칸디일이고; R₃은 페닐C_{1 - 4}알킬이고; R₄는 C_{1 - 6}알킬이고; R₅는 수소 또는 C_{1 - 6}알킬이고; R₆은 수소 또는 C_{1 - 6}알킬이다. The use of 2-amino-benzothiazole of formula (I) in the manufacture of a medicament useful for inhibiting HIV protease in a mammal infected with a mutant HIV protease:

Wherein, R ₁ is hexahydro-furo [2,3-b] furanyl, tetrahydrofuranyl, oxazolyl, thiazolyl, pyridinyl, or C _{1 - 6} alkyl, hydroxy, amino, halogen, amino C _{1 - 4} alkyl, mono- or di (C _1-4 alkyl) with one or more substituents independently selected from amino optionally substituted phenyl; R ₂ is hydrogen or C _{1 - 6} alkyl, and; L is a direct bond, -0-, C _{1 - 6} alkanediyl -O- or -OC _{1 - 6} alkanediyl gt; R ₃ is phenyl-C _{1 - 4} alkyl; R ₄ is C _{1 - 6} alkyl; R ₅ is hydrogen or C _{1 - 6} alkyl, and; R ₆ is hydrogen or C _{1 - 6} is alkyl.

Description

Broadspectrum 2-amino-benzothiazole sulfonamide HIV protease inhibitors}

This application claims priority to EP applications EP 02078231 and EP applications 02078231 and US Provisional Application No. 60 / 427,862, filed August 2, 2002, which are incorporated herein by reference.

The present invention relates to a diagnostic kit comprising 2-amino-benzothiazole sulfonamide, an aspartic protease inhibitor, in particular a widespread HIV protease inhibitor, a method of preparation thereof and a pharmaceutical composition comprising the same. The present invention also relates to the combination of this 2-aminobenzoxazole sulfonamide with another antiviral agent. It further relates to the use as reference compound or reagent in the assay.

Viruses that cause acquired immune deficiency syndrome (AIDS) include different names, including T-lymphocyte virus III (HTLV-III) or lymphadenopathy related virus (LAV) or AIDS-associated virus (ARV) or human immunodeficiency virus (HIV). Known as To date, two distinct families have been identified: HIV-1 and HIV-2. Hereinafter, HIV will normally be used to name these viruses.

One of the important pathways in the retroviral life cycle is the processing of polyprotein precursors by aspartic proteases. For example, with the HIV virus, gag-pol protein is processed by HIV protease. In order for precursor polyproteins to be correctly processed by aspartic proteases, infectious virions are assembled to target aspartic proteases of greater interest for antiviral therapies. HIV proteases are of particular interest in the treatment of HIV.

HIV proteases (PIs) commonly combined with other anti-HIV compounds such as nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleotide reverse transcriptase inhibitors (NtRTIs) or other proteases Administered to AIDS patients. Despite the fact that these antiretroviruses are very useful, they are generally limited, i.e., the enzymes targeted in the HIV virus may be mutated so that known drugs are less effective or even invalidated against these mutant HIV viruses. Can be. Or in other words, the HIV virus increases resistance to useful drugs.

Resistance to inhibitors of retroviruses, particularly HIV viruses, is a major cause of treatment failure. For example, half of patients receiving anti-HIV combination therapy do not fully respond to treatment because of the resistance of the virus to one or more drugs used. In addition, the delivery of resistant viruses to newly depleted patients results in severely limited treatment options for patients who have not administered these drugs. Thus, there is a need for new compounds for retroviral treatment, in particular AIDS. There is a particular need for compounds that are active against wild type HIV viruses as well as general HIV viruses with increased resistance.

Known antiretrovirals, often administered in a combination therapy regimen, result in resistance as a result. This often causes the clinician to raise the plasma concentration of the active drug to make the antiretroviral agent effective again against the mutated HIV virus. The result is a high unwanted increase in the pill administered. Increased plasma concentrations can also result in increased risk of noncompliance with the prescribed treatment. As such, compounds that are active against a broad range of HIV mutations are important, with little or no ratio between activity against mutant HIV viruses and activity against wild type HIV viruses (also defined as fold resistance or FR). It is also important.

Finding compounds with high activity against wild-type and a wide range of mutations is also important because it can reduce the pill burden while keeping therapeutic concentrations to a minimum. One way of reducing this pill burden is to find anti-HIV compounds with good bioavailability, ie, good pharmacokinetic and metabolic profiles, to minimize daily doses and to minimize the number of pills taken.

Another important property of a good anti-HIV compound is to minimize the plasma protein binding of the inhibitor or to be ineffective against its potential.

As such, there is a high medical need for protease inhibitors that can fight a wide range of mutations in HIV viruses with little to no change in resistance. Further advantages are protease inhibitors with little or no potency due to good bioavailability and plasma protein binding.

To date several protease inhibitors are commercially available or under development. One particular core structure (below) has been disclosed in numerous references. See, for example, WO 95/06030, WO 96/22287, WO 96/28418, WO 96/28463, WO 96/28464, WO 96/28465 and WO 97/18205. These disclosed compounds are described as retroviral protease inhibitors.

WO 99/67254 describes 4-substituted-phenyl sulfonamides capable of inhibiting multi-drug resistant retroviral proteases.

Surprisingly, it has been found that the 2-amino-benzothiazole sulfonamides of the present invention have desirable pharmacological and pharmacokinetic profiles. In addition to being active against wild type HIV viruses, they exhibit broad activity against a variety of mutant HIV viruses that are resistant to known proteases.

The present invention relates to 2-amino-benzothiazole protease inhibitors of formula (I), and N-oxides, salts, stereoisomeric forms thereof, in the preparation of a medicament useful for inhibiting HIV protease in a mammal infected with a mutant HIV protease. Relates to the use of semi-mixtures, prodrugs, esters and metabolites:

Where

R ₁ is C _{1 - 6} alkyl, hydroxy, amino, halogen, amino C _{1 - 4} alkyl, mono- or di (C _1-4 alkyl), optionally with one or more substituents selected independently from substituted phenyl, from amino-hexafluoro Hydrofuro [2,3-b] furanyl, tetrahydrofuranyl, oxazolyl, thiazolyl, or pyridinyl;

R ₂ is hydrogen or C _{1 - 6} alkyl, and;

L is a direct bond, -0-, C _{1 - 6} alkanediyl -O- or -OC _{1 - 6} alkanediyl gt;

R ₃ is phenyl-C _{1 - 4} alkyl;

R ₄ is C _{1 - 6} alkyl;

R ₅ is hydrogen or C _{1 - 6} alkyl, and;

R ₆ is hydrogen or C _{1 - 6} is alkyl.

In particular the mammal is a human.

The compounds of the present invention are particularly useful for the preparation of drugs useful for inhibiting a wide range of HIV proteases.

Of particular interest are the free base, salt or N-oxide forms of the compounds of formula (I), and their stereoisomeric forms.

Also, of interest in the manufacture of a drug to inhibit the HIV protease in a mammal infected with a mutant HIV protease R ₁ is C _{1 - 6} alkyl, hydroxy, amino, halogen, amino C _{1 - 4} alkyl and mono Or phenyl, hexahydrofuro [2,3-b] furanyl, tetrahydrofuranyl, oxazolyl, thiazolyl, optionally substituted with one or more substituents independently selected from di (C _1-4 alkyl) amino; Use of a compound that is pyridinyl.

A mutation of an HIV protease enzyme is defined as an HIV protease enzyme having at least one mutation in its amino acid sequence with respect to the amino acid sequence of a wild type HIV protease. For the purpose of referring to mutations herein we use the HXB2 wild type reference (HIV IIIB LAI wild type) whose sequence can be found in NIH's GenBank.

The criterion of "sensitivity" or otherwise "tolerance" for drugs of HIV protease enzymes is established by commercially available HIV protease inhibitors. As described above, commercially available HIV protease inhibitors may loosen the efficacy of HIV virus populations in patients over time. Under the pressure that certain HIV protease inhibitors are present, the current HVI virus population, mainly wild type HIV protease enzymes, is mutated to different mutations that may be less susceptible to the same HIV protease inhibitor. If this occurs, discuss resistant mutations. Multi-drug resistant HIV proteases are discussed when these mutations are resistant to one specific HIV protease inhibitor, as well as to one or many other commercially available HIV protease inhibitors. Of HIV protease inhibitor of mutant HIV protease inhibitor of the EC ₅₀ of the HIV protease inhibitor for the wild-type HIV protease inhibitor is one method that represents the resistance of a mutant to a particular HIV protease inhibitor EC ₅₀ To write the ratio between. This ratio is called fold resistance (FR).

Many mutations that have emerged in hospitals have at least 100 fold resistance to commercially available HIV protease inhibitors such as saquinobir, indinavir, ritonavir, and nelpinavir. Clinically related mutations of the HIV protease enzyme can be characterized by, for example, mutations at amino acid positions 10, 71 and / or 84. Examples of clinically relevant mutant HIV proteases are listed in Table 1.

Compounds of the present invention exhibit fold resistance in the range of 0.01 to 100 against at least one predominantly, clinically relevant mutant HIV protease. Certain groups of compounds of formula (I) are those of formula (I) that exhibit fold resistance to at least one mutant HIV protease in the range of 0.1 to 100, suitably in the range of 0.1 to 50, more suitably in the range of 0.1 to 30. Compound. Of particular interest are compounds of formula (I) that exhibit fold resistance in the range of 0.1 to 20 for at least one mutant HIV protease, and of further interest are 0.1 to 10 for at least one mutant HIV protease. A compound of formula (I) exhibiting a range of fold resistance.

The present invention therefore relates to the use of the compounds of formula (I) in the manufacture of a medicament useful for inhibiting the replication of HIV viruses with mutant HIV proteases, in particular with multi-drug resistant mutant HIV proteases. The invention also relates to the use of a compound of formula (I) in the manufacture of a medicament useful for treating or combating a disease associated with HIV virus infection wherein the protease of the HIV virus is a mutation, in particular a multi-drug resistant mutant HIV protease.

In other words, the present invention comprises contacting a mutant HIV protease in a mammal with an effective amount of a compound of formula (I), thereby inhibiting the mutant HIV protease, in particular a multi-drug resistant HIV protease, in a mammal infected with the mutant HIV protease. It is about a method. The invention inhibits the replication of mutant HIV proteases, in particular HIV viruses with multi-drug resistant mutant HIV proteases, comprising contacting an HIV virus with a mutant HIV protease with an effective amount of a compound of formula (I) in a mammal. It is about a method. The present invention further comprises contacting an HIV virus with an effective amount of a compound of formula (I), a protease of the HIV virus infecting a mammal, wherein the protease of the HIV virus is a mutation, in particular a multi-drug resistant mutant HIV protease. A method of treating or combating a disease in a mammal associated with an HIV virus infection.

Of particular interest are compounds of the invention that are mutated in at least one of amino acid positions 10, 71 or 84 or in a combined position of at least two of these positions or in a combined position of at least all three of these positions It may be useful in the manufacture of a drug for the treatment of a subject infected with a mutant HIV protease comprising a.

Basic nitrogen can be quaternized using any agent known to those skilled in the art, such as, for example, lower alkyl halides, dialkyl sulfates, long chain halides and aralkyl halides.

When the term "substituted" is used when defining a compound of formula (I), the expression "substituted" is substituted with one or more hydrogens on the specified atom being selected from the specified group, provided that the sum of the indicated atoms It does not exceed the valence, and means that the substitution results in a chemically stable compound, i.e., a compound that is sufficiently strong to survive in isolation from the racemic mixture to a useful degree of isolation and formulation into the therapeutic agent.

As used herein, the term "halo" or "halogen" as a group or part of a group is fluoro, chloro, bromo or iodo.

The term as part of the group or the group "C _{1 - 4} alkyl" is, for example, methyl, ethyl, propyl, butyl and 2-methyl-is defined as the straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as propyl.

Group or term as part of the group "C _{1 - 6} alkyl" is C _{1 -} groups and pentyl, hexyl, 2-methylbutyl, 1 to 6 carbon atoms having straight and branched, such as _{3-methyl-4-pentyl-defined} alkyl It is defined as a chain saturated hydrocarbon radical.

The term as part of the group or the group "C _{1 - 6} alkanediyl" is, for example, methylene, ethane-1,2-diyl, propane-1,3-diyl, propane-1,2-diyl, butane-1,4 Divalent, having 1 to 6 carbon atoms, such as diyl, pentane-1,5-diyl, hexane-1,6-diyl, 2-methylbutane-1,4-diyl, 3-methylpentane-1,5-diyl and the like It is defined as a straight and branched chain saturated hydrocarbon radical.

As used herein, the term "one or more" includes the possibility of available atoms being all available suitably one, two or three preferably substituted.

As used throughout this specification, the term “prodrug” refers to pharmacologically acceptable derivatives such as esters, amides and phosphate derivatives, wherein the in vivo biological conversion product of the derivative is an activity defined in the compound of formula (I). Goodman and Gilman (The Pharmacological Basis of Therapeutics, 8th ed, McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs", p 13-15) describe conventional prodrugs and are cited herein. do. Prodrugs of the compounds of the present invention are prepared by modifying functional groups present in the compounds, in which modifications are converted to parent compounds in vivo or in general manipulation. Prodrugs include a compound of the invention, wherein a hydroxy group, such as a hydroxy group on an asymmetric carbon atom or an amino group, is bound to a group and free hydroxy or free when the prodrug is administered to a patient Each is cleaved with amino.

General examples of prodrugs are described, for example, in WO 99/33795, WO 99/33815, WO 99/33793 and WO 99/33792, all of which are incorporated by reference.

Prodrugs are characterized by good water solubility, increased bioavailability and are readily metabolized in vivo as activity inhibitors.

In therapeutic use, the salt of the compound of formula (I) is a pharmaceutically or physiologically acceptable counter ion. However, salts with pharmaceutically unacceptable counter ions can also find use in the preparation or purification of pharmaceutically acceptable compounds of formula (I). All salts are pharmaceutically acceptable or not, or all are included within the scope of the present invention.

Pharmaceutically acceptable or physiologically acceptable addition salt forms that the compounds of the present invention can form include suitable acids, such as, for example, haloacids such as hydrochloric acid or hydrogen bromide; Sulfuric acid; nitric acid; Inorganic acids such as phosphoric acid; Or for example acetic acid, propanoic acid, hydroxyacetic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid It can be conveniently prepared under the use of organic acids such as cyclic acid, salicylic acid, p-amino-salicylic acid, and palm acid.

Conversely, the acid addition salt form can be converted to the free base form by treatment with a suitable base. Compounds of formula (I) comprising acidic protons can also be converted to their nontoxic metal or amine addition salt forms by treating appropriate organic and inorganic bases. Suitable base salt forms are, for example, ammonium salts, alkali and alkaline earth metal salts such as lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases such as benzatin, N-methyl, -D-glucamine , Hydramine salts, and salts with amino acids such as alkynine, lysine and the like.

Conversely, the base addition salt form can be converted to the free acid form by treating a suitable acid acid.

The term "salt" also includes hydrates and solvent addition forms in which the compounds of the present invention may form. Examples of such forms are hydrates, alcoholates and the like.

The N-oxide form of the compounds of the invention means that the compounds of formula (I) in which one or several nitrogen atoms are oxidized to so-called N-oxides.

The compounds of the present invention may also be present in the form of their tautomers. Although not explicitly shown in the above formula, the above forms are intended to be included within the scope of the present invention.

As used herein, the stereochemically isomeric forms of the compounds of the invention refer to all possible compounds formed with the same atoms bonded by the same bonding sequence having different three-dimensional structures that are not interchangeable with the compounds of the invention. define. Unless otherwise stated or indicated, chemical nomenclature of a compound includes mixtures of all possible stereochemically isomeric forms possessed by the compound. The mixture may comprise all the diastereomers and / or enantiomers of the basic molecular structure of the compound.

All stereochemically isomeric forms of the compounds of the present invention, either in pure form or in admixture, are intended to be within the scope of the present invention. The pure stereoisomeric forms and intermediates of the compounds referred to in the present invention define isomers substantially free of other enantiomers or diastereomers and / or enantiomers of the same basic molecular structure of said compounds or intermediates. In particular, the term 'stereochemically pure' refers to at least 80% or more (ie, at least 90% of one isomer and at most 10% of other possible isomers) to 100% of stereoisomers (ie, 100% of one isomer and other ), More particularly compounds having 90% to 100% stereoisomers, compounds having intermediates, very more particularly 94% to 100% stereoisomers, most particularly 97% to 100% stereoisomers Or to an intermediate

The terms 'enantiomerically pure' and 'diastereomeric pure' shall be understood in a similar manner, but relate to enantiomeric and diastereomeric excess, respectively, in the mixture in question. Pure stereoisomeric forms of the compounds and intermediates of the invention can be obtained by applying known methods. For example, enantiomers can each be separated by optically selective crystallization of the active acid and its diastereomeric salts. Enantiomers can also be separated by chromatographic techniques using chiral stationary phases. Such pure stereochemically isomeric forms can be derived from the corresponding pure stereochemically isomeric forms of suitable starting materials, provided that the reaction occurs stereospecifically. Preferably, if a particular stereoisomer is desired, the compound may be prepared by stereospecific preparation. These methods can benefit from using enantiomerically pure starting materials.

Diastereomeric racemates of formula (I) can be separated by known methods. Suitable physical separation methods which can advantageously be applied are, for example, selective crystallization and chromatography, eg column chromatography.

It will be apparent to those skilled in the art that it includes at least one asymmetric center and may exist in other stereoisomeric forms. The asymmetric center is indicated by an asterisk (*) as shown in the following figure.

The absolute configuration of each asymmetric center present in the compound of formula (I) can be represented by the stereochemical descriptors R and S, wherein the R and S symbols are defined in Pure Appl. Chem. Corresponds to the rules described in 1976, 45, 11-30. The carbon atom represented by an asterisk (*) and having a hydroxy group preferably has an R configuration. Carbon atoms represented by an asterisk (*) and having an R ³ group preferably have an S configuration.

The present invention is also intended to include all isotopes of atoms occurring on the compounds of the present invention. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example, without limitation, the isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.

As used herein, the term "compound of formula (I)", or "compound of the present invention" or similar term refers to a compound of general formula (I), N-oxides, salts, stereoisomeric forms, racemic mixtures thereof, Prodrugs, esters and metabolites, and their quaternized nitrogen analogues.

Some of the compounds of formula (I) below are described in WO 95/06030:

{(1S, 2R) -3-[(2-amino-benzothiazole-6-sulfonyl) -isobutyl-amino] -1-benzyl-2-hydroxypropyl} -carbamic acid benzyl ester;

{(1S, 2R) -3-[(2-amino-benzothiazole-6-sulfonyl) -isobutyl-amino] -1-benzyl-2-hydroxypropyl} -carbamic acid pyridin-3-ylmethyl ester;

{(1S, 2R) -3-[(2-amino-benzothiazole-6-sulfonyl) -isobutyl-amino] -1-benzyl-2-hydroxypropyl} -carbamic acid thiazol-5-yl Methyl esters;

{(1S, 2R) -3-[(2-amino-benzothiazole-6-sulfonyl) -isobutyl-amino] -1-benzyl-2-hydroxypropyl} -2- (2,6-dimethyl -Phenoxy) -acetamide;

3-amino-{(1S, 2R) -3-[(2-amino-benzothiazole-6-sulfonyl) -isobutyl-amino] -1-benzyl-2-hydroxypropyl) -2-methyl- Benzamide;

4-amino-{(1S, 2R) -3-[(2-amino-benzothiazole-6-sulfonyl) -isobutyl-amino] -1-benzyl-2-hydroxypropyl} -2-methyl- Benzamide;

5-amino-{(1S, 2R) -3-[(2-amino-benzothiazole-6-sulfonyl) -isobutyl-amino] -1-benzyl-2-hydroxypropyl} -2-methyl- Benzamide;

N-{(1S, 2R) -3-[(2-amino-benzothiazole-6-sulfonyl) -isobutyl-amino] -1-benzyl-2-hydroxypropyl} -2-methyl-benzamide ;

N-{(1S, 2R) -3-[(2-amino-benzothiazole-6-sulfonyl) -isobutyl-amino] -1-benzyl-2-hydroxypropyl} -4-hydroxy-2 -Methyl-benzamide;

N-{(1S, 2R) -3-[(2-amino-benzothiazole-6-sulfonyl) -isobutyl-amino] -1-benzyl-2-hydroxypropyl} -3-hydroxy-2 -Methyl-benzamide; And

{(1S, 2R) -3-[(2-Amino-benzothiazole-6-sulfonyl) -isobutyl-amino] -1-benzyl-2-hydroxypropyl} -carbamic acid (S)-(tetra Hydrofuran-3-yl) esters.

The present invention therefore relates to compounds of formula (I) and to their N-oxides, salts, stereoisomeric forms, racemic mixtures, prodrugs, esters and metabolites:

Where

R ₁ is C _{1 - 6} alkyl, hydroxy, amino, halogen, amino C _{1 - 4} alkyl, mono- or di (C _1-4 alkyl), optionally with one or more substituents selected independently from substituted phenyl, from amino-hexafluoro Hydrofuro [2,3-b] furanyl, tetrahydrofuranyl, oxazolyl, thiazolyl, or pyridinyl;

R ₂ is hydrogen or C _{1 - 6} alkyl, and;

L is a direct bond, -0-, C _{1 - 6} alkanediyl -O- or -OC _{1 - 6} alkanediyl gt;

R ₃ is phenyl-C _{1 - 4} alkyl;

R ₄ is C _{1 - 6} alkyl;

R ₅ is hydrogen or C _{1 - 6} alkyl, and;

R ₆ is hydrogen or C _{1 - 6} alkyl, and,

Provided that the compound is {(1S, 2R) -3-[(2-amino-benzothiazole-6-sulfonyl) -isobutyl-amino] -1-benzyl-2-hydroxypropyl} -carbamic acid benzyl ester ;

{(1S, 2R) -3-[(2-amino-benzothiazole-6-sulfonyl) -isobutyl-amino] -1-benzyl-2-hydroxypropyl} -carbamic acid pyridin-3-ylmethyl ester;

{(1S, 2R) -3-[(2-amino-benzothiazole-6-sulfonyl) -isobutyl-amino] -1-benzyl-2-hydroxypropyl} -carbamic acid thiazol-5-yl Methyl esters;

{(1S, 2R) -3-[(2-amino-benzothiazole-6-sulfonyl) -isobutyl-amino] -1-benzyl-2-hydroxypropyl} -2- (2,6-dimethyl -Phenoxy) -acetamide;

3-amino-{(1S, 2R) -3-[(2-amino-benzothiazole-6-sulfonyl) -isobutyl-amino] -1-benzyl-2-hydroxypropyl) -2-methyl- Benzamide;

4-amino-{(1S, 2R) -3-[(2-amino-benzothiazole-6-sulfonyl) -isobutyl-amino] -1-benzyl-2-hydroxypropyl} -2-methyl- Benzamide;

5-amino-{(1S, 2R) -3-[(2-amino-benzothiazole-6-sulfonyl) -isobutyl-amino] -1-benzyl-2-hydroxypropyl} -2-methyl- Benzamide;

N-{(1S, 2R) -3-[(2-amino-benzothiazole-6-sulfonyl) -isobutyl-amino] -1-benzyl-2-hydroxypropyl} -2-methyl-benzamide ;

N-{(1S, 2R) -3-[(2-amino-benzothiazole-6-sulfonyl) -isobutyl-amino] -1-benzyl-2-hydroxypropyl} -4-hydroxy-2 -Methyl-benzamide;

N-{(1S, 2R) -3-[(2-amino-benzothiazole-6-sulfonyl) -isobutyl-amino] -1-benzyl-2-hydroxypropyl} -3-hydroxy-2 -Methyl-benzamide; And

{(1S, 2R) -3-[(2-Amino-benzothiazole-6-sulfonyl) -isobutyl-amino] -1-benzyl-2-hydroxypropyl} -carbamic acid (S)-(tetra Hydrofuran-3-yl) ester.

Compounds of interest are compounds of formula (I) wherein R ₁ is hexahydrofuro [2,3-b] furanyl or oxazolyl.

Another compound of interest is a compound of formula (I) or a subgroup thereof, wherein R ₁ is hexahydrofuro [2, 3-b] furanyl, tetrahydrofuranyl, oxazolyl, thiazolyl and L is a direct bond It is a compound belonging to.

Another compound of interest is R ₁ is C _{1 -} one that is, or di (C _1-4 alkyl) independently selected from an _amino-6 alkyl, hydroxy, amino, halogen, amino C _{1 - 4} alkyl and mono Phenyl, hexahydrofuro [2,3-b] furanyl, oxazolyl, thiazolyl, pyridinyl, optionally substituted with the above substituents; L is a compound of formula (I) or a subgroup thereof, wherein -O-.

Compounds which are the subject of a further alternative of interest is R ₁ is C _{1 - 6} alkyl, hydroxy, amino, halogen, amino C _{1 - 4} alkyl, mono- or di (C _1-4 alkyl) amino are independently selected from Phenyl, hexahydrofuro [2,3-b] furanyl, tetrahydrofuranyl, or oxazolyl optionally substituted with one or more substituents; L is-0-C ₁ is bonded to the nitrogen of an amide _- is a compound belonging to the compound or a sub-group of ₆ alkanediyl yl Formula (I).

Compound R ₁ is hydroxy, amino, halogen, amino of interest C _{1 - 4} alkyl and a mono- or di-optionally with one or more substituents independently selected from amino substituted phenyl (C _1-4 alkyl), Hexahydrofuro [2,3-b] furanyl, tetrahydrofuranyl, oxazolyl, thiazolyl, pyridinyl; L is -O- a C ₁ that is coupled to the R ¹ group _- a compound belonging to the compound or a sub-group of ₆ alkanediyl yl Formula (I).

The compounds of the appropriate group R ₅ and R at least one of ₆ is C _{1 - 6} alkyl, in particular, and R ₅ is methyl and R ₆ is hydrogen or methyl, more in particular R ₅ is methyl and R ₆ is hydrogen of the formula (I ) Or a compound belonging to a subgroup thereof.

Of particular interest are compounds wherein -LR ₁ is -0- (hexahydrofuro [2,3-b] furanyl), -O-tetrahydrofuranyl, -O-methyl- (optionally substituted phenyl), A compound of formula (I) or a sub-subject thereof, which is -O-methyl-pyridinyl, -O-methyl-thiazolyl, -O-methyl-oxazolyl, -methyl-O- (optionally substituted phenyl) or optionally substituted phenyl It is a compound belonging to the group. Preferably, any substituent on the phenyl group is methyl, amino, hydroxy, halogen, aminomethyl.

In particular compound of interest is R ₁ is C _{1 - 6} alkyl, hydroxy, amino, chloro, bromo, amino, C _{1 - 4} alkyl, mono- or di (C _1-4 alkyl) amino are independently selected from Belonging to a compound of formula (I) or a subgroup thereof which is phenyl, hexahydrofuro [2,3-b] furanyl, tetrahydrofuranyl, oxazolyl, thiazolyl, or pyridinyl, optionally substituted with one or more substituents Compound.

Suitably, the one or more of the following conditions apply to any of the aforementioned subgroups of interest of the compound of formula (I) or in particular or specifically of subgroups of interest:

R ² is hydrogen;

R ³ is phenylmethyl;

R ⁴ is C _{1 - 4} alkyl, preferably butyl or isobutyl;

R ⁵ is hydrogen or methyl;

R < ⁶ > is hydrogen or methyl.

Of interest for compounds of formula (I) or a compound belonging to a subgroup thereof, R ² is hydrogen; R ³ is phenylmethyl; R ⁴ is C _{1 -} is formed to be a ₄ alkyl, preferably isobutyl.

Certain subgroups of compounds of formula (I) are R ⁵ And compounds of formula (I) in which both R ⁶ are hydrogen.

Another group of compounds of formula (I) or compounds belonging to subgroups of interest are those wherein -LR ¹ is -0- (hexahydrofuro [2,3-b] furanyl), -O-tetrahydro Furanyl, -O-methyl-thiazolyl, -O-methyl-oxazolyl, -methyl-O- (2,6-dimethylphenyl), -methyl-O- (4-aminomethyl-2,6-dimethylphenyl ), -Methyl-O- (4-amino-2,6-dimethylphenyl), 3-hydroxy-2-methyl-phenyl or 3-amino-2-methyl-phenyl; R ⁵ is methyl or hydrogen and R ⁶ is hydrogen.

Preferred compounds are

{3-[(2-Amino-benzothiazole-6-sulfonyl) -isobutyl-amino] -1-benzyl-2-hydroxypropyl} -carbamic acid hexahydro-furo [2,3-b] furan 3-yl ester;

{3-[(2-Amino-benzothiazole-6-sulfonyl) -isobutyl-amino] -1-benzyl-2-hydroxypropyl} -carbamic acid thiazol-5-ylmethyl ester;

{1-benzyl-2-hydroxy-3- [isobutyl- (2-methylamino-benzothiazole-6-sulfonyl) -amino] -propyl} -carbamic acid hexahydro-furo [2, 3-b ] Furan-3-yl ester;

{1-benzyl-3-[(2-dimethylamino-benzothiazole-6-sulfonyl) -isobutyl-amino] -2-hydroxy-propyl} -carbamic acid hexahydro-furo [2,3-b ] Furan-3-yl ester;

{3-[(2-Amino-benzothiazole-6-sulfonyl) -isobutyl-amino] -1-benzyl-2-hydroxypropyl} -carbamic acid benzyl ester;

N- {3-[(2-Amino-benzothiazole-6-sulfonyl) -isobutyl-amino] -1-benzyl-2-hydroxypropyl} -2- (2,6-dimethyl-phenoxy) Acetamide;

{3-[(2-Amino-benzothiazole-6-sulfonyl) -isobutyl-amino] -1-benzyl-2-hydroxypropyl} -carbamic acid pyridin-3-ylmethyl ester;

3-amino-N- {3-[(2-amino-benzothiazole-6-sulfonyl) -isobutyl-amino] -1-benzyl-2-hydroxypropyl} -2-methyl-benzamide;

N-3-[(2-amino-benzothiazole-6-sulfonyl) -isobutyl-amino] -1-benzyl-2-hydroxypropyl} -3-hydroxy-2-methyl-benzamide;

{3-[(2-Amino-benzothiazole-6-sulfonyl) -isobutyl-amino] -1-benzyl-2-hydroxypropyl} -carbamic acid tetrahydro-furan-3-yl ester;

N- {3-[(2-Amino-benzothiazole-6-sulfonyl) -isobutyl-amino] -1-benzyl-2-hydroxypropyl} -2-methyl-benzamide;

N- {1-benzyl-2-hydroxy-3- [isobutyl- (2-methylamino-benzothiazole-6-sulfonyl) -amino] -propyl} -2- (2,6-dimethyl-phenoxy C) -acetamide;

N- {3-[(2-Amino-benzothiazole-6-sulfonyl) -isobutyl-amino] -1-benzyl-2-hydroxypropyl} -3-fluoro-2-methyl-benzamide;

N- {3-[(2-Amino-benzothiazole-6-sulfonyl) -isobutyl-amino] -1-benzyl-2-hydroxypropyl} -2- (4-aminomethyl-2,6- Dimethyl-phenoxy) -acetamide;

{1-benzyl-2-hydroxy-3- [isobutyl- (2-methylamino-benzothiazole-6-sulfonyl) -amino] -propyl} -carbamic acid thiazol-5-ylmethyl ester;

3-amino-N- {1-benzyl-2-hydroxy-3- [isobutyl- (2-methylamino-benzothiazole-6-sulfonyl) -amino] -propyl} -2-methyl-benzamide ;

{1-benzyl-2-hydroxy-3- [isobutyl- (2-methylamino-benzothiazole-6-sulfonyl) -amino] -propyl} -carbamic acid tetrahydro-furan-3-yl ester;

N- {1-benzyl-2-hydroxy-3- [isobutyl- (2-methylamino-benzothiazole-6-sulfonyl) -amino] -propyl} -3-hydroxy-2-methyl-benz amides;

N-3-[(2-amino-benzothiazole-6-sulfonyl) -isobutyl-amino] -1-benzyl-2-hydroxypropyl} -2- (4-iodo-2,6-dimethyl -Phenoxy) -acetamide;

2- (4-aminomethyl-2,6-dimethyl-phenoxy) -N- {1-benzyl-2-hydroxy-3- [isobutyl- (2-methylamino-benzothiazole-6-sulfonyl ) -Amino] -propyl} -acetamide;

2- (4-amino-2,6-dimethyl-phenoxy) -N- {1-benzyl-2-hydroxy-3- [isobutyl- (2-methylamino-benzothiazole-6-sulfonyl) -Amino] -propyl} -acetamide;

N- {1-benzyl-2-hydroxy-3- [isobutyl- (2-methylamino-benzothiazole-6-sulfonyl) -amino] -propyl} -4-bromo-2-methyl-benz amides;

{1-benzyl-2-hydroxy-3- [isobutyl- (2-methylamino-benzothiazole-6-sulfonyl) -amino] -propyl} -carbamic acid oxazol-5-ylmethyl ester;

4-amino-N- {1-benzyl-2-hydroxy-3- [isobutyl- (2-methylamino-benzothiazole-6-sulfonyl) -amino] -propyl} -3-hydroxy-2 -Methyl-benzamide; N-oxides and stereoisomeric forms thereof.

Another group of interest is

{1-benzyl-2-hydroxy-3- [isobutyl- (2-methylamino-benzothiazole-6-sulfonyl) -amino] -propyl} -carbamic acid hexahydro-furo [2,3-b ] Furan-3-yl ester;

{1-benzyl-3-[(2-dimethylamino-benzothiazole-6-sulfonyl) -isobutyl-amino] -2-hydroxy-propyl} -carbamic acid hexahydro-furo [2,3-b ] Furan-3-yl ester;

N- {1-benzyl-2-hydroxy-3- [isobutyl- (2-methylamino-benzothiazole-6-sulfonyl) -amino] -propyl} -2- (2,6-dimethyl-phenoxy C) -acetamide;

N- {3-[(2-Amino-benzothiazole-6-sulfonyl) -isobutyl-amino] -1-benzyl-2-hydroxypropyl} -3-fluoro-2-methyl-benzamide;

N- {3-[(2-Amino-benzothiazole-6-sulfonyl) -isobutyl-amino] -1-benzyl-2-hydroxypropyl} -2- (4-aminomethyl-2,6- Dimethyl-phenoxy) -acetamide;

{1-benzyl-2-hydroxy-3- [isobutyl- (2-methylamino-benzothiazole-6-sulfonyl) -amino] -propyl} -carbamic acid thiazol-5-ylmethyl ester;

3-amino-N- {1-benzyl-2-hydroxy-3- [isobutyl- (2-methylamino-benzothiazole-6-sulfonyl) -amino] -propyl} -2-methyl-benzamide ;

{1-benzyl-2-hydroxy-3- [isobutyl- (2-methylamino-benzothiazole-6-sulfonyl) -amino] -propyl} -carbamic acid tetrahydro-furan-3-yl ester;

N- {1-benzyl-2-hydroxy-3- [isobutyl- (2-methylamino-benzothiazole-6-sulfonyl) -amino] -propyl} -3-hydroxy-2-methyl-benz amides;

N-3-[(2-amino-benzothiazole-6-sulfonyl) -isobutyl-amino] -1-benzyl-2-hydroxypropyl} -2- (4-iodo-2,6-dimethyl -Phenoxy) -acetamide;

2- (4-aminomethyl-2,6-dimethyl-phenoxy) -N- {1-benzyl-2-hydroxy-3- [isobutyl- (2-methylamino-benzothiazole-6-sulfonyl ) -Amino] -propyl} -acetamide;

2- (4-amino-2,6-dimethyl-phenoxy) -N- {1-benzyl-2-hydroxy-3- [isobutyl- (2-methylamino-benzothiazole-6-sulfonyl) -Amino] -propyl} -acetamide;

N- {1-benzyl-2-hydroxy-3- [isobutyl- (2-methylamino-benzothiazole-6-sulfonyl) -amino] -propyl} -4-bromo-2-methyl-benz amides;

{1-benzyl-2-hydroxy-3- [isobutyl- (2-methylamino-benzothiazole-6-sulfonyl) -amino] -propyl} -carbamic acid oxazol-5-ylmethyl ester;

4-amino-N- {1-benzyl-2-hydroxy-3- [isobutyl- (2-methylamino-benzothiazole-6-sulfonyl) -amino] -propyl} -3-hydroxy-2 -Methyl-benzamide; N-oxides and stereoisomeric forms thereof.

More preferred compounds are

Enantiomeric form of a compound of formula (I) having a (1S, 2R) -1-benzyl-2-hydroxy-propyl configuration or a compound belonging to a subgroup thereof.

The compounds of formula (I) or their subgroups in the form of hexahydro-furo [2, 3-b] furan-3-yl esters of carbamic acid derivatives are preferably in the form (3R, 3aS, 6aR), eg For example {(1S, 2R) -3-[(2-amino-benzothiazole-6-sulfonyl) -isobutyl-amino] -1-benzyl-2-hydroxypropyl} -carbamic acid

Present as (3R, 3aS, 6aR) -hexahydro-furo [2,3-b] furan-3-yl ester.

Compounds of formula (I) are usually analogous to those described in WO 95/06030, WO 96/22287, WO 96/28418, WO 96/28463, WO 96/28464, WO 96/28465 and WO 97/18205. It can be prepared using.

Specific reaction methods for preparing the compounds of the present invention are described below. In the following methods, the reaction product can be separated from the medium and, if necessary, further purified by commonly known methods such as extraction, crystallization, trituration and chromatography.

Scheme A

2-amino-6-chlorosulfonylbenzothiazole derivative (intermediate a-2) was prepared according to the method described in EP-A-0,445,926. Intermediate a-3, prepared according to the method described in W097 / 18205 and depicted in Scheme B, in the presence of a base such as triethylamine in a reaction-inert solvent such as dichloromethane and reacted with intermediate a-2 To prepare intermediate a-4. The Boc group in intermediate a-3 is a protective t-butyloxycarbonyl group. It may be replaced by another protecting group such as phthalimido or benzyloxycarbonyl. Intermediate a-4 was deprotected with an acid such as trifluoroacetic acid or hydrochloric acid in isopropanol depending on the nature of the amino group at the 2 position of benzoxazole in a suitable solvent such as a mixture of ethanol and dioxane to give intermediate a-5 Can be prepared. 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloric acid (EDC) and 1-hydroxybenzotriazole, optionally in the presence of a base such as triethylamine (for alcohols for preparing carbamate) (HOBY) (in the case of the carboxylic acid for preparing the amide) or intermediate a-5 in the appropriate solvent example dichloromethane in the presence of an alcohol example t-butanol further intermediate of formula R ₁ -LC (= 0) -OH Reacted with; Intermediate a-6 can be formed.

Conventional methods for preparing compounds of formula (I) in which R ₅ and R ₆ are both hydrogen can be prepared analogously to the process described in Scheme A, wherein either R ₅ or R ₆ is an appropriate protecting group such as acetyl Or alkyloxycarbonyl groups. In this case, deprotection may occur simultaneously with deprotection of the nitrogen atom on the left side of the molecule.

Many of the intermediates and starting materials used in the above preparations are known compounds, while others can be prepared according to known methods for preparing the above or similar compounds.

Scheme B

Intermediate b-2, corresponding to intermediate a-3 in Scheme A, can be prepared by adding the amine of formula H ₂ NR ₄ to intermediate b-1 in a suitable solvent such as isopropanol.

In City B, the enantiomericly pure compound of formula b-2 is obtained only when b-1 is enantiomericly pure. If b-1 is a stereoisomeric mixture, b-2 will also consist of a stereoisomeric mixture.

The compounds of formula (I) can also be converted to the corresponding N-oxide form by converting the tertiary nitrogen into the N-oxide form according to known methods. The N-oxidation reaction can generally be carried out by reacting the starting material of formula (I) with a suitable organic or inorganic peroxide. Suitable inorganic peroxides include, for example, hydrogen peroxide, alkali metal or alkaline earth metal peroxides such as sodium peroxide, potassium peroxide; Suitable organic peroxides are peroxy acids such as benzenecarboperoxoic acid or benzenecarboperoxoacids substituted with halo, such as 3-chloro-benzenecarboperoxoic acid, peroxoalkanoic acid, such as peroxoacetic acid, alkylhydro Peroxides such as tert-butyl hydroperoxide. Suitable solvents include, for example, water, lower alkanols, eg ethanol and the like, hydrocarbons such as toluene, ketones, eg 2-butanone, halogenated hydrocarbons, eg dichloromethane, and mixtures of these solvents.

Thus, the compounds of the present invention can be used in animals, preferably mammals, and in particular humans, as medicaments themselves, in the form of mixtures with one another or in the form of pharmaceutical preparations.

The invention also relates to pharmaceutical preparations comprising an effective amount of at least one compound of formula (I) and / or a physiologically acceptable salt thereof as an active ingredient in addition to pharmaceutically harmless excipients and auxiliaries. Pharmaceutical formulations usually comprise 0.1 to 90% by weight of the compound of formula (I) and / or physiologically acceptable salts thereof. Pharmaceutical formulations may be prepared by methods known to those skilled in the art. For this purpose, at least one compound of formula (I) and / or physiologically acceptable salts thereof, together with one or more solid or liquid pharmaceutical excipients and / or excipients, if necessary, are combined with other pharmaceutically active compounds It can be formulated into a suitable dosage form or dosage form and used as a medicine in medicine or veterinary medicine.

A medicament comprising a compound according to the invention and / or a physiologically acceptable salt thereof can be administered orally, parenterally, eg, by vascular administration, rectal administration, inhalation, or topically. And the preferred administration depends on the respective condition, for example on the particular course of the condition being treated.

Those skilled in the art know, based on their expertise, suitable adjuvants for the desired pharmaceutical formulation. In addition to solvents, gel-forming agents, suppository bases, tablet aids and other active compound carriers, antioxidants, dispersants, emulsifiers, antifoams, flavor corrigents, preservatives, solubilizers, depots Agents, buffers or coloring agents to achieve the effect) are also useful.

Due to its desirable pharmacological properties, in particular its action on multi-drug resistant HIV protease enzymes, the compounds of the invention are useful for the treatment of individuals infected with HIV and for the prevention of individuals. Typically the compounds of the present invention may be useful for the treatment of warm-blooded animals infected with viruses in which the emergence of the virus is mediated or altered by protease enzymes. Abnormalities that can be prevented or treated with the compounds of the present invention, especially those associated with HIV and other pathogenic retroviruses, include chronic diseases caused by AIDS, AIDS-related syndromes (ARC), progressive systemic lymphadenopathy (PGL), and retroviruses. CNS diseases such as HIV mediated dementia and multiple sclerosis.

The therapy comprises systemic administration to an HIV-infected subject in an amount effective to combat an abnormality associated with an HIV virus comprising a multi-drug resistant protease enzyme.

It may be found that the compounds of the invention can also be used to inhibit ex vivo samples that include or are expected to be exposed to multi-drug resistant HIV-proteases. Therefore, it can be used to contain multi-drug resistant HIV-proteases or to inhibit multi-drug resistant HIV-proteases present in body fluid samples that are expected to be exposed to multi-drug resistant HIV-proteases.

In addition, combinations of antiretroviral compounds and compounds of the present invention can be used as medicaments. Accordingly, the present invention provides a combined formulation for the simultaneous, separate or sequential use in the treatment of retroviral infections, in particular in the treatment of multi-drug resistant retroviruses, comprising (a) a compound of the invention and (b) another A product containing an antiretroviral compound. Thus, in order to combat or treat HIV infection, or infections and diseases associated with HIV infection, such as AIDS or AIDS-related syndromes (ARCs), the compounds of the present invention may, for example, bind Inhibitors such as dextran sulfate, suramine, polyanions, soluble CD4; Fusion inhibitors such as T20, T1249, SHC-C; Co-receptor binding inhibitors such as AMD 3100 (Bycyclams), TAK 779; RT inhibitors such as foscarnet and prodrugs; Nucleoside RTIs, such as AZT, 3TC, DDC, DDI, D4T, Abakavir, FTC, DAPD, dOTC; Nucleotide RTIs such as PMEA, PMPA; NNRTIs, e.g. nevirapine, delavirdin, efavirens, 8 and 9-Cl TIBO (tivirapine), lobbyide, TMC-125, TMC-120, MKC-442, UC 781, capravirin, DPC 961 , DPC963, DPC082, DPC083, Caranolide A, SJ-3366, TSAO, 4 "-deamined TSAO; RNAse H inhibitors, eg SP 1093V, PD126338; TAT inhibitors, eg RO-5-3355, K12, K37; integrase inhibitors, such as L-708906, L 731988; protease inhibitors, such as amprenavir, ritonavir, nelpinavir, saquinobir, indinavir, lopina Vir, BMS 232632, DPC 681, DPC 684, tipranavir, AG1776, DMP450, L756425, PD178390, PD178392, PNU 140135, maslinic acid, U-140690; glycosylation inhibitors such as castanospermine, deoxynori May be combined with mycin and administered together.

The combination can provide a synergistic effect to prevent, substantially reduce, or eliminate completely viral infections and their associated symptoms.

The compounds of the present invention also provide immunomodulators (eg, bropyrimin, anti-human alpha interferon antibodies, IL-2, methionine enkeparin, interferon alpha, and the like to improve, combat or eliminate HIV infection and its symptoms), and Naltrexone), antibiotics (eg pentaamidine isothiolate) cytokines (eg Th2), cytokine modulators, chemokines (eg CCR5) or hormones (eg growth hormone). The formulations may be administered simultaneously, separately and sequentially in different formulations. Alternatively, the combination may be administered in a single dosage form so that the active ingredient can be released simultaneously or separately from the dosage form.

The compound of the present invention may be administered in combination with a metabolic modulator after administration of the drug to a subject. These modulators include compounds that interfere with metabolism in cytochromes such as cytochrome P450. Several isoenzymes are present in cytochrome P450, one of which is cytochrome P450 3A4. Ritonavir is an example of a metabolic modulator by cytochrome P450. The formulations may be administered simultaneously, separately and sequentially in different formulations. Alternatively, the combination may be administered in a single dosage form so that the active ingredient can be released simultaneously or separately from the dosage form. Such modulators may be administered in the same or different ratios as the compounds of the invention. Preferably, the weight ratio of modifier to compound of the invention (modulator: compound of the invention) is 1: 1 or less, more preferred ratio is 1: 3 or less, suitable ratio is 1: 10 or less, and more suitable ratio is 1: 30 or less to be.

For formulations for oral administration, the compounds of the present invention are mixed with suitable additives, for example excipients, stabilizers or inert diluents, and by conventional methods are employed in suitable dosage forms, eg tablets, coated tablets, hard capsules. Formulations are made in aqueous, alcoholic, or oily solutions. Examples of suitable inert carriers are gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose, or starch, especially corn starch. In such cases, the preparation can be obtained as both dry and wet granulating agents. Suitable oily excipients or solvents are vegetable or animal oils, such as sunflower oil or cod liver oil. Suitable solvents for aqueous or alcoholic solutions are water, ethanol, sugar solutions, or mixtures thereof. Polyethylene glycol and polypropylene glycol are also useful as additional adjuvants for other dosage forms.

For subcutaneous or intravenous administration, the active compound is, if desired, a liquid, suspending or emulsifying agent in combination with conventional materials therefor, for example, stabilizers, emulsifiers or further auxiliaries. The compounds of formula (I) and their physiologically acceptable salts can also be lyophilized and the lyophilisates obtained can be used for the preparation of, for example, injections or sap. Suitable solvents are, for example, water, physiological saline or alcohols such as ethanol, propanol, glycerol, and sugar solutions such as glucose or mannitol solutions, or mixtures of the various solvents mentioned.

Suitable pharmaceutical formulations for administration in the form of aerosols or propellants include, for example, liquid solutions of the compounds of formula (I) and physiologically acceptable salts thereof in pharmaceutically acceptable solvents such as ethanol or water, mixtures of said solvents. , Suspension or emulsifier. If desired, the formulation may further comprise other pharmaceutical auxiliaries, for example surfactants, emulsifiers and stabilizers and propellants. The formulations usually comprise the active compound at a concentration of about 0.1 to 50% by weight, in particular about 0.3 to 3% by weight.

In order to enhance the solubility and / or stability of the compound of formula (I) in the pharmaceutical composition, it may be advantageous to use α-, β-, γ-cyclodextrin or derivatives thereof. In addition, co-solvents such as alcohols may enhance the solubility and / or stability of the compounds of formula (I) in pharmaceutical compositions. In the preparation of aqueous compositions, it is clear that the addition salt of the desired compound is more suitable due to its increased water solubility.

Appropriate cyclodextrin is α-, β-, γ- cyclodextrins (CDs) or its ethers and ether and mixed, where the anhydro glucoside mouse hydroxy group one or more units of the cyclodextrin are C _{1 - 6} alkyl, In particular methyl, ethyl or isopropyl (eg randomly methylated β-CD); Hydroxy C _{1 - 6} alkyl, particularly hydroxyethyl, hydroxypropyl or hydroxybutyl; Carboxy C _{1 - 6} alkyl, in particular, carboxymethyl or carboxyethyl; C _{1 - 6} alkylcarbonyl, particularly acetyl; C _{1 - 6} alkoxycarbonyl C _{1 - 6} alkyl or carboxy C _{1- 6} alkyloxy C _{1 - 6} ethoxylpropyl alkyl, particularly carboxymethyl or carboxy-methoxypropyl; C _{1 - 6} alkyl-carbonyl-oxy is substituted with C _{1- 6} alkyl, especially 2-acetyloxy propyl. Of particular value as complexes and / or solubilizers in particular are β-CD, randomly 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 especially 2-hydroxypropyl-β-CD (2-HP-β-CD).

The term mixed ether refers to a cyclodextrin derivative in which at least two cyclodextrin hydroxy groups are etherified with different groups, for example hydroxy-propyl and hydroxyethyl.

It is described in EP-A-721,331, which is an interesting method of formulating the compounds in combination with cyclodextrins or derivatives thereof. The formulations described in this document contain antifungal active ingredients but are also of interest for the formulation of the present antiretroviral compounds. The formulations described in this document are particularly suitable for oral administration and contain an alcoholic co-solvent which greatly simplifies the preparation of an antifungal agent as an active ingredient, an amount of cyclodextrin or a derivative thereof as a solubilizer, a water soluble acidic medium as a large amount of liquid carrier and a composition. Include. Pharmaceutically acceptable sweeteners and / or flavoring agents can be added to further enhance the taste of the formulation.

Other methods of enhancing the solubility of the compounds of the present invention in pharmaceutical compositions are described in WO 94/05263, WO 98/42318, EP-A-499,299 and WO 97/44014, which are incorporated by reference.

More particularly, the compound is a pharmaceutical composition comprising a therapeutically effective amount of particles comprising (a) a compound of formula (I), and (b) a solid dispersion comprising at least one pharmaceutically acceptable water soluble polymer. Can be formulated.

The term "solid dispersion" defines a system in the solid state (as opposed to the liquid or gaseous state) in which one component comprises at least two components in which the other component is dispersed more or less uniformly. The dispersion of components will be hereinafter referred to as "solid liquid" when the chemical and physically homogeneous or homogeneous system or when composed of one phase as defined thermodynamically. Solid liquor is a preferred physical system because the components therein can usually be readily bioavailable for the administered organism.

The term "solid dispersion" also encompasses dispersions that are less homogeneous than solid liquids as a whole. Such dispersions are not entirely physicochemically uniform or comprise one or more phases.

The water soluble polymer in the particles is advantageously a polymer having an apparent viscosity of 1 to 100 mPa · s when dissolved in a 2% aqueous solution at 20 ° C.

Preferred water-soluble polymers are hydroxypropyl methylcelluloses or HPMC. HPMCs having a methoxy substitution degree of about 0.8 to about 2.5 and a hydroxypropyl molecular substitution degree of about 0.05 to about 3.0 are generally water soluble. Methoxy degree of substitution refers to the average number of methylether groups present per anhydroglucose unit of a cellulose molecule. Hydroxypropyl molecular substitution refers to the average number of moles of propylene oxide that reacts with each anhydroglucose unit of a cellulose molecule.

The solid dispersions of the components may be prepared first, followed by optionally grinding or milling the dispersions to produce the particles according to the invention. Various techniques exist for preparing solid dispersions, including melt-extrusion, spray-drying and dissolution-evaporation, with melt-extrusion being preferred.

It may be advantageous to formulate this antiretroviral agent in the form of nanoparticles with surface modifiers adsorbed on their surface in an amount sufficient to maintain an effective average particle size of less than 1000 nm. Useful surface modifiers include those that are physically bound to the surface of the antiretroviral agent but do not chemically bind to the antiretroviral agent.

Suitable surface modifiers can preferably be selected from known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular oligomers, natural products and surfactants. Preferred surface modifiers include nonionic and anionic surfactants.

Another interesting method of formulating the present compounds is the incorporation of the present antiretroviral agent into a hydrophilic polymer and the mixture applied as a coat film on several small beads, which can be conveniently prepared and pharmaceutical for oral administration. Pharmaceutical compositions having good bioavailability obtained by preparing a composition suitable for preparation in a dosage form.

The beads mentioned comprise (a) a circular or spherical core core, (b) a coating film of hydrophilic polymer and antiretroviral agent and (c) a seal-coating polymer layer.

Suitable materials for use as cores in the beads vary as long as they are pharmaceutically acceptable and have the appropriate dimensions and firmness. Examples of such materials are polymers, inorganic materials, organic materials, and saccharides and derivatives thereof.

The route of administration may vary depending on the condition of the subject, co-drugs and the like.

Another aspect of the invention includes an effective amount of a compound of formula (I) for use as a standard or reagent in a test or assay to determine the ability of a drug that is potent to inhibit HIV protease, HIV growth, or both It relates to a kit or a container. One aspect of the invention may also find use in pharmaceutical research programs.

The compounds of the present invention can be used in phenotypic resistance monitoring assays such as preparative assays known in clinical management of resistant developing diseases such as HIV. Particularly useful resistance monitoring systems are recombinant assays known as Antivirograms. Antiarirograms are highly automated, high-power, second-generation recombinant assays capable of measuring sensitivity to the compounds of the invention, in particular viral sensitivity (Hertogs K, de Bethune MP, Miller V et al. Antirnicrob Ageyits Chemother, 1998; 42; (2): 269-276, incorporated by reference).

Interestingly, the compounds of the present invention may comprise chemically reactive moieties that can covalently bind to localized moieties to increase their residual in the tissue and increase their half-life. As used herein, the term “chemical reaction group” refers to a compound group capable of forming a covalent bond. Reaction groups are generally carboxy, phosphoryl, or conventional acyl groups that are stable in an aqueous environment and are capable of covalently bonding functional groups, such as amino groups, hydroxy or thiols, to target sites for blood components, typically albumin, eg And esters, or mixed anhydrides, or imidates, or maleimidates. The compounds of the present invention can be combined with maleimide or derivatives thereof to form conjugates.

The administered dose of the present compound or its physiologically acceptable salt (s) is usually dependent on the condition of each individual and is adapted to the condition of each individual for the best effect. Thus, the status and severity of infections and symptoms, as well as the efficacy and duration of action of the compound used in each case for recovery and treatment or prophylaxis, and the sex, age, weight and individual reactivity and therapy of the human or animal being treated It depends on whether it is acute or prophylactic. Typically, when administered to a patient weighing about 75 kg, the daily dosage of formula (I) is 1 mg to 1 g, preferably 3 mg to 0.5 g. Dosages may be administered in a single dosage form or may be separated in several, for example two, three, four single dosage forms.

< Example >

Testing Department

Compounds of Formula (I) and Preparation

The name used throughout this specification is based on the Chemical Abstracts Services Nomenclature.

Example  1: compound 2

452 mg in 825 mg 2-amino-benzothiazole-6-sulfonic acid (3-amino-2-hydroxy-4-phenyl-butyl) -isobutyl amide and 373 mg triethylamine mixture in dichloromethane 1-[[[[(3R, 3aS, 6aR) -hexahydrofuro [2,3-b] furan-3-yl] oxy] carbonyl] oxy] -2,5-pinolidine-dione (in W09967417 As described). This mixture was stirred for 12 hours at room temperature. After evaporation of dichloromethane under reduced pressure, the crude product was purified on silica gel to give 270 mg (24.8%) of compound 2.

Example  2: compound 4

210 mg in a mixture of 350 mg 2-methylamino-benzothiazole-6-sulfonic acid (3-amino-2-hydroxy-4-phenyl-butyl) -isobutyl amide and 200 mg triethylamine in dichloromethane 1-[[[[hexahydrofuro [2,3-b] furan-3-yl] oxy] carbonyl] oxy] -2,5-pyrrolidinedione (described in WO9967417). The mixture was stirred for 12 hours at room temperature. After evaporation of dichloromethane under reduced pressure, the crude product was purified on silica gel to give 260 mg (55%) of compound 4.

Example  3: compound 6

230 mg in a mixture of 420 mg 2-dimethylamino-benzothiazole-6-sulfonic acid (3-amino-2-hydroxy-4-phenyl-butyl) -isobutyl amide and 98 mg triethylamine in dichloromethane 1-[[[[hexahydrofuro [2,3-b] furan-3-yl] oxy] carbonyl] oxy] -2, described in 5-pyrrolidinedione W09967417). This mixture was stirred for 12 hours at room temperature. After evaporation of dichloromethane under reduced pressure, the crude product was purified on silica gel to yield 500 mg (90%) of compound 6.

Example  4: compound 17

800 mg 2-amino-benzothiazole-6-sulfonic acid (3-amino-2-hydroxy-4-phenyl-butyl) -isobutyl amide in 80 ml of dichloromethane, 50 mg HOBT (hydroxybenzotriazole ), 420 mg EDC and 668 mg (3,4, 5-trimethyl-benzyl) -carbamic acid t-butyl ester compound and hydroxy acetic acid mixture were stirred overnight at room temperature. The reaction mixture was washed with water and brine. The organic layer was separated, dried and the solvent was evaporated. The residue was purified by column chromatography to give 1 g (75%) of [4-({3-[(2-amino-benzothiazole-6-sulfonyl) -isobutyl-amino] -1-benzyl- 2-hydroxypropylcarbamoyl} -methoxy) -3, 5-dimethyl-benzyl] -carbamic acid t-butyl ester was obtained. This intermediate (500 mg) was further dissolved in methanol (20 ml) and 10 ml HCl solution in isopropanol (5-6N) was added dropwise. The mixture was stirred overnight at room temperature. The solvent was evaporated and the residue was purified on silica gel to give 190 mg of compound 17 (43%).

Example  5: compound 27

134 mg 2-methylamino-benzothiazole-6-sulfonic acid (3-amino-2-hydroxy-4-phenyl-butyl) -isobutyl amide, 4 mg HOBT (hydroxybenzotriazole) in dichloromethane, 66 mg EDC and 63 mg 4-bromo-2-methyl benzo phase mixture were stirred overnight at room temperature. The reaction mixture was washed with water and brine. The organic layer was separated, dried and the solvent was evaporated. The residue was purified by preparative HPLC to give 25 mg (13%) of compound 27.

Example  6: compound 28

3.45 g in a mixture of 4.48 g 2-methylamino-benzothiazole-6-sulfonic acid (3-amino-2-hydroxy-4-phenyl-butyl) -isobutyl amide and 2.73 g triethylamine in dichloromethane Carbonic acid 2, 5-dioxo-pyrrolidin-1-yl ester oxazol-5-ylmethyl ester of was added. This mixture was stirred for 12 hours at room temperature. After evaporating dichloromethane under reduced pressure, the crude product was purified on silica gel to yield 1.02 g 19% of compound 28.

The compounds in Table 1 are not intended to limit the scope of the invention and are prepared analogously to any of the above examples and tested in the demonstration of the invention.

Table 1

Antiviral Assay:

Compounds of the invention were examined for anti-viral activity in cell assays. The analysis demonstrated that the compound exhibits potent anti-HIV activity against wild type laboratory HIV strain (HIV-1 strain LAI). Cell analysis was performed according to the following method.

Cell assay method:

HIV- or mock-infected MT4 cells were cultured for 5 days in the presence of various concentrations of inhibitors. At the end of the culture, the virus was replicated in control cultures in which no inhibitor was present to kill all HIV-infected cells. Cell viability was measured by measuring the concentration of MTT, a yellow water-soluble tetrazolium dye, which is converted from the mitochondria of only living cells to purple insoluble formazan. When the resulting formazon crystal was dissolved using isopropanol, the absorbance of the solution was measured at 540 nm. This value was directly related to the number of viable cells remaining in the culture at the end of the 5 day culture. Inhibitory activity of this compound was measured on virus-infected cells and expressed as IC ₅₀ and IC ₉₀ . This value represents the amount of compound required to protect 50% and 90% of the cells, respectively, from the cytopathic effect of the virus. Toxicity of compounds was measured on mock-infected cells and denoted by CC ₅₀ , indicating the concentration of compound required to inhibit cell growth by 50%. The selectivity index (SI) (ratio CC ₅₀ / IC ₅₀ ) indicates the selectivity of the inhibitor's anti-HIV activity. If the results are recorded, for example, with pEC ₅₀ or pCC ₅₀ values, the results are shown as negative log value results, indicated as EC ₅₀ or CC ₅₀ , respectively.

Antiviral spectrum

As the emergence of drug-resistant HIV strains increased, its efficacy was tested against clinically isolated HIV strains harboring several mutations (Tables 2 and 3). These mutations are associated with resistance to protease inhibitors, which are at varying levels of expression cross-tolerance for currently commercially available drugs (saquinavir, ritonavir, lpinavir, indinavir, and amperanavir). Resulting in a virus.

Table 2 List of mutations present in protease genes of HIV strains used (A to F)

Results :

Extensive activity of the compounds of the present invention was measured and Table 3 shows the results of the antiviral test as pEC ₅₀ (log value of = -EC ₅₀ ). Fold resistance (FR), defined as FR = EC ₅₀ (mutant strain) / EC ₅₀ (HIV-1 strain LAI), is listed in Table 4. Most compounds have a fold resistance range of 0.1 to 100. Thus, the present invention is an inhibitor that is effective against a wide variety of mutant strains. Toxicity (Tox) is shown as pCC ₅₀ measured in mock transfected cells and wild type pEC ₅₀ is shown in the WT cell.

Table 3 . Toxicity test and resistance test (expressed as FR) for strains A to F. ND indicates not measured.

ND = not measured

Some compounds were tested for a broader range of mutant HIV protease viruses. For example, Compound 1 was tested against a panel of 20 or more mutant proteases (here, the pIC ₅₀ value of Compound 1 was 9.13 for the most susceptible mutation and the pIC ₅₀ value for the most resistant mutation was 8.12). This mentions that all mutations in a set of 20 or more mutant proteases are susceptible within a narrow range for IC ₅₀ values and fold resistance values.

Table 4: Fold Immunity

Protein binding assay  :

Human serum protein-like albumin (HSA) or α-1 acid glycoprotein (AAG) is known to bind many drugs and may reduce the effectiveness of the compounds of the present invention. To determine if a compound of the invention is adversely affected by this binding, the anti-HIV yellowness of the compound was measured in the presence of human serum and the efficacy of binding of the protease inhibitor to the protein was evaluated.

MT4 cells were infected with HIV-1 LAI with a multiplicity of infection (MOI) of 0.001-0.01 CCID ₅₀ (50% cell culture infection dose per cell, CCID ₅₀ ). After 1 hour incubation, cells were washed and 10% FCS (fetal bovine serum), 10% FCS + 1 mg / ml AAG (α ₁ -acid glycoprotein), 10% PCS + 45 mg / ml HSA (human serum albumin ) Or 96-well plates containing serial dilutions of the compound in the presence of 50% human serum (HS). After incubation for 5 or 6 days, EC ₅₀ (50% effective concentration in cell-based assays) is calculated by measuring cell viability or measuring HIV replication levels. Cell viability was measured using the assay described above.

In 96-well plates containing serial dilutions of the compound in the presence of 10% FCS or 10% PCS + 1 mg / ml AAG, HIV (wild-type or resistant strain) and MT4 cells were each concentrated at 200-250 CCID ₅₀ / well and 30,000, respectively. Added to cells / well. After 5 days incubation (37 ° C., 5% CO ₂ ), tetrazolium colorimetric MTT (3- [4,5-dimethylthiazol-2-yl] -2,5-diphenyltetrazolium bromide) method (Pauwels et al. J Virol. Methods 1988,20,309321).

Pharmacokinetics Data

The pharmacokinetic properties of some of the compounds of formula (I) were tested in rats and dogs. Compounds were evaluated in Whistar rats obtained from about 350 g of Iffa Credo. The animals were fasted overnight (fasting for about 12 hours) prior to dosing. The compound was dissolved in DMSO. The results shown in the table below relate to the results from oral administration of the compounds. Blood was sampled at 30 minutes, 1 hour, 2 hours, 3 hours, and samples taken before administration. The amount of compound in the biological sample was measured using LC-MS. In the following table, "or" means oral administration and "mpk" means mg per kilogram. The results are shown in Table 5.

Table 5

Formulation

The compound of formula (I) which is the active compound is dissolved in an organic solvent such as ethanol, methanol or methylene chloride, preferably a mixture of ethanol and methylene chloride. Polymer, eg 5 mPa. Polyvinylpyrrolidone copolymer or hydroxypropylmethylcellulose (HPMC) with s vinyl acetate was dissolved in an organic solvent such as ethanol, methanol or methylene chloride. Suitably the polymer was dissolved in ethanol. The polymer and compound solutions were mixed and then spray dried. The ratio of compound / polymer was selected from 1/1 to 1/6. The intermediate ranged from 1 / 1.5 to 1/3. The proper ratio was 1/6. Spray dried powders, solid dispersions were successively filled into capsules for administration. The dosage of drug per capsule depends on the capsule size used.

film- Coated  refine

Tablet core manufacturing

A well mixed mixture of 100 g of the compound of formula (I), 570 g lactose and 200 g starch, followed by wetting with a solution of 5 g sodium dodecyl sulfate and 10 g polyvinylpyrrolidone in about 200 ml of water I was. The wet powder was sieved, dried and sieved again. Then 100 g microcrystalline cellulose and 15 g hydrogenated vegetable oil were added. The whole was mixed well and compressed into tablets to prepare 10.000 tablets, each containing 10 mg of active ingredient.

coating

To a 10 g methylcellulose solution in 75 ml of modified ethanol was added 5 g of ethylcellulose solution in 150 ml of dichloromethane. 75 ml of dichloromethane and 2.5 ml 1,2,3-propanetriol were then added. 10 g of polyethylene glycol was dissolved and dissolved in 75 ml of dichloromethane. The latter solution was added to the former and then 2.5 g magnesium octadecanoate, 5 g polyvinylpyrrolidone and 30 ml dark color suspension were added to homogenize the whole. The tablet cores were coated with the mixture obtained as above in a coating machine.

Claims (17)

delete delete delete delete delete delete {3-[(2-Amino-benzothiazole-6-sulfonyl) -isobutyl-amino] -1-benzyl-2-hydroxypropyl} -carbamic acid hexahydro-furo [2,3-b] furan 3-yl ester;
{1-benzyl-2-hydroxy-3- [isobutyl- (2-methylamino-benzothiazole-6-sulfonyl) -amino] -propyl} -carbamic acid hexahydro-furo [2,3-b ] Furan-3-yl ester; Or a salt or a stereoisomer thereof, the agent for treating infection of HIV containing a mutant HIV protease. 8. The medicament according to claim 7, wherein the mutant HIV protease has at least one mutation at a position selected from 10, 71 and 84 of the amino acid sequences of the wild type HIV protease. The agent according to claim 7 or 8, wherein the compound has a fold resistance to mutant HIV proteases in the range of 0.01 to 100. delete delete delete delete delete delete delete {3-[(2-Amino-benzothiazole-6-sulfonyl) -isobutyl-amino] -1-benzyl-2-hydroxypropyl} -carbamic acid hexahydro-furo [2,3-b] furan 3-yl ester;
{1-benzyl-2-hydroxy-3- [isobutyl- (2-methylamino-benzothiazole-6-sulfonyl) -amino] -propyl} -carbamic acid hexahydro-furo [2,3-b ] Furan-3-yl ester; Or a salt or stereoisomer thereof.